Professional Documents
Culture Documents
An Illustrated Text
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Ad Rijnberk · Hans S. Kooistra (eds.)
Clinical Endocrinology
of Dogs and Cats
An Illustrated Text
Printed in Germany
ISBN 978-3-89993-058-0
Contents
5 Endocrine Pancreas
7 Ovaries
5.1 Introduction . . . . . . . . . . . . . . 155
7.1 Introduction . . . . . . . . . . . . . . 203
5.1.1 The endocrine pancreas . . . . . . . . . 155
7.2 Estrous cycle, anestrus, pregnancy,
5.1.2 Insulin synthesis and structure . . . . . . 156
and parturition . . . . . . . . . . . . . 204
5.1.3 Regulation of insulin secretion . . . . . . 156
7.2.1 Estrous cycle, anestrus, pregnancy,
5.1.4 Actions of insulin . . . . . . . . . . . . . 158
and parturition in the dog . . . . . . . . 204
5.2 Diabetes mellitus . . . . . . . . . . . . 159
7.2.1.1 Estrous cycle . . . . . . . . . . . . . . . 204
5.2.1 Classification . . . . . . . . . . . . . . . 159
7.2.1.2 Follicular phase . . . . . . . . . . . . . . 204
5.2.2 Metabolic disturbances . . . . . . . . . . 160
7.2.1.3 Preovulatory luteinization and ovulation . 207
5.2.3 Diabetes mellitus in dogs . . . . . . . . . 161
7.2.1.4 Luteal phase . . . . . . . . . . . . . . . 208
5.2.4 Diabetes mellitus in cats . . . . . . . . . 167
7.2.1.5 Anestrus . . . . . . . . . . . . . . . . . 210
5.2.5 Problems associated with the regulation
7.2.1.6 Pregnancy and parturition . . . . . . . . 211
of diabetes in dogs and cats . . . . . . . . 172
7.2.2 Estrous cycle, anestrus, pregnancy,
5.2.6 Diabetic ketoacidosis (DKA) and
and parturition in the cat . . . . . . . . . 213
hyperglycemic hyperosmolar state
7.2.2.1 Estrous cycle and anestrus . . . . . . . . 214
(HHS) . . . . . . . . . . . . . . . . . . . 172
7.2.2.2 Pregnancy and parturition . . . . . . . . 217
5.3 The hypoglycemic syndrome . . . . . 173
7.3 Medical pregnancy termination . . . 217
5.3.1 Insulinoma . . . . . . . . . . . . . . . . 174
7.4 Induction of parturition . . . . . . . 219
5.3.2 Nonpancreatic tumors associated with
7.5 Persistent estrus . . . . . . . . . . . . 219
hypoglycemia . . . . . . . . . . . . . . . 178
7.6 Split heat . . . . . . . . . . . . . . . . 220
5.3.3 Juvenile hypoglycemia . . . . . . . . . . 179
7.7 Hypoluteoidism . . . . . . . . . . . . 221
5.4 Other endocrine tumors associated
7.8 Prolonged anestrus . . . . . . . . . . 221
with the pancreas . . . . . . . . . . . . 179
7.9 Estrus induction . . . . . . . . . . . . 222
5.4.1 Gastrinoma . . . . . . . . . . . . . . . . 179
7.10 Estrus prevention . . . . . . . . . . . 222
5.4.2 Glucagonoma . . . . . . . . . . . . . . . 180
7.11 Cystic endometrial hyperplasia-
endometritis . . . . . . . . . . . . . . 226
6 Gonadal Development and Disorders 7.12 Fertility disorders in the bitch due
to breeding management problems . 228
of Sexual Differentiation
Authors
Abbreviations
Endocrinology is one of the disciplines concerned with disorders of the gland. Because the clinician’s suspicion of the
communications and controls within the organism by means presence of an endocrine disease is largely based upon pattern
of chemical messengers. The whole of intercellular com- recognition, in which the physical changes play an important
munication is covered in large part by three systems: (1) the role, many illustrations have been included. The features of
nervous system, (2) the endocrine system, and (3) the im- some endocrine diseases differ in the dog and the cat to such
mune system. Over the past few decades it has become appar- an extent that separate descriptions are needed. Chapters on
ent that the separation of these systems is artificial, in that they diagnostic and therapeutic protocols are included at the end
share many common features. The nervous system elaborates of the book to provide a quick reference for both students and
compounds that can act as local mediators or true circulating practitioners. These will suffice in many cases, but at some
hormones, while several hormones can act as neurogenic time the help of a specialist may be required.
mediators within the central nervous system. Moreover, at
the level of the hypothalamus and pituitary there is an inti- Clinical endocrinology has at least four fascinating character-
mate link between the nervous system and the endocrine sys- istics. First, hormones and thus endocrine glands are involved
tem, thereby integrating the two into one control unit. The in the regulation of the function of almost every organ sys-
immune system is now also recognized as a regulatory system tem. Therefore the study of this discipline requires the chall-
subject to endocrine control. It in turn exerts a reciprocal enging combination of broad pathophysiological interest and
controlling effect on neuroendocrine systems. specific expertise in the field of endocrinology. Second, en-
docrinology itself occupies a common ground between bio-
Within this wide spectrum of communication in the living chemistry, physiology, and clinical medicine. Third, in part
animal there are messenger substances which conform to the because of the first two features, clinical endocrinology is a
classic characteristics of hormones, i.e., products of endocrine discipline of contemplation, reflection, and stimulating dis-
glands which are transported by the blood to some distant site cussion. Fourth, it is very fortunate that many endocrine dis-
of action. Most of the endocrine diseases known to occur in orders are amenable to treatment.
dogs and cats are the result of dysfunction of one or more of
these glands and hence this book concentrates on the dis- The authors hope that this book will serve as a helpful guide
orders of these glands. to veterinary clinicians in this fascinating field.
As we complete the manuscripts and illustrations for the sec- ogy, has helped us in editing the English language of this
ond edition of this book, we pause to reflect upon the jour- book. He has done so with helpful insight and sympathy.
ney from the first to the second edition. As for the first edi-
tion, we hope that a brief general description of the For many years Mrs. Yvonne Pollak has contributed to our
multifaceted field of endocrinology has a place and is worth work in clinical endocrinology in several ways. In the 1960s
continuing. The changes with this edition are in the addition she enthusiastically began assisting in studies of iodine metab-
of newly recognized disease entities, further elucidation of olism and thyroid disease and thereafter became increasingly
mechanisms of disease, and progress in diagnosis and treat- involved in the wide range of diagnostic techniques that nu-
ment. clear medicine can offer, maintaining a special interest in the
applications to clinical endocrinology. In addition, she ap-
In this second edition the information on basic and clinical plied her varied talents to preparing the drawings for the first
endocrinology has been updated and ranges from molecular edition and with the same dedication, accuracy, and skill she
biology to the clinical approach to the patient. All of the has prepared the drawings for this edition. Mr. Joop Fama
chapters have been completely rewritten and new illustrations made several of the new photographs presented in this book
have been included. The information on calciotropic hor- and also digitalized and improved many of the older pictures.
mones is no longer distributed over three chapters but inte- Together with the drawings these photographs are very essen-
grated into a single chapter. tial for this illustrated text. His input is highly appreciated.
We are pleased that most of the authors and contributors for The editors hope that this new edition will serve as an up-to-
the first edition also helped in preparing the second edition. date guide to veterinary clinicians in the rapidly developing
At the same time, we are grateful that new authors with spe- field of clinical endocrinology of companion animals, and
cific knowledge were willing to join in. The expertise and that the book may stimulate students to study this fascinating
critical attitude of the coauthors and contributors was vital for discipline.
the writing process and occurred in a very pleasant atmos-
phere.
Utrecht, April 2009
Dr. Bruce E. Belshaw, with whom the editors and several of Ad Rijnberk
the authors have had the pleasure of working in endocrinol- Hans S. Kooistra
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Clinical
Endocrinology
2 Introduction
Figure 1.1:
Chemical communication involves hormones (H) and
neurotransmitters (N), acting on target cells via recep-
tors (R). Hormones may reach the target cells through
the circulation (endocrine), or act on neighboring cells
(paracrine), or on receptors in the same cell (auto-
crine), or act inside the cell without being released
(intracrine). Neurons release neurotransmitters from
nerve terminals. The same neurotransmitters can be re-
leased to act as hormones via the synaptic junctions or
by direct release as hormones by the neuron. The liver
and kidney serve as major sites for metabolism and ex-
cretion of hormones. (Modified from Webb and Baxter,
2007).4
Figure 1.2:
Sources of the major hormones, with examples of
each chemical type. (Modified from Webb and Baxter,
2007).4
3
1 Introduction 1
Ad Rijnberk
Jan A. Mol
1.1 Hormones examples, have both paracrine actions in the tissues in which
they are formed and classical endocrine actions at peripheral
A little more than 100 years ago the term hormone was sites. Other forms of intercellular communication studied by
coined by Ernest Henry Starling, Professor of Physiology at endocrinologists include exocrine secretion (e.g., in milk and
University College, London.1 During a conversation at a semen) and the release of pheromones (in air or water).3
dinner with the distinguished biologist William Hardy, the
two decided that they needed a word for an agent released There are strong similarities in signaling mechanisms between
into the bloodstream that stimulated activity in a different part the endocrine and nervous systems. The same molecule can
of the body. They turned to a classical colleague, who pro- be both a hormone and a neurotransmitter. For example,
duced the Greek verb for »excite« or »arouse« (ormao).2 At catecholamines are hormones when released by the adrenal
the same time, the word »endocrine« appeared, to contrast the medulla and neurotransmitters when released by nerve ter-
actions of substances secreted internally into the bloodstream minals. Thyrotropin-releasing hormone (TRH) is a hormone
with those secreted externally (exocrine) into ducts such as when produced by the hypothalamus, but has several neuro-
the lumen of the gastrointestinal tract. transmitter actions in the central nervous system.
Figure 1.3:
Examples of different types of hormones. Each circle in
the protein hormone represents an amino acid, just as
shown for the polypeptide hormone.
1.1.2 Storage, release, and transport The majority of water-soluble hormones such as proteins and
peptides are transported in blood without binding to specific
Most endocrine cells have a limited capacity to store the final proteins. This explains the half-life of only a few minutes in
product. Even in cells with well-developed organelles for plasma of most of the nonglycosylated peptide hormones.
storing hormone, such as the Golgi apparatus, the amount of The more insoluble a hormone is in water, the more impor-
hormone stored is usually very small. The major exceptions tant is the role of transport proteins. Thyroid and steroid hor-
are thyroglobulin, the precursor of thyroid hormones that is mones are largely transported bound to proteins. Protein-
stored in the thyroid follicles, and the intermediate forms of bound hormones cannot per se enter cells but serve as a
vitamin D stored in adipose tissue. reservoir from which free hormone is liberated for cellular
uptake.
The release process may involve freeing soluble derivatives
from precursors by proteolysis (thyroid hormones from thy- The distribution between bound and free hormone in plasma
roglobulin), exocytosis of storage granules (peptide hor- is determined by the amount of hormone and the amount
mones), or passive diffusion of newly synthesized molecules and affinity of the proteins that bind it. The free hormone
(steroid hormones). In many instances the rate of hormone enters and interacts with its specific receptor in target cells
release fluctuates, synthesis and release being tightly linked. and participates in the regulatory feedback mechanisms.
Many hormones, the pituitary hormones being prominent Hence, changes in the amount of transport protein can cause
examples, are released in a pulsatile fashion.5,6 considerable changes in hormone concentrations in plasma
Hormones 5
Figure 1.5:
1.2.1 DNA regions Schematic illustration of the steps involved in the gene-encoded synthesis of a
protein. The different regions of a generic gene are shown in A. The same color
Genes encoding proteins consist of several components. scheme is used in E but omitted in B–D, which illustrate RNA processing. (Adapted
Exons are the regions of the gene that are transcribed into from White, 2004.)10
messenger RNA (mRNA), which is single stranded and has
a sequence that corresponds to the coding (or sense) strand
of DNA. During transcription it is synthesized in the 5' to
3' direction by a transcriptional apparatus that »reads« the
complementary (or antisense) strand of DNA. Exons are
usually interspersed with introns. These sequences are spliced Locus control regions
out of the primary transcript before it leaves the nucleus These regions are required to establish a tissue-specific open
(fig. 1.5).10,11 chromatin domain (see chapter 1.2.2) in the vicinity of a par-
ticular locus and thus permit appropriate tissue-specific ex-
Exons consist of coding sequences that are translated into pro- pression.
tein and untranslated regions (UTRs) at both ends of the gene
(5'– and 3'-UTR). Transcription of genes is mediated by the CpG islands
interaction of many proteins with defined regulatory regions Cytosine methylation by a DNA methylase (DNA methyl-
(or cis regulatory elements) present in the promoter region lo- ation) gives rise to the formation of CpG (cytosine-guanine)
cated upstream from the transcription start site, or present islands and is associated with inactivation of gene expression.
within intron areas, or in the 3'-UTR of the gene10: This minimizes expression of permanently inactivated genes
when differentiated cells divide. Conversely, hypomethylation
Promoters is associated with active transcription.
Transcription is invariably controlled at least in part by se-
quences located in the 5' flanking region of the gene before
(5' or upstream from) the start of transcription. One element
of the promoter is the binding site for RNA polymerase II. In 1.2.2 Protein factors
many genes this region includes a short nucleotide sequence
known as a TATA box (TATAAA or related sequence), ap- Histones
proximately 30 bases upstream from the site at which tran- Within chromosomes the DNA is organized into nucleo-
scription begins. somes, each consisting of eight positively charged histone
molecules. Higher-order winding organizes nucleosomes
Enhancers and silencers into chromatin. This organization renders DNA relatively in-
The cis regulatory elements that increase transcription inde- accessible to transcription factors. Transcription can be en-
pendently of their position and orientation are called en- hanced by remodeling of nucleosomes to permit assembly of
hancers, and those that decrease transcription are called si- transcription complexes.10 In this way the information poten-
lencers. Such elements can be located within a gene itself, tial of the genome is extended beyond the limitations of the
usually in an intron, or at some distance (up to thousands of genomic code, i.e., cell specificity is achieved without expan-
nucleotides) away from it. sion of the genomic code.
Genes encoding hormones 7
General transcription factors different species, the nucleotide sequences within introns are
The promoter of a gene is bound by general transcription fac- found to be much less similar than the coding sequences. This 1
tors to form a transcription initiation complex that ultimately suggests that the exact sequence of an intron is relatively un-
has a molecular weight of greater than 2 million Da. A part of important except for sequences involved in splicing and regu-
this complex separates the DNA strands and allows binding lation of gene expression.
adjacent to the TATA box. This is followed by binding of
other protein complexes and RNA polymerase II.10 MicroRNAs
In the complex interplay of several factors influencing the
Transcriptional regulatory factors generation and expression of mRNA, small RNA sequences
Each of these factors consists of a DNA-binding domain can also play a critical role. These microRNAs (miRNAs) of
and at least one activation domain that interacts with el- 20–22 nucleotides can silence gene expression after transcrip-
ements of the transcriptional apparatus. Almost all DNA- tion. This class of regulators contains suppressors of tumor
binding domains include an a-helical protein segment that progression and metastasis.12
fits into the major groove between two turns of the DNA
helix. Many of these domains (including those of the intra-
cellular hormone receptors) are stabilized by chelated zinc 1.2.4 Translation
atoms and are called zinc fingers. The domains called home
domains are 60 amino acid motifs that are most often found Within the nucleotide sequence of the mature mRNA tran-
in transcription factors regulating embryonic development. script there is an open reading frame which is translated
An example of such a factor is Pit 1, which plays a role in into protein by the ribosomal protein synthesis apparatus that
the morphogenesis of the pituitary gland (see chapter 2.1, reads the mRNA nucleotide sequence in triplets or codons
fig. 2.5). (fig. 1.6). The ribosome reads the sequence from the start
codon AUG that encodes a methionine residue until it
reaches a stop codon (UAA, UGA, or UAG), at which point
the ribosome dissociates from the mRNA.
1.2.3 RNA processing
Codons are actually read by small transfer RNA (tRNA) mol-
The primary RNA transcript of a gene is modified in several ecules that are specific for each amino acid. A tRNA mol-
ways in the nucleus before being exported as mRNA to the ecule has a nucleotide triplet (called an anticodon) that is
cytoplasm, where it is translated into protein (fig. 1.5)10: complementary to a mRNA codon. A tRNA is charged with
the appropriate amino acid at its 3' end by a specific amino-
Cap structure acyl tRNA synthase.10
The first posttranscriptional event during the course of RNA
maturation in the nucleus is the addition of a cap. The cap
is formed by addition of a guanosine to the 5' end of the
mRNA and methylation of this guanosine and subsequent 1.2.5 Posttranslational processing
methylation of the adjacent nucleotide(s). This structure is
required for the export of mRNA from the nucleus, and it As mentioned in the introduction of chapter 1.2, secretory
also facilitates the binding of RNA to ribosomes and thus en- and cell surface proteins play a pivotal role in endocrinology.
hances the initiation of translation. These proteins are synthesized on ribosomes bound to the
endoplasmic reticulum (ER) and undergo posttranslational
Poly(A)tail processing. All of these proteins contain an N-terminal seg-
In the nucleus most transcripts are clipped 12–16 bases down- ment called the signal peptide (see for example fig. 4.4). It
stream from a consensus poly(A) addition site, AAUAA or consists of approximately 20 amino acids, most of which are
AUUAAA. Then a nucleotide sequence consisting entirely of hydrophobic. The N terminus is bound by a ribonucleopro-
repeated adenosines is added to the 3' end of the RNA. These tein complex, the signal recognition particle (SRP). This is
poly(A)tails generally range between 50 and 250 bases and then bound by the SRP receptor, which is inserted in the
may play a role in RNA stability. membrane of the ER and recruits specific proteins to form a
transmembrane channel to begin transporting the protein
Splicing of introns across the ER membrane after its synthesis.
An important aspect of the maturation of RNA is the removal
of introns by splicing. This process is mediated by spliceo- The nascent protein is transported across the ER membrane
somes, which are large complexes of small RNA molecules in an unfolded state and must then adopt the correct con-
and proteins named snRNPs (small nuclear ribonucleopro- formation. This often requires interactions with chaperone
teins, and pronounced »snerps«). The reason for the presence proteins, the formation of disulfide bonds, and glycosyl-
of interruptive introns in genes has not been established. ation.10 In addition to its contribution to proper folding or
When genes encoding the same protein are compared among stability of the protein, glycosylation may also be required for
8 Introduction
Figure 1.6:
Ribosomal protein synthesis. A, C, G, and U are nucleo-
tides in RNA. They are illustrated in mRNA only in the
region in contact with the ribosome, and only in
transfer RNA (tRNA) in the region of the anticodon that
interacts with mRNA through complementary base
pairing. aa1–7 represent successive amino acids in the
nascent polypeptide. (Adapted from White, 2004.)10
Figure 1.7:
Left: Generalized hypothalamic-pituitary system and a related endocrine gland under normal conditions and as influenced by administration of a hormone produced by
the peripheral gland. The hormone secreted by the peripheral gland is partitioned in the circulation between a small free fraction (open parts of arrows) and a large frac-
tion bound to carrier proteins (dark parts of arrows). The differences in hormone production are indicated by differences in thickness and continuity of lines and arrows.
Right: Illustration of primary and secondary (pituitary) hormone deficiency states.
one-hormone concept, adenohypophyseal cells are not irre- hormone hypersecretion is the result of expression or acti-
versibly monohormonal but may become polyhormonal. vation of receptors in an endocrine gland that does not norm-
This alteration of the morphologic features and the secretory ally harbor functional receptors of this type. For example, the
capacity of mature cell types without cell division is called adrenal cortex may express aberrant receptors such as lutein-
transdifferentiation (chapter 3.3.1).13 izing hormone receptors (chapter 4.3.5). When hormones
are used to treat nonendocrine diseases or when hormone
Excessive hormone production replacement for an endocrine deficiency is excessive, the re-
The most frequent causes of hormone excess syndromes are sulting syndrome of hormone excess is said to be iatrogenic.
hypersecretion of hormone by a tumor of the endocrine
gland (primary hyperfunction) and hypersecretion due to hy- Defective hormone synthesis
perstimulation of the endocrine gland, of which there may be Genetic defects can cause abnormalities in hormone syn-
several causes (secondary hyperfunction) (fig. 1.8). Excessive thesis. Sometimes this leads not only to hormone deficiency
hormone production may also be traced to cells that are not but also to manifestations of a compensatory adaptation, such
normally the primary source of circulating hormone (ectopic as goiter resulting from defective thyroid hormone synthesis
hormone production, see for example chapter 4.3.4). Rarely, (fig. 1.9).
10 Introduction
1.4.3 Diagnostic imaging mography (CT), and magnetic resonance imaging (MRI).18
1 The former technique is relatively inexpensive but requires
The inaccessibility of most of the endocrine glands for direct extensive operator experience, whereas the latter three may
physical examination has been progressively overcome during be easier to perform but require expensive equipment as well
the past two decades by the use of diagnostic imaging tech- as immobilization which necessitates anesthesia.
niques such as ultrasonography, scintigraphy, computed to-
References
1. STARLING EH. Croonian Lecture: On the chemical correlation 10. WHITE PC. Genes and hormones. In: Griffin JE, Ojeda SR, eds.
of the functions of the body I. Lancet 1905;2:339–341 Textbook of Endocrine Physiology, 5th ed. Oxford: Oxford Uni-
versity Press, 2004;17–48.
2. HENDERSON J. Ernest Starling and »hormones«: an historical
commentary. J Endocrinol 2005;184:5–10. 11. BOLANDER FF. Molecular Endocrinology, 3rd ed. Amsterdam:
Elsevier Academic Press, 2004.
3. RIJNBERK A. Hormones. In: Rijnberk A, ed. Clinical endocri- 12. TAVAZOIE SF, ALARCÓN C, OSKARSSON T, PADUA D,
nology of dogs and cats. Dordrecht / Norwell: Kluwer Academic WANG Q, BOS PD, GERALD WL, MASSADUÉ J. Endogenous
Publishers, 1996;1–5 human microRNAs that suppress breast cancer metastasis. Nature
2008;451:147–152.
4. WEBB P, BAXTER JD. Introduction to Endocrinology. In:
Gardner DG, Shoback D, eds. Greenspan’s basic and clinical Endo- 13. DIAZ ESPINEIRA MM, MOL JA, VAN DEN INGH TSGAM,
crinology, 8th ed. New York: McGrawHill Medical, 2007;1–34. VAN DER VLUGT-MEIJER RH, RIJNBERK A, KOOI-
STRA HS. Functional and morphological changes in the adeno-
hypophysis of dogs with induced primary hypothyroidism; loss of
5. KOOISTRA HS, DEN HERTOG, OKKENS AC, MOL JA,
TSH hypersecretion, hypersomatotropism, hypoprolactinemia, and
RIJNBERK A. Pulsatile secretion pattern of growth hormone dur-
pituitary enlargement with transdifferentiation. Domest Anim En-
ing the luteal phase and mid-anoestrus in beagle bitches. J Reprod
docrinol 2008;35:98–111.
Fertil 2000;119:217–222.
14. RIJNBERK A, KOOISTRA HS. Endocrine glands. In: Rijnberk
6. KOOISTRA HS, OKKENS AC, BEVERS MM, POPP- A, van Sluijs FJ, eds. Medical History and Physical Examination in
SNIJDERS C, VAN HAAFTEN B, DIELEMAN SJ, SCHOE- Companion Animals, 2nd ed. Oxford: Elsevier Ltd, 2009;207–212.
MAKER J. Concurrent pulsatile secretion of luteneizing hor-
mone and follicle-stimulating hormone during different phases 15. CERUNDOLO R, LLOYD DH, VAESSEN MMAR, MOL JA,
of the oestrus cycle and anoestrus in beagle bitches. Biol Reprod KOOISTRA HS, RIJNBERK A. Alopecia in pomeranians and
1999;60:65–71 miniature poodles in assocation with high urinary corticoid:creati-
nine ratios and resistance to glucocorticoid feedback. Vet Rec
7. STAHN C, LÖWENBERG M, HOMMES DW, BUTTGEREIT 2007;160:393–397.
F. Molecular mechanisms of glucocorticoid action and selective glu-
cocorticoid receptor agonists. Mol Cell Endocrinol 2007;275:71–78. 16. JAVADI S, GALAC S, BOER P, ROBBEN JH, TESKE E,
KOOISTRA HS. Aldosterone-to-renin and cortisol-to-adrenocor-
ticotropic hormone ratios in healthy dogs and dogs with primary
8. DE LANGE MS, GALAC S, TRIP MR, KOOISTRA HS. High hypoadrenocorticism. J Vet Intern Med 2006;20:556–561.
urinary corticoid /creatinine ratios in cats with hyperthyroidism. J
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Introduction 13
2 Hypothalamus-Pituitary System
Björn P. Meij
Hans S. Kooistra 2
Ad Rijnberk
2.1 Introduction
The hypothalamus and pituitary form a complex functional
unit that transcends the traditional boundary between neuro-
logy and endocrinology. Many key elements of this system are
neither purely endocrine nor purely neural. There are three
components:
(1) A neuroendocrine system connected to an endocrine sys-
tem by a portal circulation. The neuroendocrine system
consists of clusters of peptide- and monoamine-secreting
cells in the anterior and middle portions of the ventral
hypothalamus. Their products – releasing hormones and
inhibiting factors – are transported by nerve fibers to
terminals in the outer layer of the median eminence
(fig. 2.11). Here they are released into capillaries of the hy-
pothalamic-hypophyseal portal system for transport to the
anterior lobe (AL) of the pituitary, where they regulate
hormone production and secretion (fig. 2.2 and table 2.1). Figure 2.1:
Nerve fiber terminals containing corticotropin-releasing hormone (CRH) in the
outer layer of the median eminence of a dog, visualized by indirect immunofluor-
escence. Note the presence of CRH-immunoreactive fibers outside the terminal
zone in close proximity to the capillary system.1
Table 2.1:
Terminology for the parts of the hypophysis
(glandula pituitaria) according to the Nomina
Anatomica Veterinaria (N.A.V.) and the variants in
the Nomina Histologica Veterinaria (N.H.V.), and
Nomina Anatomica (N.A., for man)2
Neurohypophysis
(Lobus posterior)
Pars proximalis neuro- Infundibulum
hypophysis (infundibulum)
Pars distalis neuro- Lobus nervosus
hypophysis Figure 2.2:
Schematic representation of the relationship of the hypothalamus and pituitary. The hypothalamus
For practical reasons the terminology in this book is confined to the exerts control over the anterior lobe (AL) through releasing and inhibiting factors that reach the AL
three functional units: Anterior lobe (= Pars infundibularis and Pars cells via capillaries of the pituitary portal system. The posterior lobe (PL) of the pituitary is a down-
distalis of the adenohypophysis), Pars intermedia, and Posterior lobe ward projection of the hypothalamus. The pars intermedia (PI) is under direct neurotransmitter con-
(see also fig. 2.2). trol.
14 Hypothalamus-Pituitary System
Figure 2.3:
Schematic representation of the ontogenesis of the
pituitary gland.
(2) A neurosecretory pathway in which hormones are pro- Following proliferation of the progenitor cells, the different
duced by neurons in the anterior hypothalamus and trans- endocrine cell phenotypes arise in a distinct temporal fashion.
ported by nerve fibers that traverse the ventral hypothala- As in other species, in the fetal dog adenohypophysis ACTH-
mus and pituitary stalk to terminate on fenestrated blood immunoreactive cells are the first to differentiate from the
vessels in the neurohypophysis or posterior lobe (PL) pituitary progenitor cells.5
(fig. 2.2). The neurohypophyseal hormones are stored in
secretory vesicles in the terminal ends of the nerve fibers The rostral hypophyseal arteries form the uniquely organized
and secreted into the systemic circulation in response to capillary plexus of the median eminence that is in close pro-
an appropriate stimulus. ximity to nerve terminals of the hypophysiotropic neurons.
(3) The pars intermedia (PI) is directly innervated by pre- The blood-brain barrier is incomplete in the area of the
dominantly aminergic nerve fibers from the hypothala- median eminence, permitting protein and peptide hormones
mus. This direct neural control is largely a tonic (dopami- and other charged particles to move to the intercapillary
nergic) inhibitory influence. spaces and the nerve terminals contained therein. These ter-
minals respond to humoral and neuronal stimuli by secreting
During embryogenesis the adenohypophysis develops from releasing and inhibiting factors into the portal system. The
Rathke’s pouch, which arises from the roof of the primitive portal capillaries coalesce into a series of vessels that descend
mouth in contact with the base of the brain. Rathke’s pouch through the pituitary stalk and form a second capillary plexus
subsequently separates by constriction from the oral cavity. surrounding the AL cells (fig. 2.2).
The anterior wall thickens and forms the pars distalis of the
AL. The posterior wall of Rathke’s pouch is closely apposed Caudal hypophyseal arteries supply the PL. From the primary
to the neural tissue of the PL to form the pars intermedia, plexus of the PL blood flows not only to the systemic circu-
remaining separated from the AL by the hypophyseal cleft lation but also to the AL and the hypothalamus. The intra-
or cavity, which was the lumen of Rathke’s pouch. In the dog pituitary vascularization involved in this has not been fully
and the cat the adenohypophysis extends as a cuff or collar elucidated but there appears to be some degree of circulatory
around the proximal neurohypophysis and even envelops part flow, from the AL to the PL, from there to the infundibulum,
of the median eminence (figs. 2.3, 2.4). and then back to the AL. The vascularization of the PI is
closely linked to that of the PL, but while the PL has a rich
Pituitary gland development is primarily the result of the in- blood supply, the PI is poorly vascularized. Blood-borne fac-
teraction between neuroectodermal and oroectodermal tis- tors play a relatively less significant role in control of PI func-
sues. In recent years several of the signaling molecules and tion.
transcription factors involved in this process have been ident-
ified (fig. 2.5).3,4 The adenohypophyseal cells follow three
main pathways of differentiation:
(1) Cells expressing pro-opiomelanocortin (POMC), leading 2.2 Anterior lobe
to secretion of adrenocorticotropic hormone (ACTH)
and a-melanocyte-stimulating hormone (a-MSH) by In agreement with the main pathways of cell differentiation
corticotrophs and melanotrophs, respectively (chapter 2.1), the peptide hormones secreted by the AL can
(2) Gonadotroph cells secreting follicle-stimulating hormone be divided into three categories: (1) the somatomammotropic
(FSH) and luteinizing hormone (LH) hormones GH and PRL, (2) the glycoprotein hormones
(3) Pit1-dependent cell lines (somatotroph, lactotroph, and TSH, FSH, and LH, and (3) the corticomelanotropins
thyrotroph cells), leading to secretion of growth hormone a-MSH, ACTH, b-endorphin (b-END), and b-lipotropin
(GH), prolactin (PRL), and thyroid-stimulating hormone (b-LPH). The hormones of the third group are derived from
(TSH). the precursor POMC, which is synthesized not only in the
Anterior lobe 15
A B
C D
Figure 2.4:
(A) Sagittal section of a dog pituitary. The AL is separated from the PI and PL by the hypophyseal cavity and surrounds it up to the pituitary stalk and median eminence.
The PI is a narrow zone around the periphery of the PL. H&E stain. (Courtesy of Dr. B. E. Belshaw.)
(B) PAS-Alcian Blue-orange G stain of a sagittal section of a cat pituitary. The third ventricle extends deeply into the PL (blue), which is surrounded by a thin rim of PI.
Sections of a cat pituitary immunostained for a-MSH (C) and ACTH (D). The latter picture clearly illustrates that in the cat the AL also extends upward around the pituitary
stalk. (Courtesy of Prof. Dr. H. J. Th. Goos and Mrs. A. Slob.)
Figure 2.5:
Simplified model of the differentiation of AL cell lineages. Each type of endocrine
cell is labeled with the hormone it synthesizes. Steps in precursor cell differenti-
ation and some of the involved transcription factors are indicated.
Ptx1 = pituitary homeobox; Neuro D1 = neurogenic differentiation factor D1;
LIF = leukemia inhibiting factor; Tpit = T-box pituitary transcription factor;
Lhx3/4 = LIM-domain transcription factors 3 and 4; Prop1 = prophet of Pit1;
Pit1 = pituitary transcription factor 1, also referred to as POU1F1; SF1 = steroid-
ogenic factor 1; DAX1 = dosage sensitive sex-reversal-adrenal hypoplasia con-
genital critical region on the X chromosome 1.
16 Hypothalamus-Pituitary System
Figure 2.7:
Schematic illustration of the hypophysiotropic regulation of the secretion of hormones by the adenohypophysis.
AVP = arginine-vasopressin; CRH = corticotropin-releasing hormone; GnRH = gonadotropin-releasing hormone; GHRH = growth hormone-releasing hormone; TRH =
thyrotropin-releasing hormone; PrRP = prolactin-releasing peptide; PIF(DA) = prolactin-inhibiting factor (dopamine); ACTH = adrenocorticotropic hormone; LH = lutein-
izing hormone; FSH = follicle-stimulating hormone; GH = growth hormone; TSH = thyroid-stimulating hormone; PRL = prolactin; a-MSH = a-melanocyte-stimulating
hormone; IGF-I = insulin-like growth factor-I.
Figure 2.8:
Structure and main function of hypothalamic hypophysiotropic hormones.
18 Hypothalamus-Pituitary System
of PRL release should be viewed as a fine balance between the weights are approximately 22 and 23 kDa, respectively. The
action of dopamine as an inhibitor and several hypothalamic amino acid sequences of canine and porcine GH are identical
factors (mainly serotonin) as well as systemic and local factors, and differ by only one amino acid from that of the cat.13–15
all acting as stimulators but none of which has yet emerged as The amino acid sequences of canine PRL and feline PRL
the primary PRL-releasing hormone.10 Several candidates differ in eight amino acids.16,17 In nonprimates a single gene
have been proposed, including TRH and a PRL-releasing encodes for GH, whereas in several species there is a large
peptide (PrRP) from the hypothalamus (fig. 2.7). PrRP, a family of paralogous genes related to PRL.18,19
31-amino-acid-peptide, increases plasma PRL concentration
but by many times less than TRH. However, PrRP can in-
crease PRL responses to TRH several-fold.11 It is possible that 2.2.1.1 Pituitary growth hormone
PrRP primarily regulates food intake.12 GH release is characterized by rhythmic pulses and intervening
troughs (fig. 1.10). The GH pulses predominantly reflect the
pulsatile delivery of GHRH from the hypothalamus, whereas
GH levels between pulses are primarily under the control of
2.2.1 Somatotropin and lactotropin somatostatin (SS) or somatotropin-release inhibiting factor
(SRIF) (fig. 2.9). Five SS receptors (sst1–5) are expressed in the
Only two of the six AL hormones are discussed here, the pituitary, sst2 being the predominant subtype in the dog.20
others being discussed in detail in other chapters. Somatotro-
pin or growth hormone (GH) and lactotropin or prolactin Pituitary somatotrophs are not only stimulated via GHRH
(PRL) have similarities in amino acid composition and share and its receptor (GHRH-R), but also via receptors different
some biological activities, and for these reasons they are often from GHRH-R. Several synthetic GH secretagogues (GHSs),
classified together as somatolactotropic hormones. They are both peptidergic and nonpeptidergic in structure, stimulate
rather large, single-chain polypeptides containing 190 (GH) GH release via the GHS receptor.21,22 The endogenous ligand
and 199 (PRL) amino acids and having two (GH) or three for the GHS receptor, ghrelin, has also been identified.23 This
(PRL) intrachain disulfide bridges (fig. 1.3). Their molecular 28-amino-acid-peptide is primarily expressed in enteroendo-
Anterior lobe 19
that encoding GH in the pituitary gland.45 Progestins stimu- tin-induced epithelial changes in the mammary gland and the
late GH promoter activity in the mammary gland indirectly uterus, it is now clear that progestin-induced GH in plasma
rather than directly. In contrast to the adenohypophysis, the does not originate from uterine epithelium and that mammary
mammary gland lacks expression of the transcription factor GH is not required for the development of progestin-induced
Pit-1.46 cystic endometrial hyperplasia in the bitch.53,54
Figure 2.14:
Responses of plasma GH, PRL, TSH, LH, and ACTH to
the combined injection of four hypothalamic releasing
hormones (CRH, GHRH, TRH, and GnRH) in eight Ger-
man shepherd dogs (-앪-) with pituitary dwarfism
(means ± SEM if exceeding the size of the symbols).
The curves with shaded areas represent the responses
(mean ± SEM) in healthy beagles (-앬-)72,73.
the normal lifespan of the corpora lutea. Hypophysectomy 2.2.2 Congenital growth hormone
and treatment with dopamine agonists shorten the luteal
phase.59–61 Consistent with the secretion patterns of GH and
deficiency
PRL (figs. 2.12, 2.13), the GH-induced proliferation of mam- Inadequate GH secretion early in life causes retardation of
mary epithelium is followed by lobular-alveolar differenti- growth. Dwarfism due to GH deficiency is best known as a
ation under the influence of PRL. Not only mammogenesis genetically transmitted condition (autosomal recessive inheri-
but also lactogenesis (acquisition of the ability to produce tance) in German shepherd dogs and Carelian bear dogs.63,64
milk) and galactopoiesis (maintenance of milk secretion) de- German shepherd dogs with pituitary dwarfism have a com-
pend on PRL.58 bined deficiency of GH, TSH, and PRL, as well as impaired
release of gonadotropins, whereas ACTH secretion is pre-
As discussed in more detail in chapter 2.2.5 and chapter 7, served (fig. 2.14).65 Diagnostic imaging and histological
pregnant and nonpregnant bitches (but not queens) have examination often reveal cystic changes in the pituitary gland
similar luteal phases and similar changes in their mammary and hypoplasia of adenohypophyseal tissue.66 The search for
glands. Lactogenesis appears at the end of the luteal phase in the causative gene defect has excluded transcription factors
nonpregnant bitches, allowing them to care for and nurse a Prop-1, Pit-1, Lhx4, and the LIF-receptor gene (fig. 2.5) as
litter.62 As will be discussed in chapter 2.2.5, nonpregnant candidates for pituitary dwarfism in German shepherds.67–70
bitches not caring for pups may also undergo behavioral The gene encoding for Lhx3 appears to be the most likely site
changes in this stage of the cycle. of the mutation.71
22 Hypothalamus-Pituitary System
A B
Figure 2.15:
(A) Four-month-old German shepherd dog with pituitary dwarfism. The woolly appearance of the coat is due to complete lack of development of primary guard hairs.
(B) Dwarf German shepherd dog at one year of age, with the characteristic fox-like face and alopecia developing on the neck.
A B
Figure 2.16:
Contrast-enhanced CT images of a six-month-old dwarf German shepherd dog (A) with a pituitary of normal size (height 3.6 mm; width 4.3 mm) but having a
radiolucent area due to a cyst (arrow). At the age of three years (B) the pituitary is enlarged (height 6.5 mm; width 5.4 mm) and the greater part of it lacks contrast
enhancement due to the cyst.
Clinical manifestations Initially the dwarfed dogs are lively and alert – they can be
Affected animals are usually presented at the age of two to five amusing and even quite appealing – but eventually they be-
months because of poor growth and an abnormally soft and come lethargic, lose appetite, and turn into thin, dull, almost
woolly hair coat (fig. 2.15). The latter is due to retention of hairless animals with a sad appearance. This stage usually ap-
lanugo or secondary hairs and lack of primary or guard hairs. pears by the age of two to three years and is commonly associ-
This stagnant development of the skin and coat finally results ated with severe secondary hypothyroidism and impaired renal
in alopecia and a thin and grayish-brown-pigmented skin. As function. The latter may have both a renal and a prerenal com-
well as proportional growth retardation, the animals have a ponent, i.e., maldevelopment of glomeruli due to lack of GH
pointed muzzle, resembling that of a fox (fig. 2.15). There is and low filtration pressure due to lack of thyroid hormone.
usually no remarkable delay in dentition. Unilateral or bilat-
eral cryptorchidism is common in males and the females often Routine biochemical variables are usually not abnormal,
have frequent anovulatory estrous cycles. except that plasma creatinine is elevated in most of the pitu-
itary dwarfs. As can be expected in secondary hypothyroid-
Anterior lobe 23
A B
Figure 2.17:
A female German shepherd dog with pituitary dwarfism before (A) and after two years of treatment with medroxyprogesterone acetate and l-thyroxine (B).
ism (fig. 2.14), plasma concentrations of T4 and TSH are The amino acid sequence of IGF-I is less species specific than
low. Mean plasma IGF-I concentration (± SEM) is lower that of growth hormone and therefore it can be measured in a
(62 ± 10 µg/l) in pituitary dwarfs than in immature healthy heterologous assay. As mentioned above, plasma IGF-I con-
German shepherd dogs (345 ± 50 µg/l).65 GH deficiency has centration is usually low in German shepherd dwarfs, even
rarely been mentioned in cats but there has been a report of when age and size are taken into account. However, interpre-
an undersized kitten with bilateral corneal opacity in which tation of results must also take account of the possibility of a
GH deficiency was diagnosed on the basis of a low plasma low caloric intake and particularly a low protein intake,
IGF-I concentration.74 which may also lower plasma IGF-I concentration.37,76,77
Differential diagnosis Diagnostic imaging (CT or MRI) at a young age often reveals
Congenital hypothyroidism may be the most important dif- small pituitary cysts. They may become larger as the animal
ferential diagnosis, although it results in a quite different ap- grows (fig. 2.16), eventually becoming so large as to cause
pearance (chapter 3.2). The possibility should also be con- neurological symptoms (see also chapter 2.2.6). However,
sidered that the apparently dwarfed animal is the result of an healthy dogs, particularly those that are brachycephalic, may
unexpected and perhaps unrecognized mating with a small also harbor small pituitary cysts.
sire, or is simply a small individual within the normal bio-
logical variation. Hypochondroplastic dwarfism in Irish Treatment
setters has been reported to occur as result of a single autoso- The lack of homologous GH for therapeutic use in dogs led
mal recessive inheritance.75 Retardation of growth can also be to initial attempts at therapy with bovine and human GH.
the result of undernutrition or congenital abnormalities of This was not very successful, in part because it resulted in
vital organs such as the heart, liver, and kidneys. Corticoste- antibodies to the heterologous GH.78 The ability of progestins
roid administration at an early age also quite rapidly retards to induce expression of the GH gene in canine mammary
growth (chapter 4.3.6). tissue and the release of the resulting GH into the systemic
circulation (fig. 2.11) offered an alternative approach to cir-
Diagnosis cumvent this problem. Subcutaneous injections of medroxy-
Although the medical history and the physical changes are progesterone acetate are given in doses of 2.5 to 5.0 mg/kg
usually highly suggestive of GH deficiency, a definitive diag- body weight, initially at three-week intervals and subse-
nosis requires measurement of GH in plasma, employing a quently at six-week intervals. If the growth plates have not
homologous radioimmunoassay. Since basal GH values may yet closed some increase in body size can be expected. The
also be low in healthy animals, a stimulation test should be muzzle becomes less pointed and a complete adult hair coat
performed. To test GH secretion alone, GHRH, ghrelin, or with primary hair appears (fig. 2.17). In parallel with this
a-adrenergic drugs such as clonidine and xylazine can be used physical improvements, plasma IGF-I concentration rises and
(chapter 12.1.2). When insight in the secretory capacity of plasma GH concentration usually increases without exceed-
other pituitary hormones is required, the combined AL- ing the reference range.79 Proligestone has been reported
stimulation test (fig. 2.14 and chapter 12.1.3) is to be pre- to be similarly effective in a dose of 10 mg/kg every three
ferred over repeated single stimulation tests. weeks.80
24 Hypothalamus-Pituitary System
A B
Figure 2.19:
A male Dalmatian dog at five years of age (A) and at ten years of age after developing acromegaly (B). Note the overall increase in body size, the thick folds of skin on the
head and neck, and the enlarged tongue.
been normal. Yet in some in which there was a normal re- tisolism is discussed in more detail in chapter 4.3.1. Whether
sponse to stimulation, treatment with GH was reported to be this type of alopecia is the result of hypercortisolism in other
effective. In others, seemingly unrelated measures such as cas- breeds as well remains to be determined.
tration or administration of testosterone were followed by the
appearance of a new hair coat.84 Furthermore, in Pomeran-
ians both with and without alopecia, the mean circulating
GH concentration did not increase significantly after stimu- 2.2.4 Growth hormone excess
lation in either group.85 Thus the proposed relation between
some forms of this adult-onset alopecia and decreased GH se- Hypersecretion of growth hormone in the adult results in a
cretion is not on very solid ground. It is even unlikely that syndrome characterized by overgrowth of connective tissue,
there is a true growth hormone deficiency, for when plasma bone, and viscera. The pituitary origin of the disease in hu-
IGF-I has been measured, it has invariably been within the mans was recognized in 1886 by Pierre Marie, who derived
reference range.84 its name from the Greek words akron (extremity) and megas
(large) for the characteristic enlargement of the hands and
The fact remains that in some mature dogs with alopecia feet. In dogs and cats, as in humans, the GH excess can be
there is no response or only a weak response of plasma GH to caused by a somatotroph adenoma of the pituitary gland. In
stimulation with either GHRH or a-adrenergic agonists such addition, dogs can develop the syndrome from progestin-in-
as clonidine or its structural analog xylazine (chapter 12.1.2). duced hypersecretion of GH in the mammary gland
This lack of response is most likely a functional disturbance. A (chapter 2.2.1.2). Finally, some of the physical and biochemi-
preliminary study in miniature poodles with alopecia has led cal changes in dogs with primary hypothyroidism may be
to the proposal that mild cortisol excess may be responsible caused by GH excess resulting from the adenohypophyseal
for the altered GH responses.86 Glucocorticoids are well changes brought about by deficiency of thyroid hormone.
known to suppress the GH response to various stimuli in hu- The latter form of GH excess is discussed in chapter 3.3.1.
mans and dogs.87–90 In dogs with pituitary-dependent hyper-
cortisolism, GH release in pulses is impaired, probably as a re-
sult of alterations in pituitary somatotroph function and 2.2.4.1 Excessive pituitary growth hormone
changes in suprapituitary regulation.91 Pituitary tumors that might have secreted excessive amounts
of GH have been reported in dogs94–96, but only recently has
The hypothesis that both the alopecia and the lack of growth GH hypersecretion been confirmed in a dog with acromegaly
hormone response to stimulation might be the result of mild and a somatotroph adenoma.97 In cats the disease is less rare
hypercortisolism has recently been tested in alopecic Pomer- and probably underdiagnosed.98,99
anians and miniature poodles. Serial measurements of urinary
corticoids with low-dose dexamethasone suppression tests Clinical manifestations
satisfied two criteria of hypercortisolism in both groups, The recently described dog with acromegaly of pituitary
namely, increased cortisol production and decreased sensi- origin had very pronounced characteristics of longstanding
tivity to glucocorticoid feedback.92,93 This form of hypercor- GH excess (fig. 2.19), and is used here as the prototype for
26 Hypothalamus-Pituitary System
A B
Figure 2.20:
(A) An eleven-year-old castrated male cat with acromegaly and diabetes mellitus requiring 25 IU of insulin four times daily. Basal plasma GH was 51 µg/l and IGF-I was
3871 µg/l. The cat has a sturdy physique and somewhat coarse facial features. The owner had noticed that it was becoming larger, with a heavy head.
(B) Contrast-enhanced CT image through the pituitary fossa revealed an enlarged pituitary gland, 4.5 mm in height and 4.2 mm in width (arrow). Also visible are thick
mucosal folds of the palatum molle which almost completely obliterated the nasopharynx (arrowhead). Three weeks after transsphenoidal hypophysectomy, the cat no
longer required insulin.
description of the condition.97 The soft tissue overgrowth in- the cats, physical examination reveals a heavy head, progna-
cluded thickening of the skin, particularly of the head and thia inferior, increased distance between upper and lower ca-
neck, and enlargement of the tongue with respiratory stridor. nine teeth, and stiffness and lameness. In some there is a sys-
The osseous changes caused widening of the interdental tolic cardiac murmur and late in the course of the disease
spaces, increasing stiffness, difficulty in standing up, and neck congestive heart failure may develop. Chronic GH excess
rigidity – due to articular cartilage proliferation, periarticular leads to hypertrophy of the myocardium, with increased col-
periosteal reaction, and severe spondylosis deformans. Meta- lagen content.101 If the pituitary tumor is very large, it may
bolic changes were manifested in polyphagia, weight gain, cause impaired vision, mydriasis, and circling movements
excessive panting, and polyuria and polydipsia. Laboratory (chapter 2.2.6). Laboratory findings usually include hyper-
examinations revealed normoglycemia with impaired glucose glycemia and glucosuria without ketonuria, and there may be
tolerance. The only other remarkable finding in routine elevated levels of hepatic enzymes secondary to the hepatic
blood examinations was mild anemia. Normochromic nor- lipidosis, as well as mild hyperproteinemia and hyperphos-
mocytic anemia has been found in dogs treated with pharma- phatemia.
cological doses of porcine GH, and is associated with de-
pletion of the erythroid cell series as well as cellular atrophy in Differential diagnosis
the bone marrow. It is considered to be a species-specific ef- In cats the main differential diagnosis is hypercortisolism,
fect.100 which can also give rise to insulin resistance (chapter 4.3). Al-
though GH excess and hypercortisolism lead to different
Now that more than 100 cases of acromegaly have been de- physical changes, the difference is not always obvious and thus
scribed in cats, it is a well-recognized syndrome. It is pri- cats with insulin resistance are usually tested for both dis-
marily a disease of castrated males, six to 15 years of age. In orders. The simultaneous occurrence of both a somatotroph
principle the physical changes are the same as in the dog but adenoma and a corticotroph adenoma (double adenoma)
usually less pronounced (fig. 2.20). Almost all of the affected should also be considered.102,103
cats are presented because of poorly controllable diabetes
mellitus, due to GH-induced insulin resistance. Initially, and Diagnosis
probably prior to the development of the diabetes mellitus, In cats requiring lente insulin in doses 욷 1.5 IU/kg body
the owner may have noticed polyphagia, weight gain, and weight per injection and /or having physical signs of acro-
polyuria and polydipsia. In the stage of insulin-resistant dia- megaly, the finding of plasma GH 쏜 7.2 µg/l and IGF-I
betes mellitus, some owners have noted lameness, increasing 쏜 590 µg/l is usually diagnostic.103 Feline GH can be
size of the paws, and broader facial features. In about half of measured in heterologous radioimmunoassays, namely, the
Anterior lobe 27
species-specific assays for dogs and sheep.104,105 Since a high serum GH levels.114 A pre-entry test with a single intravenous
value can be the fortuitous result of a secretory pulse in a non- injection of octreotide was introduced recently to evaluate
acromegalic subject, it is advisable to collect three to five the potential effectiveness of octreotide treatment in acro-
samples for GH assay at 10-min-intervals. megalic cats. Those responding favorably might be candidates
for long-acting release (LAR) octreotide treatment.103 2
IGF-I is bound to a transport protein and is much less subject
to fluctuation than is GH. Its amino acid sequence is less The recently introduced GH-receptor antagonist pegviso-
species specific than that of GH. Feline IGF-I can be measured mant has been reported to be effective, safe, and well-toler-
in an assay for human IGF-I and because this is more readily ated in humans with acromegaly.120 As long as there are no
available than suitable assays for GH, it is commonly used species-specific antagonists, this approach is not an option for
to diagnose acromegaly in diabetic cats.99,106 However, the dogs and cats.
recommended cut-off value is high (1000 µg/l)99, which may
lead to underdiagnosis. Nonelevated IGF-I concentrations Prognosis
have been reported in cats with elevated plasma GH concen- In acromegalic cats the short-term prognosis may be relatively
trations.106,107 Particularly in acromegalic cats with untreated good, as long as the insulin-resistant diabetes mellitus can be
diabetes mellitus, false-negative IGF-I results can be ex- managed satisfactorily, although this usually requires large
pected.108 On the other hand, increased IGF-I levels have been daily doses of insulin at considerable expense.107 Compli-
observed in nonacromegalic insulin-resistant diabetic cats, cations such as congestive heart failure or an expanding pitu-
constituting false-positive results.109,110 Some of these incon- itary tumor usually result in death or euthanasia within one to
sistencies may be related to nutritional status, for studies in rats two years. The response to treatment of the somatotroph ade-
and humans have shown that when nutritional condition is noma by surgery, radiation, and /or a somatostatin analogue
poor, plasma IGF-I concentration may be lowered and plasma can be monitored by measurements of plasma IGF-I. In hu-
GH concentration increased.111 mans IGF-I is considered to be the best biochemical marker
for this purpose, although inconsistent results have been
When the diagnosis of acromegaly has been confirmed, the reported, i.e., elevated GH with normal IGF-I in 11 % of
pituitary gland should be visualized by computed tomography noncured patients, and elevated IGF-I with normal GH in
or magnetic resonance imaging (fig. 2.20). 24 %.121
Treatment
Although acromegaly is being recognized in cats with increas- 2.2.4.2 Excessive mammary growth hormone
ing frequency, there have been few reports of experience with As mentioned in chapter 2.2.1, the release of GH from mam-
treatment. In humans transsphenoidal adenomectomy is the mary tissue is a normal physiological process in dogs during
treatment of choice. Transsphenoidal hypophysectomy in one the luteal phase of the estrous cycle. In some middle-aged and
cat led to reversal of insulin resistance and complete cessation older bitches sufficient amounts of GH may be released to re-
of diabetes mellitus102 and cryohypophysectomy in two others sult in acromegaly (and diabetes mellitus). Because progeste-
resulted in diminished insulin resistance and lowering of rone levels in bitches during nonpregnant metestrus and preg-
plasma IGF-I concentrations.112,113 nancy are similar (chapter 7.2.1), acromegaly can also be
expected to occur during pregnancy, and recently the occur-
The most frequently reported treatment for feline acromegaly rence of this in two bitches was reported.122 Administration of
has been radiation therapy. In five cases cobalt 60 (gamma) progestins may also give rise to GH excess and signs and
radiation lowered the insulin requirement transiently and re- symptoms of acromegaly.123,124
duced the size of the pituitary tumor.114,115 In one cat in
which linear accelerator (high-energy x-ray) radiation was Progestins also induce GH expression in mammary tissue in
used, insulin resistance was reduced but plasma IGF-I con- cats125, but the GH does not reach the systemic circulation126
centration remained elevated and the acromegaly continued and consequently does not lead to acromegaly. It does, how-
as an active disease process.116 Beta radiation reduced the in- ever, have a local proliferative effect that also involves IGF-I127
sulin requirement only slightly in one cat but linear acceler- and may result in marked enlargement of one, several, or all of
ator radiation reduced the insulin dose in another cat by the mammary glands. This fibroepithelial hyperplasia can
half.117 Possible adverse effects of radiation therapy are dis- occur in young queens at the time of their first estrus. It can
cussed in chapter 2.2.6.2. also be caused by the administration of synthetic progestins
such as megestrol acetate and medroxyprogesterone acetate.128
Depending on the receptor profile of the tumor, somatostatin It is discussed in more detail under the heading of estrus pre-
analogues are effective in a high percentage of humans with vention (chapter 7.10).
acromegaly, reducing both GH and IGF-I levels and the size
of the tumor.118 In one cat treated with the somatostatin ana-
logue octreotide, plasma GH concentration was normal-
ized119 but in four others octreotide had little or no effect on
28 Hypothalamus-Pituitary System
A B
C D
Figure 2.21:
(A, B) An eight-year-old female beagle with severe acromegaly and diabetes mellitus that developed during the current metestrus. Note the heavy body and the large
tongue. During the two previous metestrus periods the owner had noticed polyuria, polyphagia, and excessive panting and snoring.
(C, D) The same dog, three months after ovariohysterectomy. The soft tissue overgrowth has regressed but the bony changes causing prognathism and widened inter-
dental spaces remain. 129
Clinical manifestations Progestins used for estrus prevention can produce similar
Canine acromegaly due to mammary GH typically begins three changes, especially when given frequently and in relatively
to five weeks after estrus and produces the same signs and symp- high doses (fig. 2.22). A comparative study of the effects of
toms characteristic of excess pituitary GH described in two progestins revealed that they resulted in similar plasma
chapter 2.2.4.1: thick folds of skin on the head and neck, fa- concentrations of GH and IGF-I, and similar degrees of insu-
tigue, respiratory stridor, prognathism with widening of the lin resistance.131
interdental spaces, and abdominal enlargement due to viscero-
megaly (fig. 2.21). Initially, most of these changes regress fol- Laboratory studies often reveal hyperglycemia and increased
lowing metestrus but with successive estrous cycles they become plasma alkaline phosphatase. The latter may be due in part to
progressively more severe, until the full clinical picture develops. the glucocorticoid activity which is intrinsic to proges-
Early mild forms are usually primarily characterized by poly- tins.132,133
uria, polydipsia, sometimes polyphagia, and fatigue and snor-
ing. The polyuria is without glucosuria unless diabetes mellitus
also develops from the repeated exposure to GH excess.129,130
Anterior lobe 29
A B
C D
Figure 2.22:
(A) A female mongrel Belgian shepherd dog at the age of three years.
(B) Two years later the dog was presented because of decreased endurance, intolerance to warmth (frequent panting, preference for cool places), exaggerated growth of
the coat, increase in abdominal size, and inspiratory stridor. It had high plasma levels of GH (욷 45 µg/l), induced by thrice yearly injections of medroxyprogesterone acet-
ate for prevention of estrus.
(C) After the coat was clipped the physical changes were more prominent: heavy head, trunk and limbs, and thick folds of skin on the neck.
(D) Physical examination revealed prognathism, wide spacing of the teeth, and a relatively large tongue.134
Differential diagnosis tory results, for the sooner treatment is started, the greater
In pronounced cases the clinical features, including the spe- the chance of preventing permanent diabetes mellitus (see
cific medical history, are not easily confused with those of below).
other diseases. However, in some dogs the metabolic changes
lead to polyuria, polyphagia, and hyperglycemia which, to- Treatment
gether with the increase in abdominal size, may mimic the Progestin-induced acromegaly can be treated effectively by
signs of hypercortisolism. Redundant folds of skin on the withdrawal of exogenous progestins and /or by ovari(ohyster)-
head and neck may also occur in primary hypothyroidism ectomy. The animal may then change dramatically (fig. 2.21),
leading to GH excess (chapter 3.3.1). due to the reversal of the soft tissue changes. The size of the
abdomen decreases, as does the thickening of oropharyngeal
Diagnosis soft tissues and thus the associated snoring. The bony changes
As in pituitary GH excess, measurement of plasma GH (at appear to be irreversible but do not appear to cause problems
10-min intervals) and of IGF-I will confirm the diagnosis. It to the animal. In cases in which the GH excess did not lead to
is usually advisable not to delay treatment pending the labora- complete exhaustion of the pancreatic b cells, the elimination
30 Hypothalamus-Pituitary System
A B
Figure 2.25:
A nine-year-old male boxer dog with a large pituitary tumor and secondary hypothyroidism, only manifested by somnolence, slight alopecia in the groins and flanks, and
a thin coat (A). There was marked atrophy of the testes (B). There were as yet no neurological symptoms.
with them and ask for treatment. For this purpose, prolactin occur in humans but have not been described in dogs and
can be suppressed and pseudopregnancy terminated by ad- cats. Clinically nonfunctional adenomas (NFAs) constitute
ministration of: 50 % of all pituitary adenomas in humans and include gon-
1. Dopamine agonists such as bromocriptine (10 µg/kg adotroph (staining for FSH, LH, and a-subunit), thyrotroph
twice daily for ten days) and cabergoline (5 µg/kg once (staining for TSH) and null cell (immunonegative) adenomas.
daily for six days). Vomiting, which frequently occurs with The main consequences of NFAs are mass effects.147 Their
bromocriptine, can be avoided by reducing the dose by occurrence in dogs and cats has not been explicitly reported.
half for the first four days and by administering the drug
after meals. It has been reported that long-term adminis- The nonendocrine manifestations of pituitary adenomas result
tration (쏜 14 days) may lead to coat color changes.141 from pressure by the tumor on adjacent brain structures. There
2. The serotonin antagonist metergoline (0.1 mg/kg twice may also be anterior pituitary failure, i.e., partial or complete
daily for ten days). This drug lowers PRL release (fig. 2.24) anterior pituitary hormone deficiency. In principle, deficien-
without the risk of vomiting, but hyperexcitation, some in- cy of all six major hormones (LH, FSH, GH, TSH, ACTH,
crease in aggression, and frequent whimpering may occur.137 and PRL) can occur. The interpretation of results of suprapi-
tuitary stimulation tests (chapter 12.1) may pose problems
when there is also hormone excess that affects the secretion of
other pituitary hormones.148 The enlarging pituitary may also
2.2.6 Pituitary tumors affect the function of the neurohypophysis (chapter 2.3.2).
Figure 2.26:
(A) Gadolinium-enhanced axial MRI scan of an eleven-
year-old female castrated Jack Russell terrier admitted
as an emergency after the sudden onset of continuous
panting, circling, and cycling movements in lateral
recumbency, and a history of epileptiform seizures.
The MRI scan revealed an irregular pituitary mass,
1.7 × 1.4 cm, compressing the surrounding brain. The
mass contained cavities filled with fluid resembling
A
blood.
(B) Necropsy revealed a necrotic and hemorrhagic
pituitary corticotroph adenoma, originating from the
B
pars intermedia.
testes become very small and soft and as a result the epididy- The mass effects may also appear rather suddenly. In humans
mis, which does not change, is more easily delineated. this is known as pituitary apoplexy and it is characterized by
Neurohypophyseal dysfunction is unusual in anterior pitu- peracute headache, vomiting, visual impairment, and loss of
itary disease that remains restricted to the pituitary fossa, but consciousness. It is caused by either hemorrhage or infarction
more common when the suprasellar extension of large tumors within a pituitary tumor (fig. 2.26) or a nontumorous pitu-
compresses the hypothalamus (chapter 2.3.3). itary gland. This syndrome has now been described in five
dogs. The three most severe cases were presented as emergen-
cies with sudden collapse and severe depression; in two there
2.2.6.2 Mass effects was blindness and bilateral mydriasis. In four dogs there was a
Continued suprasellar expansion of the tumor exerts pressure large corticotroph adenoma with hemorrhage. In the fifth
on the diaphragma sellae, the hypothalamus and – if the ex- dog the pituitary hemorrhage without tumor was probably
pansion is sufficiently rostral – the optic chiasm. Lateral supra- part of the hemorrhagic diathesis due to idiopathic throm-
sellar extension of a pituitary tumor may impair oculomotor bocytopenia.153,154
nerve function.149 The expanding tumor can be expected to
cause headache and visual field defects in the dog and cat, as Differential diagnosis
in man, but because of the lack of an autoanamnesis, often the Due in part to the nonspecific character of the signs and
veterinarian must at first rely on rather vague and nonspecific symptoms, the differential diagnoses range from other neuro-
symptoms. These include lethargy, a tendency to seek seclu- logic diseases, such as parasellar lesions and increased intra-
sion, and a decrease in appetite.150,151 Suspicion of a mass ef- cranial pressure, to metabolic disorders such as hypothyroid-
fect from a pituitary tumor may be supported by the owner’s ism and hepatic encephalopathy.
description of the animal’s tendency to lower its head to avoid
being patted. Progressive enlargement of the mass may give Diagnosis
rise to severe neurological abnormalities such as pacing, head Laboratory findings indicating low basal function of periph-
pressing, circling, and continuous howling. Seizures usually eral endocrine glands, e.g., a low plasma thyroxine level
do not occur. Very large pituitary tumors may cause pressure and low urinary corticoid excretion, may raise suspicion of
on the optic chiasm to such an extent that visual disturbances anterior pituitary failure, but the diagnosis of partial or total
are noticed by the owner.152 hypopituitarism should rest on direct evidence of deficiencies
of the pituitary hormones themselves. This can be accom-
Physical examination can reveal a variety of signs, including plished by stimulation tests with hypophysiotropic hormones
dullness, one or more of the above neurological signs, weight such as GHRH, GnRH, CRH, and TRH. Measurements of
loss due to increasing anorexia, and occasionally mydriasis the respective pituitary hormones – GH, LH, ACTH, and
with or without anisocoria. Ophthalmoscopic examination PRL – permit assessment of pituitary reserve capacity. The
rarely reveals edema of the papilla. tests can in principle be performed in an outpatient setting,
Anterior lobe 33
A B
C D
Figure 2.27:
Transverse CT images of skulls of three dogs and one cat.
(A) A healthy beagle. Contrast enhancement enables the visualization of a normal-sized pituitary, the margins of which are indicated by A–B (3.6 mm) and C–D
(5.0 mm).
(B) A twelve-year-old female mongrel greyhound with pituitary-dependent hypercortisolism. Contrast enhancement reveals a definitely enlarged pituitary (A–B = 8.6 mm
and C–D = 9.2 mm).
(C) A ten-year-old female Australian terrier with dexamethasone-resistant pituitary-dependent hypercortisolism without noticeable neurological symptoms. Contrast en-
hancement reveals a very large pituitary (A–B = 16.6 mm; C–D = 17.7 mm).
(D) A 14-year-old castrated male domestic shorthair cat presented with mild symptoms and signs of pituitary-dependent hypercortisolism and central blindness. A very
large pituitary is revealed by contrast enhancement (A–B = 13.6 mm; C–D = 17.9 mm).
but it is cumbersome to perform them separately. Hence a mediately to determine whether interference with vasopressin
combined anterior pituitary test has been developed, in which release has led to hypernatremia.153
all four hypophysiotropic hormones are injected within 20 s
and blood samples are collected for measurements of all four Contrast-enhanced helical CT (fig. 2.27) and MRI (fig. 2.28)
pituitary hormones in each sample (chapter 12.1.3). When provide imaging of the pituitary with high spatial and contrast
pituitary apoplexy is suspected, blood should be collected im- resolution, revealing pituitary enlargement and its relation-
34 Hypothalamus-Pituitary System
A B
Figure 2.28:
Sagittal MR images of the skulls of a healthy dog (A) and a dog with pituitary-dependent hypercortisolism (B). In the healthy dog the hypophyseal cleft between the an-
terior lobe and the neurointermediate lobe can be distinguished (arrow). In the dog with pituitary-dependent hypercortisolism there is suprasellar extension of the
pituitary mass.
ship to surrounding structures and bony anatomic landmarks goline decreased cortisol production and decreased tumor
for surgical intervention.155 Dynamic helical CT and MRI size. However, among the nonresponders were relatively
also allow visualization of the posterior lobe. Its displacement many dogs with large pituitary tumors.158
may reveal the location of an adenoma or microadenoma in
the anterior lobe, whereas the inability to visualize the pos- Hypophysectomy is used successfully to treat pituitary-de-
terior lobe in large pituitary tumors might be compatible pendent hypercortisolism (chapter 4.3.1) and with increasing
with vasopressin insufficiency (chapter 2.3.3.1).156 experience it has been used to remove pituitary tumors up to
2 cm in diameter. Total or subtotal removal of large pituitary
Treatment tumors with mass effects gives immediate relief in the form of
Anterior pituitary failure can be treated by substitution of the decreased neurological signs and return of appetite. The ani-
hormones inadequately produced by the target glands. Since mal can resume a normal life for months to years after surgery.
gonadal hormones are not essential, this can be limited to oral If the tumor recurs, transsphenoidal debulking can be con-
administration of thyroxine (10–15 µg/kg twice daily) and sidered.
cortisone (0.25–0.5 mg/kg twice daily). This results in some
improvement in alertness and also in appetite if the animal Radiation therapy is indicated in both dogs and cats when a
had been anorectic. Especially when by virtue of its size the pituitary tumor is already causing neurological abnormal-
tumor has already had neurological effects, any improvement ities.159 It reduces the size of the tumor and thereby the neuro-
will be temporary. Immediate corticosteroid administration is logical manifestations. The outcome is better in dogs with
indicated in cases suspected of pituitary apoplexy; in such a mild neurological signs than in those with severe signs or stu-
crisis the dose should be four to five times the long-term sub- por.160 Radiation therapy increases survival time over that in
stitution dose (chapter 4.3.6). untreated dogs.161 Median survival time has been reported to
be 22.6 months in dogs162 and 17.4 months in cats.163 Radi-
In principle there are three options to reduce the size of the ation therapy does not cause a prompt change pituitary hy-
pituitary tumor: medical therapy, hypophysectomy, and radi- persecretion and thus dogs with pituitary-dependent hyper-
ation therapy (see also discussion on the treatment of pituitary cortisolism may require continued medical treatment. Cats
GH excess in chapter 2.2.4.1). Most experience with medical with a macrotumor and diabetes mellitus may not require in-
treatment has been gained in dogs with pituitary-dependent sulin treatment after the completion of a series of fractionated
hypercortisolism. Dopaminergic drugs such as bromocriptine radiation therapy treatments (chapter 2.2.4.1).164
do not effectively decrease cortisol production157, but better
results have been obtained with the dopamine D2 receptor Acute side effects of radiation treatment include local skin
agonist cabergoline. Cabergoline has a higher affinity for the changes (erythema, hair loss, leukotrichia), pharyngeal mu-
D2 receptor and has a longer half-life than bromocriptine. cositis, and mild otitis externa. The risk of late side effects
Despite the fact that D2 receptors are only moderately ex- (hearing impairment, brain necrosis /fibrosis) depends on the
pressed in tumorous and nontumorous dog pituitaries20, in 17 volume of brain tissue treated and the daily and the total dose
out of 40 dogs with pituitary tumors, treatment with caber- of radiation administered.159
Posterior lobe 35
2.3.1 Oxytocin
Oxytocin stimulates milk ejection by contraction of the
myoepithelial cells surrounding the alveoli and ducts in the
mammary gland. The release of oxytocin is brought about
through a neuroendocrine reflex. Suckling of the nipple sends
neural impulses to the brain that reach the hypothalamus and
direct the release from the neurohypophysis. It also stimulates Figure 2.29:
rhythmic myometrial contractions in the uterus, aiding in ex- Plasma vasopressin (VP) concentration in blood samples collected every 2 min for
pulsion of the fetus. In dogs plasma oxytocin concentration 2 h in a five-year-old beagle under basal conditions (upper panel), and during os-
motic stimulation (lower panel) with hypertonic saline (infusion of 20 % NaCl at
increases during late pregnancy and further increases during
0.03 ml/kg/min for 1 h). Note the differences in scale of the y-axis. Volume and
the expulsive stage of parturition.165,166 Primary uterine iner- electrolyte losses due to blood sampling were corrected by intravenous infusion of
tia in bitches is associated with low plasma oxytocin concen- lactated Ringer’s solution.
trations.167 Therapeutically, oxytocin is widely used to sustain
uterine contractions. Oxytocin has an essential role in activat-
ing maternal behavior. Apart from its role in parental care,
oxytocin also plays a role in social attachments and affiliations.
Positive interactions between humans and dogs are associated
with several neurohumoral changes in both species, including
an increase in plasma oxytocin.168 Results of recent behavioral
studies indicate that oxytocin also increases trust among hu- centrated in the anterior hypothalamus, which is near but
mans.169 separate from the supraoptic nuclei. This area is supplied with
blood by small perforating branches of the anterior cerebral
arteries. Osmotic stimulation increases both basal and pulsa-
tile VP secretion (fig. 2.29).170 Significant changes in circu-
2.3.2 Vasopressin lating blood volume and blood pressure may also influence
VP release and the setting of osmoregulation. Significantly
As in most mammals, in dogs and cats arginine vasopressin elevated plasma VP concentrations have been found in dogs
((A)VP) or antidiuretic hormone (ADH) (in pigs: lysine with dilated cardiomyopathy.171 In addition, the stress of fear
vasopressin) plays a vital role in water conservation. VP like and the administration of preanesthetic or anesthetic agents
other pituitary hormones is secreted in a pulsatile fashion may increase plasma VP concentration.172,173 The opioid me-
(fig. 2.28).170 The major determinant of its release is plasma thadone in particular has a strong stimulatory effect on VP re-
osmolality. Specialized neurons called osmoreceptors are con- lease, considered to be a direct effect.174
36 Hypothalamus-Pituitary System
Figure 2.30:
In a medium- to large-size dog the kidneys filter about 90 liters of plasma daily. About 75 % of this is passively reabsorbed in the proximal convoluted tubule
together with the active transport of solutes such as sodium, potassium, bicarbonate, amino acids, and glucose. Following this isotonic reabsorption, an additional 5 % of
the water is withdrawn from the descending limb of Henle’s loop (without solute) by the hypertonic interstitium. The remainder is diluted to an osmolality of about
80 mOsm/kg by selective reabsorption of sodium and chloride in the ascending limb of Henle’s loop and the distal convoluted tubule. In the absence of VP urine passes
largely unmodified through the distal tubules and collecting ducts, resulting in maximal water diuresis. In presence of VP, solute-free water is reabsorbed osmotically
through the cells of the collecting ducts, resulting in the excretion of small volumes of concentrated urine. This antidiuretic effect is mediated via a G-protein-coupled V2
receptor that induces (via cyclic AMP) translocation of aquaporin (AQP2) water channels into the apical membrane. Tight junctions on the lateral surface of the cells pre-
vent unregulated water flow.
The anterior hypothalamus not only contains osmoreceptors In dogs drinking induces volume-dependent oropharyngeal
regulating VP secretion but also thirst osmoreceptors. The signals that inhibit thirst and vasopressin secretion, well before
control of vasopressin secretion and thirst sensation are par- the ingested water has left the stomach. In dehydrated dogs
tially interwoven, in that drinking not only leads to satiation drinking decreases vasopressin secretion within minutes,
of thirst but also to cessation of vasopressin secretion. The os- while Posm is still elevated.176,177
motic threshold for VP secretion is slightly lower than that for
thirst perception. Under physiologic conditions water bal- The effects of VP are mediated by three receptor subtypes: V1
ance is accomplished more by free water excretion regulated receptors on blood vessels, V2 receptors on renal collecting
by VP than by water intake regulated by thirst.175 duct epithelial cells, and V3 receptors mediating ACTH secre-
tion from the adenohypophysis (chapter 4.1). The adjust-
In addition to systemic signals – primarily plasma osmolality ments of water reabsorption needed to maintain water and
(Posm) and blood volume – influencing VP secretion and electrolyte balance occur in the distal convoluted tubules and
water intake, fluid balance is regulated by presystemic signals. in the collecting ducts (fig. 2.30), and depend on the hor-
Posterior lobe 37
Pathogenesis
Both complete and partial central diabetes insipidus (CDI)
2.3.3 Diabetes insipidus have been recognized in dogs and cats. In complete CDI there
is very little increase in urine osmolality with increasing
The term diabetes insipidus is derived from the Greek diabai- plasma osmolality. The animal is essentially devoid of re-
nein (passing through) and the Latin insipidus (without taste). leasable VP (fig. 2.32). In partial CDI there is release of VP
It is characterized by large volumes of urine with an osmolal- with increasing plasma osmolality but in subnormal amounts
ity lower than that of blood plasma and so dilute that it is al- (fig. 2.33).
most tasteless. In fact, the term diabetes insipidus (DI) only
denotes polyuria. When diabetes mellitus has been excluded, Among the possible causes of impaired VP release, an intra-
DI and polyuria can be regarded as synonymous. From a pa- cranial tumor is likely in middle-aged and elderly animals,
thophysiological point of view three fundamentally different most often a primary pituitary neoplasm.183–185 There are two
pathogenetic categories can be distinguished: possible mechanisms for the impaired release. (1) The enlarg-
쎱 A disturbance of the hypothalamic-pituitary system caus- ing pituitary adenoma in the anterior lobe increasingly com-
ing insufficient VP release (central diabetes insipidus). presses the posterior lobe in the restricted space of the pitu-
쎱 A disease or functional change of the kidney, leading to itary fossa, resulting in pressure atrophy of the posterior lobe
insufficient response to VP (nephrogenic diabetes in- and diminished VP release. During dynamic computed to-
sipidus). mography the normally characteristic and distinct contrast en-
쎱 Sustained and excessive drinking (primary polydipsia), re- hancement of the neurohypophysis (neurohypophyseal flush)
sulting in a tendency to plasma hypotonicity and conse- is less pronounced or absent.186,187 (2) Large pituitary tumors
quently little or no stimulation of VP release. with suprasellar extension can compress the hypothalamic nu-
38 Hypothalamus-Pituitary System
clei, impairing VP synthesis probably via degeneration of the head trauma remained unclear.192 Severe head injury is
hypothalamic neurons. Both mechanisms can contribute to known to be a cause of CDI, particularly in condition, and
VP deficiency and inability to react adequately to osmotic sti- there are now several reports of this cats.193–196 There may be
muli. It may be difficult to diagnose CDI in patients in which a spontaneous remission, probably by regeneration of disrupted
pituitary corticotroph adenoma has caused hypercortisolism axons in the pituitary stalk.
(chapter 4.3.1).188 CDI may be overlooked because of the
polyuria caused by the glucocorticoid excess (fig. 2.31). CDI CDI can also occur as a complication of pituitary surgery,
may become apparent when the hypercortisolism has been most often performed to treat pituitary-dependent hypercor-
eliminated by treatment.183 tisolism (chapter 4.3.1). Diabetes insipidus appears immedi-
ately following surgery197 and often disappears spontaneously
Neoplastic nonpituitary lesions reported to cause CDI in- after days to months. If the pituitary stalk is sectioned so high
clude meningioma and malignant lymphoma.185,189 A non- as to induce retrograde degeneration of the hypothalamic
neoplastic cause of CDI is the trauma and subsequent inflam- neurons, the CDI can be permanent. An immunohisto-
mation of larva migrans.190 CDI has also been described in chemical study of the hypothalamic paraventricular and su-
association with congenital pituitary anomalies191,192, al- praoptic nuclei in healthy dogs revealed that VP-positive cells
though in one of these cases the pathogenetic role of an early tend to decrease after hypophysectomy.198 The incidence of
Posterior lobe 39
Clinical manifestations
The major manifestations are polyuria, polydipsia, and a near-
continuous demand for water. In severe cases water intake and
urine volume may be immense, requiring micturition almost
every hour throughout day and night. Although in partial
CDI water intake and urine volume may be only moderately
increased, in severe cases of complete CDI water intake may
be so enormous as to interfere with food intake and thus re-
sult in weight loss. In animals in which a large neoplasm is the
underlying cause, there may be additional neurological symp-
toms and endocrine deficiencies (chapter 2.2.6). CDI caused
by head trauma may not only be associated with soft tissue
and skeletal lesions, but damage to the hypothalamus-pitui-
tary region may cause additional hormone deficiencies, such
as secondary hypothyroidism.193,194
Differential diagnosis
Apart from central diabetes insipidus there are in principal
only two basic disorders which can account for the polyuria:
nephrogenic diabetes insipidus and primary polydipsia with polyuria. In several of these conditions impaired VP
(chapter 2.3.3.2 and chapter 2.3.3.3), both of which are in- release and /or interference with its action has been docu-
frequent, but a wide variety of conditions cause polyuria. mented. These include hypercortisolism (fig. 2.31), hyperal-
Young animals may have congenital kidney disease, and at all dosteronism204, GH excess205, pyometra206, hepatoencephalo-
ages acquired kidney disease may cause polyuria. Especially in pathy207, and polycythemia (fig. 2.34).208
middle-aged and elderly animals, endocrine conditions such
as diabetes mellitus, hypercortisolism, hyperaldosteronism, It can be assumed that in some of these conditions the hor-
hyperthyroidism, pyometra, progestin-induced (luteal phase) monally induced changes (corticosteroid-induced sodium re-
GH excess, hyperparathyroidism, and hypercalcemia of ma- tention) may cause hypervolemia and thereby lead to an al-
lignancy must be considered. Other conditions such as hepa- tered setting of the osmoreceptor system and consequently to
toencephalopathy and polycythemia may also be associated delayed and decreased VP responsiveness to osmotic stimu-
40 Hypothalamus-Pituitary System
In contrast, acquired or secondary NDI is the most common In the rare patient with severe congenital NDI, urine osmo-
cause of polyuria in dogs and cats and may be caused by a lality is not increased by water deprivation in the modified
wide range of endocrine and metabolic disorders. Several of water deprivation test (chapter 12.2), nor by administration
these have already been mentioned in the section on differen- of VP. In several of the partial and acquired forms of NDI,
tial diagnoses of CDI (chapter 2.3.3.1). As discussed at the water deprivation produces some urine concentration and
end of chapter 2.3.2, in some of these conditions the polyuria VP also has some effect. Plasma VP measurements during the
may be the result of downregulation and reduced apical water deprivation test and /or during hypertonic saline infu-
plasma membrane delivery of AQP-2. In a dog that had par- sion may help to differentiate among CDI, NDI, and primary
tial NDI that disappeared upon removal of an intestinal leio- polydipsia. These approaches are discussed in more detail in
myosarcoma, it was hypothesized that the polyuria was due to chapter 2.3.3.4.
42 Hypothalamus-Pituitary System
Treatment
Oral administration of hydrochlorothiazide (Esidrex®, Novar-
tis; other brand names: Microzide®, Hydrodiuril®, Oretic®)
(2–4 mg/kg twice daily) and a low-sodium diet can decrease
2 urine volume219, albeit probably without a significant change
in urine osmolality. It has been proposed that the thiazide
diuretic and a low sodium diet cause extracellular volume
contraction. As a result, the glomerular filtration rate de-
creases and proximal tubular reabsorption of sodium and
water increases. Consequently, less sodium and water are de-
livered to the collecting tubules and urinary volume is re-
duced, but not normalized.227 However, there is increasing
evidence that sodium depletion and increased proximal tubu-
lar water reabsorption do not solely account for the antidiu-
retic effect. Hydrochlorothiazide can also directly increase
Figure 2.37: water permeability in the medullary collecting ducts, prob-
Fluctuations of urine osmolality (Uosm) in samples collected at home in two
healthy dogs with, according to the owners, unremarkable drinking and micturi-
ably by inducing AQP-2 expression independent of VP.228
tion behavior: a 9.5-year-old castrated male schnauzer (blue line) and a 2.5-year-
old male Border collie (red line).208
2.3.3.3 Primary polydipsia
Primary polydipsia occurs primarily in dogs and is character-
ized by a marked increase in water intake that cannot be ex-
plained as a compensatory mechanism for excessive fluid loss.
There is no urinary concentrating defect and at various times
during the day the dog may produce either highly diluted
urine or concentrated urine. Marked fluctuations in Uosm
may also occur even though the owner observes nothing re-
markable in the dog’s drinking behavior (fig. 2.37). In a series
of 89 healthy pet dogs, Uosm in morning urines ranged from
273 to 2620 mOsm/kg (Usg 1.009 to 쏜 1.050) with a mean
(± SD) of 1541 ± 527 mOsm/kg (Usg 1.035 ± 0.010).229 In
none of these dogs was the sometimes marked variation in
water intake and urine volume considered by the owners to
be associated with abnormal drinking.
Diagnosis
Marked fluctuations in Uosm in serial urine samples collected
at frequent intervals and some values 쏜 1000 mOsm/kg
(fig. 2.38 and chapter 12.2) provide the diagnosis of primary
polydipsia. However, the fluctuations are not so pronounced
in all dogs with primary polydipsia and in some Uosm fluc-
tuates between about 200 and 600 mOsm/kg. In such cases a
water deprivation test (chapter 12.2.2) can be very helpful.
Within 8 h of water deprivation Uosm should exceed
1000 mOsm/kg with weight loss 울 3 % and only slight in-
creases in Posm and plasma sodium concentration.232
Elevated or normal VP secretion is inappropriate in the pres- In addition to neurological manifestations, some of the re-
ence of low plasma osmolality. Reduced suppressibility of VP ported cases included polyuria, which seems paradoxical in
causes water retention and may lower plasma osmolality to the presumed VP excess. The subject of polyuria and abnormal-
Posterior lobe 45
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55
3 Thyroids
Ad Rijnberk
Hans S. Kooistra
3
3.1 Introduction a normal metabolic (euthyroid) state (chapter 3.2.2). Several
of the genes involved in the early and later stages of thyroid
In the dog and the cat the thyroid glands are separate lobes morphogenesis have been identified.1
lying beside the trachea from about the third to the eighth
tracheal ring. They are covered ventrally by the sternohyoid The basic functional unit of the thyroid is the follicle, a hol-
and sternothyroid muscles. The major blood supply is via the low sphere 30–300 µm in diameter. Its wall is a single layer of
cranial thyroid artery, a branch of the common carotid, and thyroid epithelial cells which are cuboidal or flat when qui-
the principal venous drainage is via the caudal thyroid vein, escent (fig. 3.1) and columnar when active. The lumen is fil-
which enters the internal jugular vein. Normal thyroid glands led with a colloid containing a large (~ 660 kDa) glycoprotein
are not palpable. called thyroglobulin (Tg)2 that is unique to the thyroid and
within the sequence of which the thyroid hormones are syn-
The thyroids are assembled from two different embryologic thesized and stored. The C cells are largely located in the in-
structures, reflecting their dual endocrine function. The thy- terfollicular spaces (fig. 3.1).
roglobulin-producing follicular cells originate from a midline
evagination of the pharyngeal epithelium. The calcitonin-
producing cells – parafollicular or C cells – are derived from
the neural crest, originating from the fourth pharyngeal
pouch. The thyroid primordium begins descending toward its 3.1.1 Hormone synthesis and
final position while still connected to the floor of the pharynx secretion
by a narrow channel, the thyroglossal duct and during the
descent remnants of tissue may be left along the tract. In addi- The main hormonal secretory product of the thyroid gland
tion, in their development the thyroids are intimately related is 3,5,3',5'-L-tetraiodothyronine or L-thyroxine (T4). The
to the aortic sac, which leads to the frequent occurrence of other thyroid hormone, 3,5,3'-L-triiodothyronine (T3), is se-
accessory thyroid tissue in the mediastinum of the adult ani- creted in much smaller quantities (about 20 % of that of T4).
mal. Rarely, such accessory tissue is the sole functioning Most of the circulating T3 is produced in peripheral tissues by
thyroid tissue and its secretion may be insufficient to maintain deiodination of the outer ring of T4. Inner ring deiodination
A B
Figure 3.1:
(A) Photomicrograph of the thyroid gland of a healthy adult dog, illustrating the variable size of the thyroid follicles.
(B) Immunoperoxidase stain for the calcitonin-secreting C cells or parafollicular cells in a healthy adult dog.
56 Thyroids
Figure 3.2:
Chemical structures of the amino acid tyrosine, intrathyroidally formed iodotyrosines (MIT and DIT) and iodothyronines (T4 and T3), and two products of the peripheral
deiodination of T4, namely, T3 and reverse T3 (3',5',3-triiodothyronine).
Introduction 57
Figure 3.3:
Two follicular cells, representing thyroid hormone bio-
synthesis (left) and secretion (right): (1) Active trans-
port of iodide from the blood into the thyroid cell via
sodium iodide symporter (NIS), (2) oxidation of the
iodide by thyroid peroxidase (TPO) and transfer of the
oxidized iodide to tyrosine residues of thyroglobulin
(Tg), (3) coupling of two DIT molecules to form T4 or
MIT + DIT to form T3 (see also fig. 3.2), (4) endocytosis
or pinocytosis of colloid droplets, (5) fusion of colloid
droplets with lysosomes (Ly) and subsequent hydrolysis
of Tg with release of T3 and T4, (6) deiodination of free
iodotyrosines and intrathyroidal reutilization of iodide.
results in the metabolically inactive 3,3',5'-triiodothyronine tive intermediate that is then incorporated into tyrosine resi-
(reverse T3, rT3) (fig. 3.2). dues of acceptor proteins, mainly thyroglobulin (Tg). The
iodination is catalyzed by thyroid peroxidase (TPO), a mem-
Iodide, the main building block of the thyroid hormones, brane-bound heme-protein enzyme. Studies in dog thyroid
is actively transported (»trapped«) from the extracellular cells have shown that the regulatory cascade controlling H2O2
fluid into the thyroid follicular cells by an active, saturable, generation in thyrocytes is different from that of the O2-
energy-dependent process, which derives its energy from generating system of macrophages and leukocytes.4
Na+-K+-ATPase. This iodide carrier is a large (쏜 600 amino
acids) transport protein called sodium iodide symporter (NIS), Iodination of the tyrosine residues of Tg results in the
located at the basal membrane of the thyrocyte (fig. 3.3). The formation of monoiodotyrosine (MIT) and diiodotyrosine
resulting thyroid:plasma iodide ratio is ~ 25. An additional (DIT). MIT and DIT then undergo oxidative coupling to
thyroid cell protein, called pendrin, is thought to facilitate the form the iodothyronines, which remain bound to Tg until se-
apical transfer of iodide into the follicular lumen.3 creted (fig. 3.2). This coupling reaction occurs separately
from iodination but is also catalyzed by TPO. The thiocarba-
The gastric mucosa, salivary glands, and choroid plexus are mide drugs, including propylthiouracil, methimazole, and
also able to concentrate iodide via NIS but in contrast to the carbimazole, are competitive inhibitors of TPO.5 Their result-
thyroid, they do not bind it organically. These tissues as well ing ability to block thyroid hormone synthesis makes them
as the thyroid also concentrate structurally-related mono- useful in the treatment of hyperthyroidism (chapter 3.4.1). Tg
valent anions such as thiocyanate (SCN–), perchlorate is iodinated at the apical (follicular) border of the cell and is
(ClO4–), and pertechnetate (TcO4–). However, unlike iodide, then moved into the colloid by exocytosis (fig. 3.3).
these ions are also not organically bound in the thyroid and
hence their duration within the thyroid is short. This prop- Secretion of thyroid hormones requires that Tg be taken back
erty together with a short physical half-life makes the radio- into the thyroid cell via pinocytosis (fig. 3.3). Pseudopods
isotope of pertechnetate (99mTcO4–) a valuable radionuclide from the apical plasma membrane surround a portion of the
for imaging the thyroid by scintillation scanning. colloid to form an intracellular colloid droplet.6 Each droplet
is enclosed in a membrane derived from the apical border and
Once within the thyroid cell, inorganic iodide is rapidly oxi- is combined with a lysosome. This phagolysosome moves to-
dized in the presence of hydrogen peroxide (H2O2) to a reac- ward the basal aspect of the cell and becomes smaller and
58 Thyroids
more dense with progression of the hydrolysis of Tg by the ly- be associated with severe psychomotor retardation and greatly
sosomal proteases (fig. 3.3). This digestion of Tg releases T4 elevated plasma T3 levels.14
and T3, as well as the inactive iodotyrosines, peptides, and in-
dividual amino acids. The biologically active thyroid hor- Deiodination is the most significant metabolic transformation
mones T4 and T3 diffuse from the cell into the circulation, of the thyroid hormones. About 80 % of the secreted T4 is
whereas MIT and DIT are largely prevented from release into deiodinated to form T3 and rT3, predominantly in the liver
3 the circulation by the action of intracellular deiodinase and kidney. T3 has a higher binding affinity for nuclear T3 re-
(fig. 3.3). Tg itself is normally not released into the circu- ceptors than does T4 and therefore outer ring monodeiodi-
lation in significant quantities and in healthy dogs only very nation generates a more biologically active iodothyronine. T3
small quantities can be measured in the peripheral blood by a has approximately three to four times the metabolic potency
sensitive homologous immunoassay.7 of T4, which means that almost all thyroid hormone meta-
bolic action can be ascribed to the action of T3. T4 and T3
are inactivated by inner ring deiodination to rT3 and 3,3'-di-
iodothyronine (3,3'-T2), respectively. The three deiodinase
3.1.2 Hormone transport, tissue enzymes (D1, D2, and D3) that catalyze these reactions differ
in tissue localization, substrate specificity, and physiologic and
delivery, and metabolism pathophysiologic modulation. Thus the biological activity of
thyroid hormone is additionally regulated locally by tissue-
Plasma T4 and T3 are largely bound to protein. Less than specific deiodinases.15 The notion that the thyroid itself con-
0.05 % of T4 and less than 0.5 % of T3 circulate as »free« or tributes little to the T3 pool does not apply to states of hyper-
unbound hormone, but it is the free hormone concentration function, for then the T3:T4 ratio in the thyroid secretion in-
that is maintained constant by the feedback regulatory system creases.
and that appears to parallel the rate of cellular uptake of these
hormones. Thus it is the free hormone concentration that de- Factors that impair T3 formation, such as fasting and nonthy-
termines thyroid status irrespective of the total hormone con- roidal disease, almost invariably increase plasma rT3 concen-
centration in the plasma. Dogs have a high-affinity thyroid tration. There is evidence that illness leads to increased activ-
hormone binding globulin (TBG), in addition to which albu- ity of type 3 deiodinase (D3), which primarily deiodinates the
min and prealbumin bind thyroid hormones with low affinity. inner ring. It decreases the T3:rT3 ratio in two ways: it pre-
Cats do not appear to have a high-affinity TBG, only preal- vents conversion of T4 to T3 by instead catalyzing the conver-
bumin acts as a thyroid hormone binding protein.8 In addi- sion of T4 to rT3, and it also catalyzes the degradation of T3 to
tion to these binding proteins, a minor part of the thyroid 3,3'-T2.15 There is no convincing evidence that low circu-
hormones can be bound to lipoproteins and also to trans- lating T3 concentrations in illness are associated with in-
thyretin, which in part exists as a complex with retinol (vit- adequate thyroid hormone effect at the tissue level. Indeed,
amin A)-binding protein.3 the impaired conversion of T4 to T3 is probably beneficial in
sparing protein catabolism.16
The concentration and /or capacity of circulating binding
compounds may be changed by a variety of diseases and phar- As mentioned above, T4 binds more tightly to binding pro-
macologic agents, thereby affecting primarily the plasma total teins in plasma than does T3, which results in T4 having a
thyroxine (TT4) concentration. Glucocorticoids and acetyl- lower metabolic clearance rate and longer half-life. Overall,
salicylic acid are known to lower plasma TT4 concentration the kinetics of thyroid hormone distribution and turnover are
without affecting the concentration of free T4.9,10 Breed dif- much more rapid in dogs than in humans, in part because of
ferences may also account for deviations from established ref- the lower binding of both T4 and T3 in canine plasma.17,18
erence ranges for TT4 for the total dog population. In general, The plasma half-life of T4 is about 0.6 days in dogs, compared
dogs of small breeds tend to have somewhat higher plasma to about seven days in humans.
TT4 concentrations than do those of large breeds. Low TT4
concentrations have been reported in whippets, and in sled
dogs and greyhounds both TT4 and free T4 concentrations
have been reported to be relatively low.11–13 3.1.3 Regulation of thyroid function
In recent years several plasma membrane carriers for transport Thyroid function is mainly regulated by thyrotropin (thyroid-
of both T4 and T3 to intracellular sites of action and meta- stimulating hormone, TSH), a 28 kD glycoprotein secreted
bolism have been identified. There is increasing evidence for by the anterior lobe of the pituitary. The TSH molecule con-
tissue-specific as well as generalized transporters belonging to sists of an a- and ab-subunit. The a-subunit is identical to
a number of different transporter protein families. Each of that of gonadotropins, whereas the b-subunit is distinct and
these families has many members, with small variations in confers on the TSH molecule its biological activity. In both
structure that alter the specificity of the target substance. Mu- the dog and the cat the genes encoding the b-subunit of TSH
tations in one of these carriers in humans have been found to have been cloned and sequenced.19,20 Like all pituitary hor-
Introduction 59
Figure 3.6:
Rectilinear 131I-scintiscan of a four-year-old female German
Pointer weighing 18 kg. The dog was presented because of
longstanding symmetrical areas of alopecia on the flanks. The
Figure 3.5:
dog’s growth had been retarded and it had disproportionately
Scintiscan of a dog with a bilateral thyroid tumor (palpated
short legs. There were no symptoms of reduced mental or
outlines indicated by solid lines). The patchy distribution of the
physical activity. The scan reveals only one small area of 131I
radioactivity is compatible with the heterogeneous character
accumulation, in the midline, cranial to the normal site of the
of the tumor: Areas lacking the capacity to trap radioioidide
thyroid glands. Apparently this small remnant from the thy-
(anaplastic tumor, necrosis, and /or hemorrhage) are inter-
roglossal duct was insufficient to maintain euthyroidism. Sub-
mingled with areas that do accumulate it (predominantly fol-
stitution therapy with l-thyroxine was followed by regrowth of
licular tumor tissue). Cranial to the reference mark (square dot)
hair.
on the midline over the cricoid cartilage there is an accumu-
lation of radioactivity in a thyroglossal duct remnant (at the
level of the lingual bone).
C D
Figure 3.7:
(A, B) A female Bouvier des Flandres presented at the age of one year for retarded growth and sluggishness. The dog was in good nutritional condition, but weighed only
13 kg. It had disproportionately short legs, a dull facial expression, and a large tongue. Radioiodine scintigraphy revealed complete athyreosis.
(C, D) The same dog after four months of oral substitution with l-thyroxine. Note the more alert expression and the growth in height. Probably related to the rapidly en-
suing sexual maturation (the dog came into estrus after two months of treatment), the growth plates closed and there was no further growth in height. The age in
months is indicated on each radiograph.
of autoimmune destruction of the thyroid glands occurs dur- pericardial aorta. Accessory thyroid tissue may also lie cranial
ing adolescence and as a consequence the dog’s growth can be to the thyroid glands as a remnant of the thyroglossal duct.
retarded, in addition to its developing the signs of hypothy- It may be detected because it gives rise to a neoplasm
roidism of the adult. (chapter 3.4.2) or it may be an incidental finding during scan-
ning for other reasons (fig. 3.5). It may also be associated with
the absence of normal thyroid glands and yet its function may
be insufficient to prevent hypothyroidism (fig. 3.6). Com-
3.2.2 Thyroid dysgenesis plete athyreosis has also been found (fig. 3.7). The search for
the etiology requires molecular studies of the genes involved
Ectopia of thyroid tissue is common in the dog and is also in the differentiation, migration, and growth of the thyroid
known to occur in cats.36,37 In most cases it is the result of the gland. In humans mutations have been found in the genes en-
descent of primitive thyroid tissue together with the aortic sac coding transcription factors and the TSH receptor, although
during embryonic life. In about 50 % of adult dogs, accessory their involvement in the general population of patients with
thyroid tissue can be found embedded in the fat on the intra- thyroid dysgenesis has been questioned.38–40
62 Thyroids
Treatment
As soon as the condition is diagnosed, treatment should be
started with l-thyroxine (10 µg l-thyroxine per kg body
weight, twice daily). The animal will become much more
lively and will develop a normal hair coat. When hypothy-
roidism is not detected early enough during skeletal matu-
ration, the additional growth may be marginal because ad-
ministration of thyroxine will also lead to closure of the
Figure 3.8: growth plates (fig. 3.7). The mental sluggishness disappears,
Enlarged thyroid glands of an eleven-month-old male Pomer- however, and usually there is little evidence of persisting
anian. The goitrous glands were first noticed when the dog
was five months old. There was a defect in the organification
mental retardation, a dreaded complication of late detection
of iodide in the thyroid. The animal was of about normal size of congenital hypothyroidism in children.
but had a thin hair coat and retention of deciduous teeth after
eruption of the permanent teeth.
A B
Figure 3.9:
Two eight-week-old littermate kittens. In comparison with the healthy kitten (A), the hypothyroid kitten (B) has a more infantile appearance with its round head and small
ears and also its blue irises, while those of the healthy kitten have changed to the yellow of adulthood. The thyroid glands could not be palpated. The hypothyroidism was
caused by the lack of organification of iodide by the thyroids (fig. 3.10).
Clinical manifestations
The clinical hallmark of these defects is the combination of
goiter and hypothyroidism (fig. 3.8). The severity of both the
goiter and the hypothyroidism may vary considerably and it
may also be difficult to palpate a goiter in a very young animal
(fig. 3.9). The clinical features of the hypothyroidism do not
differ from those in thyroid dysgenesis (chapter 3.2.2).
Diagnosis
The diagnosis of hypothyroidism can be confirmed by
measuring the plasma T4 concentration. When a goiter is de-
tected, stimulation with TSH is redundant, as the goiter is al-
ready evidence of increased endogenous TSH secretion.
Treatment
As in all forms of hypothyroidism except that caused by
iodine deficiency, treatment consists of oral administration of
l-thyroxine (chapter 3.2.1). This will lower TSH secretion
and as a result the goiter will shrink.
64 Thyroids
3.2.4 Central hypothyroidism sociation was found in several breeds between canine hypo-
thyroidism and a DLA-allele.60,61 Antibodies against TPO
Central hypothyroidism is due to TSH deficiency. This can seem to play little or no role in thyroiditis in dogs,58,62 in
be classified as pituitary (secondary hypothyroidism) or hypo- contrast to thyroiditis in humans. The immune-mediated
thalamic (tertiary hypothyroidism), but the distinction is not destruction is a slow process and clinical manifestations of
necessary in the initial differentiation between primary and thyroid hormone deficiency only become evident after
3 central hypothyroidism. Hyposecretion of TSH is usually ac- destruction of 쏜 75 % of the thyroid follicles.
companied by decreased secretion of other pituitary hor-
mones. The best known example of secondary hypothyroid- Although they may not be of great pathogenetic importance,
ism at an early age is that of pituitary dwarfism in German autoantibodies against Tg may serve as markers of autoim-
Shepherd puppies that is characterized by combined defi- mune thyroiditis.63 Circulating antibodies against Tg are de-
ciency of adenohypophyseal hormones. In these animals the tected in over 50 % of hypothyroid dogs. As the autoimmune
TSH deficiency is associated with absolute deficiencies of destruction progresses, thyroid follicles are replaced by fibrous
growth hormone and prolactin, while secretion of luteinizing and adipose tissue and the inflammatory cells disappear, re-
hormone and follicle-stimulating hormone is less severely im- sulting in the histological appearance of noninflammatory
paired (chapter 2.2.2).52,53 In these dogs manifestations of hy- atrophy. The absence of inflammation is likely to result in the
pothyroidism are overshadowed by those of growth hormone disappearance of antibodies from the circulation over time.58
deficiency, in part because a small but significant fraction of
thyroid gland function (~ 10–15 %) is independent of TSH; Antibodies against Tg form a heterogeneous group directed at
hypothyroidism due to central causes is less severe than pri- several epitopes. When an epitope includes a hormonogenic
mary hypothyroidism.54 site, an antibody can be directed against a fragment that con-
tains T4 or T3. These Tg antibodies occasionally interfere
Isolated TSH deficiency (monotropic deficiency) has been with immunoassays used to measure the plasma concen-
suggested as the most likely abnormality in a family of giant trations of thyroid hormones, especially T3. Depending on
schnauzers with dwarfism.55 It has been questioned whether the type of assay, antibodies recognizing epitopes of a thyroid
the presumed TSH deficiency was secondary or tertiary.56 In a hormone may cause either falsely elevated or lowered values.
young boxer with congenital hypothyroidism supposedly of Although antibodies against thyroid hormones are not un-
central origin, plasma growth hormone concentration was common, it should be noted that they rarely affect the results
elevated,57 but this is now known to be associated with pri- of the immunoassays to the extent that the reference range is
mary hypothyroidism (chapter 3.3.1). exceeded.58 This is especially true for T4.
A B
C D
Figure 3.11:
HE-stained sections of the thyroid gland of a healthy dog (A), and of thyroid biopsies (B–D) from dogs with primary hypothyroidism in different stages of loss of thyroid
epithelium:
(A) Thyroid follicles lined by low cuboidal epithelial cells and filled with colloid. Small groups of pale C cells lie between the follicles.
(B) Thyroid follicles with high cuboidal epithelium and almost no colloid. Diffuse, slight to moderate lymphocytic infiltration.
(C) Severe lymphocytic infiltration and loss of follicles. A few follicles of different sizes can still be recognized, often containing lymphocytes.
(D) Adipose tissue with small clusters of thyroid follicular cells and small aggregates of C cells.
Acquired primary hypothyroidism is mainly a condition of Central to the clinical manifestations is usually a history of
young-adult and middle-aged dogs. Although dogs of large slowing of mental and physical activities. Most hypothyroid
breeds may be affected more frequently than those of small dogs have some degree of mental dullness, lethargy, and dis-
breeds, there is no pronounced breed predisposition. The inclination to exercise (fig. 3.12). These symptoms are grad-
incidence is equally distributed between males and females.68 ual in onset, often subtle, and sometimes unrecognized by the
There has been only one convincing description of sponta- owner until after treatment has been started. Among the
neous primary hypothyroidism in an adult cat, a five-year-old observable changes in the hair and skin are alopecia (often
spayed female domestic shorthair cat.69 with pigmentation), thick folding of the skin, and a puffy fa-
cial appearance. The thickening and puffiness are evidence of
Thyroid hormones influence the function of almost all tissues cutaneous mucinosis or myxedema, which is accumulation in
of the body and thus the classical clinical picture of overt hy- the dermis of glycosaminoglycans and hyaluronic acid with
pothyroidism involves manifestations from nearly all organ associated edema.72 It may be due to both hypothyroidism
systems. There may be concurrent effects of growth hormone and growth hormone excess (figs. 3.12–3.16).70,73 Occasion-
excess (see chapter 2 and the section on diagnosis below).70 ally, hypothyroidism is associated with secondary skin infec-
The time required for clinically appreciable effects differs tions, including Malassezia infections.74,75
considerably: lethargy may be noticed within a few months
but skin changes can take almost a year.71
66 Thyroids
A B
Figure 3.15:
(A) A four-year-old female German shepherd with primary hypothyroidism. The puffy appearance due to myxedema produces a lethargic or tragic facial expression. The
blepharoptosis contributes to this appearance.
(B) These changes were especially appreciated in retrospect, when the dog was reexamined after four months of substitution therapy with l-thyroxine.
A B
Figure 3.16:
(A) A two-year-old female Leonberger in which primary hypothyroidism caused marked loss of hair, leaving a sparse, coarse, and short coat.
(B) There was an impressive regrowth of hair after seven months of substitution therapy with l-thyroxine.
68 Thyroids
Figure 3.18:
A five-year-old female boxer with primary hypothy-
roidism and signs of vestibular disease manifested by
a head tilt. There was also facial nerve palsy. These
features are regarded as manifestations of a more
Figure 3.17: generalized polyneuropathy,78,79 with hyperlipidemia
ECG recording from a four-year-old male boxer with pronounced hypothyroidism (calibration: 1 cm = 1 mV; as a serious predisposing factor.85
paper speed 25 mm/s). Left: Leads I, II, and III. Middle: Leads aVR, a VL, and aVF. Right precordial leads CV6LU,
CV6LL, CV6RL, and V10. There is low voltage of the deflections in all leads. In less pronounced (= less long-
standing) cases the ECG changes may be less remarkable or even absent.
Table 3.1 lists the clinical manifestations by organ system, of hypothyroidism to be presented for attention to cardiopul-
which some changes in the cardiovascular and nervous sys- monology (lethargy misinterpreted as exercise intolerance)
tems are illustrated in figs. 3.17 and 3.18. Changes in a single or orthopedics (locomotor disturbance). Lethargy, the most
organ system sometimes dominate to the extent of obscuring common sign of hypothyroidism, may be mistaken for
the causative disease.76 This can occur with persisting galac- metabolic (hepatoencephalopathy) or cerebrocortical disease
torrhea,77 vestibular disease,78,79 and locomotor disturbances. (encephalitis, hydrocephalus). The atrophy of the skin and its
With regard to the latter, generalized locomotor problems can adnexa must take into consideration such conditions as es-
be explained by a severe reduction in Na+-K+-ATPase cap- trogen excess (chapter 8.4) and hypercortisolism (chapter 4.3).
acity in the skeletal muscles,27 while hypothyroidism has also
been reported to be associated with generalized myopathy.80,81 Diagnosis
Rarely, a hypothyroid dog is presented as an emergency in a As a measure of thyroid function, T4 has to be preferred over
comatose state. Low ambient temperatures can cause decom- T3 because it is produced exclusively by the thyroid gland
position of hypothyroidism into myxedema coma with severe while T3 in plasma is largely derived by peripheral conversion
hypothermia.82,83 (chapter 3.1). In most dogs with primary hypothyroidism,
plasma concentrations of TT4 and free T4 (fT4) are below the
Routine laboratory examinations can reveal several hemato- reference range. However, they can also be decreased in dogs
logical and biochemical abnormalities (table 3.1). Possible without a thyroid disorder because of drugs or illness
consequences of severe hyperlipidemia include neurological (chapter 3.1.2). The terms nonthyroidal illness and sick eu-
signs due to atherosclerosis and thromboembolic events.84,85 thyroid syndrome have been introduced for this derangement
Both the nonregenerative anemia (see also chapter 10.3) and of thyroid homeostasis. Illness in this context comprises vir-
the hyperglycemia are usually mild. tually all nonthyroidal diseases, surgical and nonsurgical
trauma, and inadequate caloric intake. Consequently, the
Differential diagnosis finding of a low basal plasma thyroid hormone concentration
Because the presenting symptoms of hypothyroidism can vary is of little diagnostic value.86,87 For this reason stimulation tests
widely, a common pitfall in diagnosis is simply to overlook the using either TSH or TRH have been advocated. The TRH-
possibility that the presented problems could be due to hypo- stimulation test using measurement of plasma TT4 concen-
thyroidism. For example, it is not uncommon for dogs with tration does not distinguish with sufficient accuracy between
Hypothyroidism in adult animals 69
Figure 3.19:
Mean (± SEM) basal plasma concentrations of TSH, GH, PRL, and LH measured at two-month intervals in seven spayed beagles with induced hypothyroidism at time
point 0. Three of these dogs were followed up for 1.5 years while receiving l-thyroxine substitution (beginning of substitution marked by arrow). Asterisks indicate
statistically significant difference from value at time zero.97
dogs with hypothyroidism and those with nonthyroidal ill- TSH-stimulation test,92 albeit now usually employing recom-
ness.88 Until the end of the last century, primary hypothyroid- binant human (rh)TSH instead of bTSH.93–95 Meanwhile, the
ism in dogs was diagnosed by the finding of a low plasma TT4 gold-standard status of the TSH-stimulation test has been
(and /or fT4) concentration insufficiently responsive to stimu- questioned.96
lation with bovine TSH (bTSH).89,90
Strategies for modification of the TSH assay have been sug-
It was expected that introduction of a homologous immu- gested to improve the diagnostic value of TSH measure-
noassays for plasma TSH in dogs would greatly aid and sim- ments.92 However, there is now experimental evidence that it
plify assessment of the canine pituitary-thyroid axis by the may not be so much the assay but rather the changes in pitu-
paired measurement of T4 and TSH. It was hoped that a single itary function with time that can explain the low TSH values
blood sample would suffice to confirm the diagnosis of pri- found in some dogs with primary hypothyroidism. As illus-
mary hypothyroidism by revealing a low T4 concentration in trated in fig. 3.19, the induction of primary hypothyroidism
the presence of a high TSH concentration. However, using causes an initial increase in plasma TSH concentration but
the TSH-stimulation test as the gold standard, it was found this is followed by a gradual loss of the feedback response of
that in as many as one-third of dogs with primary hypothy- TSH to low plasma T4 concentrations. This is accompanied
roidism, plasma TSH concentration was not elevated.86,87,91 by hypersecretion of GH and hyposecretion of PRL. The
Frustration with the limitations of the available endogenous associated pituitary enlargement is characterized by thyro-
canine TSH assay caused most clinicians to resume using the trope hyperplasia, large vacuolated thyroid deficiency cells,
70 Thyroids
3
Figure 3.20:
Transverse CT images of the skull of a beagle prior
to induction of hypothyroidism (A), and three years
after thyroidectomy (B). Contrast enhancement reveals
the normal size of the pituitary gland before thyroidec-
B tomy and its enlargement after the induction of hypo-
A thyroidism.
A B
Figure 3.21:
Sections of the pituitary gland of a hypothyroid dog: (A) stained with an antibody against GH (brown) and (B) with antibodies for both GH (blue) and TSH (orange). Both
large and normal-sized cells stain positively for GH. Several cells are positive for both GH and TSH.
and double-staining cells, indicative of transdifferentiation for primary hypothyroidism. When TT4 is low but TSH is
(figs. 3.20 and 3.21). The latter is associated with the devel- within the reference range, a TSH-stimulation test can be
opment of thyrosomatotropic cells and paradoxical GH- performed (chapter 12.3.1), although the result may not be
responsiveness to stimulation with TRH.97,98 The pituitary conclusive.96 If they are not, methods not involving bio-
enlargement and the functional changes are found to be re- chemical assessment of the pituitary-thyroid axis – such as
versible by substitution with l-thyroxine.97 Similar changes a radionuclide scan or thyroid uptake measurement with
are observed in dogs with spontaneous hypothyroidism, with 99mTcO –, high-resolution ultrasonography, or even a thyroid
4
the omission of hypoprolactinemia in intact males and fe- biopsy – seem to be the most reliable for diagnosing primary
males. On the contrary, plasma prolactin concentration may hypothyroidism in dogs.96,100 In a study of 99mTcO4– uptake in
be elevated in intact females that have recently entered an es- dogs with primary hypothyroidism and nonthyroidal illness,
trous cycle and the hypothyroidism may even be associated there was no overlap in thyroid uptake at 45–120 min after
with galactorrhea.99 injection (fig. 3.22).96 In high-resolution ultrasonography of
the thyroid glands, loss of echogenicity, homogeneity, and
The results of these studies on the adenohypophyseal changes fusiform shape are particularly characteristic of primary hy-
in primary hypothyroidism provide an explanation for the pothyroidism.101,102 Demonstration of circulating antibodies
low plasma TSH concentrations that have been observed but to Tg indicates the presence of thyroiditis but provides no in-
do not resolve the diagnostic dilemma. In dogs with clinical formation about thyroid function. As indicated in the section
signs of hypothyroidism, the combination of a low plasma on pathogenesis, the absence of antibodies against Tg does
TT4 and an elevated plasma TSH concentration is diagnostic not exclude hypothyroidism. In addition, dogs with anti-
Hypothyroidism in adult animals 71
bodies against Tg may have thyroiditis that has not yet re-
sulted in hypothyroidism.
Treatment
Although T3 is the metabolically active thyroid hormone, it is
not the supplement of choice. A primary advantage of pro-
viding the »prohormone« T4 is that the body is given the op- 3
portunity to regulate the amount of T3 generated by normal
physiologic mechanisms. Appropriate T4 therapy results in
normal levels of both T4 and T3.
Prognosis
Hypothyroidism is one of the most gratifying diseases to treat,
because of the ease and completeness with which it responds
to treatment. With appropriate treatment and follow-up
examinations every half year, usually all of the alterations as-
sociated with hypothyroidism are reversible. The long-term
prognosis is excellent.
Clinical manifestations
The clinical picture is similar to that of primary hypothy-
roidism, although generally less pronounced. There may be
lethargy and alopecia, but thickening of the skin is less pro-
nounced (fig. 2.25). As described in the previous section, the
thickening that occurs in primary hypothyroidism is partly a
3 consequence of the associated growth hormone excess. In
central hypothyroidism the persisting negative feedback on
TSH secretion that is responsible for this is lacking. On
the contrary, there is often impaired secretion of other pitu-
itary hormones such as growth hormone and gonadotropins
(fig. 2.25).
Diagnosis
The diagnosis of central hypothyroidism should be based on
the demonstration of low concentrations of T4 and TSH in
plasma. In secondary hypothyroidism, plasma T4 concen-
tration increases in a TSH-stimulation test, although repeated
stimulation may be necessary (chapter 12.3.1). A TRH-
stimulation test can be used if there is reason to suspect terti-
ary hypothyroidism. A prerequisite for correct interpretation
of these tests is the certainty that the low T4 (and TSH) con-
centrations are not caused by illness or drugs.
Treatment
Treatment with l-thyroxine is the same as in primary
hypothyroidism (chapter 3.3.1). Hypofunction of any other
endocrine glands resulting from pituitary hormone deficien- Figure 3.24:
cies should also be corrected. In practice this is usually con- Progression of a functional thyroid tumor to a state of hyperthyroidism (upper
fined to treatment for a coexisting ACTH deficiency. It is figure). As hypersecretion of thyroid hormone progresses, TSH release successively
even advisable to assess pituitary-adrenocortical function and declines and the unaffected thyroid tissue becomes inactive. During development
to treat an eventual deficiency by cortisol supplementation of a nonfunctional destructive thyroid tumor (lower figure), thyroid hormone
(chapter 4.2.2) before T4 therapy is begun. This will avoid the secretion is sustained via the feedback-controlled increased secretion from the
risk of precipitating a crisis due to glucocorticoid deficiency. contralateral unaffected lobe.
Prognosis
In the spontaneous forms the prognosis is completely depen-
dent upon the course of the causative lesion in the hypo-
thalamus-pituitary area. In the iatrogenic form following
hypophysectomy, supplementation with l-thyroxine (and glu-
cocorticoids!) enables the animal to live a healthy life for
many years (chapter 4.3.1).
Hyperthyroidism and thyroid tumors 73
A B
Figure 3.25:
This twelve-year-old castrated male cat was presented for weight loss and extreme restlessness. Its nutritional condition was poor and its behavior was frantic (A). The
hypermetabolic state caused panting (B), which the owner also observed when the cat was at rest.
3.4 Hyperthyroidism and thyroid (Plummer’s disease) in humans. The thyroids of hyperthyroid
cats contain multiple hyperplastic nodules surrounded by in-
tumors active follicular tissue. Experimental transplantation of the
Neoplastic transformation of the thyroid may come to atten- adenomatous tissue into nude mice has shown that its growth
tion in two ways. In dogs, most commonly it is the physical does not depend upon extrathyroidal humoral stimulation.110
presence of the tumor that is first detected by the owner. Instead, intrinsic cell abnormalities must be responsible for its
However, if the tumor produces thyroid hormone, it may unregulated growth and function.111 The most likely candi-
with increasing size produce such an excess (fig. 3.24) that the dates are thought to be mutation of the TSH receptor or mu-
animal develops symptoms of hyperthyroidism. This is almost tation of its associated G proteins.112,113
invariably the case in cats and is only occasionally seen in
dogs. Clinical manifestations
The adenomatous glands tend not to become very large, so
A disease entity comparable to Graves’ disease in humans, in rarely is veterinary help sought because of a mass detected by
which TSH-receptor antibodies stimulate the thyroid, has not the owner. Thus it is the signs and symptoms due to effects of
been observed in dogs or cats. Because the clinical aspects of thyroid hormone excess on organ systems that lead to vet-
thyroid neoplasia differ considerably between dogs and cats, erinary examination. The classic presentation of a hyperthy-
they are discussed separately in the following sections. roid cat is that of a skinny, restless, elderly cat with an in-
creased appetite and polyuria (fig. 3.25). It is likely to give the
impression of a tense and anxious animal with an impaired
tolerance for any stress, such as restraint.114 Many organ sys-
3.4.1 Hyperthyroidism in cats tems can be affected and the associated signs and symptoms
are listed in table 3.2. This full spectrum is less likely to be
Feline hyperthyroidism is a relatively common disease of present now that the disease is usually recognized in an early
middle-aged and elderly cats, with a mean age of twelve to stage. In an elderly cat, weight loss – often together with in-
13 years. There is no breed or sex predilection. The thyroid creased appetite – may be sufficient reason to suspect hyper-
hormone excess is produced by thyroid adenomatous hyper- thyroidism.
plasia or adenoma, involving one or, more often, both thyroid
lobes. Thyroid carcinoma, which is the main cause of hyper- In about 10 % of cases the clinical picture may be quite dif-
thyroidism in dogs, accounts for only 3 % of cases in cats.109 ferent. In these cats weight loss remains an important feature,
but there is lethargy and anorexia rather than hyperactivity
The pathogenesis of adenomatous thyroid hyperplasia in cats and increased appetite. This form, called »apathetic hyperthy-
is not clear. The condition resembles toxic nodular goiter roidism«, may represent an end-stage of the disease and may
74 Thyroids
Table 3.2: Clinical manifestations of hyperthyroidism in cats hyperfiltration, and is also resolved with treatment.118 Of
more concern has been the increase in the plasma creatinine
System Common Less common or rare
concentration after treatment of hyperthyroidism, although it
Metabolism Weight loss in spite of Mild hyperthermia is often still within the reference range. Although considered
polyphagia Anorexia to be the unmasking of preexisting chronic kidney disease, it
Respiratory Panting Dyspnea seems to have little clinical significance. The survival of
3 Cardiovascular Tachycardia (gallop rhythm) Cardiac murmur
treated hyperthyroid cats does not seem to be affected by
post-treatment azotemia.119 Studies of calcium homeostasis in
Pounding heart beat Cardiac arrhythmias feline hyperthyroidism have revealed several alterations.120 Al-
Left ventricular hypertrophy Congestive heart failure though these abnormalities have not been associated with
(echocardiography) any symptom or sign, there has been one report of a hyper-
Neuromuscular Restlessness (irritability) Weakness thyroid cat with hyperphosphatemia and calcification of its
Muscle wasting paws that resolved with return to the euthyroid state.121 Con-
sistent with the effect of thyroid hormone on Na+-K+-AT-
Renal Polyuria (low urine s.g.) Mild elevation of plasma Pase (chapter 3.1.4), hypokalemia may be found, whereby
urea and creatinine the possibility of coexisting hyperaldosteronism (chapter 4.4)
concentrations* should be considered.
Gastrointestinal Increased fecal volume Diarrhea and vomiting
Differential diagnosis
Skin and Hair Unkempt hair coat There are at least two nonthyroidal disorders that may simu-
late certain aspects of the syndrome. First, the weight loss in
Hematological Neutrophilic leukocytosis with Hematocrit elevated
eosinopenia and lymphopenia combination with increased appetite and large volumes of
(= stress leukogram?) somewhat fatty feces may be mistaken for pancreatic insuffi-
ciency and less likely for gastrointestinal lymphoma, as in the
Biochemical Elevated plasma ALT, AP, LDH Mild hyperphosphatemia* latter case there will be inappetence. Weight loss in spite of
Urinary corticoid:creatinine increased appetite together with polyuria also raises the possi-
ratio elevated bility of diabetes mellitus, but routine urinalysis will immedi-
Hypokalemia ately resolve this.
* May be found, but probably not a direct manifestation of hyperthyroidism.
Diagnosis
When hyperthyroidism is suspected, the first step should be a
careful palpation of the neck area by gently sliding the thumb
and index finger along the sides of the trachea. The thyroids
are only loosely attached to the surrounding tissues and there-
fore enlargement usually causes descent along the trachea,
also be associated with cardiac disorders (see also table 3.2). sometimes even as far as the thoracic inlet. The thyroids are
This severe form of feline hyperthyroidism has also been usually easily moved along the trachea. Enlargement of one or
called »thyroid storm«, a term used for a rare clinical entity in both lobes can be found by an experienced examiner in up
humans. Radioactive iodine therapy, thyroid surgery, vigor- to 90 % of cats with hyperthyroidism. However, it should
ous thyroid palpation, and stress may cause acute elevation of be noted that occasionally thyroid enlargement is found with-
plasma thyroid hormone concentration and have been impli- out hyperthyroidism. In such cases the disease may develop
cated as possible precipitating factors for »thyroid storm«.115 with time. Rarely the thyroid enlargement arises from ectopic
A wide range of clinical features has been associated with (sometimes intrathoracic) thyroid tissue.
this form of the disease, including arterial hypertension and
hypokalemic myopathy. It is not clear whether in these cases The final diagnosis ought to rest on a direct measurement of
possible coexisting conditions such as hyperaldosteronism thyroid function. For reasons explained above (chapters 3.1,
(chapter 4.4) may play a role. 3.3.1), measurement of the plasma concentration of T4 is of
greater diagnostic value than that of T3. In about 90 % of cats
The multisystemic effects of thyroid hormone excess not only presented with the syndrome of hyperthyroidism, the T4 con-
lead to a variety of physical changes but may also give rise to centration in plasma exceeds the upper limit of the reference
several biochemical abnormalities (table 3.2). Most of these range. Plasma T4 concentration fluctuates over time and in
are reversed with treatment, including elevated plasma con- cats with mild hyperthyroidism, T4 values may be in the high-
centrations of liver enzymes and increased urinary corti- normal range. In addition, concomitant nonthyroidal disease
coid:creatinine ratios.116,117 The hemodynamic alterations of may lower the value below the reference range.122 When
hyperthyroidism are responsible for marked increases in the plasma T4 concentration falls within the reference range and
glomerular filtration rate. The often observed mild proteinu- the animal is still suspected of hyperthyroidism, the measure-
ria is regarded as a reflection of glomerular hypertension and ment of T4 can be repeated two to four weeks later.
Hyperthyroidism and thyroid tumors 75
In most cases measurement of fT4 concentration by direct perthyroid cats there is rapid uptake of the tracer to higher
equilibrium dialysis adds little or no useful diagnostic in- values than in normal cats (fig. 3.26).125 As explained in
formation. Nonthyroidal disease may be associated with false chapter 3.1 99mTcO4– is also taken up by the thyroid gland but
positive results and therefore feline hyperthyroidism should not organically bound. Nevertheless, the measurement can be
not be diagnosed solely on the finding of a high fT4 concen- valuable because it is usually higher than in healthy cats
tration.122 Recently it was reported that cats with hyperthy- (fig. 3.27).126 The best correlation of 99mTcO4– uptake with
roidism have plasma TSH concentrations (measured with an plasma T4 concentration has been found to be the 20-min
assay for canine TSH [Immulite canine TSH®, Diagnostic thyroid:salivary gland ratio (T:S ratio) using the more intense
Products Corporation, DPC, Los Angeles, CA, USA]) below image of the two thyroid lobes.127
the limit of quantification (see also fig. 3.24). This offers
an additional tool in the diagnostic approach to feline hyper- The uptake visualized in the head of the cat by routine thy-
thyroidism. Undetectable and low TSH concentrations have roid scintigraphy is largely due to pertechnetate accumu-
also been reported in cats with histological evidence of nod- lation in the zygomatic and molar salivary glands. The uptake
ular thyroid disease, i.e., mild or subclinical hyperthyroid- in the small molar glands may be superimposed over the zy-
ism.123 gomatic uptake on routine ventral planar images.128 Different
sedative-anesthetic protocols influence thyroid and salivary
One can also consider testing the suppressibility of plasma T4 gland uptake of 99mTcO4– in different ways.129,130 Another fac-
concentration in a T3-suppression test. Following seven tor complicating the interpretation of the T:S ratio may be re-
eight-hourly oral doses of 15–25 µg T3, the T4 concentration cent antithyroid medication. Enhanced thyroidal 99mTcO4–
in healthy cats is suppressed to low values. Due to the auto- uptake has been found following withdrawal, although the
nomous (TSH-independent) character of T4 hypersecretion T:S ratio was significantly elevated only at 4 h after tracer in-
in hyperthyroid cats, T4 concentration 2–4 h after the last jection.131
dose of T3 remains practically unchanged.124
In hyperthyroid cats, scintiscanning with 99mTcO4– reveals in-
Although not available in all clinics, radioiodine uptake creased uptake in hyperplastic thyroid tissue and no uptake in
studies with 131I or 123I may contribute to the diagnosis. In hy- the unaffected tissue, because TSH secretion is suppressed by
76 Thyroids
Treatment
There are three options for eliminating the excess production
of T4: (1) radioiodine ablation of the thyroid, (2) surgical thy-
roidectomy, and (3) inhibition of secretion by antithyroid
drugs. When the facilities are not a limiting factor, the first
option is to be preferred.
3
Thyroidectomy is performed by the modified intracapsular
dissection technique. After incision on the ventral side of the
gland, thyroid tissue is gently teased away from the capsule by
blunt dissection with scissors and a moistened cotton-tipped
swab. Following removal of the thyroid tissue the capsule is
excised, preserving only a small cuff of the thyroid capsule
and the blood supply to the parathyroid gland. It may be dif-
ficult to locate the parathyroid gland because of the anatomi-
A B cal changes caused by the thyroid nodule, and magnifying
glasses should be used. With this approach either unilateral or
Figure 3.28: bilateral thyroidectomy can be performed without a high
Scintigraphic images 30 min after intravenous injection of 0.5–0.8 mCi (18.5– incidence of hypoparathyroidism, depending on the skill and
27.6 MBq) 99mTcO4– in healthy cats (in dorsal recumbency).
(A) Symmetrical uptake in two normal thyroid lobes.
experience of the surgeon. EHTT in the ventral cervical or
(B) Asymmetrical uptake in two normal lobes. In both images the focal uptake in anterior mediastinal region are approached by a caudal cervi-
the head is in salivary tissue. cal incision. By careful exploration through the thoracic inlet,
the anterior mediastinum can be reached sufficiently to find
and remove the lesion.109,134
Pertechnetate scintigrams have advantages over quantitative The most serious postoperative complication is hypocalce-
uptake measurements. Apart from its value in localizing thy- mia, signs of which appear within 24–72 h after bilateral thy-
roid lesions, visual inspection of a scan has equal or greater roidectomy. They range from lethargy, anorexia, reluctance
sensitivity for the diagnosis of hyperthyroidism than calcu- to move, and muscle tremors (face, ears) to tetany and con-
lation of the T:S ratio.127 Using a pinhole collimator, foci of vulsions. Tetany may be provoked by handling the cat. Treat-
higher uptake can be identified in the scan that may represent ment should be given promptly by intravenous administration
an early stage of hyperplasia.127 Visual inspection may have of 0.5 mmol Ca2+/kg body weight as calcium gluconate. It is
lower specificity than the T:S ratio, since the observer may be better to avoid this dramatic event by routinely measuring
misled by the asymmetry of the thyroid glands that occurs in plasma calcium concentration at about 20 h after surgery.
some euthyroid cats.133 In case of doubt, quantitative uptake If plasma calcium is 쏝 2.0 mmol/l or 10 % below the pre-
measurements may be helpful if values can be compared with operative value, calcium borogluconate is given subcutaneously
appropriately obtained reference values. in a dose of 1–2 ml/kg, diluted with at least an equal volume
of Ringer’s solution. Oral supplementation with calcium car-
bonate, 15–20 mg/kg per meal, is started as soon as the cat
Hyperthyroidism and thyroid tumors 77
A B
Figure 3.29:
Thyroid scintiscans.
(A) An eleven-year-old castrated male cat with signs and symptoms of
hyperthyroidism (weight loss, polyuria, and anxious behavior) and uni-
lateral thyroid enlargement. There is high uptake in the nodule and no
visualization of the nonaffected lobe.
(B) A twelve-year-old neutered female cat with persistent weight loss,
increased appetite, vomiting of fluid and food, and irritable behavior
after bilateral thyroid surgery. There is high uptake at the location of the
right thyroid and at the thoracic inlet.
(C) An eight-year-old castrated male cat with persistence of hyper-
thyroidism after thyroid surgery. There is high uptake near the thoracic
inlet.
(D) A 13-year-old castrated male cat with weight loss and polyphagia.
There is high uptake at the location of the right thyroid and at the tho- C D
racic inlet and lower uptake at the location of the left thyroid.
resumes eating. In addition, dihydrotachysterol [Dihydral®, function may result, thereby decreasing the severity and dur-
Solvay Pharmaceuticals, Weesp, NL] is given in a dose of ation of postoperative hypocalcemia. Careful postoperative
0.05 mg once daily for three days and then lowered to monitoring of plasma calcium must be continued until this is
0.025 mg once daily. Plasma calcium concentration is ascertained.136
measured at least twice daily, gradually decreasing to once
weekly. The doses of dihydrotachysterol and calcium carbon- Oral substitution with l-thyroxine is started in a dose of 50 µg
ate are adjusted to maintain plasma calcium within the refer- twice daily on the fourth day after bilateral thyroidectomy.
ence range. Plasma T4 concentration is measured after four weeks and
then every six months. The dose is adjusted as needed to
With an experienced surgeon, hypocalcemia occurs only maintain plasma T4 concentration within the reference range.
temporarily in about 5 % of cases. However, if there is para-
thyroid damage, recovery can take weeks to months.109 Para- Radioiodine (131I) by its b-radiation selectively destroys hy-
thyroid autotransplantation has been proposed as a treatment perfunctioning thyroid cells while sparing the suppressed nor-
for accidental removal or devascularization of all parathyroid mal thyroid tissue and the parathyroid glands. The normal fol-
glands. The parathyroid gland is cut into small pieces and in- licles gradually resume function and there is usually no need
serted into a small pocket made by blunt dissection in one of for administration of thyroxine. Subcutaneous administration
the sternohyoideus muscles. Resumption of parathyroid of the radioiodide is preferred, but it can also be administered
78 Thyroids
intravenously or orally.137,138 The dose can be determined by a Of the available antithyroid drugs the imidazole derivative
scoring system that takes account of the severity of the signs methimazole is most commonly used. It exerts its effect by in-
and symptoms, the size of the thyroid gland(s) (by palpation hibiting TPO (chapter 3.1.1). The related compound carbi-
and /or imaging), and the plasma T4 concentration. Using mazole is converted to methimazole but yields only half the
this scoring system 131I dose is 3.0–6.0 mCi.138 It has also plasma methimazole concentration as the same dose of methi-
been shown that a fixed dose of 4 mCi is effective and that the mazole.145 The doses needed to control hyperthyroidism in
3 timing of discontinuation of antithyroid medication with cats differ accordingly. The starting dose of methimazole is
methimazole does not affect the response to radioiodide ther- 1.25–2.5 mg per cat twice daily. This can be increased if the
apy.139 response after two to four weeks is inadequate. For carbima-
zole the starting dose is 2.5–5 mg per cat twice daily.146 In cats
From a medical point of view, radioiodine therapy is certainly that tolerate methimazole without side effects, its efficacy is
the most attractive option. Complete cure is achieved by a greater than 90 %.145
noninvasive procedure without complications. Higher doses
are often needed for destruction of all malignant tissue in cats Side effects have been reported in 18 % of cats treated with
with thyroid carcinoma.140 With exclusion of preexisting methimazole and include blood dyscrasias (neutropenia
renal disease, the survival time has been reported to be signifi- and /or thrombocytopenia), facial excoriation, hepatotoxic-
cantly longer in cats treated with 131I than in those treated ity, and gastrointestinal upsets (anorexia, vomiting). Cats with
with the antithyroid drug methimazole.141 methimazole-induced blood dyscrasias usually recover within
a week of discontinuing the drug. Continued methimazole
Facilities for radioiodine treatment are only available in administration in the presence of thrombocytopenia has led
licensed hospitals or clinics. Apart from specific equipment, to hemorrhages, including epistaxis and oral bleeding.147
radiation safety precautions are required and the animals must There have been anecdotal reports that side effects are less
be hospitalized in a nuclear medicine isolation ward for at common with carbimazole than with methimazole, but this
least one week. Caretakers are exposed to radiation while in has not been substantiated.146
close proximity to the cat and, during the first week following
131I treatment, also to the radioactivity in urine and in saliva In keeping with the possibility of these adverse reactions to
accumulated on the cat’s coat.142 The cat is discharged from methimazole, the treatment protocol should include control
the hospital when the radiation dose has decreased to a safe examinations at two, four, and six weeks with measurement
level as determined by the local radiation control authority. of hematocrit, leukocyte and thrombocyte counts, and
When the cat has returned home the owners must also follow plasma concentrations of liver enzymes, creatinine, and T4.
certain safety precautions. This work-up should also be performed if a cat becomes
ill during methimazole treatment, to differentiate between a
Approximately 5 % of treated cats fail to respond completely. »simple« gastrointestinal disturbance, for which lowering of
If the hyperthyroid state persists for longer than three months the dose may be adequate, and blood dyscrasias or hepato-
after the initial treatment, retreatment should be considered, pathy, in which case methimazole should be discontinued.146
for it is curative in virtually all cases.137 In less than 5 % cats
treated with radioiodide, permanent hypothyroidism devel- When oral administration poses problems, methimazole can
ops within a few months, characterized by symptoms such as be administered in transdermal formulations in which plu-
lethargy, nonpruritic seborrhea sicca, matting of hair, and ronic lecithin organogel acts as a permeation enhancer to fa-
marked weight gain. The diagnosis is confirmed by the find- cilitate drug absorption across the epidermis. Chronic trans-
ing of a low plasma T4 concentration with a high plasma TSH dermal methimazole dosing (2.5 mg twice daily) is effective
concentration, or by a TSH-stimulation test (chapter 12.3.1). in lowering plasma T4 concentration in hyperthyroid
Life-long supplementation with thyroxine (50 µg twice daily) cats.148,149 Administration of carbimazole in ointment form is
is generally needed.137 With long-term follow-up the percen- equally effective (5 mg once daily for one week and then
tage of cats developing hypothyroidism may rise to 30 %. Par- twice daily).150 The ointment is applied to the inner surface of
ticularly those in which pretreatment scintigraphy revealed the pinna, alternating ears with each dose. The owner is in-
bilateral hyperactivity are at risk of developing a low plasma structed to wear gloves or finger cots for the procedure and to
T4 concentration. It has been questioned whether this is as- remove crusted material with moistened cotton before apply-
sociated with clinical manifestations of hypothyroidism.143,144 ing the ointment.
Relapse as a result of newly developed nodular hyperplasia in Although fewer gastrointestinal side effects have been re-
the remaining unaffected thyroid tissue is very uncommon. ported with transdermal treatment, it is not convincingly less
The time between treatment with radioiodide and relapse is often associated with serious side effects than oral treatment.
generally three years or more. Since both hypothyroidism and Using the same dose, it has lower efficacy than oral methima-
relapse can occur after treatment with radioiodide, it is advis- zole, probably because of lower bioavailability.149
able to test thyroid function at least once a year.137
Hyperthyroidism and thyroid tumors 79
A B
Figure 3.30:
A nine-year-old male boxer in a very poor nutritional condition as a result of hyperthyroidism (A). Removal of a small thyroid adenoma resulted in resolution of the symp-
toms and signs, including the severe polyuria. By the time of a follow-up examination five months later (B), the dog had gained 5 kg in body weight. It had also become
so lively and strong again, that it was difficult to keep on the table for the photograph.
Percutaneous ethanol injection (PEI) under ultrasono- 3.4.2 Thyroid tumors and
graphic guidance is an alternative treatment in humans.151 In- hyperthyroidism in dogs
jection of 96 % ethanol into the thyroid lesion causes hemor-
rhagic necrosis and fibrosis.152 PEI is regarded as the first-line Thyroid neoplasia accounts for about 2 % of all canine tu-
treatment for recurrent thyroid cysts and as an alternative to mors. Most of the benign tumors (adenomas) are small and
follow-up alone for small autonomously functioning nodules commonly not detected during life. They only very occasion-
in humans who refuse 131I therapy.153 There has been one re- ally become cystic and thereby large enough to be detected by
port on the use of PEI for solitary nodules in four hyperthy- the owner.157 A benign thyroid tumor may also be detected
roid cats. Plasma T4 concentration decreased and the clinical because of symptoms suggesting hyperthyroidism (fig. 3.30).
features of hyperthyroidism resolved. The disease did not Careful palpation of the neck may reveal a slightly enlarged
recur in the twelve-month follow-up period. There were no thyroid. Over 85 % of the canine thyroid tumors discovered
adverse effects other than mild dysphonia.154 The results in clinically are rather large (diameter 쏜 3 cm), solid, and ma-
seven cats with bilateral thyroid lesions were less satisfactory: lignant. Their malignant nature may already be evident dur-
euthyroidism lasted less than six months and there was a high ing physical examination, because of changes such as attach-
incidence of laryngeal paralysis and Horner’s syndrome.155 ment to adjacent structures and metastasis to regional lymph
nodes.
Percutaneous ultrasound-guided radiofrequency heat
ablation, performed in nine cats, also lowered plasma T4 Microscopic examination reveals most tumors to consist of
concentration only transiently, with a mean duration of eu- both solid and follicular tissue, while some largely consist of
thyroidism of four months.156 one type or the other. Among thyroid cancers of domestic
animals, that of the dog – particularly the follicular type –
Prognosis most closely resembles human follicular carcinoma. The simi-
In cats without severe complicating cardiac or kidney disease, larities include not only the clinical behavior of the tumor but
the prognosis for restoration of health is excellent after suc- also the pattern of circulating thyroglobulin levels and the
cessful surgery. There may be recurrence months or years after conservation of TSH receptors in the primary tumors (much
thyroidectomy; usually due to adenomatous hyperplasia in less in metastases).158,159 An intriguing difference is observed
the contralateral lobe or ectopic tissue. After radioiodine in DNA ploidy, there being a high incidence of hypodiploidy
treatment the prognosis is as good or better, for even with bi- in canine tumors.160 Mutations in tumor suppressor gene p53
lateral involvement or the presence of ectopic thyroid tissue, seem to occur infrequently in dogs with thyroid carcinoma.161
there is no risk of hypoparathyroidism and seldom need for
supplementation with thyroid hormone. In the great majority Of the possible risk factors contributing to the development
of hyperthyroid cats either methimazole or carbimazole is ef- of thyroid cancer, the influence of iodine in the canine diet is
fective, but the prognosis depends in part on whether there unclear,162 although in one study a high prevalence of thyroid
are adverse reactions to the drug. tumors in necropsy material was ascribed to insufficient
80 Thyroids
A B
Figure 3.31:
A nine-year-old female boxer (A) with an enormous thyroid tumor causing tracheal obstruction and dysphagia (note the salivation). The pertechnetate scan (B) shows it
to be functionally inactive, not concentrating pertechnetate. Such thyroid tumors are referred to as being »cold«. The large size of the tumor causes lateral displacement
of the nonaffected thyroid in which pertechnetate uptake is normal. The uptake by the parotid salivary glands (at the top of the scan) is normal.
A B
Figure 3.32:
(A) Scintiscan of a nine-year-old female miniature poodle with a midline cervical mass at the level of the hyoid bone, 48 h after intravenous administration of 3.7 MBq
(100 µCi) 131I–. There is normal uptake in both thyroids and even higher uptake in the mass. (B) radioiodide uptake in the thyroids and the mass. The mass did not produce
excessive thyroid hormone, for plasma TT4 was 46 nmol/l and uptake by the thyroids was not suppressed. Biochemical studies in similar cases have revealed that such tu-
mors produce an iodoprotein similar to albumin and almost no Tg. In this dog, the administration of 740 GBq (20 mCi) 131I– intravenously produced complete and per-
manent ablation of the tumor.
the ventral cervical region due to hemorrhage.172 Tumors Diagnosis and staging
arising from thyroglossal duct remnants develop in the ventral The location and extent of the mass is determined by careful
midline cranial to the larynx and may involve the base of palpation of the underside of the neck while the animal is sit-
the tongue and the hyoid bones (fig. 3.32). Tumors originat- ting in a relaxed position with its head lifted and tilted slightly
ing from ectopic thyroid tissue at the base of the heart may backward. Small to medium-sized tumors are usually easy to
cause arrhythmias, pericardial effusion, and anterior cervical move along the trachea, but palpation may also reveal attach-
edema.173 ment of the tumor to adjacent structures and enlargement of
the deeply located cranial cervical lymph nodes. Functional
Hypersecretion of thyroid hormone occurs in about 10 % status can be tested by measuring plasma concentrations of T4
of cases of thyroid tumor in dogs.157,174 It may result in the and TSH. A low plasma T4 and high plasma TSH, indicating
syndrome of hyperthyroidism, very similar to that cats but hypofunction, can be found in dogs in which the normal thy-
often less severe (table 3.4). Occasionally there are symptoms roid tissue is replaced by bilateral thyroid carcinoma or pre-
of hyperthyroidism without palpable thyroid enlargement, existing thyroiditis. Hyperfunctioning thyroid tumors result
in which case an intrathoracic hyperfunctioning tumor in a high plasma T4 and low plasma TSH (fig. 3.33).
(fig. 3.33) in ectopic thyroid tissue should be considered.174,175
Medullary thyroid carcinomas in humans may express genes Table 3.4: Manifestations of hyperfunctioning thyroid tumors in dogs
that are not normally expressed, or only at low levels, in nor-
mal C cells. The protein products of these genes include System or organ Common Less common or rare
somatostatin, proopiomelanocortin, vasoactive intestinal pep-
Thyroid Unilateral tumor,
tide, and gastrin-releasing peptide, in some patients causing small or medium-sized
profuse, watery diarrhea.176,177 Such systemic effects also
Metabolism Weight loss in spite of Intolerance to hot
occur in dogs: an otherwise unstoppable diarrhea in a seven-
good appetite environment
year-old collie ceased immediately after removal of a medul-
lary thyroid carcinoma.157 Respiratory system Panting
Cardiovascular system Tachycardia
Differential diagnosis Forceful heart beat
The differential diagnosis for a large cervical mass includes Renal system Polydipsia and polyuria
inflammation (pharyngeal penetration by a foreign body), Gastrointestinal system Diarrhea
hematoma, lymphoma, lipoma, and other tumors. Thyroid
Neuromuscular system Weakness Restlessness
tumors also very rarely infiltrate the skin, mimicking inflam-
Fatigue and lethargy Muscle atrophy
mation with abundant granulation tissue.
82 Thyroids
3
Figure 3.33:
Scintiscans 45 min after intravenous injection of
74 MBq 99mTcO4– in an eleven-year-old, neutered male
Jack Russell terrier presented for gradually increasing
polyuria and polydipsia. There is normal distribution of
radioactivity in the salivary glands and gastric mucosa
(B), but almost none in the thyroid glands (A). The high
uptake in the cranial portion of the thorax is due an
autonomous hyperfunctioning thyroid tumor in the
A B cranial mediastinum.175 Plasma T4 was 62 nmol/l and
TSH was 쏝 0.02 µg/l.
Figure 3.34:
(A) Scintiscan of a dog with a nonhyperfunctioning
(also called »nontoxic«) thyroid tumor. The distribution
of radioactivity in the tumor is irregular (see also
fig. 3.5). Uptake in the contralateral lobe is not sup-
pressed.
(B) Scintiscan of the boxer of fig. 3.30, showing a small
hyperfunctioning (»toxic«) tumor of the left thyroid
A B and no visualization of the right thyroid due to feed-
back suppression of pituitary TSH secretion.
Diagnostic imaging techniques such as ultrasonography, com- Staging of the tumor can be performed according to the
puted tomography, and magnetic resonance imaging can be of standardized scheme of the World Health Organization
great help in identifying cysts, regional lymph node meta- (WHO).180 In this T(tumor), N(regional lymph node), and
stases, hemorrhage, necrosis, calcification, vascular displace- M(distant metastasis) classification, T0–T3 represents the
ment, and invasion.178 Doubt as to whether a mass is of thy- range of tumor size (0, 쏝 2 cm, 2–5 cm, and 쏜 5 cm dia-
roidal origin can usually be resolved by a pertechnetate or meter), subdivided into »a« (tumor freely movable) and »b«
iodide scintiscan (figs. 3.33–3.36). Pulmonary metastases can (tumor fixed to surrounding structures). N0–N2 represents the
be detected by radiography and, if necessary, by computed to- range of lymph node involvement from none to bilateral
mography. These techniques are more sensitive for this pur- involvement, with the substages »a« (lymph node freely mov-
pose than scintigraphy because the metastases, particularly able) and »b« (lymph node fixed). M0 and M1 indicate
when solid or anaplastic, may not trap pertechnetate.178 whether or not distant metastases have been detected. Using
these indicators, four main staging groups can be distin-
Cytological examination of fine needle biopsies may reveal guished (table 3.5).180
the identity of the mass, although it may be difficult to obtain
aspirates without excessive blood and cystic tumors often Treatment
contain a mixture of bloody fluid and degenerated tumor As the great majority of the clinically detected tumors are ma-
cells.179 Blood contamination may be avoided by using a small lignant, the mass should be surgically removed without delay,
needle (쏝 22 G), inserting it into the tumor in only one di- provided it is resectable. The surgical excision of well-en-
rection, and aspirating with a syringe no larger than 5 ml.162 capsulated and freely-movable thyroid carcinomas is often
Hyperthyroidism and thyroid tumors 83
Figure 3.35:
A 13-year-old female Husky that had undergone surgery for thyroid carcinoma two years before. Recurrence of the tumor was visible in the neck for a few months.
(A) A pertechnetate scintiscan reveals no uptake by the tumor.
(B) Computed tomography (CT) reveals the mass to the right of the trachea (7.0 × 2.8 × 3.9 cm) at the level of the 2nd cervical vertebra (arrows). It appears to
accumulate contrast medium.
Figure 3.36:
A ten-year-old female West Highland white terrier with hyperthyroidism (plasma TT4: 150 nmol/l) and a palpable mass in the neck suggesting bilateral thyroid tumor.
(A) A pertechnetate scintiscan also gives the impression of bilateral hyperfunctioning thyroid tumor.
(B, C) The CT scan reveals instead a single tumor on the left and atrophy of the thyroid on the right (arrows).
84 Thyroids
Table 3.5: Clinical staging of canine thyroid tumors180 the primary tumor and regional lymph nodes in the treat-
ment field, may lead to considerable reduction in tumor vol-
Staging group Primary tumor Regional Distant
lymph nodes metastases ume, even to a clinically undetectable level. It may take
8–22 months to achieve the maximum reduction in tumor
I T1 a,b N0 M0 size.187,188 Palliative treatment can be considered in dogs that
II T0 N1 M0 are not candidates for full-course radiation therapy, such as
3 T1 a,b
T2 a,b
N1
N0 or N1 a
M0
M0
those with distant metastases and discomfort caused by the
primary tumor. The administration of four once-weekly frac-
III T3 Any N M0 tions of 9 Gy was reported to halt tumor growth in all 13 dogs
Any T N1 b or N2 b M0 studied and to result in tumor regression in most. Tumor
IV Any T Any N M1 growth rate rather than the presence of lung metastases was an
important determinant of survival time.189 Full-course radi-
ation therapy leads to acute side effects in the skin (moist skin
desquamation and hair loss) and in the mucosa of the larynx,
trachea, and esophagus (mucositis causing dysphagia, hoarse-
curative. Symptoms and signs of hyperthyroidism disappear ness, and cough). Pain is managed by application of anti-in-
(fig. 3.29).181 Excision of movable thyroid carcinomas in stag- flammatory drugs, opioids, and supportive care (e.g., soft and
ing groups II (T2a, N0, M0) and III (T3a, N0, M0) resulted in highly palatable food). In most cases the acute side effects
long-term survival in the majority of the dogs.182 Medullary are resolved in 3–4 weeks. Permanent alopecia and change in
thyroid carcinomas tend to be well circumscribed and resect- hair color and skin pigmentation are common after radiation
able.165 When there are bilateral tumors, an attempt should be treatment.190 Hypothyroidism can be a late effect of irradi-
made to spare one of the parathyroid glands, although this is ation of thyroid tumors.67,187
only be possible if the tumor is well circumscribed and an
external parathyroid can still be identified. If no parathyroid Chemotherapy with either doxorubicin or cisplatin may be
tissue can be preserved, treatment of hypoparathyroidism considered in dogs with a high risk of developing metastases,
(chapter 9.2) will be necessary in addition to thyroxine re- namely those with large and bilateral thyroid carcinoma.191
placement (chapter 3.3.1). Surgical excision of ectopic carci- Partial remissions have been reported but there are no reports
nomas at the base of the tongue poses a challenge because of on improved (progression-free) survival time.162
their close attachments to the hyoid apparatus and the tongue,
and because of abundant neovascularization.183 Ectopic tu- Prognosis
mors arising from intrathoracic thyroid tissue may be resecta- The histological grade of malignancy, taking into account
ble.173 cellular and nuclear polymorphism, capsular and vascular in-
vasion, and the frequency of mitoses, appears to be the most
Dogs with large, invasive tumors, particularly if they are bilat- important prognostic factor for canine thyroid tumors treated
eral or ectopic, are often poor surgical candidates and other by thyroidectomy.192 In addition, the size of the tumor and bi-
options should be considered. In principle, administration of lateral occurrence are critical factors.157,187 In other words, in
radioiodide is an attractive alternative (fig. 3.32). Particu- dogs with medium-sized or small well-encapsulated carcino-
larly in dogs with hypersecreting tumors the high uptake and mas, surgical resection carries a good prognosis.
complete organification of 131I should result in a high radio-
nuclide concentration within the tumor, yielding a high ef- Thyroid-cell proliferation is TSH dependent (chapter 3.1.3)
fective dose of radiation. There have been studies in which and since carcinomatous thyrocytes do have TSH recep-
131I therapy – irrespective of thyroid hormone status – ex- tors,159 it can be assumed that the prognosis can be influenced
tended survival time, even though in some cases there was favorably by TSH-suppressive treatment with l-thyroxine. In-
little or no reduction in tumor mass.184,185 Median survival deed, in humans it has been reported that tumor recurrence
time was significantly greater for dogs with local or regional rates can be lowered if l-thyroxine is given after surgery to
tumors (stage II or III) than for those with stage IV tumors.185 patients with nonmetastasized differentiated thyroid carci-
Myelosuppression has been recognized as a complication of noma.193 This treatment has two objectives: (1) hormone re-
high-dose 131I therapy.185,186 The stringent regulatory require- placement (correction of induced hypothyroidism) and (2)
ments regarding radionuclide use, the need for relatively large hormone suppression (reduction of plasma TSH levels that
and repeated doses, and prolonged hospitalization limit the might stimulate growth of persistent or recurrent neoplastic
availability of this treatment option. tissue). In low-risk patients l-thyroxine is given to return
TSH levels to within the reference range. Patients with high-
External beam radiation therapy with a linear accelerator risk thyroid cancer receive higher doses to achieve complete
or a cobalt therapy machine is indicated when complete ex- TSH suppression, which implies a state of subclinical hyper-
cision of the tumor is not possible and radioiodide therapy is thyroidism that will need careful monitoring for cardiovascu-
unlikely to be effective. Radiation protocols employing lar disease.194,195
twelve treatments (4 Gy three times weekly), including
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4 Adrenals
Sara Galac
Claudia E. Reusch
Hans S. Kooistra
Ad Rijnberk
4
4.1 Introduction The zona fasciculata is the thickest layer. It consists of col-
umns of cells extending from the zona reticularis to the zona
The adrenals are paired glands situated craniomedial to the glomerulosa. The cells are relatively large and contain much
kidneys. Each consists of two functionally distinct endocrine cytoplasmic lipid. This is lost during processing of histologic
glands of different embryological origin. The medulla of each sections, giving the cells a vacuolated appearance for which
gland consists of coalesced chromaffin cells of neuroectoder- they are called »clear cells«. In this zone glucocorticoids (cor-
mal origin that secrete epinephrine and norepinephrine. The tisol and corticosterone) and androgens are produced.
surrounding cortex arises from mesoderm and histologically
three zones can be distinguished: (1) zona glomerulosa (or ar- The cells of the zona reticularis form anastomosing columns.
cuata), (2) zona fasciculata, and (3) zona reticularis (fig. 4.1). They do not have significant lipid content but have densely
granular cytoplasm, for which they are called »compact cells«.
In recent years several factors involved in adrenal develop- This zone produces androgens such as androstenedione, but
ment have been identified, but it remains unknown which also glucocorticoids. It functions together with the zona fas-
factors are responsible for the differentiation of adrenal stem ciculata as a single unit.
cells into cells of specific zones of the fetal adrenal cortex. In
all mammalian species the growth and function of the fetal The zona glomerulosa lacks a well-defined structure. The
adrenal cortex are influenced by adrenocorticotropic hor- small, lipid-poor cells are scattered beneath the adrenal cap-
mone (ACTH) secreted by the pituitary gland. As ACTH is sule. They produce mineralocorticoids (primarily aldoste-
not a growth factor per se, at least some of its trophic actions rone) and are deficient in 17a-hydroxylase activity (see
are modulated by locally expressed growth factors such as below) and therefore cannot produce cortisol or androgens.
basic fibroblast growth factor (bFGF), epidermal growth fac-
tor (EGF), insulin-like growth factor (IGF)-II, and trans-
forming growth factors.1 Some of the genes encoding these
growth factors (particularly IGF-II) are similarly overex-
pressed in fetal adrenals and adrenocortical carcinomas of hu-
mans.2,3
A B
Figure 4.1:
(A) Histological section of the adrenal gland of a healthy dog: A = medulla; B = zona reticularis; C = zona fasciculata; D = zona glomerulosa; E = capsule.
(B) Similar section from a dog that received injections of progestagens. Their intrinsic glucocorticoid effect suppressed endogenous ACTH secretion, resulting in complete
atrophy of both the zona fasciculata and the zona reticularis, while the zona glomerulosa remained intact.
94 Adrenals
Figure 4.3:
Major biosynthetic pathways of adrenocortical steroid
biosynthesis.
scc = cholesterol side-chain cleavage; 3b = 3b-hydro-
xysteroid dehydrogenase; 11 = 11b-hydroxylase; 17 =
17a-hydroxylase / 17; 20 lyase; 21 = 21-hydroxylase.
hydrocellulose eye sponge seems to be the best material for species including the dog, most of the inactivated and conju-
collection of canine saliva.15,16 gated metabolites are readily excreted as glucuronides by the
kidney, whereas in the cat the excretion is largely as sulfates
The liver and the kidney are the major sites of corticosteroid via the bile.17,18 One to two per cent of the total cortisol se-
metabolism, which inactivates them and increases their water cretion is excreted unaltered in the urine. Measurement of
solubility, as does subsequent conjugation with glucuronide this urinary »free« cortisol gives an integrated reflection of
or sulfate groups. The conversion of cortisol to the inactive cortisol production (chapter 12.4.4).
cortisone by 11b-hydroxysteroid dehydrogenase (11b-HSD)
is the most important pathway quantitatively. In several
96 Adrenals
Figure 4.4:
Structure of the canine proopiomelanocortin (POMC) gene, its mRNA, and the processing of POMC in the anterior lobe and pars intermedia of the pituitary.
ACTH = adrenocorticotropic hormone; J PEPTIDE = joining peptide; b-LPH = b-lipoprotein; MSH = melanocyte-stimulating hormone; CLIP = corticotropin-like inter-
mediate lobe peptide; b-END = b-endorphin.
A B
Figure 4.5:
Sections of the pituitary gland of a cat immunostained with anti-ACTH (A) and anti-a-MSH (B). Compared with the anterior lobe (AL) and pars intermedia (PI) of the dog
(see fig. 2.6), there are few ACTH-positive cells in the PI but there are abundant MSH-positive cells.
4.1.3 Regulation of glucocorticoid also fig. 1.10). ACTH is a single-chain peptide of 39 amino
acid residues. It is synthesized in the anterior lobe of the pitu-
secretion itary gland from the precursor molecule proopiomelanocortin
Synthesis and release of glucocorticoids and androgens by the (POMC), together with several peptides that are released to-
middle and inner zones of the adrenal cortex are almost exclu- gether with ACTH (fig. 4.4). There is considerable amino acid
sively controlled by the plasma concentration of ACTH (see sequence homology of ACTH between species and canine
Introduction 97
In dogs and cats the PI contains two types of cells that can also
synthesize POMC.20 One is similar to the corticotropic cells
of the anterior lobe, in that it reacts with anti-ACTH
(fig. 2.6). In the other, ACTH is cleaved into ACTH1–14 (pre-
cursor of a-MSH) and corticotropin-like intermediate-lobe
peptide (ACTH18–39 or CLIP) (figs 4.4, 4.5). As for all ade-
nohypophyseal hormones in the dog, the release of a-MSH is 4
pulsatile, albeit in only a few pulses per 24 h (fig. 4.6).21,22 PI
secretory activity is under almost permanent inhibitory con-
trol by dopamine (fig. 4.7). In contrast, the PI in cats is ac-
tively secreting, responsive to the stress of physical restraint
and b-adrenergic stimulants (fig. 4.8).23,24
Central nervous system events regulate both the number and responses to stress. In laboratory dogs several emotional or
magnitude of ACTH bursts, ranging in the dog from six to neurogenic stresses did not stimulate secretion of ACTH or
twelve per 24 h period.21,30 The episodic secretion in dogs a-MSH13 and only profound stress such as long-term immo-
and cats does not seem to increase in the early morning hours bilization consistently resulted in elevations of plasma corti-
to the extent of a demonstrable circadian rhythm of cortisol sol.14 Among privately-owned dogs, only those known to be
concentration in plasma or saliva, as occurs in humans.31,32 afraid of gunshots responded to this noise by an increase in
plasma cortisol.35 However, using urinary cortisol as a
ACTH and cortisol are secreted within minutes following the measure of integrated cortisol production, the stress of intro-
onset of stress such as anesthesia and surgery.33,34 Stress duction into a novel kennel or exposure to veterinary pro-
responses originate in the central nervous system and increase cedures is reflected in elevated urinary corticoid:creatinine
the release of hypothalamic hypophysiotropic hormones such ratios.36–38 In cats, on the other hand, mild stress such as hand-
as CRH and VP. Dogs and cats seem to differ in their ling and intradermal skin testing causes impressive increases in
98 Adrenals
Figure 4.7:
Regulation of adrenocortical secretion of glucocorti-
coids and androgens. Central nervous system afferents
(episodic influences and stress) are mediated by hypo-
physiotropic hormones such as CRH and AVP to stimu-
late ACTH release from the anterior lobe of the pitu-
itary. ACTH stimulates the cells of the middle and inner
zones of the adrenal cortex to produce chiefly cortisol,
which inhibits the secretion and influence of the hypo-
physiotropic hormones on the corticotropic cells of the
anterior pituitary. The melanotropic and corticotropic
cells of the pars intermedia are largely under dopami-
nergic (DA) inhibitory control. The activation of the hy-
pothalamic-pituitary-adrenocortical axis as evoked by
challenges to the immune system is shown on the
right.
Figure 4.8:
Plasma concentrations of cortisol, ACTH, and a-MSH in six cats after intradermal skin testing between
t0 and t5 and reading of the skin reactions at t15. Blood was collected via previously placed jugular ca-
theters. (Adapted from Willemse et al., 1993).23
Introduction 99
Figure 4.9: 4
Regulation of aldosterone secretion by the zona
glomerulosa of the adrenal cortex. The two main regu-
lators are angiotensin-II and potassium (K+).
the plasma concentrations of cortisol, ACTH, and a-MSH hypothalamic-pituitary-adrenocortical axis are also subject to
(fig. 4.8).23 Corticoid:creatinine ratios in urines collected in a feedback regulation by glucocorticoids, which not only im-
clinic were considerably higher than those in urines collected pair the hypothalamic response to cytokine activation but also
at home (chapter 12.2.4).39 block cytokine production in macrophages (fig. 4.7). Thus a
bidirectional communication exits between the neuroendo-
The third major regulator of ACTH and cortisol secretion is crine system and the immune system.43
feedback inhibition. The inhibitory action of glucocorticoids
is exerted at multiple target sites, of which two have been un- In recent years it has become clear that apart from these four
equivocally identified being the neurons in the hypothalamus ACTH-dependent mechanisms, ACTH-independent mech-
that produce corticotropin-releasing factors (CRH and AVP) anisms also have a role in fine tuning and modulating the
and the corticotropic cells in the anterior lobe. The feedback response of the highly sensitive adrenocortical stress system
actions of glucocorticoids are exerted through at least two appropriately to physiological needs. Studies of pulsatility and
structurally different receptor molecules, i.e., a mineralocor- hormone kinetics have revealed asynchrony in ACTH and
ticoid-preferring receptor (MR) and a glucocorticoid-prefer- cortisol responses, indicating that signals other than ACTH
ring receptor (GR). The MR has a 20-fold higher affinity influence cortisol secretion (fig. 4.6).44 Multiple systemically-
than the GR for cortisol. Inhibition of basal secretion of derived factors (neuropeptides, neurotransmitters, growth
ACTH by glucocorticoids appears to be mediated via occu- factors, cytokines, adipokines) and intra-adrenal paracrine
pancy of the MR. The dog brain and pituitary contain very regulation can influence release of corticosteroids. Adreno-
high levels of MR, the highest being in the septohippocampal cortical cells express a great variety of receptors for these fac-
complex and the anterior lobe of the pituitary.40 The GR is tors, enabling direct effects on cortisol release in health and
more evenly distributed in the brain, the amounts in the an- disease. In several disease states, including critical illness, sep-
terior lobe being about twice as high. The latter GR is mainly ticemia, and inflammation, there may be disorderly basal cor-
involved in the feedback effect of glucocorticoids released as a tisol release independent of ACTH.45 Overexpression of re-
result of stress-induced ACTH secretion. ceptors for neuropeptides, neurotransmitters, hormones, or
cytokines may give rise to hypercortisolism with suppressed
Challenges to the immune system by infections invariably ac- plasma ACTH concentrations (chapter 4.2.3)
tivate the hypothalamic-pituitary-adrenocortical axis. These
responses are mediated by proinflammatory cytokines, a
group of polypeptides released from colonies of activated im-
mune cells. Although other cytokines, such as interleu- 4.1.4 Regulation of mineralocorticoid
kin(IL)-6 and tumor necrosis factor a (TNFa), are also associ- secretion
ated with the responsiveness to stress, IL-1 particularly
activates the hypothalamic-pituitary-adrenocortical axis.41 It The two primary mechanisms controlling aldosterone release
is released from activated macrophages in the periphery and are the renin-angiotensin system (RAS) and potassium. The
also produced in the brain.42 The regulatory actions of the cy- RAS keeps the circulatory blood volume constant by promot-
tokines are exerted predominantly at the level of the hypotha- ing aldosterone-induced sodium retention during periods of
lamus, where CRH is the major mediator of the hypotha- hypovolemia and by decreasing aldosterone-dependent so-
lamic response. These cytokine-mediated activations of the dium retention during hypervolemia (fig. 4.9). Potassium
100 Adrenals
Figure 4.10:
Three major pathways of interaction of angiotensin-II with one of its receptors
(AT1 receptor).
Figure 4.11:
VR = vascular resistance; LVH = left ventricular hypertrophy. (Modified after Wil-
Angiotensin-II synthesis and its interaction with two receptor subtypes, AT1R and
liams, 2005.)46
AT2R.
ACE = angiotensin converting enzyme.
Figure 4.13:
Bidirectional conversion of cortisol and cortisone by 4
isoenzymes (type 1 and type 2) of 11b-hydroxysteroid
dehydrogenase (11b-HSD).
latory role opposing AT1R-mediated vasoconstriction. In ad- inactive glucocorticoid cortisone (fig. 4.13). The type 2
dition, activation of AT2R leads to suppression of renin bio- enzyme is predominantly expressed in mineralocorticoid tar-
synthesis and release.47,48 get tissues such as the kidney (chapter 4.1.6). Expression of
both isoenzymes of 11b-HSD is important in controlling tis-
Angiotensinogen is the precursor of several angiotensin pep- sue-specific action of glucocorticoids. Studies in humans sug-
tides, including angiotensin-II. Angiotensinogen is produced gest that 11b-HSD1 can facilitate glucocorticoid action by
mainly in the liver from its precursor preproangiotensinogen. generating cortisol from inactive cortisone in, for example,
In the circulation angiotensinogen is cleaved by renin and adipose tissue.50 Among the species studied, feline 11b-HSDs
other enzymes to release angiotensin-I. The angioten- have the highest homology with the comparable enzymes in
sin-converting enzyme (ACE) converts the inactive decapep- humans.51 In dogs the tissue distribution of both 11b-HSDs is
tide angiotensin-I to the active octapeptide angiotensin-II similar to that in humans and rodents.52 In a study of the
(fig. 4.11). ACE-inhibiting compounds are used clinically to species-specific variability of the catalytic efficiency in the re-
disrupt the RAS, as in the treatment of heart failure.49 duction of cortisone, the dog was found to have the lowest ac-
tivity.53
The proteolytic enzyme renin is synthesized in the juxtaglo-
merular cells of the kidney. Stimulation of renal baroreceptors The cortisol-activated receptor interacts with specific DNA
is the most potent mechanism for its release. These stretch re- sequences on target genes, resulting in changes in mRNA
ceptors in the afferent arteriole stimulate renin release in synthesis and subsequent synthesis of specific proteins. The
response to reduced renal perfusion pressure. Additional regu- transcription of target genes is also influenced by transcrip-
lation is provided by the macula densa, a group of modified tional coactivators and corepressors recruited by the GR. In-
cells of the distal tubule near the end of the loop of Henle hibition of gene expression is a key component of glucocor-
and intimately associated with the juxtaglomerular cells ticoid action. For example, in immune cells GR inhibits the
(fig. 4.12). Sodium concentration in the tubular lumen is action of nuclear factor-kappa B (NF-kB), a transcription
monitored by the cells of the macula densa and low sodium factor that regulates the expression of several cytokine path-
levels trigger communication between the macula densa and ways, thereby exerting multifaceted effects to inhibit the im-
the juxtaglomerular cells, resulting in renin release. mune response (chapter 4.3.6). These mechanisms together
with the presence of GR splice variants and tissue-specific
posttranslational modifications (phosphorylation, ubiquiti-
nation) are thought to account for the wide array of actions of
4.1.5 Glucocorticoid action cortisol.54 In recent years insight into this diversity of actions
has been further extended by the notion that glucocorticoids
Tissue-specific actions of glucocorticoids are not only deter- not only exert genomic effects, but also direct nongenomic
mined by their production rates and the activation of gluco- effects (chapter 1.1.3).
corticoid receptors (GRs). In peripheral tissues, cortisol is
metabolized at a prereceptor level by the enzyme 11b-hydro- Central to the metabolic effects of glucocorticoids is the syn-
xysteroid dehydrogenase (11b-HSD). This enzyme occurs in thesis of mRNAs which lead to synthesis of key enzymes
two isoforms. Type 1 is widely distributed in many tissues, in- in gluconeogenesis, such as pyruvate carboxylase, fructose-
cluding liver, gonad, and adipose tissue. In vivo it acts pre- 1,6-diphosphatase, and fructose-6-phosphatase. Especially in
dominantly as a reductase, generating active cortisol from the the fasted state, glucocorticoids contribute to the mainten-
102 Adrenals
Figure 4.14:
Effects of cortisol excess on intermediary metabolism.
Increased gluconeogenesis leads to hyperglycemia,
which is controlled initially by increased insulin secre-
tion. This in turn causes increased lipogenesis. Thus the
end result of glucocorticoid excess is the catabolism of
peripheral tissues such as muscle and skin to deliver
the substrate for increased gluconeogenesis and lipo-
genesis.
ance of normoglycemia by gluconeogenesis and by the pe- cortisol and corticosterone, but not aldosterone, to their
ripheral release of substrate. The latter is achieved via de- 11-keto analogs (chapter 4.1.5, fig. 4.13). These analogs can-
creased glucose uptake and metabolism and decreased protein not bind to MR, thereby enabling aldosterone to occupy this
synthesis leading to increased release of amino acids. In addi- receptor.55
tion, lipolysis is stimulated in adipose tissue. However, in situ-
ations of glucocorticoid excess the latter may be overruled by As the major mineralocorticoid, aldosterone has two import-
the hyperglycemia-induced hyperinsulinemia that promotes ant actions: (1) it regulates extracellular fluid volume and (2) it
the opposite, i.e., lipogenesis and fat deposition (fig. 4.14). is a major determinant of potassium homeostasis. These ef-
fects are mediated by the binding of aldosterone and /or
Through these effects on intermediary metabolism and other deoxycorticosterone (DOC) to the mineralocorticoid recep-
effects, glucocorticoids affect almost all tissues and many pro- tor in the cytosol of epithelial cells, predominantly in the kid-
cesses, including blood cells and immunologic functions. ney. Aldosterone and DOC have approximately equal affin-
Most of these effects are clinically relevant and will be dis- ities for the mineralocorticoid receptor and circulate at
cussed in sections on adrenocortical disease. roughly similar concentrations, but aldosterone is quanti-
tatively more important because much more of it circulates as
free hormone (chapter 4.1.2). In the distal convoluted tubule
aldosterone and DOC increase the reabsorption of sodium
4.1.6 Mineralocorticoid action and the excretion of potassium.
The widespread mineralocorticoid receptors (MR) have Once the hormone-receptor complex has reached the nu-
equal affinity for aldosterone and the glucocorticoids cortisol cleus, it initiates a sequence of events leading to activation of
and corticosterone, but the latter two hormones circulate at amiloride-sensitive epithelial sodium channels in the apical
much higher concentrations than that of aldosterone. This has membrane. Thereafter, increased sodium influx stimulates the
raised the question how the MR is protected from activation Na+K+-ATPase in the basolateral membrane. As aldosterone
by cortisol. In the classic aldosterone targets (kidney, colon, increases active sodium reabsorption, an electrochemical
salivary gland) this is accomplished by the enzyme 11b-hydro- gradient is established that facilitates the passive transfer of po-
xysteroid dehydrogenase type 2 (11b-HSD2), which converts tassium from tubular cells into urine. Thus potassium is not
Adrenocortical insufficiency 103
Figure 4.15:
Electrolyte transport in the distal renal tubule.
Na+,K+-ATPase in the basolateral membrane is a major
driving force for electroneutral cotransport by keeping
intracellular Na+ low and the cell interior negative. Po-
tassium leaves the cell through conductance channels,
driven by a concentration gradient. Aldosterone acti-
vates sodium channels, which can be inhibited by thia-
zide diuretics, amiloride, and atrial natriuretic peptide 4
(ANP). Aldosterone also activates potassium channels
and Na+,K+ATPase.
excreted in direct exchange for sodium, but rather in a Many putative CASHs have been proposed, including
manner that depends directly on the active reabsorption of POMC derivatives, prolactin, and IGF-I, but definite proof is
sodium (fig. 4.15). If almost all sodium is reabsorbed more lacking.59
proximally in the nephron, as in the presence of severe vol-
ume depletion, little sodium reaches the distal reabsorptive In the absence of gonads, adrenocortical androgen production
site. Hence, despite high levels of aldosterone, there is mini- does not meet physiological requirements (chapter 8.2). In
mal potassium excretion in the absence of sodium delivery to contrast to humans, dogs and cats with increased androgen se-
the distal tubule. Conversely, a high sodium intake will in- cretion accompanying ACTH-dependent hypercortisolism
crease potassium excretion. This is particularly true if the ani- do not develop dermal or behavioral symptoms of androgen
mal is receiving a diuretic that blocks part of the proximal excess. Their clinical manifestations are primarily determined
reabsorption of sodium, causing even more sodium to reach by the glucocorticoid excess. However, occasionally sex ste-
the distal reabsorptive site.56 roid production by an adrenocortical tumor leads to physical
and behavioral changes due to androgen excess (see also
In recent years it has become clear that the classical character- chapter 4.3.3).
ization of aldosterone as an electrolyte-regulating hormone is
too narrow. In addition to its effects on classic epithelial tar-
gets such as kidney, colon, and salivary gland, aldosterone has
major actions on other epithelial and nonepithelial tissues. 4.2 Adrenocortical
Actions of aldosterone, probably in part nongenomic, on en- insufficiency
dothelial cells and on cardiac tissue contribute to blood press-
ure homeostasis.57 It appears that aldosterone may increase The term adrenocortical insufficiency includes all conditions
blood pressure through two main mechanisms: (1) miner- in which the secretion of adrenal steroid hormones falls below
alocorticoid-induced expansion of plasma and extracellular the requirement of the animal. Its two major forms are:
fluid volume and (2) increased total peripheral resistance. (1) primary adrenocortical insufficiency due to lesions or
With regard to the nonepithelial actions, it should be added disease processes in the adrenal cortices and (2) secondary ad-
that long-term mineralocorticoid excess may lead to micro- renocortical insufficiency due to insufficient ACTH release
angiopathies with fibrosis and proliferation of endothelial and by the pituitary. In addition to these conditions of absolute
smooth muscle cells, in tissues such as heart and kidney (see hormone deficits, there can be relative adrenocortical insuffi-
also chapter 4.4.1).58 ciency.
4 B
Figure 4.16:
Cross-section of an adrenal of a healthy dog (A) and a dog with Addison’s disease (B) in which the adrenal medulla is only surrounded by the capsule.
A B
Figure 4.17:
(A) Section of an adrenal of a dog with primary adrenocortical insufficiency. The adrenal medulla is only surrounded by the fibrous capsule. All three zones of the cortex
have completely disappeared.
(B) Lymphocytic adrenalitis throughout the cortex (HE, x10). Lymphocytic adrenalitis is probably an immune-mediated process that destroys the adrenal cortex with the
end result as shown on the left.
toms and signs (fig. 4.16). The atrophy that is often found The immune-mediated destruction typically terminates
(fig. 4.17) is probably the end result of immune-mediated de- in absolute deficiencies of glucocorticoids and mineralo-
struction. The condition is also termed Addison’s disease, corticoids, together with high plasma levels of ACTH due to
after Thomas Addison, a physician who in 1855 first de- pronounced negative feedback to the hypothalamus and pitu-
scribed the syndrome in man, which at that time was usually itary (fig. 1.8). The destruction may also be confined to the
the result of tuberculosis. Adrenocortical autoantibodies have middle and inner zones of the adrenal cortex, resulting in what
been reported in most human patients with nontuberculous is known as atypical primary hypoadrenocorticism. This may
Addison’s disease. The major autoantigens involved in the be more common than is generally appreciated, for it is easily
reaction with the adrenocortical autoantibodies include overlooked because of the absence of mineralocorticoid defi-
21-hydroxylase, 17a-hydroxylase/17,20-lyase, and choleste- ciency, the main determinant of the symptoms and signs of
rol side-chain cleavage enzyme, with 21-hydroxylase being typical or classic primary hypoadrenocorticism.62 In a minor-
the most common.60 Primary hypoadrenocorticism in dogs ity of cases, atypical primary hypoadrenocorticism progresses
was first described in 1953 by Hadlow.61 to include mineralocorticoid deficiency within months after
the initial diagnosis.62 There has also been one reported case of
isolated hyperreninemic hypoaldosteronism in a dog.63
Adrenocortical insufficiency 105
Figure 4.18:
Lateral (A) and dorsoventral (B) radiographs of a two-year-old male dog that arrived in a hypovolemic crisis due to primary hypoadrenocorticism.
Hypovolemia is clearly evident in the microcardia and the poor filling of the caudal vena cava and pulmonary vessels.
As mentioned in chapter 3.3.1, primary hypoadrenocorticism most breeds. Genetic studies have shown that in Portuguese
may be part of a polyglandular deficiency syndrome.64 Con- water dogs, standard poodles, and Nova Scotia duck tolling
current endocrine gland failure may include primary hypo- retrievers it is an inherited disorder under the control of a
thyroidism, type I diabetes mellitus, and primary hypopara- single autosomal recessive locus.66,70,71
thyroidism.
In cats hypoadrenocorticism is also a disease of young to
Other possible causes of primary adrenocortical insufficiency middle-aged animals but it appears to be very rare in this
include adrenocortical hemorrhage, fungal infection, and species.72,73 In the limited number of cases reported thus far,
metastatic disease,65 but they appear to be rare. Finally, treat- no sex predilection has been observed. There have been two
ment of hypercortisolism with o,p'-DDD or trilostane may reported cases of primary hypoadrenocorticism in cats due to
deliberately or unintentionally destroy the adrenal cortices to infiltration of the adrenals by malignant lymphoma.74
the extent that iatrogenic hypoadrenocorticism ensues
(chapter 4.3.1). As the disease is usually caused by gradual autoimmune
destruction of the adrenal cortices, one might expect an in-
Clinical manifestations sidious onset of slowly progressive weakness, fatigue, ano-
Primary hypoadrenocorticism is an uncommon disease of rexia, and vomiting. Although this can be the case, frequently
primarily young to middle-aged dogs (mean four years) with the animal is presented as an emergency in a state of severe de-
a predilection for females.64 The disorder has been docu- pression, weakness, and hypotonic dehydration (fig. 4.18).
mented in dogs as young as eight weeks.66 Great Danes, Por- The initial symptoms may have been very mild or scarcely
tuguese water dogs, Rottweilers, standard poodles, West recognized by the owner except in retrospect. Apparently the
Highland white terriers, bearded collies, Leonbergers, Nova animal has been able to cope with the hormone deficits until
Scotia duck tolling retrievers, and soft coated wheaten ter- a critical threshold in the maintenance of fluid and electrolyte
riers have a higher relative risk of developing hypoadreno- homeostasis has been passed.
corticism than dogs of other breeds. Moreover, familial oc-
currence has been documented.67–69 Despite the breed Although glucocorticoid deficiency may cause some lethargy,
predisposition and occurrence in certain families, the mode weakness, gastrointestinal disturbances, and mild nonregener-
of inheritance of hypoadrenocorticism is undetermined in ative anemia, all of which will certainly contribute to the
106 Adrenals
Figure 4.19:
4 ECG recordings (leads I, II, and III) of a four-year-old
dog with primary hypoadrenocorticism (calibration:
1 cm = 1 mV; paper speed 25 mm/s).
(A) Before treatment (Na+ = 131 mmol/l; K+ =
8.7 mmol/l) there was extreme bradycardia and no
P-waves.
A B (B) Treatment more than doubled the heart rate and
P-waves reappeared.
Figure 4.20:
ECG recordings (leads I, II, and III) of a three-year-old
female beagle with primary hypoadrenocorticism (cali-
bration: 1 cm = 1 mV; paper speed 25 mm/s).
(A) Before treatment (Na+ = 137 mmol/l; K+ =
6.8 mmol./l) the R-waves (lead II) were low and the
T-waves were high and spiked.
A B (B) After treatment the R-waves became normal and
the polarity of T-waves was reversed.
Figure 4.21:
Results of an ACTH-stimulation test in healthy cats (blue area) and in a cat with
primary hypoadrenocorticism (solid line).
The atrophy of the adrenal cortices reduces the length and despite treatment.72 The oral maintenance therapy (see also
thickness of the adrenal glands as determined by ultraso- chapter 13.2.1) consists of a glucocorticoid, a mineralocorti-
nography, but dimensions in dogs with hypoadrenocorticism coid, and salt (mixed with the food). If the salt causes vomit-
overlap those in healthy dogs.76,85 ing directly after the meal, it can instead be added to the
drinking water or given in tablet form. Including salt in the
Treatment treatment provides flexibility in the adjustment of the miner-
Animals presented in hypovolemic shock and suspected of alocorticoid dose based on plasma electrolyte values (see
having primary hypoadrenocorticism are treated without below). However, it has been reported that dogs do well
waiting for laboratory results. The aim is to correct the hypo- without the addition of salt to glucocorticoid and miner-
volemia and electrolyte imbalance by fluid therapy and corti- alocorticoid substitution.89
costeroid administration (fig. 4.24). Just prior to starting fluid
administration, blood and urine are collected for routine lab- Client instruction and follow-up
oratory analyses (table 4.2). If later the suspicion of hypoad- At discharge the importance of accuracy in administering the
renocorticism is removed, it is reassuring to know that the substitution therapy is explained to the owner. The first fol-
core of the protocol is the correction of hypovolemia and that low-up examination is made two to three weeks later. Plasma
this and the corticosteroids will not be harmful in hypovol- sodium and potassium concentrations are measured to deter-
emic shock due to other causes. mine whether adjustments are needed in the doses of miner-
alocorticoid and salt. These adjustments are made as follows:
The initial treatment scheme for an acute crisis of suspected 쎱 A slight increase or decrease in sodium combined with a
primary hypoadrenocorticism consists of fluid therapy and normal potassium is corrected by adjusting the dose of salt
parenteral administration of a glucocorticoid and a miner- alone.
alocorticoid (see chapter 13.2.1). If the hyponatremia is 쎱 If sodium is low and potassium is high, or vice versa, only
severe, plasma sodium should be monitored during initial the dose of fludrocortisone is changed.
treatment to avoid a too rapid increase that can damage 쎱 If sodium is normal and potassium is abnormal, the dose
the CNS.86–88 Most dogs and cats with primary hypoadreno- of fludrocortisone is changed and the measurements are
corticism improve rapidly after treatment is started. Usually repeated in two to three weeks to determine whether the
dogs begin to eat on the following day, so that oral main- dose of salt must also be changed.
tenance therapy can be started. In cats the signs of weak-
ness, lethargy, and anorexia may persist for three to five days
Adrenocortical insufficiency 109
Prognosis
With satisfactory replacement therapy, primary hypo-
adrenocorticism has an excellent prognosis in both dogs and
cats.89 Once therapy is stabilized, follow-up examinations are
made twice yearly.
covery of pituitary ACTH release. The likelihood of adreno- Once there is biochemical certainty about the presence of
cortical insufficiency, its magnitude, and its duration all de- spontaneous secondary hypoadrenocorticism, the pituitary
pend on the dose of the corticosteroid that has been given, its area should be visualized to search for a lesion causing the
intrinsic glucocorticoid activity, and the schedule and dur- ACTH deficiency (chapters 2.2.6, 3.3.2).
ation of its administration. The condition is also be discussed
in chapter 4.3.6. Treatment
Although dogs seem to be able to live reasonably well in spite
Another iatrogenic form of the disorder is ACTH deficiency of cortisol deficiency, oral glucocorticoid administration in-
due to hypophysectomy (chapters 4.3.1, 13.1.1). creases activity and alertness. Cortisone acetate is given in a
4 daily dose of 0.5–1.0 mg/kg or prednisolone acetate is given
Clinical manifestations in a daily dose of 0.1–0.15 mg/kg. In addition to a glucocor-
In secondary adrenocortical insufficiency mineralocorticoid ticoid, treatment of other deficiencies (see chapters 2.2.6,
production is virtually unaffected, as it is primarily regulated 3.3.2) may be required. The animals are especially at risk dur-
by extrapituitary mechanisms (chapter 4.1.4). Hence there is ing stress, and in those situations the glucocorticoid dose
not the tendency to hypotension and shock that gives primary should be increased to prevent a crisis (chapter 4.2.1).
adrenocortical insufficiency its dramatic features. On the
contrary, although glucocorticoid deficiency may result in Prognosis
slight depression, anorexia, gastrointestinal disturbances, and As in secondary hypothyroidism (chapter 3.3.2), the progno-
mild nonregenerative anemia, the condition may escape at- sis is highly dependent upon the development of the causative
tention for a long time. Nevertheless, it must be regarded as lesion.
potentially dangerous because of the animal’s inability to cope
with stress by activating the pituitary-adrenocortical system.
Major surgery or trauma might cause a crisis and /or failure to
recover from anesthesia unless glucocorticoid supplemen- 4.2.3 Relative adrenocortical
tation is given (see also chapter 4.2.1). In addition, hypocor- insufficiency
tisolism may give rise to severe chronic hypoglycemia.92
Several factors, such as trauma, surgery, and challenges to the
Thus it may happen that the condition is recognized more or immune system by infections, activate the hypothalamic-pi-
less incidentally during routine endocrine studies for prob- tuitary-adrenocortical axis. The resulting hypercortisolemia is
lems such as lethargy or alopecia, or that a pituitary tumor has an essential part of the stress response required for adequate
been diagnosed and subsequent studies of pituitary function adaptation to these noxious stimuli in order to restore homeo-
reveal ACTH deficiency. stasis and enhance survival (chapter 4.1.3, fig. 4.7). An inade-
quate response is potentially fatal. In critically ill humans the
Diagnosis secretory capacity of the adrenal cortices is commonly insuf-
Suspicion of secondary adrenocortical insufficiency is raised ficient to compensate for the increased demand for cortisol.94
by finding a low urinary corticoid:creatinine ratio Because it is not an absolute deficiency of cortisol but rather
(chapter 12.4.4) in the absence of hyponatremia and hyper- an imbalance between adrenal output and cortisol demand,
kalemia. In an ACTH-stimulation test (chapter 12.4.1), the this disorder is called relative adrenocortical insufficiency or
basal plasma cortisol level will be low and the response to critical illness-related corticosteroid insufficiency (CIRCI).
ACTH will be (1) normal or somewhat impaired or (2) ab- CIRCI is defined as inadequate corticosteroid activity for the
sent. The former response excludes primary hypoadrenocor- severity of the illness of a patient.95
ticism but not secondary hypoadrenocorticism, for a response
might still be present soon after onset of the condition. The Pathogenesis
absence of a response can be the result of a longstanding The underlying mechanisms of relative adrenocortical insuf-
ACTH deficiency. However, there remains the possibility of ficiency are largely unknown. It is characterized by insuffi-
primary adrenocortical insufficiency with selective atrophy of cient corticosteroid-mediated down-regulation of inflamma-
the zona fasciculata and zona reticularis but with little or no tory transcription factors. Comparable to diabetes mellitus
involvement of the zona glomerulosa.62,75 For differentiation type 2, it is a consequence of both inadequate circulating glu-
between these possibilities further studies are required, in- cocorticoid and resistance to glucocorticoids at the tissue
cluding measurements of plasma ACTH and a CRH-stimu- level.96
lation test (chapter 12.1.1). In dogs with primary adrenocor-
tical insufficiency, basal plasma ACTH concentration is high Cytokines such as tumor necrosis factor-a (TNF-a) and in-
and there is an exaggerated response to CRH. In dogs with terleukin-1 have been shown to be involved in the develop-
secondary adrenocortical insufficiency, ACTH levels are low ment of resistance to glucocorticoids at the tissue level.97
and nonresponsive to stimulation with CRH.93 These cytokines have also been implicated in the reversible
dysfunction of the hypothalamic-pituitary-adrenocortical
axis during critical illness. TNF-a impairs CRH-stimulated
Glucocorticoid excess 111
ACTH release, and studies in humans and dogs have revealed Treatment
inappropriately low plasma ACTH levels in some patients Routine administration of pharmacological doses of cortico-
with critical illness.98–102 In addition, TNF-a has been shown steroids to patients with critical illness is inadvisable, because
to reduce cortisol synthesis by inhibiting the stimulatory ac- it does not improve outcome and enhances the risk of com-
tions of ACTH on adrenocortical cells.103 Adrenal hypoper- plications associated with the use of steroids.106 The risk:be-
fusion and microvascular disease resulting from disseminated nefit ratio of corticosteroid administration should therefore
intravascular coagulation may also contribute, and may even be assessed in each patient. It seems reasonable to initiate
result in long-term adrenal dysfunction. treatment with corticosteroids in critically-ill patients with
systemic hypotension refractory to fluid loading and a sub-
Clinical manifestations normal response to ACTH administration. In these cases, the 4
Systemic hypotension refractory to fluid loading and requi- corticosteroids should ideally be administered in a physiologi-
ring vasopressors is a common manifestation of relative adre- cal stress-dose, i.e., a dose sufficient to suppress the proinflam-
nocortical insufficiency in humans and dogs with critical ill- matory response without causing excessive immune paresis.
ness.100,102,104 The systemic hypotension may be due to Low doses of hydrocortisone have been reported to improve
down-regulation of smooth muscle adrenergic receptors; the pressor responsiveness and survival in septic humans with
expression of these receptors is modulated by glucocorticoids. relative adrenocortical insufficiency.107 There are no reports
In addition, the relative glucocorticoid deficiency may inter- of studies on the effects of low doses of corticosteroids in
fere with catecholamine production. companion animal patients with critical illness. The duration
of corticosteroid therapy should be guided by the duration of
Diagnosis the underlying systemic inflammation.
Unlike patients with classic hypoadrenocorticism, those with
relative adrenocortical insufficiency generally have normal Prognosis
to elevated plasma cortisol concentrations, but a blunted Following recovery from the critical illness the dysfunction of
response in an ACTH-stimulation test. However, there is much the hypothalamic-pituitary-adrenocortical axis generally re-
controversy concerning the appropriate dose of synthetic solves spontaneously.
ACTH and interpretation of the test results.105 Several studies
in humans have used an intravenous dose of 250 µg, whereas
others have used a total dose of only 1 µg per adult human.
In dogs the ACTH dose has ranged from 5 µg/kg to 4.3 Glucocorticoid excess
250 µg/dog.100–102 With regard to interpretation, what con-
stitutes a normal adrenal response to critical illness is un- Cortisol is the principal glucocorticoid released by the ad-
known, as is the amount of cortisol that is required or is op- renals in dogs and cats (chapter 4.1.1). Thus endogenous glu-
timal for a given critical illness in an individual patient. The cocorticoid excess is essentially hypercortisolism. Prolonged
latter is especially hindered by the lack of a test that quantifies exposure to inappropriately elevated plasma concentrations of
glucocorticoid activity at the tissue level. Consequently, the free cortisol leads to symptoms and signs often referred to as
endocrine diagnosis of relative adrenocortical insufficiency Cushing’s syndrome, after Harvey Cushing, the neurosurgeon
remains somewhat elusive at this time. who in 1932 first described the syndrome in man. Identical
symptoms and signs are elicited by exogenous glucocorticoids
Results of two recent studies indicate that relative adrenocor- in long-term therapy (chapter 4.3.6).
tical insufficiency is common in critically-ill dogs with sepsis,
severe trauma, or gastric dilatation-volvulus. An increment of In about 80 % of cases of spontaneous hypercortisolism in
쏝 83 nmol/l in the plasma cortisol concentration after syn- both dogs and cats the disease is the result of excessive ACTH
thetic ACTH administration was associated with increased secretion by a pituitary adenoma (chapter 4.3.1). In most
incidence of systemic hypotension, higher likelihood to other cases the disease is ACTH-independent, due to hyper-
require vasopressor treatment, and decreased survival.100,102 secretion by adrenocortical tumor (chapter 4.3.2). There have
Relative adrenocortical insufficiency could not be demon- been case reports of two other forms of hypercortisolism, one
strated in dogs with critical illness due to canine babesiosis, al- ACTH dependent (chapter 4.3.4) and the other ACTH inde-
though the increment in plasma cortisol after ACTH admin- pendent (chapter 4.3.5). The discussion of these different
istration tended to be lower than in control dogs. However, disease entities is preceded by a description of the common
dogs with babesiosis having an increment in plasma cortisol denominator of the clinical manifestations, glucocorticoid
쏝 83 nmol/l had a significantly higher cortisol:ACTH ratio excess.
than those with an increment 쏜 83 nmol/l, indicating that
delta cortisol concentrations as sole variable to assess the se-
cretory capacity of the adrenal cortices should be viewed with
caution.101
112 Adrenals
A B
Figure 4.27:
A nine-year-old female dachshund with hypercortisolism.
(A) The coat on the enlarged abdomen is thin and the atrophic skin readily bunches up into thin folds.
(B) The skin around two nipples showing keratin accumulation in atrophic hair follicles.
Clinical manifestations The abdominal fat accumulation has been related to over-
Many of the symptoms and signs can be related to the actions expression of 11b-HSD1 (chapter 4.1.5) in visceral fat, but
of glucocorticoids presented in chapter 4.1.5 and fig. 4.14, in Cushing’s syndrome due to adrenocortical tumor the
namely, increased gluconeogenesis and lipogenesis at the ex- expression of this enzyme is not increased in omental adipose
pense of protein. In dogs the cardinal physical features are tissue, as it is in human obesity.108 It is also questionable
central obesity and atrophy of muscles and skin (table 4.3, whether this concept holds true for the dog, in which most,
figs. 4.25–4.28). Polyuria and polyphagia are also frequently if not all, splanchnic cortisol production occurs in the
dominating features. liver.109 An alternative explanation for the abdominal fat
accumulation might be in the autonomic nervous system,
Glucocorticoid excess 113
A B
C D
Figure 4.28:
Various manifestations of calcinosis cutis in dogs with hypercortisolism.
(A) Calcium deposits in the skin on the dorsal midline above the shoulder of an eight-year-old female boxer. Palpation revealed irregular firm plaques extending caudally
to the lumbar area.
(B) Close-up above the shoulder of the dog in fig. 4.26.
(C) Erythema and calcinosis cutis in the lumbosacral area of a nine-year-old male mongrel dog.
(D) Gray plaques of calcinosis cutis in areas of skin easily traumatized and bleeding in an eleven-year-old male boxer. Calcinosis cutis occurs not only on the dorsal midline
but also on the ventral abdomen and inguinal areas.
which is known to modulate lipolysis, lipogenesis, and fat ceral fat tissue and, together with the abnormal hepatic
cell number in a compartment-specific manner.110 This meta- AMPK activity, contributes to the development of fatty liver,
bolic puzzle may have been largely resolved by recent obser- dyslipidemia, and insulin resistance. In the hypothalamus glu-
vations in rodents and humans that glucocorticoid excess cocorticoids increase the AMPK activity, which leads to in-
changes the activity of AMP-activated protein kinase creased hunger.111,112
(AMPK), a sensor of cellular energy status and regulator of
enzymes in lipid metabolism, in a tissue-specific manner. Glucocorticoid excess leads to muscle atrophy, primarily by
Glucocorticoid excess causes inhibition of adipose tissue inhibiting protein synthesis, to which the suppression of
AMPK, which may explain the accumulation of lipids in vis- growth hormone secretion must contribute (see also
114 Adrenals
fig. 4.29).113,114 The decreased exercise tolerance and inability The situation in cats is somewhat different from that in dogs.
to climb stairs and to jump into a car, well-known symptoms The cutaneous manifestations may initially give the impres-
of hypercortisolism in dogs, are also due to a generalized de- sion of being less pronounced than in dogs (fig. 4.30). How-
crease in skeletal muscle Na+K+-ATPase.115 The effects of ever, in some cases the skin is very fragile and tears during
glucocorticoid excess on the skin, hair follicles, and connect- routine handling, leaving the cat with a full thickness skin de-
ive tissue include reduced proliferation of keratinocytes and fect.120 Furthermore, glucocorticoid excess results in poly-
fibroblasts, disturbed metabolism of extracellular matrix pro- uria /polydipsia much less readily than in dogs and may only
teins, and disturbed synthesis of skin lipids.116 Depending on become obvious when diabetes mellitus develops. Cats are
the duration of glucocorticoid excess, the changes in dogs more susceptible than dogs to the diabetogenic effects of glu-
range from cessation of shedding, lack of regrowth of clipped cocorticoids and diabetes mellitus has been present in most of
hair, and some thinning of the coat to alopecia and a thin and the reported cases of hypercortisolism in cats. Suspicion of
easily-wrinkled skin (fig. 4.27). Probably related to the glu- hypercortisolism has often arisen specifically because of insu-
cocorticoid-induced alterations in bone metabolism lin resistance encountered in the treatment of diabetes melli-
(chapter 9.7), calcium can be deposited in the dermis, causing tus.121 Only about 10 % of dogs with hypercortisolism de-
skin lesions (fig. 4.28). Skin atrophy and immune suppression velop overt diabetes mellitus.
increase susceptibility to skin lesions and skin infections such
as mycobacterial panniculitis and demodicosis.117,118 It is no The disease usually begins insidiously and progresses slowly
exaggeration to say that an adult animal with demodicosis until the combination of symptoms and signs can be recog-
should be suspected of hypercortisolism or hypothyroidism nized as the syndrome of glucocorticoid excess. However,
(see also chapter 3.3.1). especially in the beginning, there may be only one or two
symptoms (fig. 4.31). Very rarely dogs with glucocorticoid
In dogs the polyuria of glucocorticoid excess is known to be excess are presented as an emergency in respiratory distress.
due to both impaired osmoregulation of vasopressin release This might be due to the combination of intolerance to a hot
and interference with the action of vasopressin (chapter 2.3.2, environment and impaired ventilatory mechanics because of
fig. 2.31). Urinary tract infections, detected by positive urine the physical changes (muscle wasting and enlarged abdomen).
cultures, are common in dogs with hypercortisolism. How- However, in such a patient it is also possible that the hyper-
ever, symptoms are rare and the urinalysis may be normal.119 cortisolism is complicated by pulmonary embolism. This state
of hypercoagulability is in part due to elevation of procoagu-
Glucocorticoid excess 115
lant factors and a decrease in the naturally occurring antico- Diagnostic imaging may help to complete the picture of the
agulant factor antithrombin.123 Glucocorticoid excess has also physical changes that can be associated with glucocorticoid
been reported as a factor predisposing for the rarely occurring excess. On a lateral radiograph of the abdomen, which is
aortic / iliac thrombosis in dogs.124,125 often distended, there is usually good contrast due to the ab-
dominal fat. In addition, hepatomegaly and a distended
Endogenous and exogenous glucocorticoid excess increases bladder may be seen, but abdominal radiography is of little use
blood pressure and the highest values are found in dogs with in the diagnostic work-up of dogs suspected of hypercortisol-
severe hypercortisolism.126,127 This hypertension is mediated ism.131 Thoracic radiographic abnormalities may include
by a variety of mechanisms involving the kidneys and vascu- bronchial and interstitial mineralization, particularly in dogs
lature, and including substrate saturation of 11b-HSD2. In se- with hypoxemia.132 Dystrophic calcifications in the skin and
vere hypercortisolism all available cortisol cannot be inacti- subcutis may also be visualized in the areas of predilection for
vated to cortisone and thus spills over onto the MR, to cause calcinosis cutis. In summary, radiography can help to paint the
mineralocorticoid hypertension (see also chapter 4.4).128 This picture, but is often superfluous. Ultrasonography, computed
may be particularly important when renal function is im- tomography (CT), and magnetic resonance imaging (MRI)
paired, for in humans with renal disease 11b-HSD2 ex- are the imaging techniques now most frequently used,
pression is decreased.129 In principle hypertension is a risk especially in the search for the location and characterization
factor for congestive heart failure, but this complication is rare of the source of the hormone excess.
in dogs with hypercortisolism.
Differential diagnosis
Among the routine laboratory data (table 4.3) a consistent For the differential diagnoses concerning the two main clini-
finding is elevation of plasma alkaline phosphatase (AP).130 In cal features, i.e., polyuria and alopecia, the reader is referred
dogs this is mainly due to the induction of an isoenzyme hav- to chapter 14, where algorithms for these problems are pres-
ing greater stability at 65 °C than other AP-isoenzymes and ented. Anticonvulsant therapy with phenobarbital may cause
therefore easily measured by a routine laboratory procedure. symptoms mimicking those of mild hypercortisolism, namely,
In most dogs with hypercortisolism plasma T4 is decreased as a polyphagia, polyuria, and a slight gain in weight. In contrast
consequence of altered transport, distribution, and meta- to tests of thyroid function (chapter 3.1.2), tests of adrenocor-
bolism of T4, rather than due to hyposecretion (chapter 3.1.2). tical function in dogs have not been reported to be affected by
this treatment.133,134 In humans phenobarbital induces liver
116 Adrenals
4.3.1. Pituitary-dependent
P-450 cytochrome enzymes, leading to increased steroid hypercortisolism
clearance and falsely positive dexamethasone suppression tests
in patients with Cushing’s syndrome.135 In both dogs and cats pituitary-dependent hypercortisolism is
a disease of middle-aged and older animals, although it can
Diagnosis occur in dogs as young as one year. In dogs there is no pro-
The biochemical diagnosis of hypercortisolism depends on nounced sex predilection, but in cats most reported cases have
the demonstration of two principal characteristics of all forms been in females.141 It occurs in all dog breeds with possibly a
of the condition: (1) increased production of cortisol, and (2) slight predilection for small breeds such as dachshunds and
decreased sensitivity to glucocorticoid feedback.136 Measure- miniature poodles. The incidence is much higher in dogs
ment of the urinary corticoid:creatinine ratio (UCCR) pro- than in humans and has been reported to be one to two cases
vides an integrated assessment of the secretion of cortisol over per 1000 dogs per year.142 In cats the disease is rare.
a period of time and adjusts for fluctuations in plasma levels
caused by the pulsatile release of cortisol (fig. 4.6). For the The physical changes and the routine laboratory findings are
routine test the owner collects a morning urine sample on those of glucocorticoid excess, as described in the previous
two consecutive days and the UCCRs in these two samples section. Clinical manifestations that it is of pituitary origin are
are averaged (chapter 12.4.4). In dogs the predictive value of a only observed when a pituitary tumor becomes large enough
positive test result is 0.88 and that of a negative test result is to cause neurological symptoms. These are often vague,143
0.98.137 In some dogs there is considerable day-to-day vari- consisting of lethargy, inappetence, and mental dullness (see
ation in the UCCR, which in mild forms of hypercortisolism also chapter 2.2.6.2).
occasionally leads to UCCRs just within the reference range,
whereas collections on other days might have revealed one or The pituitary lesions producing excess ACTH range from
two elevated UCCRs. The uncertainty can be resolved by small nests of hyperplastic corticotroph (or melanotroph) cells
measuring the UCCR in urine samples collected on ten con- (fig. 2.6) to adenomas (fig. 4.33) and large tumors (figs. 2.20,
secutive days (fig. 4.32).138 4.34).144 As discussed in chapter 2.2.6, some pituitary adeno-
mas infiltrate surrounding tissues such as the cavernous sinus,
The sensitivity of the pituitary-adrenocortical system to sup- dura mater, brain, and rarely the sphenoid bone. These are
pression is tested by administering a synthetic glucocorticoid called »invasive adenomas«, whereas only the exceptional
in a dose that discriminates between healthy animals and ani- tumors with extracranial metastasis are considered to be car-
mals with hypercortisolism. A potent glucocorticoid such as cinomas.145,146 Corticotroph adenomas may coexist with
dexamethasone is used so that the dose will be too small to somatotroph adenomas (chapter 2.2.4.1). The combined
contribute significantly to the laboratory measurement. In occurrence of pituitary-dependent hypercortisolism and cor-
Glucocorticoid excess 117
tisol-producing adrenocortical tumor has also been re- both the AL and the PI. In about one-fourth to one-fifth of
ported, as has the combination with pheochromocytoma cases there is an adenoma in the PI, but tumors may also occur
(fig. 4.67).147,148 Pituitary-dependent hypercortisolism may in both lobes.158,159 This is of clinical interest not only because
also be a component of a syndrome of multiple endocrine the PI tumors tend to be larger than the AL tumors,144 but
neoplasia.149,150 also because of the specific hypothalamic control of hormone
synthesis in the PI. As mentioned briefly in chapter 2.1, the
As with several other tumors, the development of pituitary PI is under direct neural control, principally tonic dopami-
tumors from corticotroph or melanotroph cells is regarded a nergic inhibition,160 which suppresses the expression of glu-
multistep process requiring more than one mutation in the cocorticoid receptors. This explains why pituitary-dependent
proto-oncogenes involved in hormone production and /or hypercortisolism of PI origin is resistant to suppression by
cell proliferation and possibly also in tumor suppressor genes. dexamethasone.161
An inherited aberration may be the earliest step.151,152 Ex-
pression and mutation analysis has been performed in dogs However, this is not an absolute difference from AL lesions, as
with pituitary-dependent hypercortisolism for factors in- pituitary lesions causing hypercortisolism do not maintain the
volved in pituitary organogenesis and corticotroph differenti- regulation characteristics of the lobe of origin.162 Cortico-
ation, such as Tpit (see fig. 2.5), and for ras proto-onco- troph adenomas in the AL become less sensitive than normal
genes.153,154 In addition, the possible role of hypothalamic corticotroph cells to the suppressive effect of glucocorticoids.
hormones and intrapituitary growth factors has been investi- As mentioned in chapters 4.3 and 12.4 this is the functional
gated.155,156 These studies have not provided conclusive in- hallmark of pituitary-dependent hypercortisolism that is used
sight into the molecular pathogenesis of the formation of cor- to differentiate normal animals from those with hypercorti-
ticotroph adenomas in dogs. There is now evidence that the solism in the low-dose dexamethasone suppression test
hallmark of pituitary-dependent hypercortisolism – resistance (LDDST). This loss of suppressibility can be thought of as
to glucocorticoid feedback regulation of the POMC gene by being on a sliding scale in both dogs and cats, resistance to
the GR – is caused by loss of nuclear proteins involved in glucocorticoid feedback ranging from scarcely demonstrable,
transcriptional repression. These deficiencies may also con- in the LDDST, to complete resistance even to high doses of
tribute to tumorigenesis.157 dexamethasone, in the high-dose dexamethasone suppression
test (HDDST, chapter 12.4).163,164
In chapter 4.1 it was explained that in dogs and cats both the
pituitary anterior lobe (AL) and pars intermedia (PI) have Resistance to glucocorticoid feedback is significantly corre-
cells that can synthesize POMC, albeit with different post- lated with the size of the pituitary (fig. 4.35).165 Not only
translational processing. Thus ACTH excess may originate in do large tumors tend to be more resistant to the suppressive
118 Adrenals
effect of dexamethasone, they also release ACTH precursors differentiation between different forms is combined in one
(POMC, pro-ACTH; fig. 4.35) more often than do small test using UCCRs and oral dexamethasone administration
corticotroph adenomas.166,167 Dogs with high plasma levels of (fig. 4.36).
the PI-peptide a-MSH have higher plasma levels of the pre-
cursors than do those in which plasma a-MSH is not ele- When there is 쏝 50 % suppression, the hypercortisolism may
vated.166 The release of incompletely processed or unprocessed still be pituitary dependent, due to a pituitary ACTH excess
POMC by dedifferentiated corticotroph macroadenomas may that is extremely resistant to dexamethasone suppression.
result in high plasma levels of POMC peptides without excess Further differentiation requires measurements of plasma
ACTH and consequently without hypercortisolism.168 A cat ACTH. In animals with hypersecreting adrenocortical tu-
with a melanotroph PI adenoma and extremely high plasma mors, basal ACTH concentration is usually suppressed. If in-
concentrations of a-MSH was found to have no evidence of terpretation of ACTH values is uncertain, as may occur with
ACTH-dependent hypercortisolism.146 the simultaneous occurrence of both entities, further studies
are required: a CRH-stimulation test (chapter 12.1.1) and
Diagnosis visualization of the adrenals and the pituitary. It may also be
When hypercortisolism has been confirmed it is necessary to helpful to measure plasma a-MSH; high values occur
distinguish between pituitary-dependent hypercortisolism especially with PI tumors, which are often dexamethasone
and other forms. Despite decreased sensitivity to suppression resistant and rather large (chapter 4.3 and fig. 4.37).
by glucocorticoids, ACTH secretion in most animals with
pituitary-dependent hypercortisolism due to a corticotroph As mentioned in chapter 2.2.3, dogs with skin atrophy in
adenoma in the AL can be suppressed by a ten-fold higher breeds such as the miniature poodle and Pomeranian have
dose of dexamethasone, resulting in decreased secretion of been found to satisfy two criteria of hypercortisolism: in-
cortisol. In the other forms of glucocorticoid excess the hy- creased cortisol production and decreased sensitivity to glu-
persecretion of cortisol is not dependent on pituitary ACTH cocorticoid feedback.138 The routine tests for hypercortisol-
and is therefore not influenced by the high dose of dexame- ism (chapters 12.4.2, 12.4.4) are often negative, but serial
thasone (see also fig. 1.9). Two procedures are used, one em- measurements of the UCCR for ten days may demonstrate
ploying plasma cortisol and the other employing the UCCR the presence of mild and fluctuating hypercortisolism
(chapters 12.4.3, 12.4.4). In both, a decrease of 쏜 50 % from (figs. 4.32, 4.38). Following treatment for hypercortisolism
baseline values confirms pituitary-dependent hypercortisol- the hair coat returns (fig. 4.39).169
ism. Often the test for diagnosing cortisol excess and for the
Glucocorticoid excess 119
4
Figure 4.38:
Two dexamethasone suppression tests using UCCRs, in a seven-year-old male
miniature poodle with longstanding and gradually progressing alopecia; they
were interpreted as indicating suppressible normocorticism. However, when the
UCCR was measured daily for ten days, it was found to fluctuate between normal
and elevated values (see also fig. 4.32 and legend to fig. 4.36).
Figure 4.37:
Results of an iv-HDDST test (chapter 12.4.3) in a ten-year-old female standard
schnauzer. Dexamethasone-resistant hypercortisolism was indicated by UCCR
values (basal 39 and 66 × 10–6 and after dexamethasone 31 × 10–6). Plasma con-
centrations of cortisol and ACTH did not decrease in the iv-HDDST, which together
with elevated plasma a-MSH levels, was compatible with a pituitary tumor orig-
inating in the PI. Diagnostic imaging revealed both a pituitary tumor and bilateral
adrenal tumors.149
A B
Figure 4.39:
A seven-year-old male miniature poodle with mild pituitary-dependent hypercortisolism (fig. 4.38), only manifested by gradually progressing alopecia, before (A) and
seven months after destruction of the adrenal cortices with o,p'-DDD (B).
120 Adrenals
Figure 4.40:
Transverse dynamic CT image through the pituitary
fossa at the moment of maximal contrast enhance-
ment of the arterial cerebral circle in a 6-year-old York-
shire terrier (A) and a 7-year-old Maltese dog (B) with
4 pituitary-dependent hypercortisolism. (A) The pituitary
is not enlarged and the pituitary flush (arrow) is dis-
placed dorsally and to the right indicating an adenoma
ventrally and to the left. (B) The pituitary gland is not
enlarged.
A B
Figure 4.42:
Transverse CT images of the head of a nine-year-old female Bouvier-cross with pituitary-dependent hypercortisolism, before (A) and three months after hypophysectomy
(B). Prior to surgery contrast enhancement revealed a pituitary tumor 7.3 mm high and 8.3 mm wide, but no pituitary tissue could be visualized after surgery. In this dog
the hypercortisolism was characterized as dexamethasone-resistant because the UCCR after dexamethasone suppression (23 × 10–6) was 쏜 50 % of the average of the
two basal UCCRs (33 × 10–6). The high basal plasma ACTH (238 and 240 ng/l) and a-MSH (185 and 235 ng/l) concentrations suggested that the tumor originated from
melanotroph cells of the pars intermedia. After surgery the UCCR on two consecutive days was 쏝 0.5 and 1.1 × 10–6. The dog lived for five more years and died from an
unrelated condition at the age of 14 years.
A B
Figure 4.43:
(A) Six-year-old castrated male affenpinscher with signs of glucocorticoid excess (polyphagia, alopecia, weight gain, and lethargy)
and elevated UCCRs (25 and 13 × 10–6; ref. range: 0.3–8.3 × 10–6) and basal plasma ACTH (56 and 50 pmol/l; ref. range:
0.4–21 pmol/l). CT revealed an enlarged pituitary and dynamic CT revealed a pituitary adenoma (see fig. 4.40). Four months after
hypophysectomy (B) there was good regrowth of the hair coat and UCCRs were 0.5 and 0.4 × 10–6.
122 Adrenals
A B
Figure 4.44:
An eight-year-old male miniature poodle with pituitary-dependent hypercortisolism and diabetes mellitus before (A) and six months after (B) destruction of the adrenal
cortices with o,p'-DDD. In addition to the recovery from hypercortisolism, the insulin demand decreased considerably and remained stable and low.
A B
Fig. 4.45:
A nine-year-old castrated male dachshund with pituitary-dependent hypercortisolism (basal UCCRs 42 and 48 × 10–6; after three oral doses of 0.1 mg dexametha-
sone/kg: 6 × 10–6). The dog’s ravenous appetite was of greatest concern to the owner, illustrated by the empty can which the dog had tried to eat (A). Following
destruction of the adrenal cortices with o,p'-DDD and replacement therapy the dog and owner resumed a normal life (B, photograph seven months after initiation of
treatment).
Glucocorticoid excess 123
that neuropharmacological approaches with an antiserotoni- cases in which selective destruction is the aim, there are one
nergic drug and a monoamine-oxidase inhibitor were unsuc- or more relapses of hypercortisolism during treatment.190 In
cessful.179–181 The medical treatment of pituitary-dependent order to circumvent these complications a treatment schedule
hypercortisolism of PI origin, characterized by high plasma has been devised with the aim of complete destruction of
a-MSH concentrations, was aimed at increasing dopaminer- the adrenal cortices and substitution for the induced hypo-
gic inhibitory tone with the dopamine-agonist bromocrip- adrenocorticism (figs. 4.44, 4.45).191,192 This nonselective
tine. Although a short-term effect was observed, the drug did destruction has been reported to be associated with fewer re-
not prove to be efficacious in lowering UCCRs.182 currences than with selective destruction.193 Since the intro-
duction of trilostane for the medical management of pitu-
In the interests of new medical therapies the expression of so- itary-dependent hypercortisolism, o,p'-DDD is seldom used 4
matostatin receptor subtypes (mainly subtype sst2) and dopa- for this purpose. Its main use now is for the treatment of ad-
mine receptor subtypes (subtype D2 modestly expressed) has renocortical tumors (chapter 4.3.2).
been identified on canine corticotroph adenomas.183 The
D2-agonist cabergoline has been reported to decrease plasma Trilostane is a competitive inhibitor of the 3b-hydroxysteroid
ACTH and a-MSH concentrations and UCCRs in slightly dehydrogenase / isomerase system which is essential for the
less than half of dogs with pituitary-dependent hypercortisol- synthesis of cortisol, aldosterone, progesterone, and andros-
ism.184 Investigators in the same clinic also tested retinoic tenedione (fig. 4.3). Trilostane also inhibits other enzymes
acid, a ligand for the nuclear receptor peroxisome prolifer- involved in steroid biosynthesis, such as 11b-hydroxylase and
ator-activated receptor-g (PPAR-g), that arrests pituitary possibly 11b-hydroxysteroid dehydrogenase.194,195
tumor growth in a nude mouse model. They observed im-
provement in both the physical changes and the endocrine In dogs with pituitary-dependent hypercortisolism (PDH),
variables in all dogs treated.185 In both studies it is difficult to trilostane has the potential of significantly reducing basal and
evaluate the reported recovery, for the UCCRs were lowered ACTH-stimulated plasma cortisol concentrations.196–201 The
but remained around the relatively high upper limit of their resulting loss of negative feedback, leads to increased plasma
reference range and the reduction in size of the pituitary ACTH levels.197,202,203 Very high plasma ACTH may indicate
tumor was not completely convincing. trilostane overdosage.203
As discussed in chapter 2.2.6.2, the main indication for radio- Trilostane treatment also causes a slight decrease in plasma
therapy is to reduce the size of a pituitary tumor that is com- aldosterone concentration and although it usually remains
pressing the brain. Since it usually does not reduce sufficiently within the reference range,197,199 the decrease leads to hypo-
the hypersecretion of ACTH, additional therapy at the ad- volemia and activation of the RAS (chapter 4.1.4, fig. 4.9),
renal level (see below) is required. often with significant increases in plasma renin activity.203
Treatment at the adrenal level Trilostane is absorbed rapidly from the gastrointestinal tract.
This consists of eliminating the glucocorticoid excess by bi- Administration with food significantly increases the rate and
lateral adrenalectomy or by medical therapy. Total adrenalec- extent of absorption. There is marked variation in the optimal
tomy achieves a complete cure of the hypercortisolism and dose and to avoid adverse effects due to overdosage, treatment
the prognosis with glucocorticoid and mineralocorticoid re- is started at a relatively low oral dose of 2 mg/kg once daily.
placement (chapter 4.2.1) is good unless or until expansion The dose is then adjusted according to the clinical response
of the pituitary tumor causes neurological problems (chap- and the results of ACTH-stimulation tests (chapter 13.2.2).
ter 2.2.6.2). The perioperative and postoperative medication The efficacy of treatment is also monitored by clinical signs
is described in chapter 4.3.2. In the absence of alternatives, and measurements of plasma sodium, potassium, urea, creati-
bilateral adrenalectomy has also been used in cats, but with nine, liver enzymes, and ACTH.203
complications such as sepsis, thromboembolism, and poor
wound healing.186,187 Presurgical treatment with metyrapone, It has been reported that the UCCR cannot be used as an al-
an inhibitor of steroid synthesis (see below), together with ternative to the ACTH-stimulation test to determine the op-
perioperative administration of antimicrobials and heparin timal dose of trilostane.198,204 In more than half of the dogs
can aid in preventing these complications.188,189 with pituitary-dependent hypercortisolism in a recent study
the UCCR did not decline below the upper limit of the ref-
For many years the most common form of treatment of pitu- erence range within two months after the dose of trilostane
itary-dependent hypercortisolism in dogs has been use of the was considered to be satisfactory. However, in those that de-
adrenocorticolytic drug o,p'-DDD. Some treatment sched- veloped hypocortisolism, based on clinical manifestations and
ules aim at selective destruction of the zona fasciculata and an ACTH-stimulation test, the UCCR was below the upper
zona reticularis, sparing the zona glomerulosa. However, in limit of the reference range several weeks before hypocorti-
5–6 % of the dogs in which this is attempted, the zona glome- solism was diagnosed. Consequently, in long-term follow-up
rulosa is also destroyed to such an extent that iatrogenic hy- the UCCR may serve as an early indicator of hypocortisol-
poadrenocorticism develops. Also, in more than half of the ism.204
124 Adrenals
A B
Figure 4.46:
(A) An eight-year-old male dachshund with polyphagia, polydipsia, polyuria, and alopecia. The basal UCCRs were 47 and 44 × 10–6 and the UCCR was reduced to 13 ×
10–6 after high oral doses of dexamethasone. CT revealed mild contrast enhancement in a normal-size pituitary. Both adrenals were slightly enlarged.
(B) Treatment with trilostane 30 mg once daily resulted in complete recovery.
Within about a week on an appropriate dose of trilostane there Overdosage of trilostane results in cortisol deficiency and
is a clear reduction in water intake, urine output, and appetite, sometimes even mineralocorticoid deficiency.201,203,212,213 In
followed by improvement in the coat and skin, reduction of addition, necrosis, apoptosis, and hemorrhage in the zona
central obesity, and increased physical activity (fig. 4.46). Tri- fasciculata and zona reticularis may cause life-threatening hy-
lostane’s inhibiting effect on aldosterone secretion may cause pocortisolism.211 If hypoadrenocorticism occurs trilostane
plasma potassium to increase slightly.196,197,199,201 Its short dur- must be stopped immediately and corticosteroid substitution
ation of action may be responsible for the lack of improvement started (chapter 13.2.1). In most cases adrenocortical function
in some hyperadrenocorticoid dogs.200,205 This may be re- recovers sufficiently within a few weeks and substitution can
medied by twice daily administration, beginning at 1 mg/kg be stopped, but some dogs require long-term substitution
per dose. therapy.201,203
Trilostane can be used in cases of hypercortisolism due to The median survival time for treatment with trilostane once
functional adrenocortical tumors if neither adrenalectomy daily (662 days) is similar to that for selective adrenocorti-
nor destruction of adrenocortical tissue with o,p'-DDD colysis with o,p'-DDD (708 days).214 The median survival
(chapter 4.3.2) is an option.206 It can also be used as palliative time for treatment with trilostane twice daily (900 days) is
treatment in cases of metastasis of a functional adrenocortical also comparable to that for nonselective adrenocorticolysis
tumor.207 It holds promise for cats with pituitary-dependent with o,p'-DDD (720 days).193 In both studies, body weight
hypercortisolism,208,209 but there is as yet little actual experi- and age at diagnosis were negatively correlated with survival.
ence with its use in cats and more studies are needed before
this can be generally recommended.209 Another therapeutic option could be the inhibition of adre-
nocortical steroidogenesis by ketoconazole, a synthetic imida-
Treatment of pituitary-dependent hypercortisolism with tri- zole analogue used as a broad-spectrum antifungal agent re-
lostane may produce distinct changes in the ultrasonographic sulting from its binding to yeast and fungal cytochrome
appearance of the adrenal glands. In most trilostane-treated P-450. At high concentrations, ketoconazole also affects cer-
dogs there is a clear increase in the thickness of the adrenal tain cytochrome P-450 enzymes in microsomal and mito-
glands, due to the continuing stimulation by ACTH. Long- chondrial fractions of mammalian cells.215 It has been used in
term trilostane treatment may result in adrenal glands with an dogs in the treatment of both pituitary-dependent hypercor-
irregular shape and a nodular appearance.197,210,211 tisolism and hypercortisolism due to adrenocortical tumor.
The initial dose is 5 mg/kg twice daily for seven days and
Glucocorticoid excess 125
Figure 4.48:
Large adrenocortical tumor removed at autopsy from a nine-year-old male boxer
with hypercortisolism. Tumor tissue protrudes into the longitudinally opened vena
cava.
Figure 4.47:
Cut surface of a small adrenocortical tumor in the
cranial pole of the left adrenal. The tumor was surgi-
cally removed from a ten-year-old female miniature
schnauzer with hypercortisolism. The atrophic ad-
renal cortex is visible as a small rim surrounding the
medulla at the caudal pole.
then 10 mg/kg twice daily. Some dogs require 15 mg/kg 4.3.2. Hypercortisolism due to
twice daily to control hypercortisolism, but this may have ad-
verse effects such as anorexia, vomiting, diarrhea, and icterus.
adrenocortical tumor
These may be resolved by administering ketoconazole with Histologically adrenocortical tumors can be divided into
food and temporarily reducing the dose.216 The major limi- adenomas (fig. 4.47) and carcinomas (fig. 4.48), a distinction
tations in using ketoconazole in dogs are adverse effects and that is by no means always straightforward.219 Microscopic
failure of some dogs to respond.217 In some countries keto- examination of a seemingly benign tumor may reveal its ex-
conazole is the only legally available drug for veterinary use. pansion into blood vessels.147 Whether adrenocortical carci-
noma develops from adrenocortical adenoma or occurs as a
Aminoglutethimide, another inhibitor of steroidogenesis, has separate entity has yet to be determined, but there are indi-
been used in dogs with pituitary-dependent hypercortisolism, cations that in humans adrenal tumorigenesis is a multistep
but low efficacy and adverse effects limit its use.218 Metyra- process progressing from normal to adenomatous cells and ul-
pone reduces cortisol synthesis by blocking the conversion of timately to malignant cells.220 Increased mRNA expression of
11-deoxycortisol to cortisol (fig. 4.3). As mentioned above, it IGF-II is one of the dominant transcriptional changes in
has been used for controlling the harmful effects of hypercor- human adrenocortical carcinoma.221 Data on the expression
tisolemia prior to bilateral adrenalectomy.120 of genes involved in adrenal tumorigenesis in dogs and cats are
still lacking.
Prognosis
With the above methods for either destruction of the adrenal Adrenocortical tumors can be either endocrinologically silent
cortices or inhibition of steroidogenesis, hypercortisolism can or hormonally active. Silent tumors may be found during
be satisfactory controlled. Most animals can continue satisfac- diagnostic imaging of the abdomen for other purposes. An
torily for several years (figs 4.44–4.46), provided that the pi- adrenal tumor discovered incidentally during diagnostic
tuitary lesion does not expand to cause neurological signs. imaging for reasons unrelated to adrenal pathology is referred
Because of this possibility hypophysectomy is preferred where to as an incidentaloma.222 Adrenocortical tumors causing
possible. hypercortisolism occur in both dogs and cats in middle and
old age with no definite sex predilection.147,223 Most adreno-
cortical tumors are unilateral solitary lesions, the two glands
being affected about equally, but bilateral tumors occur in
about 10 % of cases.147,224,225 The clinical findings are those of
126 Adrenals
Diagnosis
Some dogs with adrenocortical tumor have only moderate
cortisol excess and thus moderate symptoms and signs. In
these cases the UCCR is often around the upper limit of the
reference range, but suspicion is aroused by the finding that it
4 is not suppressed by dexamethasone. Although adrenocortical
tumors usually greatly exceed the size of the normal gland,
the tumor tissue is often only moderately active, i.e., the neo-
plastic transformation results in lower function per unit of
volume (fig. 4.49).
glucocorticoid excess (chapter 4.3). There may also be mass- The preferred procedures for visualization of the adrenals are
related symptoms and signs caused by metastases or non- magnetic resonance imaging (MRI) and computed tomo-
specific features of malignancy such as weight loss and ano- graphy (CT) (fig. 4.50).240 Ultrasonography is less expensive,
rexia. A palpable abdominal mass, vascular obstruction by requires less time, and does not require anesthesia, and so it is
tumor thrombi of the caudal vena cava (fig. 4.48),226 or often used first even though it is more difficult to perform and
hemo(retro)peritoneum secondary to rupture of an adrenal to interpret than CT or MRI. It provides a good estimate of
tumor are rare consequences of adrenocortical tumor.227–229 the size of the tumor and may reveal information about its ex-
pansion (fig. 4.51).224,241 It is sometimes difficult to distin-
In addition to cortisol, adrenocortical tumors may also pro- guish between macronodular hyperplasia and adrenocortical
duce other adrenocortical hormones in excess. Hypersecre- tumor by ultrasonography and so CT or MRI may also be
tion of adrenal sex hormones by cortisol-secreting adrenocor- needed. Whatever is used, the findings should be interpreted
tical tumors has been reported to be quite common.230,231 in conjunction with those of biochemical studies,242 i.e., basal
Androgen hypersecretion may reflect dedifferentiation of ad- plasma ACTH and if necessary a CRH-stimulation test
renocortical tumors, with steroidogenesis proceeding to its (chapter 12.1.1).
final product, cortisol, in hyperplastic and well-differentiated
benign adrenocortical tissue but dedifferentiated adrenocorti- When the presence of an adrenocortical tumor has been con-
cal tumors being unable to carry steroidogenesis efficiently to firmed, the possibility of distant metastases should be con-
term.232 Mixed cortisol- and aldosterone-producing adreno- sidered. During abdominal ultrasonography for identification
cortical tumors have also been reported in dogs.233–236 of the adrenals the liver should also be examined for meta-
Glucocorticoid excess 127
stases. If possible metastases are found, ultrasound-guided will consist of 1 mg cortisone acetate/kg body weight twice
biopsy can be performed. Thoracic radiographs or a CT scan daily, gradually reduced and then stopped six to eight weeks
of the thorax should be made to exclude metastases in the after surgery.147 After bilateral adrenalectomy lifelong substi-
lungs. tution with a glucocorticoid and a mineralocorticoid is
required, according to the treatment protocol for primary
Treatment hypoadrenocorticism (chapter 4.2.1).
Treatment has two objectives: removal of the adrenocortical
tumor and containment of hypercortisolism. When diag- Hypercortisolism due to adrenocortical tumor can also be
nostic imaging has revealed no metastases and it is likely that treated medically. Drugs for this purpose are classified as ad-
there is a resectable unilateral tumor, it should be removed by renocorticolytic or adrenocorticostatic. Adrenocorticolytic
surgery. Successful removal of the affected adrenal will result drugs destroy adrenocortical cells and thereby reduce steroid
in complete recovery without the need for lifelong medi- synthesis, whereas adrenocorticostatic drugs interfere with
cation. Adrenalectomy can be performed via a ventral midline steroidogenesis without cell damage.
celiotomy, with a paracostal extension of the incision when
needed, or via a paracostal approach.147,243–246 In humans ad- Administration of the adrenocorticolytic drug o,p'-DDD is
renalectomy is now often performed by laparoscopy, with often the treatment of choice in dogs in which tumor tissue
lower perioperative morbidity and mortality than by open cannot be completely removed surgically or when the disease
transabdominal surgery.247 Laparoscopic adrenalectomy may recurs after adrenalectomy. It is also used in cases of metastas-
also become the surgical procedure of choice in veterinary ized adrenocortical tumor. Because of the potential of toxic
medicine,248 but most surgeons still prefer transabdominal ac- effects of o,p'-DDD in both humans and animals, owners
cess because it provides maximal exposure of the tumor and must be given careful instructions on how to recognize and
vessels, and in particular of tumor thrombi in the caudal vena respond to them. o,p'-DDD should preferably not be used in
cava, thereby minimizing the chance of tumor spillage. a household in which there is a pregnant woman or young
child. Although the hypercortisolism per se due to adreno-
Because of the atrophy of the nontumorous adrenocortical cortical tumor may be treated successfully by selective
tissue due to the longstanding glucocorticoid excess, gluco- destruction (chapter 4.3.1),249 the aim of o,p'-DDD treat-
corticoid substitution is needed initially. At the time of anes- ment should be complete destruction of all adrenocortical
thesia, when intravenous fluid administration is started, 5 mg cells and substitution therapy for the induced adrenocortical
hydrocortisone/kg body weight is added to the first bottle for insufficiency. The treatment protocol for complete adreno-
administration over a period of 6 h. Subsequently 0.5 mg hy- cortical destruction consists of 25 days of oral administration
drocortisone/kg is administered subcutaneously at 6 h inter- of 50–75 mg o,p'-DDD/kg body weight per day.191 In dogs of
vals until oral medication is possible (chapter 13.2.1). This low body weight o,p'-DDD doses up to 100 mg/kg per day
128 Adrenals
may be required for complete destruction. o,p'-DDD is given least once weekly and whenever questions or problems arise.
daily for the first five days, thereafter on alternate days. The The owner is also instructed very clearly to stop giving
daily dose is divided into three or four portions and adminis- o,p'-DDD if partial or complete inappetence develops, but,
tered with food (fig. 4.52). On the third day, substitution with equal emphasis, to continue adrenocortical hormone
therapy is begun with cortisone acetate (2 mg/kg per day), substitution and to contact the veterinarian, who may in-
fludrocortisone acetate (0.0125 mg/kg per day), and sodium crease the cortisone substitution temporarily. If a loss of ap-
chloride (0.1 g/kg per day), all divided into at least two por- petite is ignored and o,p'-DDD is continued, the dog may
tions. If for any reason the dog cannot take or retain the tab- begin to vomit, refuse substitution therapy, and develop a hy-
lets and salt two times in succession, injectable medications poadrenocorticoid crisis. However, with good instructions
should be started (chapter 13.2.1). A written instruction for this is rare and usually the o,p'-DDD administration can be
owners is presented at the end of chapter 13. resumed after a few days without further problems.
After 25 days of o,p'-DDD administration, a follow-up exam- Despite this treatment with o,p'-DDD, there are recurrences,
ination is made. The cortisone dose is reduced to 0.5– causing the owner to contact the veterinarian because the
1.0 mg/kg per day, but is always doubled for one or two days animal’s appetite and water intake have increased. Omitting
in the event of anesthesia, severe physical stress, or injury. the cortisone substitution may ameliorate the symptoms tem-
Complete adrenocortical destruction results in very low porarily, but possible recurrence should be investigated by re-
UCCRs in morning urine samples collected after omitting peating UCCR measurements. Two morning urine samples
the cortisone and fludrocortisone administration on the are collected at an interval of four to five days, each time
preceding evening. The doses of fludrocortisone and salt are omitting cortisone and fludrocortisone on the preceding
adjusted by measurements of plasma sodium and potassium evening. UCCRs exceeding the upper limit of the reference
(see also chapter 4.2.1). o,p'-DDD is then continued for at range indicate glucocorticoid excess and o,p'-DDD is again
least three months at the same dose once weekly (fig. 4.53). given daily for 25 days and then once weekly for at least half a
year or even lifelong.
Owner compliance is essential for successful chemotherapy
with o,p'-DDD. During the first month the owner reports at
Glucocorticoid excess 129
A B
C AD
Figure 4.54:
Diagnostic images in a ten-year-old castrated female miniature pinscher of 8 kg with hypercortisolism due to a tumor of the right adrenal cortex. The abdominal ultra-
sonogram (A) can be compared with the CT image (B) in lateral recumbency. A large tumor of the right adrenal gland is shown between the aorta (1), caudal vena cava
(2), and right kidney (3). One year after surgical removal of the tumor, in which there was microscopic expansion into blood vessels, the hypercortisolism had recurred.
The expiratory radiograph of the thorax of this obese dog (C) revealed several nodular densities (arrows) consistent with pulmonary metastases. The dog was given
125 mg o,p'-DDD four times daily for 35 days and corticosteroid replacement was started. o,p'-DDD was continued once weekly for 1.5 years and two years after the
start of o,p'-DDD there was no evidence of recurrence of hypercortisolism or lung metastases (D).
If adrenalectomy or adrenocortical destruction with ance therapy for induced hypoadrenocorticism is required
o,p'-DDD is not an option, the adrenocorticostatic drug tri- after bilateral adrenal resection. Dogs with irresectable adre-
lostane can be used. It has been used successfully in a dog with nocortical tumor or recurrence after resection can be treated
hypercortisolism due to a functional adrenocortical tumor206 with o,p'-DDD according to the above schedule. This often
and can also be used as palliative treatment in case of meta- leads to complete and permanent remission of the hypercor-
stases of a functional adrenocortical tumor.207 tisolism (fig. 4.53) and ultrasonographic examinations may
reveal that the size of the tumor has decreased considerably.250
Prognosis Even lung metastases may disappear (fig. 4.54).
The prognosis is excellent after complete surgical resection of
adrenocortical tumor that has not metastasized. This is true
for bilateral as well as unilateral tumors, although mainten-
130 Adrenals
4.3.3. Hypersecretion of sex hormones This condition has been documented in an eight-year-old
German shepherd dog. The UCCRs (236 and 350 × 10–6)
by adrenocortical tumor and plasma ACTH concentrations (159 and 188 ng/l) were
Adrenocortical tumors can produce various hormones other very high and not suppressible with dexamethasone. These
than cortisol or aldosterone. This is most pronounced in neu- findings were initially interpreted as being consistent with pi-
tered pet ferrets, in which excessive secretion of sex hor- tuitary-dependent hypercortisolism. However, histological
mones by unilateral or bilateral adrenocortical tumors is the examination of the tissue removed by transsphenoidal hypo-
most common form of hyperadrenocorticism. Plasma con- physectomy revealed no adenoma. The clinical manifestations
centrations of cortisol and ACTH are usually not affected.251 exacerbated, including severe hypokalemia (2.2 mmol/l).
4 In this species, the neoplastic adrenocortical tissue expresses Both the UCCR (1518 and 2176 × 10–6) and plasma ACTH
functional LH receptors. Activation of these receptors by the (281 ng/l) were further increased. CT of the abdomen re-
high plasma LH concentrations due to the neutering causes vealed a tumor in the region of the pancreas and laparotomy
excessive secretion of androstenedione, 17a-hydroxyproges- revealed a 5 mm nodule in the pancreas, a 3 cm metastasis in
terone, and /or estradiol, leading to vulvar swelling in neu- an adjacent lymph node, and metastases in the liver. Partial
tered female ferrets, recurrence of sexual behavior in neutered pancreatectomy and extirpation of the lymph node were per-
male ferrets, and symmetrical alopecia.252 formed and histological examination revealed a neuroendo-
crine tumor with metastasis in the lymph node. The second
Increased secretion of progesterone or other sex hormones surgical intervention did not alter the course of the disease,
from noncortisol-secreting adrenocortical tumor has also probably because of additional metastatic tumor tissue that
been reported in cats253–257 and dogs,231,232 but seems to be was not discovered. Nevertheless, the dog did well for more
rare in both species. A sex steroid hormone-secreting adreno- than two years on treatment with trilostane.259
cortical tumor should be considered in neutered animals with
newly developed physical and behavioral sexual changes such Thus ectopic ACTH secretion should be suspected when
as urine spraying and aggression in neutered male cats. The there is very severe hypercortisolism and highly elevated
castrated male cat develops spines on the penis (fig 8.5) plasma ACTH concentrations that are not suppressible with
whereas the castrated female develops hyperplasia of the high doses of dexamethasone and in the absence of a demon-
vulva. Hypersecretion of progesterone by a well-differenti- strable pituitary tumor. Diagnostic imaging may reveal a
ated adrenocortical carcinoma in a castrated male Himalayan neuroendocrine tumor. The condition may not be extremely
cat was associated with bilateral alopecia.253 Endocrine test- rare, as there have been two more reports of individual cases
ing may reveal elevated plasma concentrations of andros- in which this diagnosis has been proposed. In another Ger-
tenedione, testosterone, estradiol, 17-hydroxyprogesterone, man shepherd dog a primary hepatic carcinoid was held
and /or progesterone, and these values may increase following responsible for severe hypercortisolism with persistent hypo-
stimulation with ACTH.231 Information about the size of the kalemia.260 In a dachshund with hypokalemia an extrapitui-
tumor, its expansion, and the presence of metastases can be tary ACTH-producing microadenoma was considered, but
obtained by ultrasonography, CT, or MRI (chapter 4.3.2). no tumor was found and there was some suppression of the
plasma cortisol concentrations in the LDDST.261
Adrenalectomy is the treatment of choice and usually results
in resolution of clinical manifestations, including regression
of penile spines.
4.3.5 Food-dependent glucocorticoid
excess
4.3.4 Ectopic ACTH syndrome In addition to autonomous cortisol secretion by adrenocorti-
cal tumors (chapter 4.3.2), ACTH-independent hypercorti-
In about 15 % of humans with Cushing’s syndrome, the glu- solism may be due to expression of ectopic or hyperactive eu-
cocorticoid excess is the result of ACTH secretion by nonpi- topic hormone receptors. In humans, various adrenocortical
tuitary tumors. These are often malignant tumors originating membrane-bound receptors functionally coupled to steroido-
from cells of the diffuse neuroendocrine system (chap- genesis have been reported, including gastric inhibitory poly-
ter 10.1), and include thymic, pancreatic, and gastrointestinal peptide (GIP), catecholamine, vasopressin, serotonin, and LH
tumors. They may be small and therefore difficult to locate. receptors.262,263 As mentioned in chapter 4.3.3, activated LH
Plasma ACTH concentrations and cortisol secretion rates can receptors on adrenocortical tumor cells in ferrets cause ex-
be extremely high. Consequently the clinical manifestations cessive secretion of androstenedione, 17a-hydroxyprogeste-
can be very pronounced, including hypokalemia due to the rone, and /or estradiol252 (chapter 4.3.3) and in exceptional
severe cortisol excess exceeding the capacity of 11b-HSD2 cases also cause hypercortisolism.264
(chapter 4.1.6).258
Glucocorticoid excess 131
Figure 4.56:
The anti-inflammatory action of glucocorticoids. Corti-
sol binds to the cytoplasmic glucocorticoid receptor
4 (GR). Conformational changes in the receptor-ligand
complex result in dissociation from heat shock proteins
(HSPs) and migration to the nucleus. There it binds to
specific glucocorticoid-response elements in associ-
ation with the activator protein-1 (AP-1), comprising
c-fos and c-jun. The anti-inflammatory effects of gluco-
corticoids are mediated via (1) Induction of the in-
hibitory protein 1kB, which binds and inactivates the
transcription factor NF-kB, (2) binding of the GR-glu-
cocorticoid complex to NF-kB, thus preventing initi-
ation of an inflammatory process, and (3) competition
of both GR and NF-kB for the limited availability of
coactivators. (Modified from Stewart, 2008).54
4.3.6.1 Glucocorticoids as pharmacological agents The side effects of glucocorticoid therapy are not confined to
Glucocorticoids are used for substitution in adrenocortical in- the manifestations of glucocorticoid excess, which may in-
sufficiency (chapter 4.2.1) and for the diagnosis and differen- clude diabetes mellitus.268,269 Suppression of the immune
tial diagnosis of hypercortisolism (chapter 4.3). However, this response may precipitate fatal infections.270 In addition, there
constitutes only a small part of their application in practice, is increased risk of complications such as pancreatitis, and gas-
where they are widely used for the treatment of various aller- trointestinal hemorrhage, ulceration, and perforation.271
gic, autoimmune, inflammatory, and neoplastic diseases.
There is no simple mechanism of action underlying the many 4.3.6.3 Iatrogenic secondary hypoadrenocorticism
effects of glucocorticoids on inflammatory and immune Both systemic and topically applied corticosteroids cause
responses. Many hundred glucocorticoid-responsive genes prompt and sustained suppression of the hypothalamic-pitu-
have been identified (chapter 4.1.5). Two particular transcrip- itary-adrenocortical axis (chapter 4.2.2).272–274 Depending
tion factors seem to be important in mediating anti-inflam- on the dose, the continuity, the duration, and the preparation
matory effects of glucocorticoids. Activator protein-1 (AP-1) or formulation, this suppression may continue for weeks
is a proinflammatory transcription factor induced by cyto- or months after cessation of corticosteroid administration
kines. The GR-ligand complex can prevent interaction with (fig. 4.58).275
AP-1, thereby mediating inhibitory effects of glucocorti-
coids. Similarly, functional antagonism exists between the GR An animal may appear to be healthy during corticosteroid
and nuclear factor kappa B (NF-kB). NF-kB is a widely ex- therapy, but nevertheless it lacks the ability to increase cortisol
pressed transcription factor that activates a series of genes in- secretion sufficiently in response to stress. If stressed, it may
volved in lymphocyte development, inflammatory response, develop signs of acute adrenocortical insufficiency, such as
host defense, and apoptosis.54 hypotension, weakness, anorexia, and vomiting. It may not
recover from surgery without additional glucocorticoid
supplementation. Similar long-lasting suppression of the hy-
4.3.6.2 Iatrogenic hypercorticism pothalamic-pituitary-adrenocortical system occurs in dogs
As in spontaneous hypercortisolism, the development of signs treated with progestins.276 Also in cats, where progestins are
and symptoms of glucocorticoid excess depends on the sever- used in the treatment of various dermatologic and behavioral
ity and duration of the exposure. The effects vary among in- disorders, the affinity of the GR for these compounds may
dividual animals and initially seem to be less pronounced in cause a similar suppression of the pituitary-adrenocortical sys-
cats. Within days after the start of glucocorticoid adminis- tem.277
tration polyuria /polydipsia and polyphagia develop. After
several weeks of glucocorticoid therapy, the classic physical During prolonged glucocorticoid treatment, tests of pitu-
changes such as centripetal obesity, muscular weakness, and itary-adrenocortical reserve function (chapters 4.2.2, 1.2.4.1,
skin atrophy develop (fig. 4.57). fig. 4.58) are not needed. A test is indicated when the gluco-
Glucocorticoid excess 133
A B
Figure 4.57:
(A) A three-year-old female mongrel dog that was treated for six months with injections of 9F,16-methylprednisolone and 6-methylprednisolone for pruritus due to an
underestimated flea infestation. Note the obesity and the thin coat.
(B) With antiparasitic treatment and omission of the corticosteroids the dog regained its normal shape and a thick hair coat.
Long acting
Bethamethasone 25 No
Dexamethasone 30 No
134 Adrenals
Figure 4.60:
Histological sections of adrenals stained with neuron-
specific enolase (NSE). In the healthy cat (left), the
staining of the cortex (C) is confined to the zona
glomerulosa with only slight staining of the outer part
of the zona fasciculata. In the cat with primary hyperal-
dosteronism (right), the cortex consists of multiple hy-
perplastic nodules, staining positively for NSE. Staining
of the adrenal medulla (M) is similar in the two sec-
tions. Bar = 200 µm.
Figure 4.61:
The main routes for development of hypokalemia.
Figure 4.62:
Changes in plasma renin activity (PRA) and plasma aldosterone concentration (PAC) that can occur in hypokalemia developed via the renal route. The congenital con-
ditions described in humans but not (yet) in dogs or cats are marked with an asterisk.
Mineralocorticoid excess 137
Diagnosis
In primary mineralocorticoid excess, the plasma concen- Control populations of both dogs and cats have been studied.
tration of aldosterone (or DOC) is characteristically high and In dogs the ARR ranged from 0.1 to 1.5, and both PAC and
plasma renin activity (PRA) is immeasurably low. In hyperal- the ARR were slightly lower in spayed than in intact female
dosteronism due to adrenocortical tumor plasma aldosterone dogs. In cats the ARR was 0.3–3.8, being somewhat higher
concentration (PAC) is usually highly elevated. In cats with in neutered than in intact cats. The ARR was higher in cats
idiopathic hyperaldosteronism PAC is usually only slightly 욷 5 years of age than in younger cats. Blood samples were
elevated or within the upper limit of the reference range. As collected with the animals in various positions and sampling
hypokalemia is a predominant factor in lowering PAC,298 in was associated with a wide variety of stress responses. Never-
the presence of hypokalemia moderately elevated aldosterone theless, the reference ranges were similar to the relatively nar-
values can be regarded as inappropriately high. The PRA row range obtained in humans under standardized conditions.
must also be taken into account. The combination of a high- PRA and PAC are much higher in blood collected from hu-
normal or elevated PAC and low PRA indicates persistent al- mans in the upright rather than in the supine position. This
dosterone synthesis in the presence of little or no stimulation physiological response to rapid pooling of blood in the lower
by the renin-angiotensin system. In humans the PAC:PRA extremities and to shifts in plasma fluid in surrounding tissues
ratio (ARR) is considered to be a very useful aid in diagnos- is a less important factor in small quadrupeds such as
ing primary hyperaldosteronism. This also seems to be true cats.301,302
for cats with idiopathic hyperaldosteronism (fig. 4.63).293
An alternative diagnostic approach may be measurement of
The ARR is elevated in 10–20 % of human patients with ar- the urinary aldosterone:creatinine ratio (UACR). Cats ex-
terial hypertension and most of these have excess aldosterone crete smaller quantities of aldosterone and its 18-glucuroni-
production from both adrenal cortices.299 The diagnostic dated metabolite in urine than do humans or dogs, but never-
value of the ARR is principally determined by the sensitivity theless the UACR can be determined.303 This would allow
of the renin assay and interpretation should rest upon com- the development of a dynamic test, such as employing a sup-
parison with an appropriate control population. The ARR is pressive agent that would reduce the UACR in healthy indi-
currently regarded as the most reliable means of detecting pri- viduals but have little or no effect in those with primary hy-
mary hyperaldosteronism, but the measurements should be peraldosteronism. In 42 healthy cats the upper limit for the
repeated if the initial result is inconclusive or difficult to in- UACR was 46.5 × 10–9. The administration of sodium chlor-
terpret because of suboptimal sampling conditions.300 ide did not significantly lower the UACR but administration
of fludrocortisone (0.05 mg/kg body weight) reduced it by
138 Adrenals
44–97 % (median 78 %). In a cat with an aldosterone-produc- of hypercortisolemia due to adrenocortical tumor (chap-
ing adrenocortical carcinoma the UACR was within the ref- ter 4.3.2), temporary fludrocortisone therapy could also be
erence range and was not lowered by fludrocortisone admin- considered. However, in the reported cases such postsurgical
istration.304 This test may prove to be a practical noninvasive measures have not been necessary and their omission does not
diagnostic tool, but further evaluation is required, particularly seem to have had deleterious effects.
with regard to its discriminatory power in diagnosing idio-
pathic hyperaldosteronism. If surgery is not possible or if the adrenocortical disease is bi-
lateral, medical treatment is possible with the mineralocorti-
Subtype classification – differentiating between tumorous and coid-receptor antagonist spironolactone and oral supplemen-
nontumorous mineralocorticoid excess – requires diagnostic tation with potassium gluconate. The initial doses are 2 mg
imaging. Ultrasonography and computed tomography have spironolactone/kg and 0.5 mmol potassium gluconate/kg,
been used in dogs and cats to identify and characterize adrenal twice daily. Persistent arterial hypertension can be treated
tumors.279,305 As in humans the findings are not always im- with the calcium blocker amlodipine (1–2 mg/kg). In cases of
mediately conclusive.306 The visualization of a small aldoste- adrenocortical tumor medical treatment may lead to reso-
ronoma may pose problems while nodular hyperplasia might lution of symptoms and signs such as the myopathy in cats and
be interpreted as microadenoma.279,293 the polyuria in dogs, but complete normalization may not be
achieved (fig. 4.64).279,291 Particularly plasma potassium tends
Treatment to remain below the reference range, despite increasing doses
Unilateral adrenalectomy is the treatment of choice for con- of both spironolactone and potassium. Doses of spironolac-
firmed unilateral primary hyperaldosteronism. There have tone 쏜 4 mg/kg may cause anorexia, diarrhea, and vomiting.
been several reports of successful surgical treatment,279,288,291 These side effects may be due to interference by spironolac-
including the successful excision of an adrenocortical tumor tone with aldosterone action on transepithelial electrolyte
and the associated caval thrombus.307 Preoperatively and peri- transport in the distal colon.308
operatively hypokalemia should be controlled as well as pos-
sible, by oral and intravenous supplementation. Postoperative Experience is very limited, but medical treatment appears to
intravenous fluids can be confined to 0.9 % sodium chloride be preferable in cats with hyperaldosteronism due to bilateral
solution without potassium chloride, unless plasma potassium adrenocortical hyperplasia. The hyperaldosteronism is usually
remains below 3.0 mmol/l. In principle during the first few somewhat milder than in cases due to tumor and normokale-
weeks after surgery a generous dietary intake of sodium can mia may be maintained for a long period with spironolactone
be provided to avoid hyperkalemia that could develop from alone or together with low doses of potassium.293
hypoaldosteronism due to chronic contralateral adrenocorti-
cal suppression. Analogous to the postoperative management
Adrenal medulla 139
Prognosis
After complete removal of a unilateral nonmetastasized min-
eralocorticoid-producing tumor, the prognosis can be excel-
lent, without any medication. In both forms the disease may
be associated with renal insufficiency.291,293 Successful removal
of the tumor will probably prevent further progression of al-
dosterone-induced arteriolar sclerosis and interstitial fibrosis
in the kidneys (chapter 4.4.1). The prognosis may not be as
favorable in cats with idiopathic hyperaldosteronism treated
with spironolactone, for this treatment will not abolish the 4
mineralocorticoid excess as definitely as surgery may do.
Catecholamines include epinephrine (adrenaline), norepi- Secretion of catecholamines is part of the activation of the
nephrine (noradrenaline), and dopamine. In contrast to cor- sympathetic nervous system. Examples for stimuli are exer-
ticosteroid production by the adrenal cortex, adrenal medul- cise, perceived danger, surgery, hypovolemia, hypotension,
lary catecholamine synthesis is not essential for survival, i.e., and hypoglycemia. The plasma half-life of catecholamines is
after bilateral adrenalectomy extra-adrenally produced cate- very short (1–3 min). They are metabolized to the inactive
cholamines fill the need. Catecholamines are synthesized compounds normetanephrine, metanephrine, and vanillyl-
from tyrosine by a process of hydroxylation and decarboxy- mandelic acid. They may also be inactivated in the liver by
lation (fig. 4.65). With these features the adrenal medulla be- conjugation with sulfate or glucuronide. Excretion is via the
longs to a system previously called APUD system (amine pre- urine (fig. 4.66).
cursor uptake decarboxylase system; see also chapter 10).
Catecholamines are stored within the chromaffin cells in Catecholamines bind to receptors in the plasma membrane,
cytoplasmic vesicles, together with various other substan- from which signal transduction to intracellular sites takes
ces such as chromogranin-A, somatostatin, enkephalins, syn- place via G-proteins. Adrenergic receptors are of two broad
apophysin, vasoactive intestinal polypeptide, ACTH, and categories: a- and b-receptors, which are further divided into
CRH.310 All of the epinephrine in the circulation is derived subgroups (a1, a2, b1, b2, b3). The a-receptors have about the
from the adrenal medulla, whereas circulating norepinephrine same affinity for norepinephrine and epinephrine, whereas
is mostly from postganglionic sympathetic neurons and only b-receptors (in particular b2-receptors) have a much higher
to a small extent from the adrenal medulla. affinity for epinephrine. The effects of catecholamines de-
140 Adrenals
Table 4.5: Catecholamine receptor types and subtypes Although pheochromocytomas tend to grow slowly, they
should be considered potentially malignant tumors. In up to
Organ / tissue Receptor type Effect
50 % of cases the tumor is locally invasive and extends into
Cardiovascular system b1 Increase in heart rate, the lumen of adjacent vessels and other tissues. Pheochro-
increase in contractility mocytomas may metastasize to lymph nodes, spleen, liver,
a2 Vasoconstriction kidney, pancreas, lung, heart, bone, and CNS. Extraluminal
b2 Vasodilatation in skeletal
muscle arterioles, coronary
compression of vessels by large tumors also occurs.314,316,317
arteries, and all veins
Clinical manifestations
4 Bronchial muscles b2 Relaxation
Pheochromocytomas occur most often in older dogs. There is
Gastrointestinal tract b2 Decrease in motility no apparent sex or breed predilection. Symptoms and signs
Pancreatic islets a2 Decrease in insulin and result from secretion of excessive amounts of catecholamines,
glucagon secretion or, infrequently, from the space-occupying or invasive nature
b2 Increase in insulin and of the tumor. Hormone secretion is sporadic and unpredict-
glucagon secretion able and the clinical presentation is highly variable. Symptoms
Liver b2 Increase in glycogenolysis are often episodic and may only recur after weeks or months
and gluconeogenesis or may appear several times per day. They may be dramatic
Adipose tissue b2 Increase in lipolysis and life-threatening or they may be unapparent.
Urinary bladder a2 Increase in sphincter tone
b2 Relaxation of M. detrusor The symptoms and signs can be categorized as:
쎱 Nonspecific: anorexia, weight loss, lethargy.
Eye a1 Mydriasis
쎱 Related to the cardiorespiratory system and /or to hyper-
pend on the density of the different subtypes of receptors pacing, muscle tremors, seizures.
on specific organs and on the relative concentrations of epi- 쎱 Miscellaneous: polyuria /polydipsia, vomiting, diarrhea,
nephrine and norepinephrine (table 4.5). These effects are abdominal pain.
modulated by reflex mechanisms, e.g., as the blood pressure
increases the heart rate is slowed and cardiac output tends to Large tumors may cause abdominal distension, ascites, and
decrease. Additionally, the central nervous system (CNS) hind-limb edema, or rarely intra-abdominal or retroperito-
plays an important integrative role, so that one vascular bed neal hemorrhage due to tumor rupture.314, 316–321
may be dilated while others remain unchanged.309,310,312
Diagnosis
Since clinical manifestations are nonspecific, variable, and
easily explained by disturbances of other organ systems, diag-
4.5.2 Pheochromocytoma nosis of pheochromocytoma is challenging. There are no
consistent abnormalities in routine hematology, blood bio-
Pheochromocytomas are catecholamine-producing neuro- chemistry, or the urinalysis. There may be anemia, neutrophi-
endocrine tumors arising from either chromaffin cells of the lia, increased liver enzymes, azotemia, and hypoalbuminemia.
adrenal medulla or extra-adrenal paraganglia. The latter are Although arterial hypertension is one of the hallmarks of the
referred to as extra-adrenal pheochromocytoma or paragan- disease, it is detected in only approximately 50 % of dogs by
gliomas.313 Most tumors are derived from the adrenal medulla; the time of examination. Due to its episodic nature, hyper-
paragangliomas have thus far been described in only a few case tension might be detected in a higher percentage of patients
reports. Pheochromocytoma is considered to be rare in dogs by repetitive blood pressure measurements, but even so it is
and even less frequent in cats. However, due to the difficulties not pathognomonic for pheochromocytoma.
in diagnosing pheochromocytoma, quite a few may be over-
looked and therefore the prevalence may be higher than gen- Tumor size varies greatly, from a diameter of a few millimeters
erally assumed. Most tumors are unilateral; only occasionally and 쏜 10 cm. In most dogs the pheochromocytoma is of suf-
are both adrenal glands affected. Pheochromocytomas may ficient size to be visualized by ultrasonography. Ultraso-
coexist with glucocorticoid-producing adrenocortical tu- nography also enables identification of tumor invasion of
mors, ACTH-producing pituitary tumors (fig. 4.67), or other surrounding tissue and vessels. However, no pattern of echo-
endocrine tumors and as such be part of a multiple endocrine genicity or architecture is specific for pheochromocytoma
neoplasia syndrome.148,149,314 Inherited multiple endocrine (fig. 4.68).322,323 The differential diagnoses for an adrenal mass
neoplasia syndromes (MENs) known to occur in humans315 include nonfunctional lesions such as myelolipoma, cyst, ab-
have thus far not been identified in dogs or cats. scess, hematoma, and metastasis, and hypersecretory tumors,
Adrenal medulla 141
producing cortisol or a cortisol precursor, pheochromocy- The work-up of human patients with a suspected pheochro-
toma, and aldosteronoma. In dogs cortisol-producing tumors mocytoma routinely includes biochemical testing, i.e.,
are by far the most common hypersecretory adrenal tumors measurement of urinary catecholamines and their metabolites
and the clinical manifestations may be similar to those of metanephrine, normetanephrine, and vanillylmandelic acid.
pheochromocytoma. Hence it may be necessary to rule out Measurement of free metanephrines in plasma and urine is a
hypercortisolism due to an adrenocortical tumor in some more recent test. Measurements of free metanephrines in
cases. On rare occasions both diseases occur simultaneously, plasma and 24 h urine are reported to be more sensitive than
further complicating the work-up. measurements of plasma or 24 h urinary catecholamines. This
higher sensitivity may be explained by the fact that although
CT and MRI are more sensitive than ultrasonography in pheochromocytomas produce catecholamines they do not al-
identifying adrenal masses and characterizing the extent ways release them but rather their metabolites. There is some
of local invasion. However, they do not provide a definitive controversy concerning the preferability of testing blood or
diagnosis. Anesthesia and contrast media may provoke a urine. Plasma metanephrine measurements may have a higher
hypertensive crisis and arrhythmias. Other advanced diag- sensitivity than measurements of 24 h urinary metanephrines,
nostic imaging procedures such as scintigraphy with 123I-la- but their specificity may be lower.325,326
beled metaiodobenzylguanidine (123I-MIBG) and positron
emission tomography with p-[18F]fluorobenzylguanidine Evaluation of these variables in veterinary medicine has just
([18F]MFBG) take advantage of the fact that these radiophar- begun. In a preliminary study the urinary concentrations of
maceuticals have similarities to norepinephrine and accumu- dopamine, norepinephrine, epinephrine, normetanephrine,
late in the adrenal medulla. These techniques may therefore and metanephrine, all related to creatinine concentration,
be more specific for the diagnosis of pheochromocytoma, but were determined in healthy dogs and in dogs with pheochro-
they have only been described in a small number of dogs and mocytoma. The normetanephrine:creatinine ratio had the
no data on sensitivity, specificity, and predictive values are highest discriminating power (fig. 4.69).327 This may be sur-
available.324,325 Similarly, information on the diagnostic value prising in light of the fact that epinephrine (which is meta-
of fine-needle aspiration (FNA) is scarce. The risks and disad- bolized to metanephrine) and not norepinephrine (which is
vantages (hypertensive crisis, arrhythmias, nondiagnostic metabolized to normetanephrine) is the main secretory prod-
samples, misinterpretation) of FNA have to be carefully uct of the adrenal medulla. However, in dogs with pheochro-
weighed against the potential benefits. mocytoma the situation may be similar to that in humans, in
which most tumors contain less epinephrine than the normal
medulla, or even none.328 Stress associated with the hospital
142 Adrenals
Figure 4.69:
4 Urinary normetanephrine:creatinine ratios in healthy
dogs and in six dogs with pheochromocytoma. In the
healthy dogs urine was collected at different times: day
0, in the hospital following the physical examination,
and day –7, day 1, and day 7, at home seven days prior
to and one and seven days after the hospital visit.
Blue circles = dogs of clients; pink circles = dogs of
staff. In the dogs with pheochromocytoma (Pheo) urine
was collected once. * Indicates significant difference.
visit and the urine sampling increases urine catecholamine perioperative monitoring. An a-adrenergic blocker should be
excretion. Urine collection should therefore take place at started immediately after diagnosis and given for at least one
home after adaptation to the procedure.327 Sample collection to two weeks before adrenalectomy.314 The aim is to reverse
and urine processing require certain conditions, including the effects of excessive adrenergic stimulation (hypertension,
acidification, avoidance of light, and cooled or frozen storage. hypovolemia) and to minimize perioperative complications.
Close collaboration with the laboratory is necessary for provi- Phenoxybenzamine is used most often. The initial dose of
sion of reference ranges and technical assistance. No studies of 0.25 mg/kg BID should be gradually increased every few days
plasma metanephrine measurements in dogs have been until signs of hypotension or adverse drug reactions such as
published and it may well be that they are less suitable in dogs vomiting occur or the maximal dose of 2.5 mg/kg is reached.
because of the adverse influence of hospital-associated stress.
Potential complications after surgery include hemorrhage,
Treatment hypotension, hypertension, arrhythmias and tumor recur-
Adrenalectomy is the treatment of choice and should be per- rence. Perioperative mortality is approximately 20–30 %.
formed as soon as possible. If the tumor has invaded adjacent Dogs pretreated with phenoxybenzamine have a decreased
vessels and other tissues, the surgery can be extremely de- mortality rate compared with untreated dogs.314 Animals sur-
manding and should be performed by an experienced sur- viving this initial period may live for several years, even with
geon. The patients carry a high anesthetic risk due to poten- advanced stage disease.329–331
tial hypertensive crisis and arrhythmias requiring professional
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155
5 Endocrine Pancreas
Claudia E. Reusch
Joris H. Robben
Hans S. Kooistra
5.1 Introduction
5.1.1 The endocrine pancreas 5
The pancreas is an essential organ, responsible for both diges-
tion and glucose homeostasis. It is located in the epigastric
and mesogastric segments of the abdominal cavity and con-
sists of a thin, slender right (duodenal) lobe and a shorter,
thicker left (splenic) lobe, which are united at the pancreatic
body. The form is that of a V, the apex of which lies caudo-
medial to the pylorus (fig. 5.1).
The islets are highly vascularized and their capillaries are fe-
nestrated, increasing permeability. An islet-acinar portal sys-
tem communicates between the endocrine and exocrine pan-
creatic tissue. It is assumed that blood coming from the islets
flows into the acinar capillaries before leaving the pancreas
and that islet hormones have a role in regulating the exocrine Figure 5.2:
pancreas.6 The islets are innervated by sympathetic and para- Histologic section of the pancreas of a healthy cat, showing an islet of Langerhans
sympathetic fibers which influence the release of pancreatic surrounded by exocrine tissue. b-cells (red) are shown by immunohistochemical
hormones. staining for amylin.
156 Endocrine Pancreas
(fig. 5.5). Orally administered glucose triggers more pro- Table 5.1: Species differences in the amino acid sequence of insulin
nounced insulin secretion than does glucose given intra-
A8 A10 A18 B30
venously. This phenomenon is due to the actions of so-called
incretin hormones, the most important being glucagon-like Human Thr Ile Asn Thr
peptide-1 (GLP-1) and glucose-dependent insulinotropic Porcine Thr Ile Asn Ala
polypeptide, also called gastric inhibitory polypeptide (GIP).
Canine Thr Ile Asn Ala
Incretins are secreted by endocrine cells in the gastrointestinal
tract in response to nutrients and are then carried in the Bovine Ala Val Asn Ala
bloodstream to the pancreatic islets, where they interact with Feline Ala Val His Ala
their receptors on b-cells to amplify insulin secretion. In sev-
eral species GLP-1 has additional effects, such as reduction of
glucagon secretion and stimulation of b-cell differentiation
and proliferation, but it is not known whether these also
occur in dogs and cats. In addition to glucose and other
sugars, amino acids and fatty acids also stimulate insulin secre-
tion. Stimulation can be direct or potentiated by incretins.
The autonomous nerve system also exerts a modulating in- Table 5.2: Factors influencing insulin secretion
fluence on islet hormone release, but its importance is still Stimulants of insulin secretion Inhibitors of insulin secretion
unclear. In general terms, insulin secretion is stimulated by
vagal nerve fibers and inhibited by sympathetic nerve fibers Glucose Somatostatin
(table 5.2). Several other sugars Epinephrine, norepinephrine
(e.g., xylitol, sorbitol)
Several other pancreatic hormones influence insulin secretion Amino acids
directly or indirectly. Amylin (islet amyloid polypeptide, Fatty acids
IAPP) is a single-chain 37-amino-acid peptide cosecreted
Incretins (e.g., GLP-1, GIP)
with insulin. Several effects of amylin, which have been dem-
onstrated in humans and rodents, are of physiological rele- Other intestinal hormones
vance and contribute to the regulation of nutrient me- (gastrin, cholecystokinin)
tabolism. They include inhibition of food intake, modulation Glucagon
of glucagon release, and delay of gastric emptying. Amylin Keto acids
and its metabolic effects may play a role in the development of
Acetylcholine
human and feline type 2 diabetes mellitus.8
158 Endocrine Pancreas
Glucagon, a single-chain peptide of 29 amino acids, has long act as docking proteins between the insulin receptor and a
been a »neglected« hormone, but there is increasing evidence complex network of intracellular molecules. How the intra-
that glucagon disturbances play an important role in diabetes cellular signals lead to the final biological effects of insulin is
mellitus. It is a major catabolic hormone acting in concert the focus of very active research. Dysregulation within the
with insulin to maintain normal blood glucose concentration signaling cascade may lead to insulin resistance, in which IRS
by opposing many of the key metabolic effects of insulin. molecules seem to play a major role.
After food intake, insulin secretion increases to conserve
energy and to prevent hyperglycemia. As the interval after Within seconds after insulin binds to its receptor, the so-
food intake increases and blood glucose begins to decrease, called rapid insulin actions lead to the cellular uptake of glu-
glucagon is secreted to prevent hypoglycemia and to mobilize cose, amino acids, potassium, and phosphate. Intermediate
energy stores. Changes in the ratio of insulin to glucagon are actions occur within a few minutes, mainly affecting protein
5 largely controlled by the blood glucose concentration and to a and glucose metabolism, followed several hours later by de-
lesser extent by the concentration of amino acids. There is layed actions which mainly concern lipid metabolism.
paracrine signaling between insulin and glucagon, such that
insulin inhibits glucagon secretion and glucagon stimulates Glucose is a polar molecule and cannot diffuse across cell
release of insulin. membranes. Its transport is facilitated in several tissues by a
family of glucose transporter (GLUT) proteins or (in the
Somatostatin is a 14-amino-acid peptide that has been iden- intestine and kidney) by active transport with sodium. At
tified in many tissues. Pancreatic somatostatin has an in- least 14 different GLUT proteins have been identified in hu-
hibitory effect on absorption and digestion and on motility of mans, named in order of their discovery, GLUT 1–14. Each
the gastrointestinal tract. It is a potentially important para- appears to have evolved for a specific task. GLUT 4 is the
crine inhibitor of insulin and glucagon secretion. major insulin-responsive transporter and is found almost ex-
clusively in muscle and adipose tissue. Insulin stimulates glu-
The hormones mentioned here have additional effects and in- cose transport in these two tissues by causing the translocation
terrelations and there are certainly other hormones and effects of GLUT 4 molecules from the cytosol to the cell membrane,
which are not yet known. In short, however, it is obvious that with which they fuse and function as pores for glucose entry
the pancreatic islets finely tune metabolism during times of (fig. 5.6). When insulin levels decrease, the GLUT 4 mol-
feeding as well as during food deprivation. ecules are removed from the cell membrane. In various other
tissues such as brain, liver, kidney, and intestinal tract, glucose
uptake is insulin-independent and occurs via other GLUT
proteins.1
5.1.4 Actions of insulin
Insulin is the most important anabolic hormone in the body
Insulin regulates numerous metabolic processes through bind- and prevents catabolism of nutrient stores. Its main function is
ing to high-affinity cell surface receptors. These receptors are to ensure storage of glucose as glycogen, amino acids as pro-
widely distributed throughout the body and are found in tis- tein, and fatty acids as fat. The main target tissues for insulin
sues in which insulin mediates glucose uptake (such as muscle are liver, muscle, and adipose tissue (fig 5.7). Insulin facilitates
and adipose tissue) as well as in those in which it does not the oxidation of glucose to pyruvate and lactate by the induc-
(such as liver, brain, kidneys, and erythrocytes). tion of enzymes such as glucokinase, phosphofructokinase,
and pyruvate kinase. Insulin promotes glycogen synthesis in
Like the receptors for other protein hormones, the receptor liver and muscle by increasing glycogen synthetase activity.
for insulin is embedded in the plasma membrane. It is a tetra- Gluconeogenesis is decreased by insulin because insulin pro-
meric protein, composed of two a-subunits and two b-sub- motes protein synthesis in peripheral tissues, decreasing the
units linked by disulfide bonds. The a-subunits are extracel- availability of amino acids for gluconeogenesis. Additionally,
lular and contain insulin binding domains, while the insulin decreases the activity of hepatic enzymes involved in
b-subunits penetrate through the cell membrane (fig. 5.6). the conversion of amino acids to glucose.
The insulin receptor belongs to the large group of tyrosine ki-
nase receptors. They mediate their activity by transferring In adipose tissue insulin promotes the synthesis of lipids and
phosphate groups to tyrosine residues on intracellular target inhibits their degradation. Insulin activates the enzymes pyru-
proteins. vate dehydrogenase and acetyl-CoA carboxylase, which pro-
mote the synthesis of fatty acids from acetyl-CoA. Insulin also
Binding of insulin to the a-subunits triggers the tyrosine ki- increases the activity of lipoprotein lipase, an enzyme located
nase activity of the b-subunits, leading to autophosphory- in the endothelium of capillaries of extrahepatic tissues,
lation which activates the catalytic activity of the receptor. which promotes the entry of fatty acids into adipose tissue.
The »substrate« proteins phosphorylated by the insulin recep- Inhibition of lipolysis is mediated by inhibition of hormone-
tor are called insulin-receptor substrate (IRS) molecules. sensitive lipase.
They are key mediators in the insulin signaling pathway and
Diabetes mellitus 159
Figure 5.6:
Simplified scheme of insulin action. Glucose binding to
its receptor protein initiates activation cascades that
result in translocation of GLUT 4 to the cell membrane.
This facilitates glucose influx and the synthesis of gly-
cogen, protein, and lipid, as well as regulation of cell
growth and expression of various genes. IRS (insulin
receptor substrate) acts as a docking protein between 5
the receptor and a complex network of intracellular
signaling molecules.
In type 1 diabetes, which accounts for about 10 % of cases in are also included in this category. The extent of glucose
humans, the cause is an absolute deficiency of insulin secre- intolerance varies widely and insulin therapy may or may
tion due to T-cell mediated autoimmune destruction of the not be required; overt diabetes only develops in those individ-
b-cells. A marker of the disease is the presence of circulating uals having a susceptibility to the disease. These disease
islet-related autoantibodies such as islet-cell autoantibodies associations should be differentiated from the coexistence
(ICA), insulin antibodies (IA), glutamic acid decarboxylase of type 1 diabetes with endocrine diseases that result from
(GAD) autoantibodies, and tyrosine phosphatase IA-2 anti- common autoimmune destructive processes, e.g., diabetes
bodies. There is a genetic contribution and the autoimmune with hypothyroidism (chapter 3.3.1) or Addison’s disease
process is triggered by environmental factors that are still (chapter 4.2.1).
poorly defined. The disease is typically diagnosed in children
and adolescents, but it may also have a slow and initially mild The fourth category in humans, gestational diabetes, is of
5 course with manifestation later in life (latent autoimmune little importance in dogs and cats, but the diabetes associated
diabetes in adults, LADA). There is a subgroup of type 1 dia- with diestrus in dogs can be considered its equivalent
betes, termed idiopathic, which is strongly inherited with no (chapter 2.2.4.2).
evidence for autoimmunity.
Figure 5.8:
Overview of the effects of insulin deficiency.
Protein metabolism shifts toward decreased protein synthesis 5.2.3 Diabetes mellitus in dogs
and increased proteolysis. The increased availability of amino
acids further accelerates hepatic gluconeogenesis. The conse- Diabetes mellitus is one of the most common endocrine dis-
quences are negative nitrogen balance, loss of muscle mass, orders in dogs, having a prevalence of 0.3–0.6 %.14,15 In many
and possibly cachexia. dogs the disease is similar to human type 1 diabetes, which is
caused by autoimmune destruction of b-cells in genetically
In diabetic humans there are chronic complications that se- predisposed individuals. Antibodies against b-cells and several
verely affect the quality of life and life expectancy. These in- islet components (insulin, GAD65, IA2) have been demon-
volve the vascular system (microvascular and macrovascular strated in the serum of dogs with newly diagnosed diabetes,
disease) and the nervous system, skin, and lenses. The hypo- suggesting that these antigens are involved in the autoimmune
theses that have been proposed to explain these include in- process.16,17 The observation that certain breeds of dogs are
creased activity of the polyol pathway with accumulation of predisposed to diabetes18 recently led to genetic studies. The
sorbitol, increased formation of advanced glycation end prod- risk of diabetes was shown to be associated with certain
ucts, and decreased antioxidant status. dog leukocyte antigen (DLA) haplotypes. Since most dogs
are middle-aged to elderly at the time of diagnosis, canine
The serious chronic complications in humans – nephropathy type 1 diabetes seems to correspond best to the subgroup of
and cardiovascular disease – are rare in diabetic dogs and cats, type 1 diabetes termed latent autoimmune diabetes in adults
most probably because of the shorter lifespan. The most com- (LADA).19–24
mon diabetic complication in dogs is cataract. Recent studies
have shown that the activity of the enzyme aldose reductase in Dogs with diabetes may have concurrent endocrine diseases
the lens is increased, which leads to accumulation of sorbitol. of possible autoimmune etiology (such as hypothyroidism and
Because sorbitol is hyperosmotic, there is an influx of water, Addison’s disease), a combination which may be equivalent to
swelling and rupture of lens fibers, and altered membrane per- human autoimmune polyendocrine syndrome type 2. Hu-
meability. Aldose reductase activity is low in the lenses of mans who carry a particular HLA genotype are at a higher
older cats, which may in part explain why cats have much less risk of diabetes, a situation similar to the high risk DLA ha-
serious diabetic cataracts.11 plotype in dogs.25
Electron microscopic studies of peripheral nerves have re- Diabetes mellitus occurs occasionally in dogs less than twelve
vealed that more than 90 % of diabetic dogs and cats have months of age, most likely not due to autoimmune destruc-
neuropathies similar to those in diabetic humans.12,13 Al- tion but to b-cell aplasia or abiotrophy. There has been no
though neuropathy is rarely recognized clinically in dogs, it is evidence that dogs develop an equivalent of human type 2
a common problem in cats. The reasons for this difference diabetes. Other forms of diabetes (a category previously
and the underlying mechanism are unknown. called secondary diabetes) include pancreatic destruction due
to acute or chronic pancreatitis or pancreatic neoplasia, and
insulin resistance due to other diseases or factors. Evidence
for acute or chronic pancreatitis was reported in 13 % of dogs
162 Endocrine Pancreas
Figure 5.10:
Strength and duration of action of short-, inter-
mediate-, and long-acting insulin.
and certain drugs.33 Measurement of fructosamine is not Routine hematology, plasma or serum biochemistry, urinaly-
required for the diagnosis per se in dogs, but it is useful in sis, and urine culture should be performed. Typical findings
long-term management and an initial measurement provides include a stress leukogram, hyperlipidemia, slight to moderate
a reference point and is therefore recommended.34 elevation of alanine aminotransferase (ALT) and alkaline
phosphatase (ALP), urine specific gravity 쏜 1.020 despite
Fructosamine is the product of an irreversible reaction be- polyuria, and glucosuria, proteinuria, and bacteriuria with or
tween glucose and amino groups on plasma proteins and it re- without pyuria. There may be a trace of ketone bodies in the
flects the mean blood glucose concentration in the preceding urine even in uncomplicated diabetes. Additional diagnostic
one to two weeks. It is not affected by short-term changes in procedures that may be indicated include radiographs, ab-
blood glucose concentration. Reference ranges differ slightly dominal ultrasonography, measurement of trypsin-like immu-
between laboratories, but are usually about 200–350 µmol/l. noreactivity (TLI), and canine pancreatic lipase immunoreac-
It is unusual for a diabetic dog or cat to have a normal fruc- tivity (cPLI). Testing for hypercortisolism should be delayed
tosamine level at the time of diagnosis but diabetes of very until treatment of the diabetes is stabilized. Measurement of
short duration (쏝 5 days) or hypoproteinemia are possible circulating insulin concentration is not helpful in most cases.
reasons.35 In a newly diagnosed diabetic dog, fructosamine is
usually 쏜 400 µmol/l and may be 쏜 1000 µmol/l. Glycated Treatment
hemoglobin is another indicator of long-term metabolic con- The aims of therapy are to eliminate the symptoms and signs
trol, but for technical reasons it is rarely used in veterinary of diabetes mellitus and prevent short-term complications
medicine. (hypoglycemia and ketoacidosis), thereby enabling the animal
to have a good quality of life. It is not necessary to maintain
Further workup should answer the following questions: normal or near normal blood glucose levels, as is the aim in
쎱 How severe is the disease, i.e., is diabetic ketoacidosis humans, for most diabetic dogs and cats appear to do well
present? when the blood glucose ranges between 15 mmol/l before
쎱 Are there concurrent diseases such as stomatitis /gingivitis insulin administration and 5 mmol/l at the time of the glu-
or urinary tract infection, which could hinder manage- cose nadir (= lowest plasma glucose concentration).
ment of the diabetes?
쎱 Is there evidence for underlying disease /factors which Successful treatment requires that the owner be highly moti-
could have caused the diabetes, such as pancreatitis, hy- vated and work in close collaboration with the veterinarian,
percortisolism, diestrus, or diabetogenic drugs? who follows a strict protocol (see chapter 13.3.1). Treatment
consists of insulin therapy, dietary management, body weight
reduction if the dog is overweight, daily exercise, cessation of
diabetogenic drugs, and control of concurrent or underlying
problems. All dogs with diabetes should be treated with insu-
164 Endocrine Pancreas
lin. Oral hypoglycemic drugs are ineffective for metabolic One of the most important periods in the owner’s care of a
control, even though a-glucosidase inhibitors or chromium diabetic pet is the time during which the veterinarian or the
may have slight auxiliary effects. nurse teaches the technical aspects of the treatment. The
owner must be able to mix the insulin correctly (gentle roll-
Insulin preparations are categorized according to duration of ing, not shaking), load a syringe without air bubbles, admin-
action as short-, intermediate-, and long-acting (fig. 5.10). In ister an injection subcutaneously on the lateral wall of the
dogs with uncomplicated diabetes, treatment is started with chest, know how to deal with such problems as injection pain
an intermediate-acting insulin, which is porcine-derived, or bleeding and injection into the fur rather than the subcutis.
lente-type insulin (Caninsulin® / Vetsulin®, Intervet) licensed The owner must recognize the symptoms of hypoglycemia,
for use in dogs. In some countries, other insulins (Insuvet® recurrence of polyuria and polydipsia, and symptoms of dia-
Lente, Insuvet® PZI, both Schering Plough; PZIVet®, betic ketoacidosis, and understand that these require consul-
IDEXX) are also available for veterinary use. Lente insulin is a tation with the hospital. The owner should also know that the
mixture of 30 % short-acting amorphous and 70 % long-act- insulin should be stored in the refrigerator in the up-right
ing crystalline insulin. The starting dose is 0.25–0.5 U/kg, position and that Caninsulin is a U-40 insulin, in contrast to
administered twice daily. Once-daily administration of a U-100 insulins for humans, and that only a U-40 syringe
higher dose is not recommended because it increases the risk should be used.
of hypoglycemia.36,37 The diabetic patient should receive
meals of constant composition and caloric content, fed at the It usually takes two to three months for reasonable glycemic
same times each day, just before each dose of insulin. A high- control to be achieved, but lifelong supervision and periodic
fiber diet (쏜 8 % fiber on a dry-matter basis) is preferred.38,39 adjustment of therapy is usually needed. Follow-up examin-
To simplify treatment, dogs are fed two meals of equal size. In ations should be made at one, three, six to eight, and ten to
those that are obese, the meals should be reduced to achieve a twelve weeks after diagnosis, and then approximately every
1 % reduction in weight per week. Concurrent severe disease four months. The examination includes assessment of the
such as pancreatitis or renal failure usually requires a different owner’s observations of symptoms, measurement of body
dietary regimen, which has priority over the dietary manage- weight, and measurement of blood glucose and fructosamine
ment of diabetes. concentrations. The presence or absence of polyuria, poly-
dipsia, polyphagia, lethargy, and weight loss are used to assess
Intact bitches that have developed diabetes during diestrus the quality of metabolic control.40
should be castrated as soon as possible, eventually after one to
three days of stabilization with insulin. Most remain hyper-
Diabetes mellitus 165
Figure 5.13:
Obtaining a blood drop from the inner surface of the pinna of
a diabetic dog, using the slight suction created by a lancing
device.
levels of stress and exercise. Individual curves may thus not re-
flect the true glycemic situation, regardless of whether they
are obtained in the hospital or at home. However, one of the
major advantages of HM is that it enables the BGC to be
measured frequently, which may be of particular importance
in animals that are difficult to regulate or in which insulin re-
sistance is likely to decrease and needs close supervision
(fig. 5.14).
It is currently assumed that in approximately 80 % of diabetic diabetes. When b-cells are healthy, the adaptive response to
cats the disease resembles type 2 diabetes, based on clin- obesity and insulin resistance is an increase in insulin secre-
ical characteristics and islet histology.21 Type 2 diabetes is a tion, so that normal glucose tolerance is maintained. How-
heterogeneous disease involving a combination of impaired ever, when there is b-cell dysfunction, glucose tolerance is
insulin action (insulin resistance) and b-cell failure. Environ- impaired and eventually type 2 diabetes results. Initially, the
mental and genetic factors play a role in the development of first phase of insulin release is markedly reduced, whereas the
both factors, but the genetic factors have not yet been char- second phase is delayed and often exaggerated. This is the
acterized in cats. The most convincing arguments for the threshold situation before the development of overt hyper-
existence of genetic factors have been derived from studies in glycemia and symptoms of diabetes, and it occurs when insu-
Australia and the UK in Burmese cats, in which the fre- lin secretion capacity is reduced by 80–90 %.54,55
quency of diabetes was shown to be about four times higher
than in domestic cats.45,46 Additional risk factors include in- It is not yet known what is responsible for the reduction in in-
creasing age, male gender, being neutered, physical inactivity, sulin secretion and the progression to diabetes: amyloid de-
glucocorticoid and progestin administration, and obes- position, glucotoxicity, and /or lipotoxicity? Islet amyloid is
ity.44,46,49 As in humans, the most important risk factor in cats derived from amylin (also called islet amyloid polypeptide), a
is obesity and it has been shown that obese cats are 3.9 times hormone cosecreted with insulin from b-cells. Cats are
more likely to develop diabetes than those of optimal among the few species in which the amino acid sequence of
weight.50 In healthy experimental cats an average weight gain amylin predisposes it to fold into b-pleated sheets. These are
of 1.9 kg during a feeding trial was associated with a more deposited as amyloid in the islets, leading to loss of b-cells
than 50 % decrease in insulin sensitivity. Male cats tended to (fig. 5.15). It is assumed that amyloid deposition is accelerated
have lower insulin sensitivity prior to the trial and gained in a state of insulin resistance, which leads to increased cose-
more weight than did female cats, which might explain their cretion of insulin and amylin. Amyloid deposition is found in
greater risk for diabetes.51 about 90 % of cats with diabetes, but it is also a frequent find-
ing in older healthy cats56 and hence it probably should be re-
In humans it is now well accepted that adipose tissue is an im- garded as a contributing factor and not the primary cause of
portant endocrine organ, producing various factors col- b-cell failure.
lectively termed adipokines that influence insulin sensitivity.
Among them are leptin, adiponectin, and proinflammatory Glucose toxicity is the concept that prolonged hyperglycemia
cytokines such as TNF-a and IL-6 (see also chapter 5.2.1).52 impairs insulin secretion by the b-cells. The phenomenon can
Preliminary studies in obese cats have shown that, as in hu- be nicely demonstrated in healthy cats in which insulin secre-
mans, adiponectin levels decrease in obesity while leptin and tion ceases after three to five days of continuous induction of
TNF-a levels increase.53 It is important to note that although high blood glucose levels.57 Initially, the suppression of insulin
obesity induces insulin resistance, not all obese cats develop secretion is reversible, but eventually the b-cell damage be-
168 Endocrine Pancreas
comes permanent. Lipotoxicity is the analogous effect of ex- have overt signs of diabetic neuropathy, such as hind limb
cessive fatty acids on the b-cells, although the damage has not weakness, decreased ability to jump, and plantigrade posture
been shown as convincingly as with glucose. These are very (fig. 5.17). There is rarely weakness of the front legs as well.
important concepts because immediate treatment of diabetes Lethargy and a dry, unkempt haircoat are common. Physical
may reverse the adverse effects of glucose toxicity and in- examination often reveals hepatomegaly and neurological ab-
creases the probability of complete remission of the diabetes. normalities consistent with peripheral neuropathy. Cats have
Due to glucose toxicity, circulating insulin concentration at long been assumed not to develop diabetic cataracts, but a re-
the time of diagnosis is usually low58 and thus measuring in- cent study of 50 diabetic cats showed that almost all had lens
sulin does not help to predict whether remission is possible. opacities that were more pronounced than in nondiabetic
cats. They were much less severe than in diabetic dogs, being
Other specific types of diabetes (formerly called secondary detected only by ophthalmic examination, and none of the
diabetes) in the cat account for approximately 20 % of cases. cats was blind.60
The causes include pancreatitis, hypercortisolism, hyperso-
matotropism (acromegaly), and exposure to diabetogenic In cats with concurrent disease such as pancreatitis, hypercor-
hormones (progestins, glucocorticoids). Pancreatic lesions are tisolism, or hypersomatotropism, other symptoms and signs
often identified by ultrasonography or by islet histopath- may be more prominent. Those with diabetes complicated
ology,59 but they are often mild and thus probably not the by ketoacidosis or hyperosmolar nonketotic syndrome are
initiating cause of diabetes. Some cats, however, have serious usually presented with lethargy, anorexia, reduced water in-
pancreatitis, which could be the factor that triggers diabetic take, and vomiting (see below).
ketoacidosis. It is generally difficult to decide which of the
two – diabetes or pancreatitis – is the cause and which is the Diagnosis and workup
effect (see also chapter 5.2.3). Glucocorticoids and growth The diagnosis and workup are generally similar for dogs and
hormone have strong diabetogenic actions, and approxi- cats but a few differences should be noted. First, the renal
mately 80 % of cats with hypercortisolism and presumably threshold is higher in cats than in dogs (cats ~ 15 mmol/l,
100 % of those with hypersomatotropism are diabetic. dogs ~ 10 mmol/l) and thus glucosuria does not occur until
blood glucose reaches a higher level. Second, cats are prone to
Signalment and clinical manifestations stress-induced hyperglycemia that may be difficult to differ-
Diabetes occurs most often in middle-aged to elderly cats, entiate from diabetes; it can be mild but concentrations
more than 95 % being older than five years. There is a strong 쏜 15 mmol/l are not exceptional and thus glucosuria may
sex predilection, approximately 70 % being male. Burmese also be present.61,62 Stress hyperglycemia may be recognized
cats are at risk, but no other breed has been reported to when repeated blood glucose measurements also reveal nor-
be. Approximately 60 % of diabetic cats are overweight mal values, but some cats have stress hyperglycemia during
(fig. 5.16), 35 % are of normal weight, and 5 % are under- their entire stay in the hospital. This can be resolved by
weight. measuring fructosamine, which is above 400 µmol/l in dia-
betic cats and may be as high as 1500 µmol/l, but is not elev-
Most diabetic cats have classical symptoms of diabetes: poly- ated in cats with stress hyperglycemia. Fructosamine concen-
uria, polydipsia, polyphagia, and weight loss. About 10 % tration may also be normal when diabetes is of very recent
Diabetes mellitus 169
Treatment
The aim of therapy is identical in dogs and cats, namely, good Since 80 % of diabetic cats have type 2 diabetes, oral hypogly-
control of the clinical features. This is usually achieved if cemic drugs may in theory be used. Five classes of these drugs
blood glucose is maintained between 15 and 5 mmol/l have been approved for treatment of type 2 diabetes in hu-
throughout the day. Cats can be more difficult for the owner mans and others are under investigation (table 5.3). Except
to treat and it is very important to provide sufficient for sulfonylureas, they have either not been investigated in
information on all relevant aspects of the disease as well as diabetic cats (meglitinide, thiazolidinediones) or have been
ready access to veterinary support when needed. Treatment found unsuitable for use as the sole agent (biguanide, a-glu-
should follow a precise and easily understood protocol (see cosidase inhibitors). Sulfonylureas stimulate insulin secretion
chapter 13.3.1), with written instructions for the owner. and thus some residual b-cell function is required for them to
170 Endocrine Pancreas
The initial dose of lente insulin is 1 U/cat twice daily for cats
weighing 쏝 4 kg and 1.5–2.0 U twice daily for those weigh-
ing 쏜 4 kg. If blood glucose is 쏝 20 mmol/l at the time of
diagnosis, the initial dose is no more than 1 U twice daily, in-
dependent of body weight.
5 The cat may be hospitalized for one to two days until the
workup is completed. Blood glucose is measured three to four
times over the day and the dose of insulin is reduced if glucose
is found to be 쏝 5 mmol/l. The twice-daily dose is increased
in increments of 0.5–1.0 U at intervals of five days. Satisfac-
tory regulation is usually achieved in one to three months.
The initial workup and onset of treatment can also be man-
aged on an outpatient basis.
Intermediate-acting insulins are preferred in cats with un- Opinions on diets for diabetic dogs and cats have changed in
complicated diabetes. A porcine derived, lente-type insulin recent years. The cat is a true carnivore, which distinguishes it
(Caninsulin® / Vetsulin®, Intervet) is licensed for use in cats clearly from the omnivorous dog. The natural diet of wild fe-
Diabetes mellitus 171
5.2.5 Problems associated with the 5.2.6 Diabetic ketoacidosis (DKA) and
regulation of diabetes in dogs and hyperglycemic hyperosmolar
cats state (HHS)
Most animals can be adequately stabilized within the first DKA and HHS are the two most serious complications of
three months of therapy, but periodic adjustments continue to diabetes mellitus. Both are potentially life threatening and
be needed, as in the case of further loss of b-cells or a change require immediate intense therapy.
in insulin sensitivity due to other disease. If symptoms persist
in spite of insulin therapy, the following stepwise approach DKA is defined as hyperglycemia, metabolic acidosis, and hy-
can be used. perketonemia (with ketonuria). It is frequently the initial pres-
5 enting manifestation of diabetes, but it may also occur at any
First step. Confirm that the initial workup and treatment time during treatment. It results from a relative or absolute de-
thus far have been according to the protocol in chap- crease in insulin together with an increase in glucagon and other
ter 13.3.1. Then increase the dose of lente insulin every five stress hormones. In at least two-thirds of cases there is a con-
to seven days until it reaches 1.0–1.5 U/kg twice daily. current disease, such as urinary tract infection or pancreatitis,
which may increase stress hormone release and trigger DKA.78,79
Second step. Confirm that the insulin used by owner is not
outdated, has not been diluted, frozen, or heated, and is Insulin deficiency and stress hormone excess cause the release
mixed correctly before being drawn into the syringe. Con- of large amounts of free fatty acids from adipose tissue, which
firm that the syringe is for U-40 insulin and not U-100. Ob- are then transported to the liver. Hepatic reesterification of
serve the owner’s method of mixing, drawing up, and inject- the fatty acids is impaired, in favor of their entry into mito-
ing the insulin. Review the diet and exercise regimen. chondria and oxidation to ketone bodies (acetoacetate, b-hy-
droxybutyrate, and acetone). Acetoacetate and b-hydroxy-
This second step in problem-solving is often neglected, but butyrate are acids that cause metabolic acidosis. They are
the technical errors it covers are frequent causes of problems eliminated via the kidney, which exacerbates osmotic diuresis,
in regulation. dehydration, and electrolyte loss. Additionally, hepatic gluco-
neogenesis and glycogenolysis are enhanced and peripheral
Third step. Perform a BGC to determine whether there may glucose utilization is reduced, which causes hyperglycemia,
be a Somogyi effect or short duration of insulin effect. Blood osmotic diuresis, and volume depletion.
glucose should be measured at home every 1–2 h for at least
12 h. The symptoms depend on the stage at the time of presentation.
Classical symptoms of diabetes (polydipsia, polyuria, polypha-
Fourth step. If no explanation for the problem has been gia, weight loss) have usually occurred previously but have
identified, diseases causing insulin resistance should be con- been unnoticed or disregarded by the owner. As the metabolic
sidered. In principle, any concurrent disease – inflammatory, situation deteriorates, lethargy, anorexia, vomiting, abdominal
infectious, or neoplastic – may cause insulin resistance. The pain, dehydration, weakness, collapse, and mental dullness
most relevant possibilities are pancreatitis, pancreatic neopla- usually develop. Mental depression (sopor, stupor, or even
sia, hypercortisolism, hypersomatotropism (cat), diestrus coma) can be due to dehydration, shock, severe acidosis, and
(dog), infection of oral cavity or urinary tract, chronic renal hyperglycemia / hyperosmolality. Dehydration results from os-
failure, and obesity. motic diuresis together with insufficient water intake due to
anorexia and /or vomiting. Kussmaul respiration (a slightly in-
Poor absorption of insulin can be considered in cats receiving creased, deep breathing pattern) can be observed in severe cases
PZI insulin and can be evaluated by changing to lente insulin. due to respiratory compensation of metabolic acidosis. The pa-
Circulating insulin antibodies can also be considered and it tient’s breath can have a fruity or acetone odor. Abdominal pal-
may be worth trying insulin of a different species. pation may reveal hepatomegaly. Icterus is a frequent pres-
enting sign in cats with DKA, due to severe hepatic lipidosis,
Hypoglycemia is always a potential problem during insulin pancreatitis, or pancreatic neoplasia causing extrahepatic cho-
therapy. It may be the result of decreasing insulin resistance, lestasis. Signs of a concurrent disease may also be present.
remission of the diabetes, twice daily administration of a
long-acting insulin, inappetence, or vomiting. Typical laboratory findings are ketonuria and metabolic aci-
dosis (reduced blood levels of bicarbonate and total carbon
dioxide, TCO2), together with hyperglycemia, glucosuria,
and elevated plasma fructosamine. Increased plasma levels of
liver enzymes are also common. Hypovolemia can cause an
elevated hematocrit, prerenal azotemia, elevated total protein
and albumin, and lactic acidosis. As a result of the osmotic
The hypoglycemic syndrome 173
diuresis and acid-base disturbances, hyponatremia, hypokale- glycemia alone, but – according to Whipple’s triad – hypo-
mia, and hypomagnesemia may be present. Hypophosphate- glycemia accompanied by symptoms that are relieved by ad-
mia is also possible which, especially in cats, may cause an ministration of glucose (or feeding).81
acute hemolytic crisis (plasma phosphate concentration often
쏝 0.5 mmol/l). A low blood glucose value, especially if unexpected, may be an
artifact (table 5.4). PBGM devices measure glucose quickly
b-hydroxybutyrate is the most abundant ketone body in DKA and conveniently, but are less accurate than measurements in
but it is not detected in urine by most test strips for ketones. an accredited veterinary laboratory. To exclude artifact as the
Hence the test for ketonuria may be only moderately positive cause of a low glucose values, an accurate measurement should
in an animal with DKA. be made in two or more separately-collected blood samples
before undertaking an extensive diagnostic workup.
DKA is one of the most complex metabolic emergencies and 5
its treatment is demanding. It requires 24 h surveillance with The symptoms of hypoglycemia are due to activation of the au-
frequent reevaluation of clinical and laboratory parameters tonomic nervous system, i.e., neuronally-released transmitters
and appropriate adjustments of therapy (see also protocol in as well as epinephrine and norepinephrine released by the ad-
chapter 13.3.2). Rehydration should be started immediately renal medulla, and the lack of an energy substrate available to
with a balanced electrolyte solution at a rate that will normalize the central nervous system (neuroglycopenia) (table 5.5). The
hydration in ~ 12 h. In most cases, correction of hypovolemia
will also restore the acid-base balance quickly and additional
treatment with bicarbonate to correct metabolic acidosis is
often unnecessary and can even be detrimental. Potassium Table 5.4: Causes of artifactual hypoglycemia
deficits may be severe, although the initially measured value
A. Collection and handling of the blood sample
may be normal, and correction must be started before treat-
ment with regular insulin is begun. Since plasma phosphate le- Prolonged storage of blood (쏜 1 h) before separation of serum / plasma from the
cell component, particularly if blood is not collected in a sodium fluoride-coated
vels may also be low or may decrease quickly with fluid therapy, tube. (Sodium fluoride inhibits glucose metabolism by blood cells.)
phosphate may also be supplemented. Concomitant potassium
Hemolysis of the blood sample can interfere with the measurement technique.
supplementation should be reduced if potassium phosphate is
Especially in sodiumfluoride-coated tubes hemolysis can be severe (centrifuge
used for phosphate supplementation. Initially, electrolytes within 30 min after collection).
should be reevaluated every 4–6 h. Regular insulin therapy
Plasma or serum samples older than 24–48 h.
should be started ~ 4 h after the beginning of fluid therapy and
correction of electrolytes. Intermittent IM injection of insulin B. Measurement
is used most often but constant IV infusion is also a good option
Portable blood glucose meters (developed for human diabetes mellitus patients)
(see chapter 13.3.2). Fluid therapy can be tapered off and lente can give erroneously low glucose concentrations due to
insulin can be started when the animal is stable, eats and drinks, 쎱 insufficient application of blood, despite »beep« given by device as an
and does not vomit. The prognosis is guarded and ~ 25 % of pa-
indication of the opposite,
tients with DKA die or are euthanized. 쎱 tendency of these devices to give lower than actual blood glucose values*,
쎱 blood samples with a high hematocrit value.
HHS is much less common than DKA. Patients with HHS Incorrect use of other laboratory devices to measure glucose.
have severe hyperglycemia (쏜 30 mmol/l), severe hyperos-
Error of other laboratory devices used to measure blood glucose.
molality (쏜 340 mOsm/kg), and profound dehydration,
without acidosis or ketonuria. The pathogenesis of HHS is * Note that glucose concentration measured by a PBGM is lower in venous blood than in
similar to that of DKA, but why some diabetic patients DKA capillary blood, which is lower than in arterial blood. The differences can be several tenths
and others develop HHS is not known. In most cases, serious of a mmol per liter.
concurrent diseases contribute to the development of HHS,
renal failure being particularly common. The principles of Table 5.5: Symptoms and signs of hypoglycemia
treatment are identical to those of DKA. The prognosis is
guarded to poor and most animals die or are euthanized.80 Autonomic symptoms Neuroglycopenic symptoms
Adrenergic symptoms Lethargy
Muscle twitching Behavioral changes
Muscle tremors Confusion
5.3 The hypoglycemic syndrome Anxiety Generalized muscular weakness
Polyuria /polydipsia Posterior paresis
The hypoglycemic syndrome is primarily characterized by Cholinergic symptoms Visual impairment (»blindness«)
a low circulating glucose concentration. Values below Hunger Ataxia
2.8 mmol/l are often accompanied by symptoms, but values Polyphagia Seizures
just below the lower limit of the reference range may not be. Loss of consciousness
Death
Hence the hypoglycemic syndrome is not defined by hypo-
174 Endocrine Pancreas
severity of the symptoms and signs depends on the glucose 5.3.1 Insulinoma
nadir: convulsions and loss of consciousness often occur when
plasma glucose concentration is 쏝 2.8 mmol/l. The rate of Insulin-secreting pancreatic endocrine tumors (PETs), more
decrease and the duration of the hypoglycemia also determine commonly known as insulinomas (fig. 5.21), continue to pro-
the severity of the symptoms and signs. The blood glucose duce insulin despite the hypoglycemia they provoke. Immu-
threshold for symptoms of hypoglycemia also depends on in- nohistochemical staining of these insulin-secreting PETs
dividual variation and the underlying disease. often reveals that they are also positive for somatostatin, glu-
cagon, gastrin, pancreatic polypeptide, and /or growth hor-
Glucose is the primary energy substrate for the brain. In mone.85–87 In addition, IAPP immunoreactivity and IAPP-
contrast to other tissues, the brain cannot utilize free fatty derived amyloid deposits have been found in 25 % of primary
acids as an energy source. In addition to glucose it can use ke- PETs.88
5 tone bodies, which are metabolites of free fatty acids, but they
can only provide up to half of the energy requirement. More- The first case of insulinoma in a dog was reported in 1935 by
over, in adult dogs fasting leads to an appreciable ketosis after Slye and Wells.89 Since then, insulin-secreting PETs have
only days to weeks.82 Thus preservation of the function of the been diagnosed in many dog breeds, especially medium-to-
central nervous system in postprandial or fasting states is large breeds, and rarely in small breeds, such as the West
mainly dependent upon increased production of glucose. Highland white terrier.90,91 There is no pronounced breed or
sex predisposition. At the time of diagnosis the dogs’ ages vary
Initially the glucose is derived almost exclusively from hepatic between 4 and 13 years, with an average of about 8½ years.92
glycogen (fig. 5.7), but glycogenolysis can only sustain the Insulinomas are rare in cats; reports are confined to single
plasma glucose concentration for a short period and after cases.93–95
about two days of fasting, liver glycogen stores are completely
depleted.83 Secondly, glucose production in the liver and kid- Canine insulinomas are often solitary (~ 90 %) and usually
neys is activated. The precursors for hepatic glucose synthesis 쏝 2.5 cm in diameter. Ten to 14 % of insulinomas are
are glycerol released from adipose tissue and lactate /pyruvate multiple or grow diffusely.96,97 In the dog they are often ma-
and amino acids derived from muscle. In the adult dog the lignant (쏜 95 %) and there are macroscopically visible meta-
catabolic state of fasting is primarily the result of a decrease in stases, primarily in regional lymph nodes and the liver, in
insulin release; secretion of the counterregulatory hormones 40–50 % of cases at the time of surgery.
glucagon and growth hormone does not change signifi-
cantly.82 Clinical manifestations
Symptoms related to insulinoma are almost always the result
When these corrective mechanisms do not compensate in- of hypoglycemia (see table 5.5) and only rarely due to mass
creased peripheral glucose utilization (demand-side hypo- effects. Initially, the changes in locomotion and behavior due
glycemia) or decreased availability of glucose (supply-side to hypoglycemia are often subtle and are commonly disre-
hypoglycemia), the syndrome of hypoglycemia may occur. garded by the owner. The symptoms occur intermittently and
There are several, often critical, illnesses in which the hypo- can frequently be related to fasting, excitement, or exercise.
glycemia is not severe (쏜 3.0 mmol/l) and symptoms do not There may be weight gain if the owner has responded to the
occur. In diseases such as sepsis, severe parenchymal liver dis- animal’s increased appetite. This is an important clue, for in-
ease, or hypoadrenocorticism, hypoglycemia is often an inci- sulinoma is one of the few diseases that can cause an increase
dental finding and the clinical manifestations of the disease are in body weight. In most dogs the diagnosis is made within five
not related to it. In addition, symptoms and signs that may be months of the onset of symptoms. Apart from occasional
ascribed to hypoglycemia, such as lethargy, muscle weak- obesity, no abnormalities are found by physical examination.
ness, and confusion, may also be related to other aspects Peripheral neuropathy is a rare occurrence with insulinoma.
of the disease. Long-term starvation (especially in young The associated proprioception deficits and depressed spinal
individuals), portosystemic shunting, hypoadrenocorticism reflexes are the result of degenerative changes in the radial and
(chapter 4.2), and polycythemia are examples of disorders ischiadic nerves.98,99 Apart from the hypoglycemia, results of
that rarely present with symptoms related to hypoglycemia routine laboratory investigation are usually unremarkable.
alone.84 An example in which the symptoms are solely due to
hypoglycemia is increased utilization of glucose due to an Differential diagnosis
overdose of exogenous insulin or oral hypoglycemic drugs In middle-aged and elderly dogs, other causes of the hypogly-
such as sulfonylurea derivatives (chapter 5.2). The following cemic syndrome are limited to nonpancreatic tumor, porto-
discussion is confined to disorders that are mainly character- systemic shunting, hypoadrenocorticism, and polycythemia.
ized by symptoms and signs of the hypoglycemic syndrome: However, in the latter disorders there are rarely symptoms of
insulinoma, nonpancreatic tumors associated with hypoglyce- hypoglycemia.
mia, and juvenile hypoglycemia.
The hypoglycemic syndrome 175
Diagnosis
When a presumptive diagnosis has been made on the basis of
the signalment and a detailed medical history but the plasma
glucose concentration is not low, it should be measured on
two or more occasions before feeding in the morning, after
fasting overnight. If hypoglycemia is not found but there have
been convincing symptoms of it, a supervised fast can be
undertaken. Fasting for 24 h is in most cases sufficient to re-
veal hypoglycemia, but if not, fasting is prolonged for up to
72 h, with repeated measurements of blood glucose. The
chronic nature of this disease often results in few or no symp-
toms at plasma glucose concentrations even 쏝 2.8 mmol/l. 5
For glucose to pass the blood-brain barrier, it requires a car-
rier system consisting of membrane-associated glycoproteins,
i.e., glucose transporters (GLUT) (see chapter 5.1.4). It has
been postulated that patients with insulinoma have increased
uptake of glucose by the brain via changes in the setup of
these glucose transporters.100,101 Hence requiring Whipple’s Figure 5.21:
triad to be fulfilled by the presence of symptoms in order to Insulinoma of a ten-year-old male Malinese shepherd during surgery.
confirm the diagnosis of the hypoglycemic syndrome could
be hazardous. However, the medical history and a low plasma
glucose concentration are often sufficient, so that it is not
necessary to provoke signs of hypoglycemia. Plasma fructos-
amine or glycosylated hemoglobin concentrations can be
measured as complementary investigations; low plasma con- Measurements of circulating C-peptide and proinsulin con-
centrations of these may be indicative of prolonged hypo- centrations (chapter 5.1.2), which are used in the diagnosis of
glycemia in dogs with insulinoma.102,103 insulinoma in humans, have not been developed for dogs, but
could support the presumptive diagnosis and differentiate
The hallmark of the diagnosis is the association of persistent exogenous hyperinsulinism.108,109 Provocation tests, such as
hypoglycemia and inappropriately high plasma insulin the intravenous glucose tolerance test and glucagon tolerance
concentrations. Circulating insulin concentrations are typi- test, have been used in dogs with insulinoma.104,110 However,
cally within the reference range or higher despite hypogly- as in humans, the value of these tests has been too limited to
cemia. The simultaneous occurrence of blood glucose justify their routine use and, in addition, they may provoke
쏝 3.5 mmol/l and plasma insulin 쏜 10 mU/l (70 pmol/l) is severe hypoglycemia.96,97
diagnostic.104 Insulin:glucose ratios, such as the amended in-
sulin-to-glucose ratio (AIGR), have been advocated to im- The survival time and quality of life of dogs with insulinoma
prove the diagnostic value of glucose and insulin measure- treated surgically may be longer and better than that of dogs
ments. However, there are two major reasons that limit the treated medically.111,112 Accurate detection, localization, and
presumed additional value of these ratios: staging of the primary tumor and metastases are essential for
쎱 Reference ranges vary between laboratories and assay the selection of appropriate candidates for surgery. A few
methods. More modern monoclonal antibody-based reports have described the use of transabdominal ultraso-
assays, such as the immunoradiometric assay (IRMA), nography, with varying results in detecting the primary pan-
measure lower plasma insulin immunoreactivity than the creatic tumor (36 % and 75 %).113–115 However, transabdomi-
outdated polyclonal antibody-based assay or radioimmuno- nal ultrasonography may be useful in detecting lesions in the
assays (RIA) in dogs with insulinoma.105 liver or peripancreatic tissues (regional lymph nodes) sug-
쎱 There are very erratic oscillations in plasma insulin con- gestive of metastatic disease or neoplasia of nonpancreatic
centration in human patents with insulinoma.106 The ac- origin. In a recent comparative study of three diagnostic im-
tion of insulin on the liver and peripheral tissues, and thus aging techniques [abdominal ultrasonography, computed to-
indirectly on plasma glucose concentration, may persist mography (CT), and somatostatin receptor scintigraphy
for 40 min or longer.107 Hence measuring glucose and in- (SRS)], CT was best in detecting and localizing the primary
sulin in the same sample will not necessarily reveal a direct tumor but often failed to identify metastatic lesions correctly
causative relationship. (fig. 5.22).115
176 Endocrine Pancreas
5
A B
Figure 5.22:
(A) Ventral view of a three-dimensional reconstruction of a SPECT
study performed 6 h after injection of [111In-DTPA-D-Phe1]-octreotide
in a seven-year-old neutered female beagle with a solitary b-cell
tumor in the left lobe of the pancreas. Radioactivity accumulated in
the kidneys, gall bladder (G), and gastric fundus (F), and in the pri-
mary tumor (T) in the left lobe of the pancreas. Some radioactivity
was detected in the intestinal tract.
(B, C) Corresponding transverse CT and SPECT images in the same
C dog. On the CT image the right kidney (K) and spleen (S) can be ident-
ified. (Modified from Robben et al., 2005.)115
Transabdominal ultrasonography and CT provide in- of the organs of interest or by use of intravenous methylene
formation on anatomical relations and the localization of blue infusion remain the standard for localization of primary
lesions. SRS provides more information on the nature of the tumors, and to a lesser extent, metastases.121
lesion. In vitro and in vivo studies have demonstrated that ca-
nine insulinoma tissues express somatostatin receptors.114,116 Treatment
At the mRNA level, expression of four somatostatin receptor Treatment of hypoglycemia due to insulinoma consists of life-
subtypes (SSTR1, 2, 3, and 5) was demonstrated in canine in- style changes, medical therapy, and /or surgery. Whenever
sulinoma tissues.117 SRS uses the 111In-labelled somatostatin possible, surgery is the treatment of choice, because it is the
analogue octreotide that binds with high affinity to soma- only option that can result in complete remission of the hy-
tostatin receptors, especially SSTR2 and to a lesser extent poglycemic syndrome. Owners should be informed that dogs
to SSTR5. The thus concentrated radionuclide can be vi- with insulinoma often have micrometastases and that the hy-
sualized with regular scintigraphy and even better with poglycemic syndrome frequently recurs after surgery because
single photon emission computed tomography (SPECT) of growth of these functional metastases.
(fig. 5.22).115–117 These scan results also could have predictive
value for the effectiveness of treatment with octreotide or oc- The goal of therapy should be alleviation of symptoms and
treotide-based radiotherapy.118 Currently, the described diag- not normalization of plasma glucose concentration per se.
nostic imaging techniques have a modest accuracy in detect- Most dogs with insulinoma appear to be comfortable even
ing canine insulinomas. A better understanding of the use of with subnormal plasma glucose concentrations. Physical ex-
CT and SRS in insulinoma could improve their accuracy, as ercise should be limited and excitement avoided to reduce the
could the combination of different imaging techniques.115,119 risk of a hypoglycemic crisis. A third important initial step is
Also, other currently available techniques – endoscopic and to divide the dog’s food over five to eight meals per day,
intraoperative ultrasonography – could prove useful in insuli- thereby shortening the intervals between meals. Changes in
noma detection.120 To date, the intraoperative localization the diet are not advised, for changes in diet composition have
and staging of canine insulinoma by inspection and palpation not been proved to be beneficial and they carry the risk of
The hypoglycemic syndrome 177
5
Figure 5.23:
Plasma concentrations (median and range) of glucose,
insulin, and glucagon after a single subcutaneous in-
jection of 50 µg octreotide at T = 0 min. Left panels:
healthy dogs, fasted overnight. Right panels: dogs with
insulinoma, without food for 4–6 h. Note the differ-
ence in response to octreotide (thus far unexplained):
In the healthy dogs a decrease in plasma insulin and
glucagon concentrations coincides with a minor de-
crease in plasma glucose concentration. In contrast, in
the dogs with insulinoma a decrease in insulin concen-
tration without a significant effect on plasma glucagon
concentration coincides with a significant increase
in plasma glucose concentration. Also note the wide
range of basal plasma insulin concentrations in the
dogs with insulinoma, in comparison with the healthy
dogs.
* Significantly different from baseline values. (Adapted
from Robben et al., 2006.)105
gastrointestinal disturbances that could increase the risk of a food. If side effects develop (ptyalism, anorexia, vomiting, and
hypoglycemic crisis. If symptoms of hypoglycemia persist in diarrhea), they can be stopped by reducing or temporarily
spite of these measures, the total amount of food fed over the stopping the drug. However, in a dog with insulinoma,
day could be increased, even though this could lead to weight necessitating a continuous intake of food, even these side ef-
gain. These simple measures may stabilize the dog for months fects can be hazardous. Hence lower doses of diazoxide can be
and should not be underestimated. combined with glucocorticoid therapy, which will also re-
duce the costs of therapy. Bone marrow depression and dia-
If these measures do not suffice, or no longer do so, and sur- betes mellitus are rare side effects of diazoxide.
gery is not an option, medical treatment can be undertaken to
control hypoglycemia. Glucocorticoids interfere with the ac- If these measures fail to prevent hypoglycemic symptoms, al-
tion of insulin and promote gluconeogenesis. The initial daily ternative medical therapies can be considered. Chemotherapy
dose of prednisolone is 0.5–1.0 mg/kg divided in two to with alloxan and streptozotocin has been tried to treat insuli-
three doses; this can be increased gradually if needed. Often noma, but the clinical results have been variable and protocols
high doses are needed, which frequently give rise to the side to reduce the risk of nephrotoxicity have not been well estab-
effects of iatrogenic hypercorticism. As an alternative, treat- lished.122 The somatostatin analogue octreotide (Sandosta-
ment can be started with diazoxide (Proglicem®, Schering- tin®, Sandoz, 50, 100 or 200 µg octreotide/ml) inhibits the
Plough, 100 mg diazoxide /capsule). This is a benzothiadia- secretion of insulin by unaffected and neoplastic b-cells. The
zide diuretic that inhibits insulin secretion. It also stimulates effect of a single dose of octreotide on plasma insulin and glu-
hepatic gluconeogenesis and glycogenolysis, and inhibits cose concentrations has been reported in dogs with insuli-
peripheral use of glucose. The initial dose is 10 mg/kg body noma (fig. 5.23).105 In contrast to humans, all dogs responded
weight divided in two daily doses. Doses as high as 60 mg/kg/ to a single subcutaneous dose of 50 µg octreotide. In humans,
day may be necessary to prevent symptoms of hypoglycemia the absence of high affinity somatostatin receptors can cause
Adverse reactions may be prevented or postponed by slowly worsening of hypoglycemia due to inhibition of the release of
increasing the dose to effect and by administering it with the counterregulatory hormones glucagon and growth hor-
178 Endocrine Pancreas
mone.123 The suppressive effect of octreotide on plasma insu- mia. These complications and /or nonresectable tumor mass
lin concentration in dogs lasts only 3–4 h, which could ex- may be reason for euthanasia.
plain treatment failures in dogs with insulinoma. The effect of
a slow-release formulation of octreotide has not yet been In most dogs, hypoglycemia due to insulin-secreting PETs re-
studied in dogs.124,125 curs after surgery, which suggests that most have metastasized
before they are diagnosed and surgery is attempted. For those
If despite treatment such serious hypoglycemic effects as that benefit from surgery, the mean survival time without
ataxia, convulsions, or even coma, develop, an emergency symptoms or the need for medication is 1–1.5 years, which
protocol should be started (see protocol in chapter 13.3.3). can be extended (in some cases to three years or more) by re-
This includes glucose administration, but should be followed suming the dietary measures and medication with diazoxide
as soon as possible by additional measures to maintain an or prednisolone or both.112
5 adequate plasma glucose concentration. If octreotide is being
considered, one should be aware that the delayed rise in
plasma glucose concentration in some dogs can be preceded
by an initial decrease (fig. 5.23).105 Hence it is preferable to 5.3.2 Nonpancreatic tumors associated
combine octreotide with other emergency measures. Fur- with hypoglycemia
thermore, it is important to note that somatostatin has been
shown to prevent the diazoxide-induced hyperglycemia in Pathogenesis
healthy dogs.126 Hypoglycemia may also result from a variety of tumors of
both epithelial and mesenchymal origin, most often the latter.
Surgery is undertaken not only to remove the tumor tissue, if The most frequent nonpancreatic tumors are leiomyoma,
possible, by partial pancreatectomy, but also for thorough in- leiomyosarcoma, hepatoma, hepatocellular carcinoma, and
spection of the abdomen for metastases, which may be of tumors with extensive hepatic metastases.128–130 In the past,
great prognostic importance. Depending on the findings dur- several mechanisms have been suggested to explain the hypo-
ing surgery, lymph node excision and partial hepatectomy glycemia: deranged tumor metabolism with excessive uti-
may also be necessary. A major concern is the perioperative lization of glucose, parenchymal liver destruction with failure
control of plasma glucose concentration. Medical treatment is of gluconeogenesis and glycogenolysis, ectopic insulin pro-
started preoperatively and if liquid diets are used in the final duction, and inhibition of glucagon release. Now there is
12–24 h before surgery, fasting can be reduced to the final convincing evidence that incompletely processed insulin-like
6 h. The use of a2-agonists during surgery may be beneficial growth factors (pro-IGF-II and IGF-I) cause the hypoglyce-
to control plasma glucose concentration. They inhibit insulin mia in humans,131,132 a mechanism that has also has been
release by postsynaptic a2-adrenoreceptor stimulation of pan- documented in a few cases of hypoglycemia in dogs (see also
creatic b-cells, although they may also activate hepatic gly- chapter 10.1).130,133
cogenolysis and stimulate growth hormone release.127 Plasma
glucose concentration is checked and corrected by infusion of Clinical manifestations and diagnosis
glucose, if necessary. Postoperatively, plasma glucose concen- The symptoms can be the result of the underlying tumor
tration is monitored closely and if there is euglycemia or hy- disease or the hypoglycemia (chapters 5.3, 5.3.1). The com-
perglycemia, any glucose infusion is gradually stopped. Small bination of a low plasma glucose concentration and a nonpan-
amounts of food and water are offered as soon as the dog is creatic tumor makes a paraneoplastic syndrome likely. The
able to accept them. Postoperative hypoglycemia is usually presumptive diagnosis can be strengthened by exclusion of
the result of incomplete removal of the tumor and /or meta- other differential diagnoses. Finding a low plasma glucose
stases. Successful surgery is often followed by hyperglycemia concentration together with a low plasma insulin concen-
for days or weeks, until the normal b-cells recover from sup- tration can help to exclude insulinoma (chapter 5.3.1). Find-
pression. Only rarely is insulin therapy needed to bridge over ing increased plasma levels of insulin-like growth factors is
this temporary deficiency. Pancreatitis can complicate post- one of the few options to support the cause-effect relation be-
operative stabilization. Depending on its severity and the tween the tumor disease and the occurrence of hypoglycemia.
associated vomiting and abdominal pain, and whether there is Resolution of hypoglycemia after successful treatment of the
persisting hypoglycemia, intravenous glucose and medi- tumor disease also supports the diagnosis of this paraneo-
cations (see above) will be necessary. plastic syndrome.
A presumptive diagnosis can be confirmed by finding an elev- Surgical resection is the first treatment option. Medical ther-
ated plasma glucagon concentration in the absence of hypo- apy with somatostatin analogues might be an option. Corti-
glycemia. Presurgical diagnostic imaging and exploratory la- costeroids should be avoided, as development of diabetes mel-
parotomy can help to localize the primary pancreatic tumor litus worsens the situation.143 The long-term prognosis is
and any metastases. As with other PETs, immunohisto- poor, because most glucagonomas are malignant and dogs
chemistry supports a definitive diagnosis (fig. 5.24). with this tumor are often seriously debilitated by the time of
diagnosis.
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130. ZINI E, GLAUS TM, MINUTO F, ARVIGO M, HAUSER B, NEUTEBOOM J. Hepatocutaan syndroom. Tijdschr Dierge-
REUSCH CE. Paraneoplastic hypoglycemia due to an insulin-like neeskd 2007;132:920–922.
growth factor type-II secreting hepatocellular carcinoma in a dog.
J Vet Intern Med 2007;21:193–195.
186 Gonadal Development and Disorders of Sexual Differentiation
Figure 6.1:
Schematic representation of male and female differentiation and development from the undifferentiated state under stimulation and inhibition of sex steroids and
regulatory peptides. The presence of a Y chromosome leads to male differentiation of the gonad with subsequent secretion of testosterone and Antimüllerian Hormone
(AMH). Testosterone stabilizes the former Wolffian (or mesonephric) duct. Dihydrotestosterone (DHT) is required for complete development of the external male genitalia
and closure of the urethra. Secretion of AMH by the fetal Sertoli cells is necessary to inhibit the growth and development of the Müllerian ducts into female internal
genitalia.
187
Figure 6.2:
Molecular events in mammalian sex determination.
Genes believed to have key functions are depicted:
WT1 = Wilms’ tumor gene; SF-1 = steroidogenic fac-
tor 1 gene; LHX9 = LIM homeobox protein 9 gene;
DAX-1 = dosage-sensitive sex reversal-adrenal hypo-
plasia congenita critical region on the X chromosome;
6 GATA4 = GATA binding protein 4 gene; SRY = sex de-
termining region of the Y chromosome; SOX9 = sex
determining region Y-box 9 gene; DMRT1 = doublesex
and mab-3 related transcription factor 1 gene; PAX2 =
paired box gene 2; PAX8 = paired box 8 gene; EMX2 =
empty spiracles homeobox 2 gene.
on the X chromosome, gene 1), a transcriptional regulator male ducts. The proximal part of the Wolffian duct coils and
that inhibits target genes.8 GATA4 encodes a transcription forms the epididymis and the distal part forms the vas defer-
factor that promotes SRY expression in the XY gonad.7 The ens. The seminal vesicles develop from lateral outgrowths of
LHX9 (LIM-homeobox 9) gene, encodes a homeodomain the caudal end of the vas deferens.
transcription factor that has been described as essential for
gonad formation in mice and gives rise to the development of In the absence of AMH and testosterone, female organo-
both Sertoli and granulosa cells.9 DMRT1, the doublesex and genesis proceeds by regression of the mesonephric Wolffian
mab-3 related transcription factor 1, is conserved among ver- ducts and stabilization of the Müllerian ducts (fig. 6.1). De-
tebrates, is involved in testis differentiation in mammals, birds, velopment of the Müllerian ducts takes place in the cranio-
reptiles, amphibians, and fish, and is associated with Sertoli caudal direction, to give rise to the female internal genitalia.
cell maturation. The cranial portion of the Müllerian duct gives rise to the
oviducts. The middle portion gives rise to the uterine horns,
which fuse caudally to form the body of the uterus. The cau-
dal portion gives rise to the uterovaginal plate with the par-
6.1.3 Development of the Wolffian ticipation of both Müllerian and Wolffian duct components,
and Müllerian ducts to form the cervix and cranial vagina. The urogenital tubercle
of the female undergoes limited growth and remains exposed
The internal genitalia derive from the genitourinary tract, as a cleft into which the vagina and urethra open.11,12 The
which is initially identical in male and female embryos Wolffian ducts recede in female mammals but remnants may
(fig. 6.1). At the indifferent stage, male and female embryos be present in the form of an appendix vesiculosa, epoopho-
have two identical sets of paired ducts: the Müllerian ron, paroophoron, or duct of Gartner.13
(paramesonephric) ducts and the Wolffian (mesonephric)
ducts.1 Whether there is development of Wolffian ducts for
the male or the Müllerian ducts for the female depends on 6.1.3.1 Genes essential for development of Wolffian
autosomal genes that permit or prevent the production of and Müllerian ducts
AMH (anti-Müllerian hormone or Müllerian inhibiting sub- Several genes are involved in the initial development of the
stance (MIS)) in the Sertoli cells of the fetal gonad. AMH is Wolffian and Müllerian ducts. Thus, contrary to the older
the first secretory product of the fetal testis and thus marks the view that fetal ovarian development is passive, female germ
end of the testis induction period and the beginning of testis cell differentiation and normal fetal ovarian morphogenesis
function.6 Müllerian duct regression in male dogs begins by require the expression and collaboration of various genes.
day 36 of gestation and is completed at day 46.10 PAX2 (paired box gene 2), a transcriptional regulator of the
paired-box family, is expressed in the epithelium of the me-
When the Leydig cells in the male gonad begin to produce sonephric tubules as well as in the Wolffian and Müllerian
testosterone, it determines the further development of the ducts. PAX8 is coexpressed with PAX2 and has additional
Abnormal sexual differentiation 189
Figure 6.4:
Four male cats with the tortoiseshell coat color indicat-
ing a chromosomal anomaly. The two at the top of
the picture had the XXY syndrome and the two at the
bottom were XX / XY chimeras. The latter two were
presumed to be fertile because spermatogenesis was
observed in some seminiferous tubules.
tein, Y-linked) gene. Gonadal sex should be determined by Chimeras arise from fusion of two or more zygotes after con-
histological examination of the gonads by a person experi- ception, while mosaics originate from a single zygote and the
enced in this field; ultrasonographic examination is not con- chromosome abnormality usually results from a mitotic non-
clusive. Phenotypic sex can be determined by physical exam- disjunction. Neither disorder is considered to be inherited.
ination, diagnostic imaging of the abdomen, and hormone
measurements. XX / XY chimeras have been described in several dog breeds.
A uterus, cervix, and ovaries with follicles were found in a
dachshund with a small prepuce and a scrotum lacking testes.
The penis could not be extruded from the prepuce.20 An
6.2.1 Disorders of chromosomal sex XX / XY karyotype was also demonstrated in a Belgian shep-
herd dog with male behavior, abdominal testes, and a
6.2.1.1 Chimerism and mosaicism of uterus.21 Ovotestes and a uterus were present in a schipperke
sex chromosomes with an enlarged clitoris.22 An abnormal phenotype has been
Errors in the constitution of the sex chromosomes can in- found in all of the reported cases of an XX / XY karyotype in
fluence gonadal differentiation. The majority of animals with dogs. Cases of 78,XX / XY chimerism with both ovarian and
sex chromosome abnormalities have few symptoms, the most testicular tissue are termed true hermaphrodites.
common being primary anestrus in phenotypic females and
infertility in phenotypic males.18 In some cases ambiguous Chimerism of sex chromosomes is also known in cats, occur-
genitalia provide an impetus for further investigation.19 ring most often in fertile tortoiseshell (calico) colored tom
cats (fig. 6.4). Most of these have both a 38,XX and a 38,XY
In both chimerism and mosaicism of the sex chromosomes cell line.23–25 Among 38 tortoiseshell colored tom cats, 7 had
the animal has two or more genetically different cell lines. the XX / XY karyotype.26 Some were fertile males or pre-
Abnormal sexual differentiation 191
sumed to be fertile. A 38,XX /38,XY chimera with ovotestes The most prominent manifestation of gonadal dysgenesis is
was reported by Leaman et al.27 The presence of an ovotestis is primary anestrus. The onset of puberty occurs at six to
often seen in chimeras in other species, but this is the only re- 23 months of age in the normal bitch and at four to
ported case in cats. 21 months of age in the queen, and in both species the diag-
nosis of primary anestrus requires the absence of pubertal es-
Chimerism in cats and dogs is usually whole body, i.e., in all trus by 24 month of age.35 For the diagnosis of gonadal dys-
tissues. Blood chimeras, well known in freemartin cows, have genesis other possible causes of primary anestrus must be
not been reported in cats or dogs and are unlikely because of excluded. These include mosaicism, chimerism, XX- or XY-
the difference in placental structure. sex reversal syndrome, male or female pseudohermaphrodit-
ism, oophoritis, and hypothyroidism. The plasma concen-
The only reported case of mosaicism involving the sex chro- trations of LH and FSH will be elevated in the absence of
mosomes in a dog was an infertile female toy poodle with a ovarian tissue. The final diagnosis should rest upon the cyto-
77,X0/78,XX karyotype and no signs of intersexuality.28 As genetic demonstration of X-monosomy. In addition, histo-
in the X0 syndrome (see below), there was dysgenesis of both logical examination of gonadal tissue obtained by laparoscopy
gonads. In addition to small ovaries, there was a relatively or at laparotomy can confirm the diagnosis of gonadal dys- 6
small uterus without a functional body. genesis.
Karyotyping is necessary for the diagnosis of chimerism or In an unusual case in an Eskimo dog, there was persistent
mosaicism in order to define the sex chromosome error. This proestrus which necessitated ovariohysterectomy,29 but in
can be performed on peripheral blood lymphocytes or cul- most cases no therapy is required for there are no physical
tured fibroblasts. changes that interfere with the health of the animal.
Figure 6.5:
Karyotype of a cat with two X chromosomes and a
Y chromosome (similar to Klinefelter’s syndrome
6 in man). Chromosomes are arranged according to a
standardized system developed for the domestic cat.
(Courtesy of Dr. A.A. Bosma, Department of Functional
Morphology, Faculty of Veterinary Medicine, Utrecht
University.)
allele is expressed. The same situation occurs in tom cats with year-old Labrador retriever bitch with anestrus.47–49 The
the XXY syndrome. Tortoiseshell tom cats often have a XXX syndrome has not been reported in cats, but one case of
39,XXY karyotype (fig. 6.5), but other observed karyotypes 37,X0/39,XXX mosaicism has been reported in a pregnant
include 38,XX /39,XXY, 38,XX /57,XXY, 38,XY/ cat with one normal ovary containing follicles and one dys-
57,XXY, 38,XY/39,XXY/40,XXYY, and 38,XX /38,XY/ genetic ovary lacking corpora lutea or developing follicles.50
39,XXY/40,XXYY.26,42–45 Not all cats with the XXY syn-
drome have the tortoiseshell coat color.46 They can also have a The reported dogs with XXX syndrome were examined be-
single coat color, but it is the tortoiseshell or calico coat that is cause of infertility. There are several acquired conditions lead-
usually the reason for cytogenetic investigation. The tortoi- ing to infertility in dogs, such as cystic endometrial hyperpla-
seshell or calico coat color occurs not only in male cats with sia and hypothyroidism. In addition, mosaicism, chimerism,
the XXY syndrome, but also in XX / XY or XY/ XY chim- XX or XY sex reversal syndrome, and male pseudoherma-
erism. phroditism can also result in an almost normal female pheno-
type with infertility. The final diagnosis should rest on cyto-
All XXY cats are infertile. The testes descend but are small genetic demonstration of X trisomy. Patients with XXX
and lack spermatogenesis. The cats have a normal male phe- syndrome require no special treatment, for the physical
notype but are somewhat small. Most have normal male be- changes do not interfere with general health.
havior.
regulations that results in testicular induction, gonadal devel- special interest to dog breeders because monogenic autosomal
opment is started or stopped independent of the presence of recessive inheritance has been demonstrated in the American
an SRY gene. In XY sex-reversed individuals the cascade cocker spaniel and is most likely to occur in other affected
stops even though testicular induction began in the presence breeds.54 The anomaly is known in several dog breeds, includ-
of a Y chromosome, while in XX-sex reversed individuals ing the beagle, Chinese pug, Kerry blue terrier, Weimaraner,
testicular induction begins even though no Y chromosome is German shorthaired pointer, West Highland white terrier,
present. basset hound, Doberman, viszla, Walker hound, soft-coated
wheaten terrier, Norwegian elkhound, Jack Russell terrier,
German pinscher, cocker spaniel, and Komondor.55–59
6.2.2.1 XY sex reversal syndrome (XY SRS)
The XY sex reversal syndrome has not been reported in cats, Even though there is no Y chromosome but – as in a female –
and only once in a dog. This three-year-old Yorkshire terrier two X chromosomes, one or both gonads contain testicular
with an enlarged clitoris, bilateral ovotestes, epididymis, and tissue. The most frequent combination in XX sex-reversed
uterus had a male chromosome complement. There were two dogs is bilateral ovotestes (fig. 6.6). Less frequent are one ovo-
types of X chromosome, one cell line being normal and the testis and one ovary, one ovotestis and one testicle, or both
other having a translocation involving the X chromosome gonads completely developed to cryptorchid testicles. Rarely
and an autosome. Thus the dog was presumably a mosaic with there is a testicle on one side and an ovary on the other. If
a karyotype of 78,XY/ 78,XYrcp(X;autosome) and not both ovarian and testicular tissue are present, the individual is
strictly sex reversed.51 a true hermaphrodite (hermaphroditismus verus). If only tes-
ticular tissue is present, the individual is called an XX male
In humans with XY SRS, both mutations in the sex-deter- (fig. 6.7). The underlying defect is a single etiologic form of
mining SRY gene52 and mutations in other autosomal genes XX sex reversal in which the degree of gonadal masculiniz-
of the cascade, such as in SF-1, WT1, and SOX9, have been ation may be partial or complete. The reason why some XX
reported to be responsible for the XY sex reversal syn- sex-reversed individuals develop into true hermaphrodites
drome.1,53 The mutations are presumed to interrupt the cas- and others become XX males is not known. Although in
cade required for testes development. those with much testicular tissue the oviducts can be absent,
the uterus is always present.60 The external appearance of XX
sex-reversed dogs can be ambiguous. In a female phenotype
6.2.2.2 XX sex reversal syndrome (XX SRS) there may be an enlarged clitoris or abnormally large vulva, or
The XX sex reversal syndrome occurs frequently in dogs but the anogenital distance can be altered. The degree of mascu-
has not been reported in cats. This congenital anomaly is of linization in true hermaphrodites depends directly on the
194 Gonadal Development and Disorders of Sexual Differentiation
Differential diagnosis
A female phenotype with masculinization also occurs in male
and female pseudohermaphrodites, chimeras, mosaics, and
possibly XY sex-reversed dogs. A female phenotype without
overt masculinization can also occur in X monosomy, tri-
somy, cystic endometrial hyperplasia, and hypothyroidism
(see also chapter 7).
Diagnosis
6 Elevation of the plasma testosterone concentration after
stimulation with hCG or GnRH provides a presumptive di-
agnosis (chapter 12.5.1). Ultrasonography and retrograde
Figure 6.8: contrast radiography can reveal female internal genitalia in
Empty scrotum and hypoplastic prepuce and penis of a true hermaphrodite cocker dogs with a male appearance (fig. 6.10). Affected dogs cannot
spaniel. The skin irritation has been caused by urinary incontinence.
usually be differentiated from normal females during
gonadectomy, because testicular tissue is usually in the center
of the gonad and therefore not visible. A definitive diagnosis is
based upon histological examination of the gonads by a path-
ologist who is familiar with XX-SRS and upon cytogenetic
demonstration of a female XX karyotype. Affected dogs have
amount of testicular tissue in the gonads (fig. 6.8). In most a complete uterus and many have epididymes adjacent to the
true hermaphrodites there is no visible difference in the phe- ovotestes or testes.56
notype. For example, Meyers-Wallen and Patterson found the
external phenotype in 20 of 22 true hermaphrodites to be in- Treatment
distinguishable from normal females.54 These animals are fer- Vulvar irritation caused by a protruding clitoris can be re-
tile and mostly remain undiscovered in the dog population. solved by resection of the os clitoris. Gonadectomy has been
recommended when there is intra-abdominal testicular tissue,
In humans a translocation of the SRY gene to an autosome is which carries an increased risk of Sertoli cell neoplasia (see
often responsible for the XX sex reversal syndrome, the indi- also chapter 8). Hysterectomy has been recommended in true
vidual being termed SRY-positive. However, all of the re- hermaphrodites because of the risk of endometritis. These
ported XX-SRS dogs have no SRY sequence and are thus risks must be weighed against the associated morbidity and
SRY-negative.56 In dogs mutations in several of the autosomal mortality of abdominal surgery.
genes leading to activation of the cascade of testis differenti-
ation have been suggested to result in SRY-negative SRS and Prognosis
attempts have been made to identify the mutation resulting in Local irritation of the vulva usually resolves after removal of
XX-SRS in the American cocker spaniel. Candidate genes in the enlarged clitoris or the os clitoris. XX-SRS is an in-
humans and goats – such as FOXL2, PISRT1, WT1, GATA1, herited disorder and breeding should be discouraged to pre-
FOG2, Lhx1, SF-1, SOX9, and Lhx9 – have been shown not vent the homozygous fertile hermaphrodite from transmitting
to be responsible for the XX-SRS in the American cocker the recessive trait. Heterozygous carriers resemble normal
spaniel population.7,9,61–64 This supports the notion that there males and females and at present there is no practical means of
are still unknown genes in the cascade responsible for testis identifying them. Because XX SRS is presumably a mono-
differentiation. genic, autosomal recessive inherited disorder, it is likely that
the male and female siblings of an XX sex-reversed dog are
Clinical manifestations carriers of the disease allele or that the females may be true
Several true hermaphrodites and XX males have a female hermaphrodites.
phenotype with some degree of masculinization, ranging
from a small clitoric protuberance with a small os penis up to
a hypoplastic penis (fig. 6.9). Depending on the amount of
ovarian tissue, affected dogs can have normal estrous cycles,
be fertile (always as females), and be able to deliver normal
litters.65 The symptoms and signs may include infertility, pri-
mary anestrus, irregular estrous cycles, and urinary inconti-
Abnormal sexual differentiation 195
Figure 6.9:
Rudimentary male genitalia of four unrelated XX sex
reversed dogs of different breeds (Komondor, mixbred,
German pinscher, and American cocker spaniel).
synthetic androgens during pregnancy and thus they were If there is endometritis, ovariohysterectomy is the treatment
considered to be true hermaphrodites, but the reason why of choice. An enlarged clitoris or os clitoris may be removed
they developed testicular tissue is unknown.72 surgically if it causes irritation. Less severe cases of masculin-
ization due to administration of androgens during ges-
Congenital adrenocortical hyperplasia due to 11b-hydroxy- tation may not require treatment. In congenital adrenocorti-
lase deficiency, which results in endogenous androgen expo- cal hyperplasia, administration of a glucocorticoid will reduce
sure, has only been described in one cat, a female pseudoher- pituitary ACTH release and consequently the excessive pro-
maphrodite.73 This cat had a calico-colored coat and an XX duction of sex steroids in the adrenal glands.
karyotype, and a fully formed penis, prepuce, and scrotum,
but no palpable testes. Laparotomy revealed two ovaries, two
uterine horns, and a uterine body. Congenital adrenocortical 6.2.3.2 Male pseudohermaphroditism
hyperplasia is the most common cause of ambiguous genitalia (pseudohermaphroditismus masculinus)
in children, in which it is inherited as an autosomal recessive Male pseudohermaphrodites have a male karyotype (XY) and
disorder resulting in a deficiency of either 21-hydroxylase or two testes, but the genital ducts and /or external genitalia are
11b-hydroxylase required for adrenocortical synthesis of cor- incompletely masculinized, leading to internal and /or exter-
tisol and aldosterone. The low secretion of cortisol results in nal parts of the female genital tract. Male pseudohermaphro-
high ACTH release and consequently increased secretion of dites can be classified as having: (1) defective regression of the
adrenal androgens. Müllerian ducts, or (2) disturbances in androgen-dependent
masculinization. In principle, these maldevelopments can be
The clinical manifestations depend on the duration and the result of: (1) defective testicular differentiation,(2) an
amount of androgen exposure. Like male pseudohermaphro- error in the release or action of AMH, (3) an error in the syn-
dites, female pseudohermaphrodites may be presented with thesis of testosterone, or (4) defects in the androgen-depend-
symptoms suggesting lower urinary tract disease and endome- ent target tissues such as 5a-reductase deficiency and low or
tritis. In less severe cases the irritation caused by the enlarged absent androgen receptor activity.
clitoris may require surgery (fig. 6.12).
The persistent Müllerian duct syndrome (PMDS) is the
A female phenotype with masculinization is also seen in sex most common form of male pseudohermaphroditism in dogs.
reversed dogs, male pseudohermaphrodites, chimeras, and A defect in AMH (MIS)-induced Müllerian duct regression
mosaics. Low or undetectable plasma testosterone concen- is responsible for the presence of oviducts, Fallopian tubes,
trations before and after stimulation with hCG or GnRH in- uterus, cervix, and cranial vagina in otherwise completely
dicate the absence of testicular tissue (fig. 6.13). normal male dogs (fig. 6.14). These dogs have a normally de-
veloped penis with a prepuce and scrotum.38,56,74 Half of the
Abnormal sexual differentiation 197
Figure 6.14:
6
Schematic representation of persistent Müllerian ducts in a male dog. Note that
the vasa deferentia terminate in the wall of the uterus.
Figure 6.13:
Schematic illustration of plasma testosterone concentrations before and after
stimulation with hCG or GnRH (chapter 12.5.1). Both basal testosterone concen-
tration and the response to stimulation depend on the amount of functional tes-
ticular tissue, as shown by the different values in the two cases of true herma-
phroditism.
Figure 6.15:
Radiograph of a two-year-old mixbred cryptorchid PMDS dog with malformation
of the os penis.
affected dogs have scrotal testes, while the other half are uni- bioactive in the critical period of Müllerian duct regression.81
laterally or bilaterally cryptorchid. Most of the affected dogs Thus defects at the receptor or postreceptor level, as demon-
are fertile. strated in comparable cases in humans, are the most likely ex-
planation.74 PMDS has not been reported in cats.
PMDS was first described in the miniature schnauzer and an
autosomal recessive mode of inheritance in this breed has Dogs with PMDS can be fertile if the testes have descended
been proved by breeding experiments.74,75 A single case in this and the epididymis is not affected by inflammatory changes.
breed was diagnosed in Germany.76 PMDS has also been Animals with PMDS are often presented with symptoms sug-
found in other dog breeds, including the basset hound77 and gesting lower urinary tract disease. Endometritis is probably
poodle,78 and in two cocker spaniels with an enlarged clitoris the most common problem and may result in hematuria,
and a scrotum with undescended testes.59 PMDS was also sus- abdominal pain, and systemic illness. Symptoms suggesting
pected in a dachshund bitch with an enlarged clitoris and ab- lower urinary tract disease can be so prominent that the
dominal testes.79 Moreover, PMDS has been reported in a underlying condition is overlooked, for the veterinarian is
two-year-old mixbred cryptorchid dog with an underdevel- unlikely to think of endometritis (or even pyometra) in a
oped penis, a hypoplastic uterus, and hypospadia of the glans dog that appears to be male. This may cause severe delay in
penis, in which radiographic examination revealed a mal- correct diagnosis. In miniature schnauzers the associated high
formed os penis (fig 6.15).80 Studies in miniature schnauzers incidence of cryptorchidism may give rise to Sertoli cell neo-
and basset hounds demonstrated that AMH is produced and is plasia.38,56
198 Gonadal Development and Disorders of Sexual Differentiation
Abdominal radiography and retrograde contrast radiography pending on the primary defect. This varying phenotype can
may reveal female internal genitalia in dogs with a male ap- be the result of: (1) defects in the production of luteinizing
pearance. However, in some patients with PMDS the internal hormone (LH) or its receptor, (2) defects in androgen pro-
female genitalia cannot be detected by radiographic examin- duction, (3) partial or complete absence of androgen receptor
ation although they can easily be found by ultrasonography activity, or (4) defective conversion of testosterone to di-
(fig. 6.16), CT, or MRI. In dogs with descended testes, nor- hydrotestosterone by 5a-reductase.82,56 Indeed, defects in LH
mal male external genitalia, and an XY karyotype, the finding synthesis and in the LH receptor as well as in androgen pro-
of a uterus provides the diagnosis of PMDS. duction and androgen dismantling are known in humans and
some animal species, but not as yet in the dog. It has been sug-
PMDS dogs with endometritis can be treated successfully by gested that in the absence of dihydrotestosterone the labios-
hysterectomy (fig. 6.17). Most also require orchidectomy be- crotal folds fail to fuse and the urogenital sinus fails to close,
cause of abnormalities of the epididymis or testis. Selective resulting in periscrotal hypospadias and the blind pouch that
hysterectomy or vasectomy can be performed in dogs with resembles a vagina.83
PMDS having unaffected testes and epididymes.
Male pseudohermaphroditism due to a failure of target organ
Breeding of dogs with PMDS should be discouraged. As both response to androgens is referred to as testicular femini-
parents of affected animals are carriers, the veterinarian zation.56 A defect in the androgen receptor gene results in
should inform the breeder about the inheritance and the fact partial or complete absence of androgen-dependent mas-
that affected dogs with or without unilateral cryptorchidism culinization. Less severe mutations cause compromised mas-
contribute to spreading of the defective allele in the dog culinization, while severe gene mutations cause complete
population (fig. 6.18). androgen insensitivity. The physical result ranges from am-
bivalent appearance to phenotypic male – but sterile – dogs.
In addition to defective regression of the Müllerian ducts, in Since they have bilateral testes and secrete normal amounts of
rare cases defective androgen-dependent masculinization can testosterone and anti-Müllerian hormone, no Müllerian duct
also result in male pseudohermaphroditism. Affected dogs derivates are present. In all animal species this is assumed to be
have testes and female-appearing external genitalia with a an X-chromosomal recessive trait, but complete testicular fe-
cul-de-sac caudal vagina. Under the influence of AMH the minization in the dog has not yet been reported. One dog
Müllerian ducts regress and so that there is no uterus or with incomplete testicular feminization had a female pheno-
cranial vagina, but the genital duct and /or external genitalia type with testes bilateral to the vulva and no uterus. Studies
are incompletely masculinized.56 The resulting phenotype with fibroblast cultures suggested that the androgen receptor
can vary from complete (severe) to incomplete (mild), de- was nonfunctional. The testicular feminization was incom-
Abnormal sexual differentiation 199
Figure 6.18:
Schematic representation of familial relations in basset hounds with persistent Müllerian duct syndrome (PMDS). Mating of assumed male carriers nos. 26 and 27 with
related females resulted in affected offspring such as nos. 14 and 21. Offspring of affected male no. 7 include even more affected littermates, supporting an autosomal
recessive mode of inheritance: (Courtesy of Dr. R.F. Nickel.)
200 Gonadal Development and Disorders of Sexual Differentiation
plete, for an epididymis and partially developed ductus defer- In dogs and cats with a female phenotype the finding of ele-
ens were present as Wolffian duct derivates.82 vated plasma testosterone concentrations after stimulation
with hCG or GnRH can prove the presence of testicular tis-
There have been two reported cases of male pseudoherma- sue (chapter 12.5.1). Without karyotyping, chimerism or
phroditism in cats due to testicular feminization. One cat had mosaicism cannot be distinguished from a disorder of an-
a vulva and clitoris of normal size and shape, no uterus, but drogen-dependent masculinization.
two abdominal testes at the caudal poles of the kidneys. The
chromosome complement was 38,XY and the cat was Resection of an os clitoris stops vulvar irritation. If necessary,
thought to be a case of complete testicular feminization.84 a complete clitoridectomy can be performed. Orchidectomy
The other case consisted of a Himalayan cat with testes in a may be necessary in some cases. In all cases of testicular fe-
blind scrotum, an enlarged clitoris protruding from a vulva- minization the breeder should be informed of the X-recessive
like structure, and no Müllerian duct derivates.85 inheritance of the trait in humans.
6
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203
7 Ovaries
Auke C. Schaefers-Okkens
Hans S. Kooistra
7.1 Introduction the last one or two ribs (dog) or to the diaphragm (cat). The
ovaries are connected to the cranial ends of the uterine horns
The ovaries lie caudal to the kidneys, at the level of the third by the proper ligaments of the ovary (fig. 7.1). The ovaries of
or fourth lumbar vertebra. They are attached by the broad the dog are enclosed completely, and those of the cat partially,
ligaments to the dorsolateral wall of the abdominal cavity and in a peritoneal pouch, the ovarian bursa (fig. 7.2). The bursa
by suspensory ligaments to the middle and ventral thirds of contains the uterine tubes and is usually opaque in the dog
Figure 7.2:
Lateral aspect of the left ovary, with opened ovarian bursa. (Modified from Evans
and Christensen, 1993.)1
Figure 7.1:
Dorsal view of the genitalia of the bitch, partially opened on the midline. (Modi-
fied from Evans and Christensen, 1993.)1
204 Ovaries
Figure 7.4:
(A) Mean plasma concentrations of LH, FSH, estradiol,
and progesterone before and after the preovulatory LH
surge (at time = 0), i.e., during the follicular phase,
ovulation, and the fertilization phase, in 6 bitches.
(B) Plasma FSH concentration in two beagle bitches
during the follicular phase (until 100 h before the pre-
ovulatory LH surge). Note the decrease in plasma FSH
in the early follicular phase.
(C) Plasma concentrations of LH and estradiol from
100 h before until 100 h after the preovulatory LH
surge in a beagle bitch with a preovulatory surge in
plasma estradiol coinciding with the start of the pre-
ovulatory LH surge. Note the bifurcated preovulatory
LH surge. (Modified from De Gier et al., 2006.)2
206 Ovaries
A B
7 Figure 7.5:
The vulva of a Beagle bitch during anestrus (A) and proestrus /estrus (B).
Figure 7.8:
Vaginoscopic view in the bitch at the onset of the follicular phase. Note the swollen, pale mucosal folds with a
smoothly rounded surface (balloons) and the bloody secretion between the folds.
Estrous cycle, anestrus, pregnancy, and parturition 207
Figure 7.10:
7
Ovary of the bitch at the time of ovulation. The bursa which normally encloses the
ovary has been removed.
fertilization usually occurs 90 h or more after ovulation in secretion and less GH secreted in pulses during stages having a
metaphase II oocytes.4 There was no significant influence of high plasma progesterone concentration, i.e., during the first
breed or age on ovulation rate, maturation, and developmen- part of the luteal phase (fig 2.12).10 This is most likely the re-
tal kinetics. The most peculiar aspect in the canine species is sult of partial suppression of pituitary GH release by proges-
oocyte meiotic maturation, while fertilization follows the terone-induced GH production in the mammary gland (see
same pattern as in other mammals.4 also chapter 2.2.1).15
Plasma progesterone concentration is around 6–13 nmol/l The pattern of secretion of progesterone thus influences the
at the time of the LH surge and 15–25 nmol/l at the time pattern of secretion of both GH and prolactin in the bitch.11
of ovulation, 36–48 h later. The start of estrus behavior is High plasma progesterone concentrations during the first half
usually synchronous with the preovulatory LH surge, but in of the luteal phase induce elevated plasma GH concentrations
some bitches it begins days before the LH surge and others and the decline in the progesterone concentration during the
not until days thereafter or never. Shrinkage of the vaginal second half of the luteal phase increases prolactin release.
mucosa starts about midway through the follicular phase and These hormonal changes may promote the physiological pro-
continues through the phase of preovulatory luteinization and liferation and differentiation of mammary gland tissue during
ovulation, whereby many longitudinal folds can be observed the luteal phase in the bitch. Growth hormone, in concert
7 (fig. 7.11). with insulin-like growth factor (IGF)-I, IGF-II, and IGF-
binding proteins, initiates mammary proliferation,16 whereas
prolactin promotes final mammary differentiation, i.e., lobu-
7.2.1.4 Luteal phase loalveolar development.17
Plasma estradiol-17b concentrations are significantly higher
throughout the luteal phase than at four to nine days after the Progesterone-induced GH production may also have an effect
LH surge.5 The concentration of progesterone, coming from on uterine epithelium. During each luteal phase, regardless of
the corpora lutea, increases in the peripheral blood during the whether or not the bitch is pregnant, progesterone-depend-
remainder of estrus and the onset of metestrus (diestrus). ent uterine epithelial changes occur. In progestagen-treated
Thus estrus behavior is observed in the bitch during the dogs the hyperplastic changes in the uterine epithelium are
period of increasing progesterone concentration. This reaches associated with the intracellular presence of immunoreactive
a plateau from about day 10 to day 30 after the LH surge. In GH.18 Progesterone-induced GH production may also have
nonpregnant bitches it then declines slowly to a basal level of metabolic effects. Progestagen-induced GH excess leads to
3 nmol/l for the first time about 75 days after the onset of the insulin resistance.15 The exposure to progesterone-induced
luteal phase (fig. 7.12). What initiates regression of the corpus elevated plasma GH concentrations during the first half of the
luteum in the bitch remains unknown. It is not prostaglandin luteal phase may also cause some insulin resistance. For an
F2a from the endometrium, as in the cow and ewe, for hyster- animal such as the dog, evolving from predators, there may
ectomy does not influence the length of the luteal phase in have been evolutionary advantages in this temporary insulin
the bitch.6 During the first half of the luteal phase the canine resistance during the first half of pregnancy. Especially during
corpus luteum functions independent of pituitary support.7 long periods between catches of prey, insulin resistance may
Thereafter experimentally induced inhibition of prolactin se- be a safeguard against hypoglycemia.19 It could serve to main-
cretion causes a sharp decline in progesterone secretion tain blood glucose concentration immediately after the intake
(fig. 7.13), which has led to the assumption that prolactin acts of a low carbohydrate meal (a prey), while insulin is secreted
as a luteotropic factor in the second half of the luteal phase.8,9 in response to other food components such as amino acids.
There are no strong indications that LH has luteotropic prop- Finally, high GH concentrations have been demonstrated in
erties in the bitch. canine mammary gland secretions and particularly in colos-
trum, through which GH may promote gastric and intestinal
The secretion patterns of prolactin, growth hormone (GH), development in the newborn.20
FSH, and LH are characterized by a fluctuating baseline
with occasional distinct elevations, indicating pulsatile secre- The transition from estrus to metestrus (diestrus) occurs dur-
tion.3,10–12 The mean plasma LH concentration scarcely ing the initial part of the luteal phase. In this period the cy-
changes during the luteal phase, except for a slight increase in tology of the vaginal mucosa changes from chiefly superficial
the second half of the luteal phase. The mean plasma prolactin cells to chiefly intermediate and parabasal cells and leukocytes
concentration increases slightly but significantly during the (fig. 7.14). This is an indication that the fertile period is over.
progression of the luteal phase (figs. 7.12, 7.13).11 In overtly At the time of the maturation of the oocytes, the shrinkage of
pseudopregnant bitches (see chapter 2.2.5) and in pregnant the vaginal mucosa continues and increasing numbers of
bitches the rise in plasma prolactin concentration is much sharp-edged summit profiles appear in the vagina. In the tran-
greater.13,14 Plasma GH concentration is higher in the first sition period from estrus to metestrus, the mucosa thins and
part of the luteal phase than in the second half of the luteal profiles become round. In the beginning of metestrus there is
phase and anestrus (fig 2.12).10 Pulsatile secretion of GH also a visible patchwork of red and white areas (fig. 7.15).
changes during the luteal phase, there being greater basal GH
Estrous cycle, anestrus, pregnancy, and parturition 209
Figure 7.11:
Vaginoscopic view at the time of ovulation. Plasma
progesterone concentration was 22 nmol/l.
(A) The mucosal shrinkage has resulted in longitudinal
folds.
(B) Close-up showing shrinkage of the longitudinal A B
folds of the dorsal median fold in the cranial vagina.
Figure 7.16:
Mean (± SEM) basal plasma concentrations of FSH and
LH in six beagle bitches during early, mid-, and late an-
estrus.
* Significantly different from early anestrus. Progres-
sion of anestrus is associated with a significant rise in
plasma FSH concentration but no significant change in
plasma LH concentration. (Modified from Kooistra et
al., 1999.)3
7.2.1.5 Anestrus pothalamic mRNA encoding for the estrogen receptor and in
The time of onset of anestrus depends on the criterion used the expression of the gene encoding for P450 aromatase,
to define the end of the luteal phase, i.e., when mammary which catalyzes estrogen biosynthesis.27,28 Although there are
development subsides after two to three months, or when sporadic elevations, plasma estradiol concentration is usually
plasma progesterone concentration falls below 3 nmol/l, or low and does not begin to rise until late anestrus.
when the influence of progesterone on the endometrium is
no longer evident. In any case, the transition from the luteal Apart from changes in the hypothalamic-pituitary-ovarian
phase to anestrus is gradual and varies considerably among axis, there is involvement of dopaminergic influences in the
bitches. The estrous cycle can begin at any time throughout initiation of a new follicular phase in the bitch. Adminis-
the year and there appears to be little, if any, seasonal in- tration of dopamine-2 agonists, such as bromocriptine and
fluence. Variation in mean interestrous intervals may be breed cabergoline, shortens anestrus and is associated with a lower-
related and there may also be differences among strains with- ing of plasma prolactin concentration (fig. 7.17). Conse-
in breeds. In the collie, for example, the mean interval is quently, it has been suggested that the shortening of anestrus
36 weeks and in the German shepherd dog it is 20–22 weeks. by dopamine agonists is the result of suppression of prolactin
The basenji and the Tibetan mastiff both have a single annual secretion, as prolactin may inhibit gonadotropin release.29,30
estrous cycle, which may be influenced by the photoperiod. However, although low dosage metergoline decreases prolac-
Other environmental factors can also affect the interestrous tin release via a serotonin-antagonistic pathway, it does
interval; placing an anestrous bitch in close proximity to a not shorten anestrus, indicating that it is not the decrease
bitch in estrus may cause the onset of proestrus to be ad- in plasma prolactin concentration but another dopamine-
vanced by several weeks. Moreover, bitches housed together agonistic influence that is responsible for the transition to
often have synchronous cycles. a new follicular phase.31 Also, administration of bromocrip-
tine in a dose too low to decrease plasma prolactin concen-
The endocrine changes that lead to termination of anes- tration nevertheless induces a premature new follicular phase
trus, and thus to the start of a new estrous cycle, are not com- (fig. 7.18).32 Finally, under physiological conditions plasma
pletely understood in the bitch. The increase in basal plasma prolactin concentration is low during anestrus and does not
FSH concentration which occurs during the progression change during the transition from anestrus to the next follicu-
of anestrus is critical in the initiation of folliculogenesis lar phase.33
(fig. 7.16).3,21 The progression from early to late anestrus is
also characterized by a greater number and greater amplitude Bromocriptine-induced shortening of anestrus is associated
of gonadotropin-releasing hormone (GnRH) pulses.22 In ad- with a prompt rise in basal plasma FSH concentration with-
dition, there is increased pituitary sensitivity to GnRH and out a concomitant increase in basal plasma LH concen-
increased ovarian responsiveness to gonadotropins from early tration,12 similar to what occurs during normal late anestrus
to late anestrus23,24 and there is increased LH pulsatility (fig. 7.16). This further supports the notion that in the bitch
shortly before the onset of proestrus.3,25,26 There is some evi- an increase in the circulating plasma FSH concentration is a
dence that factors that decrease opioidergic activity promote critical event in the initiation of ovarian folliculogenesis.3,12
LH release and the termination of anestrus.25 Finally, during
the course of anestrus in the bitch, there is an increase in hy-
Estrous cycle, anestrus, pregnancy, and parturition 211
Figure 7.17:
Plasma concentrations of progesterone and prolactin
in a bitch treated with the dopamine agonist bromo-
criptine (bar), from ovulation in the first estrous cycle
to the onset of the next follicular phase. The luteal
phase and especially anestrus are considerably short-
ened. (Modified from Okkens et al., 1985.)29
7
Figure 7.18:
Mean (±SEM) interestrous interval in control bitches and in bitches receiving the
dopamine agonist bromocriptine in oral doses of 5 (n = 60), 20 (n = 6), and 50
(n = 8) µg/kg body weight twice daily starting 28 days after ovulation and con-
tinuing until the next ovulation. * Indicates significant difference. In the bitches
receiving 5 µg/kg twice daily, the difference in mean plasma prolactin concen-
tration before and during treatment was not significant but the interestrous inter-
val was significantly shorter than that of the control bitches. In the bitches receiv-
ing 20 or 50 µg/kg twice daily, plasma prolactin concentration was significantly
lower during treatment than before treatment. (Modified from Beijerink et al.,
2003.) 32
7.2.1.6 Pregnancy and parturition concentration, which strongly correlates with the preovula-
The length of gestation varies greatly in dogs. In dogs of vari- tory LH surge. The gestational period was 61.4 days, with a
ous breeds the mean gestational period was 62.0 days (n = variation of 8 days (58–65). The variation in the length of ges-
184) with a variation of 24 days (54–77).34 The length of ges- tation within any one of the six breeds was low, with a range of
tation and litter size were negatively correlated. In a beagle four to seven days, or even less when litters of one pup were
colony the mean gestational period was 65.3 days (n = 290), excluded. There were one to 15 pups per litter, with a median
with a variation of 16 days (57–72).35 The variation was, how- of eight pups. The length of gestation correlated negatively
ever, reduced to three days (64–66) (n = 54) when gestation with litter size for litters of 13 or fewer pups. However, within
was calculated as the interval from the preovulatory LH surge an individual breed the number of pups had no influence on
to parturition. In another study the length of gestation was the length of gestation. This study indicates that breed is a
calculated in bitches of six breeds (n = 113) that had been major determinant of the length of gestation in the bitch and
mated at a fixed time after ovulation.36 The optimal time for that this is coupled to breed-related differences in litter size.36
mating was based on the rapid increase in plasma progesterone
212 Ovaries
7
Figure 7.20:
(A) Plasma concentrations of progesterone and prostaglandin F2a metabolite (PGFM) at 12 h (P4) and 6 h (PGFM) intervals around the time of expulsion of the first pup (t
= 0) in a three-year-old beagle bitch.
(B) Mean (± SEM) plasma progesterone (red bars) and PGFM concentrations (blue bars) in six bitches during late gestation (days 54–58 of pregnancy), before parturition
(30–0 h before expulsion of the first pup), the day after parturition (0–24 h after expulsion of the last pup), and the 2nd and 3rd days after parturition (24–72 h after ex-
pulsion of the last pup). Different superscripts A,B,C and 1,2 denote significant differences. (Modified from Baan et al., 2008.)14
Figure 7.21:
Mean serum concentrations of progesterone, cortisol,
and prolactin in the period around parturition and lac-
tation in a group of six beagle bitches. (Modified from
Concannon et al., 1978.)39
7.2.2 Estrous cycle, anestrus, pregnancy, Queens can go through several periods of estrus per season
and parturition in the cat (seasonally polyestrous). Cats kept in a common household
can become nonseasonal breeders as a result of night-time
Puberty occurs at between four and 18 months of age in the illumination.
queen and its onset is influenced by the season of the year. It
often occurs when the hours of daylight are increasing. Physi- Queens are induced ovulators. Copulation, vaginal stimu-
cal condition is also an important factor, for puberty does not lation, and administration of gonadotropin or GnRH ana-
usually occur before body weight reaches about 2.5 kg. Pu- logues induce ovulation within 24–48 h.41 It is likely that
berty may occur earlier in short-haired breeds than in long- ovulation can also be induced by external stimuli such as stro-
haired breeds. king. Although considered to be induced ovulators, as many
as 60 % of unmated female domestic cats ovulate without
known external provocation.42
214 Ovaries
7
Figure 7.22:
Plasma estradiol and progesterone concentrations during pregnancy, pseudopregnancy, and polyestrus in the cat. (Modified from Verhage et al., 1976.)43
Figure 7.23:
Mean serum LH concentration in cats confirmed to have ovulated following one
copulation (red line), four copulations within 26–81 min (green line), or 8–12
copulations during 4 h (blue line), and in cats which did not ovulate following a
single copulation (black interrupted line). All copulations were on the third day of
estrus. (Modified from Concannon et al., 1980.)44
Estrous cycle, anestrus, pregnancy, and parturition 215
A B
Figure 7.24:
7
(A) The ovary of a queen six days after mating, with luteal tissue called corpora rubra because of its red color.
(B) Microscopic section of a corpus luteum of a queen 21 days after mating. It consists primarily of large luteal cells and blood vessels (bv). (H&E stain, x475).
If breeding is permitted, LH release begins within minutes approximately 60 days in the pregnant queen. Plasma pro-
after copulation, peaks within 2–4 h, and returns to the basal gesterone concentrations in pseudopregnancy and pregnancy
level within 24 h. In the early follicular phase there may be a are similar until day 21. Thereafter plasma progesterone con-
period of refractoriness to this copulation-induced LH re- centration is lower in pseudopregnancy than in pregnancy
lease. A rise in plasma LH concentration does not always (fig. 7.22). The interestrous interval for a pseudopregnant
occur following a single mating, but the LH peak is higher queen is approximately seven weeks. During the progeste-
and more prolonged when multiple matings are permitted rone-dominated phase, particularly at the end of this phase,
(fig. 7.23).44 The increase in LH release due to multiple mat- there can be follicle growth (and regression) which causes
ings is, however, not indefinite and the LH response declines elevations in plasma estradiol concentration.
after a certain number of matings. The duration of estrus ap-
pears to be similar in queens regardless of whether there is co- Anestrus is a period without cycle activity. Plasma estradiol
itus with ovulation, coital contact without ovulation, or no and progesterone concentrations are at baseline levels. In the
coital contact. An estrus in which the queen has not been in- northern hemisphere this phase occurs during late autumn
duced to ovulate is followed by a postestrus period with an and the onset of winter (October, November, December) in
average duration of eight to ten days, after which the next es- queens exposed to natural daylight.
trus begins. Plasma progesterone concentration is at its basal
level during the postestrus period. Photoperiods influence the reproductive processes via the
pineal gland and its principal hormone, melatonin, which af-
Ovulation usually occurs 24–48 h after copulation and the fects the hypothalamic-pituitary-ovarian axis. Plasma melato-
occurrence of the LH peak, but it can be delayed for up to nin and prolactin concentrations change congruently with
90 h. Ovulation is followed by pregnancy or a luteal phase photoperiod changes and are highest during periods of dark-
without pregnancy (called »pseudopregnancy«). Pseudopreg- ness (fig. 7.25).45 Folliculogenesis and estradiol secretion are
nancy in the queen does not give rise to signs and symptoms stimulated during days with 14 h of light, leading to an es-
and is thus not comparable to that in the bitch (chapter 2.2.5). trous cycle frequency of two per month.46 Estrus can be in-
In both pregnancy and pseudopregnancy, plasma progester- duced with as little as 12 h of light if a social stimulus such as
one concentration begins to rise 24–48 h after ovulation, ac- the presence of a tomcat or a queen in estrus is introduced
companied by the development of luteal tissue. The luteal three weeks after an increase to 12 h of light.47 Estrous activ-
tissue is initially red and therefore sometimes referred to ity ceases immediately and estradiol concentration decreases
as corpora rubra, but it subsequently develops into yellow rapidly after a change from 14 h to 8 h of light (fig. 7.26). Al-
corpora lutea (fig. 7.24). The progesterone-dominated phase though gonadotropin secretion may be decreased during a
lasts about 38 days in the pseudopregnant queen and short light period, continuous exposure to light does not ap-
216 Ovaries
Figure 7.26:
Plasma estradiol concentration in two cats during a photoperiod regimen of 14 h
of light, then 8 h of light, and then 14 h of light again. The purple horizontal bars
indicate periods of sexual receptivity. (Modified from Leyva et al., 1989.)46
pear to be optimal. Cycle frequency decreases to one per cystic endometrial hyperplasia, pyometra, and bone marrow
month with exposure to 24 h of light. Estradiol secretion dur- suppression,51 although using low doses of estradiol benzoate
ing estrus under exposure to 24 h of light appears to be ap- (three, five and seven days after mating) decreases the inci-
proximately twice that observed under exposure to 14 h of dence of these adverse effects.52
light, while the number of large antral follicles doubles about
45 days after the onset of continuous light. This may cause a Maintenance of pregnancy in the bitch depends on ovarian
depletion of the tertiary follicle population, after which a secretion of progesterone by the corpus luteum throughout
long interval is necessary for tertiary follicle restoration.46 gestation (chapter 7.2.1). During the second part of the luteal
phase, luteotropic factors from the pituitary, such as prolactin,
are essential for maintenance of the corpus luteum.8,53 Con-
7.2.2.2 Pregnancy and parturition sequently, unwanted pregnancy in dogs can be terminated by
In the cat, progesterone, produced throughout the entire pharmacological agents that suppress prolactin secretion (dur-
pregnancy by the corpora lutea, is probably responsible for ing midgestation) or interfere with the synthesis or action of
maintaining pregnancy. The placenta either does not secrete progesterone. The use of many of the abortifacients is accom-
progesterone or secretes it in amounts insufficient to maintain panied by unwanted and sometimes severe side effects.
pregnancy. Plasma progesterone concentration increases con-
tinuously through days 25–30, then slowly declines during Repeated administration of prostaglandin F2a or its analogues 7
the second half of pregnancy (fig. 7.27).48 during midterm pregnancy in the bitch results in luteolysis.54
The narrow margin between a lethal dose (LD50) and a thera-
It is not yet clear why there is a difference between pseudo- peutic dose, side effects (vomiting, diarrhea, hyperpnea, and
pregnant and pregnant animals in the functional activity of cor- ataxia), and the need for repeated administration are import-
pora lutea. Pregnancy involves pregnancy-specific secretion of ant factors limiting the use of prostaglandins in veterinary
luteotropic hormones of placental or pituitary origin, of which practice. Dopamine agonists such as cabergoline, which is
prolactin appears to be important. Prolactin secretion in the better tolerated than bromocriptine, cause luteolysis by sup-
pregnant queen begins to increase around day 35, reaches a pla- pressing pituitary secretion of prolactin. Reports on the effi-
teau at about day 50, and increases again just before delivery cacy of the dopamine agonists differ, depending on the dose
(fig. 7.27).49 If prolactin secretion is suppressed by treatment and the day of pregnancy on which administration is begun.
with the dopamine agonist cabergoline, progesterone secretion The combined use of cabergoline and prostaglandins has also
decreases and abortion may follow. Prolactin secretion does not been reported.55 When used in combination, they are gen-
increase in the pseudopregnant queen, which may be the cause erally effective at lower doses than with single administration
of the early regression of the corpora lutea. and there are fewer side effects.
Fertilization of oocytes by spermatozoa of different males Because of the undesirable side effects of the above men-
(superfecundation) is common in domestic cats. Fertilization tioned drugs, attention has been given to agents that prevent
and subsequent development of an ovum when a fetus is al- the action of progesterone, i.e., progesterone receptor anta-
ready present in the uterus (superfetation) has, however, never gonists. Progesterone receptor blockers (antiprogestins), such
been proved. The explanation for fetuses of different ages as mifepristone, registered for use in humans, and aglepri-
could be arrested development. stone, have a chemical structure related to that of progeste-
rone, but they carry a p-(dimethylamino) phenyl group at the
The first estrus after parturition can be expected within one 11b-position of the steroidal skeleton. Antiprogestins revers-
to 21 weeks. Little is known about fertility during this estrus, ibly bind to the progesterone receptor, thereby preventing en-
but if it occurs during lactation, which is not uncommon, fer- dogenous progesterone from occupying its binding site,
tility may be lower than normal. which limits its biological activity. Aglepristone has a binding
affinity for the progesterone receptor that is probably three
times greater than that of the native hormone. The mean resi-
dence time for a single administration of 20 mg/kg body
7.3 Medical pregnancy weight or 10 mg/kg body weight administered twice with a
termination 24 h interval is six days. This rather long mean residence time
is due to both slow absorption from the injection site and
For many decades unwanted pregnancy in dogs has been slow excretion. Around 60 % of the administered dose is ex-
avoided early in gestation by administering relatively large creted within the first 10 days and a total of around 80 % in
doses of estrogens. This prolongs the transport time in the 24 days. Excretion is essentially via the feces. Antiprogestins
oviduct and tightens the utero-tubular junction, resulting may also interact with the glucocorticoid receptor, different
in failure of implantation and hence embryonic death.50 antiprogestins having different binding affinities for the pro-
However, the use of estrogens can result in side effects such as gesterone and glucocorticoid receptors.
218 Ovaries
Figure 7.29:
(A) Follicular cyst (fc) and luteinized follicular cysts (lfc) in a four-year-old bitch
with shortened interestrous intervals and persistent estrus symptoms. During
7
these estrus periods the measured plasma progesterone concentration did not
reach levels normally observed at the time of ovulation.
(B) Close-up, showing the wall of the follicular cyst (fc) and the wall of a luteinized
A follicular cyst (lfc). Note the luteinized cells bordering the luteinized follicular cyst.
(H&E stain).
Differential diagnosis
A split heat is a heat that stops before ovulation and starts
again after an interval of days to weeks. A split heat may be
difficult to distinguish from persistent estrus if the interval is
7 Figure 7.30:
very short or unobserved.
Granulosa cell tumor of a nine-year-old Belgian shepherd dog that had estrus be- Therapy
havior for four months. The plasma concentrations of progesterone and estra-
diol-17b were 7 nmol/l and 270 pmol/l, respectively. The estradiol-17b concen-
Cysts can be treated by giving GnRH, such as gonadorelin or
tration in the cyst fluid was 1195 pmol/l. buserelin (repeated subcutaneous doses of 0.1 ml/kg body
weight), but this does not always resolve the problem. If lu-
teinization of cystic follicles or further luteinization of lutein-
ized cysts takes place, estrus will stop, plasma progesterone
concentration will increase, and the vaginal smear will con-
tain mainly intermediate and parabasal cells and leukocytes. If
Young dogs generally respond well to treatment and luteini- the problem persists estrus can be stopped by oral adminis-
zation follows, and a normal follicular phase and ovulation tration of low, once daily, doses of megestrol acetate (first
can be expected during their next cycle. In contrast, the week: 0.1 mg/kg body weight; second week: 0.05 mg/kg
problem in older dogs is often recurrent. Ovarian follicular body weight). Ovarian tumors should be removed.
cysts producing estrogens are common in queens. They may
arise from mature or atretic follicles and their occurrence may
increase with age.
7.6 Split heat
Functional, hormone-producing, ovarian tumors, which fre-
quently originate from sex cord stroma, are the other import- As mentioned above, a split heat is a heat which stops before
ant cause of persistent estrus (fig. 7.30). They occur mainly in ovulation and starts again after days or weeks. The vaginal dis-
older dogs and cats, but are sometimes observed in young charge changes from red to brown and the vaginal smear con-
bitches or in bitches with ovarian tissue left in situ as a result tains intermediate cells, parabasal cells, and leukocytes. Vagi-
of incomplete ovariectomy. This functional tumor is usually a noscopy reveals that the swelling of the vaginal mucosal folds
granulosa cell tumor. is diminishing. Split heat is observed fairly often in both
young and older bitches and especially in certain breeds, such
Furthermore, estrogens administered to terminate an un- as the German shepherd dog. It is probably caused by prema-
wanted pregnancy occasionally cause persistent estrus, pos- turely regressing follicles. Ovulation usually occurs if proes-
sibly by inducing ovarian cysts. Rarely, liver disease is the trus returns. Treatment is usually not necessary but close
cause of persistent estrus, supposedly because of defective he- monitoring of the estrous cycle is essential to determine the
patic metabolism of reproductive steroid hormones.66 appropriate mating period.
Diagnosis
The diagnosis is based on the persistence of sanguineous dis-
charge, vaginal cornification, estrus behavior, vaginoscopic
findings, and the plasma concentrations of progesterone and
estradiol. Plasma progesterone concentration is lower than
16 nmol/l, but plasma estradiol concentration is not consist-
Prolonged anestrus 221
쎱 Measurement of plasma concentrations of thyroxine and proestrus occurred but not estrus had all been treated in early
TSH. If the results are inconclusive and hypothyroidism is anestrus.75 The rapid increase of plasma estradiol concen-
still suspected, thyroid scintigraphy and /or a TSH-stimu- tration that is observed after LH treatment suggests that an in-
lation test may be performed (chapter 3.3.1). crease in follicular steroidogenesis is a primary effect of LH.
쎱 Measurement of plasma concentrations of LH and FSH. The insufficient response to porcine LH in bitches in early
High FSH and LH values indicate gonadal absence (apla- anestrus may be due to lack of FSH or follicular FSH recep-
sia, ovariectomy) or failure. Although not essential for tors in this stage of anestrus. Follicular aromatase in rats and
diagnosis, it is of interest that an elevated LH, but not of most other species studied appears to be primarily under up-
FSH, can be further stimulated with GnRH.72 regulation control by FSH.76
쎱 A GnRH-stimulation test with measurement of plasma
testosterone concentrations (chapter 12.5.1): This test can Shortening of anestrus and thus stimulation of folliculogenesis
confirm male pseudohermaphroditism or true herma- can also be induced by administration of dopamine agonists
phroditism in a phenotypically female dog. such as bromocriptine and cabergoline.25,29,32 The result of
쎱 Determination of the karyotype. Abnormalities in sexual treatment with dopamine agonists depends on the dose of the
differentiation may present as primary anestrus in pheno- administered dopamine agonist and the period in the estrous
typically female dogs. The abnormalities may include the cycle or anestrus in which treatment is started. When bromo-
7 presence of abnormal complements of sex chromosomes criptine was started during the luteal phase, in an oral dose of
as well as sex chromosome complements that do not 20 mg/kg twice daily, the mean interestrous interval was
match the animal’s phenotype (chapter 6.2.1).69 shortened from 216 to 96 days (fig. 7.18).32 When it was
쎱 Laparoscopy or laparotomy, to examine the genital tract started in the same dose during anestrus, 100 days after ovu-
and collect tissue for histological examination. lation, the next proestrus appeared after a mean interval of
쎱 Abdominal ultrasonography usually does not reveal the about 45 days.77 The fertility of estrus initiated by bromocrip-
cause of prolonged anestrus. tine treatment appears to be normal.
Treatment
Treatment depends on the cause of the prolonged anestrus.
Hypothyroidism is treated with l-thyroxine (chapter 3.3.1). If 7.10 Estrus prevention
the animal has silent heats, estrus can be detected by cytologi-
cal examinations at regular intervals and close visual examin- Estrus can be prevented medically or surgically. Ovariectomy
ation of the vulva. The optimal mating period can be deter- has certain advantages. It is effective after a single procedure.
mined by measuring progesterone. In most cases of true It considerably lowers the risk for mammary cancer if per-
hermaphroditism or pseudohermaphroditism, treatment is formed before or after the first luteal phase but in any case
not possible. If no specific cause for the prolonged anestrus is before about 2.5 years of age. It also prevents the develop-
found, estrus may be induced (chapter 7.9). ment of pyometra and progesterone-induced GH excess
(chapter 2.2.4.2). There are, however, several disadvantages,
such as the risk of anesthesia and surgery, and the irrever-
sibility of the procedure. There are also possibile side effects,
7.9 Estrus induction such as urinary incontinence or unwanted changes in the hair
coat. Early-age gonadectomy is associated with an increased
Induction of a follicular phase can be achieved by several incidence of cystitis.78 The risk of urinary incontinence is
methods, including the use of synthetic estrogens, GnRH greater if the intervention is carried out prior to the first es-
agonists, exogenous gonadotropins (LH, FSH, human Cho- trus (see also chapter 8.2).78 Urinary incontinence occurs
rionic Gonadotropin, equine Chorionic Gonadotropin, and mainly in dogs of large breeds. The boxer, Doberman, Bou-
human Menopausal Gonadotropin), dopamine agonists, and vier des Flandres, giant schnauzer, Irish setter, Old English
opiate antagonists (naloxone). These methods vary widely in sheepdog, Weimaraner, and Rottweiler appear to be es-
their efficacy of inducing estrus as well as the resulting fertility pecially at risk for developing urinary incontinence.
of the induced estrus.41 In a study in which GnRH was ad-
ministered in pulses of 15–500 ng/kg body weight every In the cat ovariectomy is the treatment of choice. It does not
90 min for seven to nine days to 36 anestrous bitches, treat- lead to urinary incontinence. Furthermore, endogenous pro-
ment resulted in proestrus in 26, estrus in 20, ovulation in 16, gesterone and progestagens are, as in the bitch, tumorigenic
and pregnancy in 12 bitches. Efficacy was dose-dependent.73 and mammary tumors in the cat are quite often malignant.79,80
A fertile estrus could also be induced by administering a
timed-release GnRH agonist, followed by a GnRH analogue Medical prevention of estrus can be accomplished with sev-
on the first day of induced estrus.74 Anestrus in the bitch can eral types of drugs, not all of which can be used in every
also be terminated by administering LH. In one study proes- country. Progestagens are the most important among them
trus was induced by porcine LH in all of 16 bitches, of which but androgens can also be used, primarily for short-term pre-
twelve came into estrus and seven ovulated. Those in which vention.
Estrus prevention 223
Androgens probably inhibit pituitary gonadotropin release, The progestagens most frequently used for estrus prevention
thus preventing follicular development. One orally adminis- in the dog are proligestone and MPA. The single subcu-
tered synthetic androgen, mibolerone, is also anabolic. It has taneous injection dose recommended by the manufacturer for
no progestational or estrogenic activity and its advantage proligestone ranges from 10 mg/kg for a dog of about 60 kg,
therefore lies in its minimal influence on the endometrium. to 30 mg/kg for a dog of 3 kg, and for medroxyprogesterone
Thickening of the myometrium may occur but only when acetate the single subcutaneous injection dose is 2 mg/kg
excessive doses are used. Although subsequent fertility in (with a maximum dose of 60 mg). They should be adminis-
bitches treated with this drug appears to be good, it is not tered during anestrus, about one month before the expected
recommended in the U.S.A. for use in breeding bitches or in follicular phase (fig. 7.34). In most bitches the first estrus after
bitches prior to the first estrus. Androgens may also have side injection of proligestone can be expected within nine to
effects, including clitoral hypertrophy, vaginal discharge, liver twelve months; after injection of MPA it may be up to two to
dysfunction, and weight gain. Androgens are contraindicated three years. MPA can also be administered orally, 5 mg once
in bitches with a liver or kidney disease. Furthermore, an- daily (10 mg for large dogs during the first five days) for as
drogens can induce development of mammary tumors. If ad- long as estrus prevention is wanted or for a maximum of
ministered to a pregnant dog, androgens may cause defects in 21 days. Estrus recurs after two to nine months. In the U.S.A.
the urogenital tract of female puppies. In addition, androgens the advised dose of megestrol acetate, a progestagen which
may cause an increase in aggressiveness and a change in mic- probably has a stronger progestagenic effect than MPA, is 7
turition behavior. Bitches may begin to urinate like a male 0.5 mg/kg orally once daily for 32 days starting in anestrus,
dog and queens may develop urine spraying behavior. or 2 mg/kg for eight days starting at the onset of proestrus.
Considering the results which are obtained with lower doses
GnRH agonists administered at high doses over a long of MPA, this recommended dose seems quite high.
period of time also prevent estrus by down-regulation of
GnRH receptors on pituitary gonadotropes. However, the In the usual household the queen is not affected by photo-
early stimulatory effect of GnRH analogues, which causes es- period influences and may cycle throughout the year. This
trus if they are administered in anestrus and sometimes also if can be prevented by oral administration of 5 mg MPA or
administered in the luteal phase, make them less suitable for 2 mg megestrol acetate once weekly. Alternatively, owners
clinical use.81 In one study, GnRH agonist implants, applied who can detect the symptoms that precede estrus can admin-
before puberty (mean age: 4.9 ± 0.3 months), prevented re- ister these drugs only when these symptoms occur. The side
productive function for one year. Following removal of the effects of oral administration appear to be less serious than
implant estrus occurred naturally in seven of ten bitches and those accompanying injections. In addition, should the queen
could be induced in the other three after 1.2–14.3 months.82 unexpectedly be found to be pregnant, the oral medication
The age at puberty of the treated bitches was 25.5 ± 5 can be stopped and parturition allowed to occur normally.
(18–31) months. Long-acting GnRH antagonists, suitable for Another option is to reduce estrus frequency in the queen by
use in clinical practice, have not yet been marketed. inducing ovulation. This can be accomplished by mechanical
stimulation of the vagina (touching the vestibulum /vagina
Progestagens. The mechanism of the contraceptive action with a cotton probe) or by treatment with a gonadotropic
of progestagens is still unclear. In some species there is evi- hormone or GnRH during estrus. The induced pseudopreg-
dence that contraceptive progestagens inhibit gonadotropin nancy delays the recurrence of estrus.
release. However, high doses of medroxyprogesterone acetate
administered to beagle bitches for several months did not re- Side effects associated with the use of progestagens for estrus
duce the increased circulating LH concentration in ovariec- prevention:
tomized bitches nor did it lower LH concentration in intact 쎱 Development of cystic endometrial hyperplasia (chap-
during anestrus, nor was the hypersecretion of LH and FSH ministered subcutaneously at the onset of the follicular
that occurs in ovariectomized bitches suppressed.84 Chronic phase and the bitch is mated. The gestation will be pro-
medroxyprogesterone acetate (MPA) treatment did not affect longed and a caesarian section may be needed.
FSH secretion, except for an increase two months after the 쎱 Hypersecretion of mammary GH (chapter 2.2.4.2).
start of treatment, and did not affect LH secretion (fig. 7.33).85 쎱 Diabetes mellitus. In cats, this is usually caused by the glu-
Pulsatile FSH and LH release is maintained during MPA treat- cocorticoid effects inherent in progestagens.87,88 In dogs,
ment, but there are indications of changes in the pulsatile se- however, apart from glucocorticoid effects, diabetes mel-
cretion pattern of the gonadotropins. In general, LH pulses litus is largely due to GH excess.15 The hypersecretion of
coincide with an FSH pulse, but during MPA treatment LH GH caused by progestagen administration can be treated
pulses coincided with small and sometimes insignificant FSH successfully by the progesterone-receptor blocker agle-
pulses (fig. 7.33).86 The results of this study also suggest that pristone.89
there may be a direct negative effect of medroxyprogesterone 쎱 Increased risk of neoplastic transformation of mammary
acetate on follicle development in the ovary.86 tissue. This ranges from hyperplasia to adenomas and
224 Ovaries
Figure 7.33:
Six-hour plasma profiles of FSH and LH in a three-year-old beagle bitch before and three, six, nine and twelve months after the start of treatment with medroxy-
progesterone acetate (10 mg/kg, every four weeks).
* Significant pulses of both FSH and LH. ^ Significant LH pulse without significant increase in FSH. (Modified after Beijerink et al., 2008.)86
Estrus prevention 225
Figure 7.34:
Optimal period for progestagen treatment for estrus prevention in the bitch.
Clinical manifestations
Bitches and queens with uncomplicated CEH do not exhibit
signs of systemic disease. Infertility due to failure of implan-
tation or to fetal resorption can, however, be observed. If in-
fection is also present the signs and symptoms are often de-
pendent upon cervical patency. The systemic disease is usually
B milder when the cervix is open than when it is closed.
Massive quantities of pus may be found in the lumen of the
Figure 7.36:
(A) Cystic endometrial hyperplasia in an eight-year-old bitch. The lumen of the
uterus, especially if the cervix is closed (pyometra). In this
uterus is filled with aggregates of bulging cysts arising from the endometrium. situation the animal is lethargic and may be anorectic. The
(B) Multicystic proliferation in the bitch due to cystic endometrial hyperplasia with enlarged uterus may cause abdominal distention. With an
papillary overgrowth of the endometrium, which is mainly composed of epithelial open cervix vaginal discharge ranges from yellow to choc-
tissue with scant connective tissue. (H&E stain, x40). olate or red, depending on the presence or absence of blood.
The bacterial infection may cause deposition of immune
complexes in the glomerular capillary walls. This may cause
proteinuria, but it does not usually lead to permanent renal
7.11 Cystic endometrial hyperplasia- failure. The elevated plasma urea and creatinine concen-
endometritis trations are generally prerenal in origin, i.e., due to hypovol-
emia. Vomiting associated with the uremia may be an aggra-
Pathogenesis and pathology vating factor. One must also be alert to the possibility of
Cystic endometrial hyperplasia (CEH) is a common disorder peritonitis due to a perforated uterus.
of the uterus of the bitch and the queen. If the endometrial
hyperplasia is accompanied by inflammation the condition is The bacterial infection and more specifically E. coli antigens
called CEH-endometritis. CEH can develop either as a may cause loss of medullary hypertonicity.91 In addition, a de-
consequence of repeated endogenous progesterone influence crease in renal sensitivity to vasopressin has been demon-
during successive luteal phases or as a consequence of exo- strated in dogs with pyometra.92 These changes may lead to a
genous progestagens. It is therefore a common disorder in decreased ability to concentrate urine. The associated poly-
older bitches, which have completed several luteal phases. It is uria and polydipsia are common in dogs with CEH-endo-
not the result of »retained« corpora lutea. metritis, but rare in cats.
GH has been demonstrated by immunohistochemistry in the Anemia is present in about 40 % of bitches with CEH-en-
hyperplastic glandular epithelial cells of the uterus of proges- dometritis. This may be the result of blood loss in the uterus,
tagen-treated dogs. Although endogenous progesterone and but the inflammatory process can also lead to decreased ery-
exogenous progestagens may induce both development of thropoiesis.
CEH and hypersecretion of GH in mammary tissue, the latter
does not seem to play a role in the pathogenesis of CEH.18
Cystic endometrial hyperplasia-endometritis 227
A B
Figure 7.37:
7
(A) Mucometra with a thin uterine wall in a seven-year-old Bouvier des Flandres, treated for several years with high doses of progestagens.
(B) Transverse ultrasonogram of the abdomen of the same bitch. The uterus is severely dilated (delineated by interrupted line) and filled with fluid (F). Inspissated mucus
(M) causes amorphous echogenicity in the dependent part of the uterine horns.
Figure 7.39:
Ultrasonogram of the abdomen of a seven-year-old
bitch with cystic endometrial hyperplasia. The uterus
Figure 7.38: is slightly dilated, fluid-filled, and has an irregularly
Lateral radiograph of the abdomen of a seven-year-old mixbred dog with pyo- thickened wall with small cysts.
metra. The dilated, fluid-filled uterus causes displacement of other viscera.
Figure 7.40:
Vaginal septum between the vestibule and the
7 vagina in a bitch, observed during anestrus.
U = urethral orifice.
Figure 7.42:
Plasma concentrations of LH and progesterone during
the periovulatory period (LH surge at time = 0) in two
bitches: Lower panel: six-year-old beagle; after the
initial increase, plasma progesterone concentration
remains stable for three days. Upper panel: five-year-
old beagle; plasma progesterone concentration in-
creases markedly within 24 h. Also note the bifurcated
LH surges. (Modified from De Gier et al., 2006.)2
late as four to five days after the LH surge. Moreover, some tration increases slightly at the time of the preovulatory LH
bitches never exhibit estrus behavior. Hence it is clear that surge and then rapidly at the onset of ovulation, thereby ex-
breeding a bitch on a standard day in the cycle will usually ceeding 16 nmol/l. The optimal time for mating begins 24 h
give poor results. Breeding according to estrus behavior will later (fig. 7.41) and is based on the time needed for matu-
give better results, but some bitches will still be bred too early ration of the oocytes and capacitation of the sperm. The latter
and others too late. Determination of the ovulation period is requires at least 7 h. By determining the optimal time for
therefore of the utmost importance. Several methods have mating using a rapid radioimmunoassay for plasma progeste-
been described to determine the ovulation period and the rone, pregnancy was achieved in 105 of 112 (94 %) bitches
optimal time for mating. The primary methods are measure- with normal fertility and 81 of 104 (78 %) of those with sub-
ment of plasma progesterone and vaginoscopy. optimal fertility.95 In the latter group only 23 % of previous
matings had been successful.
The ovulation period can be defined satisfactorily by thrice-
weekly measurements of plasma progesterone. The concen-
230 Ovaries
Determining the preovulatory LH surge would also be suit- There are, however, no reliable changes in the smear indica-
able for estimating the time of ovulation. Rapid radioimmu- tive of the preovulatory LH surge or of ovulation. During the
noassays for determination of the plasma LH concentration transition from estrus to metestrus the percentage of round
are not yet available, but in-hospital ELISA LH kits are avail- cells increases rapidly and leukocytes reappear. However, an
able. However, more frequent blood sampling would be early metestrus smear can easily be confused with an early
required than for progesterone because of the risk of missing proestrus smear. Hence the use of vaginal cytology is not suit-
the preovulatory LH surge. More importantly, the time able for determining the appropriate period for mating the
between the preovulatory LH surge and the rapid rise in bitch.
plasma progesterone concentration (indicating ovulation and
formation of corpora lutea) varies (fig. 7.42). Hence plasma Also ultrasonography can be used for ovulation deter-
progesterone concentration is the preferred variable for esti- mination, but because both pre-ovulatory follicles and post-
mating the ovulation period. ovulatory corpora lutea have cavities, examination must be
performed by experienced persons with excellent equipment,
Vaginoscopy can also be used to attempt to determine preferably twice a day. This method appears to be less practi-
the ovulation period (chapter 7.2.1). The mucosal changes cal than detection of ovulation via determination of the
are, however, a response to hormone-controlled alterations plasma progesterone concentration.96,97
7 and are therefore secondary changes. Interpretation of the
changes is also subjective. Vaginoscopy is thus a less reliable In spite of correctly timed breeding, some bitches will refuse
method for estimating the ovulation period than measuring the dog or other mating problems may arise. Some breeds,
plasma progesterone. For the experienced veterinarian it is a such as English and French bulldogs and the Newfoundland
useful tool for monitoring the stages of the estrous cycle, but dog, are especially prone to mating problems. The cause of
mating advice based on vaginoscopy should include the the mating problem can be related to the dog (abnormal anat-
recommendation to mate at least twice, with an interval of omy, inexperience, behavioral problems), the bitch (behavio-
48 h. ral problems, vaginal abnormalities), or the owner (inexperi-
ence). With due regard for possible hereditary consequences,
Vaginal cytology is very useful in diagnosing early proestrus, artificial insemination can be used.
progressing proestrus-estrus, or metestrus (chapter 7.2.1).
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Endocrinol 1991;125 (Suppl 1):32–37.
234 Ovaries
94. GOBELLO C, CASTEX G, KLIMA L, RODRÍGUEZ R, 96. SILVA LDM, ONCLIN K, VERSTEGEN JP. Assessment of ovar-
CORRADA Y. A study of two protocols combining aglepristone ian changes around ovulation in bitches by ultrasonography, laparo-
and cloprostenol to treat open cervix pyometra in the bitch. The- scopy and hormonal assays. Vet Radiol Ultrasound 1996;37:
riogenology 2003;60:901–908. 313–320.
95. VAN HAAFTEN B, DIELEMAN SJ, OKKENS AC, WILLEMSE 97. HAYER P, GÜNZEL-APEL AR, LÜSSEN D, HOPPEN HO.
AH. Timing the mating of dogs on the basis of blood progesterone Ultrasonographic monitoring of follicular development, ovulation
concentration. Vet Rec 1989;125:524–526. and the early luteal phase in the bitch. J Reprod Fertil 1993;
Suppl 47:93–100.
7
235
8 Testes
Jeffrey de Gier
Frederik J. van Sluijs
8.1 Introduction testes. However, aged dogs often have testicular tumors which
affect spermatogenesis and are often not clinically detectable.2
In the dog the testes lie obliquely within the scrotum, their
long axis directed caudodorsally. The epididymis, which is Sertoli cells, which line the seminiferous tubules, have an im-
relatively large in dogs, is attached along the dorsolateral portant supportive function during spermatogenesis. They
border of the testis and consists of a head, body, and tail. The express androgen receptors and receptors for follicle-stimulat-
head arises from the testis cranially and is the thickest part. ing hormone (FSH) and are thought to regulate development
The body or middle part is slightly smaller and the tail is at- of the germ cells via the synthesis and secretion of molecules
tached to the caudal end of the testis and is continuous with which act upon the surrounding germ cells. Androgens and
the ductus deferens. In the cat the testes are located closer to androgen receptors are essential for maintenance of sperma-
the anus and their long axis is directed caudoventrally. togenesis, whereas males are still fertile without the influence
of FSH. 3 8
Tubules with seminiferous epithelium make up about 80 % of
the testis. They are composed of supporting cells and sperma- In the basal region of the seminiferous epithelium the plasma
togenic cells (fig. 8.1). Seminiferous tubules are the site of membranes of adjacent Sertoli cells form specialized junc-
spermatogenesis, i.e., where spermatogonia develop into tional complexes which constitute the structural basis of the
spermatozoa. This occurs in three distinct phases: (1) the pro- Sertoli cell barrier. The primary function of this barrier,
liferation phase, in which undifferentiated spermatogonia previously known as the blood-testis barrier, is probably to
undergo rapid cell multiplication by mitotic divisions, (2) the insure proper conditions for germ cell development in the
meiotic phase, in which spermatocytes develop, and (3) the tubules. Some molecules enter the tubules nearly instant-
differentiation phase or spermiogenesis, in which spermatids aneously, while others are almost completely excluded. For
are transformed into spermatozoa. After completion of sper- example, testosterone and glucose appear to have accelerated
matogenesis, the spermatozoa are released into the lumen of entry rates, while peptide hormones (including the gonado-
the seminiferous tubules, a process referred to as spermiation.1 tropins) are generally excluded. Peptide hormones produced
With increasing age there is neither deterioration in sperma- or secreted into the tubular lumina are retained there by the
togenesis nor a change in tubular diameter in healthy canine barrier and probably do not function as endocrine factors
A B
Figure 8.1:
Cross section of a seminiferous tubule in the dog. Sc = Sertoli cells; spc = spermatocytes; spt = spermatids; spz = spermatozoa; sp = spermatogonia; pt = peritubular
cells; Lc = Leydig cells; bv = blood vessel ([A] schematic, [B] PAS-hematoxylin stain, x475). (Courtesy of Dr. K.J. Teerds, drawing by H. Halsema.)
236 Testes
Figure 8.2:
Schematic illustration of the conversion of testosterone to dihydrotestosterone
and estradiol, catalyzed by 5a-reductase and aromatase, respectively.
8
Figure 8.3: 씰
Endocrine control of testicular function. Androgen secretion is regulated by LH,
with feedback from testosterone (T2). Spermatogenesis is controlled by FSH, with
feedback from inhibin. Testosterone is converted to dihydrotestosterone in several
target tissues.
outside the testis. Sertoli cells also produce androgen-binding which has a higher affinity for the receptor. The conversion is
protein, which is required to maintain the high concen- effected by an NADPH-dependent 5a-reductase (fig. 8.2),
trations of testosterone in the tubular compartment needed which is not present in the tubular compartment of the
for spermatogenesis.4 testes.4 Testosterone can also be converted to estradiol by the
aromatizing enzyme system that is present in mammalian
Between the seminiferous tubules lie groups of interstitial or testes as well as in adipose tissue, prostate, and bone.3 The
Leydig cells. They are the main constituent of the endocrine peripheral contribution to total estradiol production appears
portion of the testis and produce the androgens that drive the to be large (of the order of 75–80 %) as compared to the tes-
spermatogenic process.3,4 ticular contribution. Testicular steroids are secreted into
blood, lymph, and tubular fluid. Blood is quantitatively the
most important effluent system because the flow rate is
20 times that of lymph or tubular fluid.
8.1.1 Hormone synthesis and secretion
Another hormone secreted by the testis is inhibin, a glyco-
The main hormones secreted by the testes are androgens and protein hormone produced primarily by the Sertoli cells
estrogens. Androgens are produced by the interstitial or Ley- (fig. 8.3). It consists of two dissimilar, disulphide-linked sub-
dig cells, which are stimulated by luteinizing hormone (LH). units termed a and either bA or bB. The b subunit of inhibin
The primary androgen is testosterone. Like other steroid hor- shares a sequence homology with members of the transform-
mones it is produced from cholesterol, which is converted in ing growth factor b family such as TGFb, activin, and anti-
the mitochondria to pregnenolone. Pregnenolone is further Müllerian hormone (AMH).
metabolized outside the mitochondria to several other ste-
roids via various pathways (see also fig. 4.3). Apart from direct
interaction of testosterone with the androgen receptor, many
effects are exerted after its conversion to dihydrotestosterone,
Hypogonadism 237
Figure 8.4:
Plasma concentrations of LH and testosterone in a dog
after administration on day 0 of an implant that slowly
releases the GnRH agonist deslorelin.
8.1.2 Regulation of testis function In rare cases it may be due to a chromosomal defect, such as in
8
male tricolor cats with a 39,XXY karyotype (chapter 6.2.1).9
Testicular function is controlled by the gonadotropins. An-
drogen secretion is regulated by LH and spermatogenesis is The ultimate form of primary hypogonadism is that resulting
controlled by FSH and locally produced androgens (fig. 8.3). from castration. It is very common in dogs and cats, although
its prevalence varies markedly from country to country, de-
LH is secreted by the hypophysis in a pulsatile pattern with a pending on cultural factors, the urban or rural location of the
frequency of approximately 4.5 pulses every 6 h. LH pulses household, and the species: male cats are more likely to be
are usually followed by a testosterone pulse within 60 min.5 castrated than male dogs. The behavior of most sexually intact
Diurnal rhythmicity has been described, with lowest levels in male cats makes them undesirable as pets.10
the morning and peak levels in the afternoon (LH) or evening
(testosterone).6 FSH is also secreted in a pulsatile fashion, but Secondary hypogonadism occurs rarely, as a consequence of
synthesis and secretion of LH and FSH are differentially regu- low concentrations of gonadotropins due to a pituitary
lated by the frequency of GnRH pulses from the hypothala- tumor. Isolated gonadotropin deficiency has not yet been de-
mus. Pituitary LH and FSH secretion are under negative feed- scribed in dogs or cats. Antiandrogens such as cyproterone
back control by testosterone. In addition, pituitary FSH acetate may act as progestagens and their therapeutic use may
secretion is inhibited specifically by inhibin.7 inhibit gonadotropin secretion, with reversible secondary hy-
pogonadism. The same holds true for corticosteroids. Both
Within the testis, androgens mainly act as paracrine agonists. endogenous and exogenous corticosteroids reduce the plasma
Together with other locally produced factors, such as endo- LH concentration.11 Administration of supraphysiological
genous opioids and proteins produced by the peritubular cells doses of androgens also results in hypogonadotropic hypo-
(P-Mod-S), they regulate Sertoli cell function and thereby in- gonadism.4,12 The high plasma androgen concentration sup-
directly the process of spermatogenesis.8 presses pituitary gonadotropin secretion and consequently
testicular testosterone secretion. Because the testosterone
concentration in testicular tissue is normally much higher
(25–100×) than in plasma, the LH-dependent testicular tes-
8.2 Hypogonadism tosterone concentration will become too low to stimulate tes-
ticular function.
Male hypogonadism refers to all forms of endocrine and
secretory hypofunction of the testes. The term hypogenital- A more recently introduced iatrogenic cause of secondary hy-
ism is used for underdeveloped external genitalia. Two forms pogonadism in dogs is the use of implants of slow-release
of hypogonadism are recognized: (1) primary or hyper- GnRH-agonists, such as deslorelin. These causes plasma LH
gonadotropic hypogonadism, and (2) secondary or hypo- and testosterone concentrations to first rise and then decline
gonadotropic hypogonadism. Primary hypogonadism – to low values for prolonged periods of time (fig. 8.4), result-
atrophy of the testes in the presence of normal or increased ing in temporary loss of fertility, as testosterone is vital for
plasma concentrations of gonadotropins – may result from spermatogenesis.13–15 This opposite effect is due to GnRH-
many diseases, such as orchitis of either infectious (Brucella receptor down-regulation, internalization, and signal un-
canis) or autoimmune etiology, trauma, and testicular torsion. coupling after sustained exposure to the GnRH analogue.15
238 Testes
Figure 8.5:
Penis of an intact (A) and castrated (B) tomcat. The
A B typical barbs on the penis of the intact male are absent
in the castrated male.
8
Clinical manifestations With time the main changes after gonadectomy seem to be
Testis atrophy is characterized by small and soft testes. The consequences of increased appetite, in cats leading to in-
atrophy does not affect the epididymis, which is relatively creased body weight and increased plasma concentrations of
large and firm in comparison with the adjacent testis. Sec- insulin, leptin, IGF-I, and prolactin.23,24 The increase in food
ondary reversible hypogonadism induced by implants releas- intake, body weight, and body fat mass can be prevented al-
ing GnRH agonists also induces transient testicular atrophy, most completely by treatment with estradiol, which is con-
which can be used clinically to assess the duration of action of sistent with studies in rodents demonstrating the importance
an implant. of gonadal estrogen in increasing the satiating potency of
cholecystokinin released in response to ingested lipid.25,26
If testis atrophy occurs at an early age the androgen defi- The possible clinical consequences of overweight are covered
ciency may result in underdevelopment of secondary sexual in chapters 5.2.4 and 11.
characteristics, i.e., hypogenitalism. Affected tomcats do not
have a typical feline masculine appearance and the prepuce In male dogs gonadectomy does not result in hyperprolac-
and penis remain underdeveloped. The penis lacks the barbs tinemia, but LH concentrations are high because of the ab-
that are typical of male felidae (fig. 8.5). Hypogonadism also sence of androgen feedback.27 Gonadectomy does not gen-
affects male behavior, lessening the tendency to marking and erally affect thyroid or adrenocortical function, although
roaming as well as aggressive behavior toward other males.16 slight differences have been found between gonadectomized
and intact dogs in some test results.27,28 Decreased plasma an-
Gonadectomy is often carried out before the cat reaches pu- drogen concentration following gonadectomy in dogs is ac-
berty and initially leads to no serious physical or behavioral companied by loss of bone volume and increased plasma PTH
problems.10,17 When performed prior to physeal closure, it concentration,29 but not to the extent that it leads to clinically
delays that closure and leads to significant, although not noticeable problems.
readily visible, lengthening of long bones (see also chapter 9.7
and table 9.2).18 In cats, spontaneous femoral capital physeal Sex steroid deprivation and persistently high plasma gonado-
fractures, with histological signs of necrosis of the epiphysis, tropin concentrations also affect the biology of collagen and
have been reported to be associated with prepubertal gonad- muscle. Gonadectomy leads to a slightly increased occurrence
ectomy.19–22 The vast majority of the affected cats were over- of injuries of the anterior cruciate ligament.30 It also alters the
weight, neutered males. proportion of collagen and muscle fibers along the lower uri-
nary tract. Regardless of gender, there is a larger proportion
of collagen in gonadectomized dogs than in intact dogs.31 The
resulting decrease in tissue elasticity has an adverse effect on
the collecting phase of micturition and on bladder contrac-
tion, but in contrast to female dogs (chapter 7.10), male dogs
rarely develop neutering-induced urinary incontinence.
Cryptorchidism 239
8
Differential diagnosis 8.3 Cryptorchidism
Hypogonadism (including the result of castration) should be
differentiated from cryptorchidism. Ectopic testes are difficult Cryptorchidism is a developmental defect in which there
to detect by palpation in obese animals and in abdominal is failure of complete descent of one or both testes into the
cryptorchids. In tomcats the presence of barbs on the penis scrotum. The reported incidence in dogs varies from 1.2 %
(fig. 8.5) indicates secretion of androgens by testicular Leydig to 9.7 %,33,34 depending on the population studied. It is a
cells. The presence of an endocrinologically functional testis congenital disease and is considered to be a sex-limited
can be demonstrated unequivocally by a GnRH-stimulation inherited trait in dogs.35 Cryptorchidism occurs more often in
test (chapter 12.5.1). purebred than in crossbred dogs and bilateral cryptorchid dogs
are reported to be more inbred than unilateral cryptorchids.
Diagnosis Although a single autosomal recessive allele has been cited as a
The consistency of the testes is determined by palpation. probable cause, transmission of the defect is probably due to
Their size can be measured with calipers (fig. 8.6) or esti- more than one gene. Cryptorchid dogs are considered to be
mated with Prader’s orchidometer (fig. 8.7). In the dog the homozygous for the defect and their removal from the breed-
dimensions of the testes depend on the body mass.32 They ing line generally causes a decrease in frequency of the abnor-
range from 1.5 × 1.5 × 2 cm in toy breeds to 3 × 3 × 5 cm in mal allele. Because cryptorchidism is a sex-limited trait that
large breeds. In the cat the testes have a diameter of approx- can only be detected in males, the genotype of the carrier fe-
imately 1 cm. male can only be assessed by progeny testing. This requires
large numbers of puppies and makes the condition difficult to
Treatment eliminate from a canine population. Cryptorchidism has been
The most frequent cause of hypogonadism is castration. This found in at least 68 canine breeds.35 A retrospective study36
has usually been elected by the owner and requires no treat- of 2912 dogs identified 14 breeds with a significantly in-
ment. In the rare cases in which treatment of hypogonadism is creased risk: toy poodle, Pomeranian, Yorkshire terrier,
requested, androgen replacement therapy may be given. The miniature dachshund, Cairn terrier, Chihuahua, Maltese,
treatment of obese orchiectomized cats with estradiol has not boxer, Pekingese, English bulldog, Old English sheepdog,
been investigated in long-term studies. miniature poodle, miniature schnauzer, and Shetland sheep-
dog. The incidence of cryptorchidism in the cat has been re-
Prognosis ported to vary from 1.7 % to 3.8 %.37,38 Persian cats were
Primary hypogonadism is usually incurable but testosterone overrepresented in both studies.
replacement can be given lifelong. The prognosis in second-
ary hypogonadism depends on the course of the primary dis- Normal testicular descent can be divided into three phases:
ease (chapter 2.2.6).
240 Testes
Figure 8.8:
Schematic representation of the normal descent of the
testis (A 씮 D). 1 = testis; 2 = gubernaculum; 3 = vagi-
nal process; 4 = external oblique abdominal muscle;
5 = internal oblique abdominal muscle; 6 = perito-
neum; 7 = cremaster muscle; 8 = external spermatic
fascia. (Modified from Wensing, 1980.)104
(1) abdominal testis translocation, specifically retention near toward the inguinal area and then through the inguinal canal.
the neck of the developing bladder as the abdominal cavity These steps constitute abdominal translocation and transin-
enlarges, followed by slight testis relocation to the future in- guinal migration. After completion of the outgrowth, the gu-
guinal ring; (2) transinguinal migration of the testis, moving bernaculum regresses and pulls the testis further caudally. This
the cauda epididymis and testis through the abdominal wall; is the inguinoscrotal migration that moves the testis into the
and (3) inguinoscrotal migration of the testis, from a subcu- scrotum. Complete absence of the outgrowth reaction has not
taneous location outside the inguinal canal to the final posi- been observed, but substantial underdevelopment does occur
tion in the bottom of the scrotum.39 The process of descent is with low frequency. In these cases there is a partial migration
controlled by the gubernaculum testis (fig. 8.8). This is a mes- of the testis from its original position just caudal to the kidney
enchymal cord that extends from the caudal pole of the testis to the vicinity of the internal inguinal opening. The final re-
to the inguinal canal. During the process of descent, the sult in such cases is either permanent low abdominal crypt-
gubernaculum increases in size just distal to the external orchidism or delayed testicular descent. Abnormal location of
opening of the inguinal canal. At the same time, the cranial the gubernaculum can take three forms (fig. 8.9). First, the
suspensory ligament between the cranial pole of the testis and extra-abdominal part of the gubernaculum does not expand
the abdominal wall close to the diaphragm regresses. The en- beyond the inguinal canal but, instead, thrusts back into the
largement or outgrowth of the gubernaculum exerts traction abdominal cavity (reversed outgrowth). The traction norm-
upon the intra-abdominal part of the gubernaculum and this ally developed by the outgrowth is absent, and the testis fails
pulls the testis and epididymis distally through the abdomen to leave its original position caudal to the kidney. This results
Cryptorchidism 241
Figure 8.9:
Schematic representation of three forms of abnormal
descent of the testis. (A) Reversed outgrowth of the
gubernaculum. (B) Outgrowth of the gubernaculum
partly in the abdomen. (C) Outgrowth of the guber-
naculum partly outside the abdomen. The numbers
refer to the same structures as in fig. 8.8. (Modified
from Wensing, 1980.) 104
in high abdominal cryptorchidism. Secondly, the outgrowth Several possible etiologies for cryptorchidism have been sug-
occurs partly in the inguinal canal and partly within the ab- gested, such as abnormal testicular differentiation, deficient
domen. Only slight displacement of the testis in the direction androgen production, deficient production /action of anti-
of the internal inguinal opening will then occur. Thirdly, the Müllerian hormone (AMH), and deficient action of Insl3.
outgrowth reaction is partly outside the abdomen, in which But in most cases the etiology is unknown, albeit that in dogs
case descent will progress further and the testis may even predisposing factors such as familial occurrence, litter size,
reach the internal inguinal opening. The final outcome is dif- and sex ratio in the litter have been documented.43,44 In hu-
ficult to predict, but low abdominal or inguinal cryptor- mans cryptorchidism is associated with impaired germ cell
chidism is the most likely result. development, and altered plasma concentrations of gonado-
tropins and inhibin, which has led to the suggestion that there
Abdominal translocation of testes is dependent on insulin-like may be primary developmental disorders in cryptorchid
peptide 3 (Insl3), produced by the fetal Leydig cells. Insl3 testes.45 However, it is not clear whether these abnormalities
stimulates growth of the gubernaculum to form an anchoring are a cause or a consequence of cryptorchidism.46
structure. Directional guidance for inguinoscrotal testis mi-
gration is provided by calcitonin gene-related peptide Clinical manifestations
(CGRP) released from the genitofemoral nerve, descending The most striking abnormality is the absence of one or both
down with the developing gubernaculum. Testosterone testes from the scrotum. Dogs with bilateral cryptorchidism
stimulates production or release of CGRP, which acts as a are considered to be infertile. Dogs with unilateral cryptor-
chemoattractant and induces the developing tip of the guber- chidism are generally regarded as being potentially fertile, but
naculum to grow toward the source of CGRP.40–42 Testoste- their fertility is probably lower than that of normal dogs.35
rone and AMH are not obligatory for the thinning and elong- Plasma concentrations of testosterone and estradiol in dogs
ation of the cranial suspensory ligament and the expansion of with unilateral inguinal or abdominal cryptorchidism do not
the gubernaculum.39 In most species abdominal translocation differ from those in normal dogs.47 Cats with unilateral crypt-
is the longest phase of testicular descent, but in the dog ingui- orchidism, in which the scrotal testis has been removed, have
noscrotal migration requires a similar interval as the abdomi- the behavioral characteristic of intact males.38
nal translocation. Transit through the inguinal canal is rapid,
requiring less than two to four days.39 There is an increased risk of neoplasia in cryptorchid testes
and some types of testicular neoplasms may cause femini-
zation and blood dyscrasias (chapter 8.4).
242 Testes
A B
Figure 8.10:
(A) Contrast-enhanced transverse CT image of the abdomen of a five-year-old male miniature schnauzer with persistent Müllerian duct syndrome (PMDS), presented with
8 unilateral cryptorchidism and signs of feminization, showing an intra-abdominal neoplastic testis (T). In addition, a fluid-filled uterus (UB, uterine body) and uterine horns
(UH, arrow) can be identified.
(B) The neoplastic cryptorchid testis (T) was in close proximity to the uterine horn (UH). It contained a Sertoli cell tumor. Li = ligament; P = pampiniform plexus.
Differential diagnosis There is disagreement in the literature about the time of tes-
Unilateral cryptorchidism should be differentiated from ticular descent in dogs and cats. Detailed data have been pub-
monorchism, in which no testicular tissue is present. Monor- lished only for beagle and mongrel puppies.48 In these dogs
chism has been described in two cats.38 the testes reached their final position in the scrotum at 35 and
40 days postpartum. Based on these findings, puppies should
Diagnosis be examined at six to twelve weeks of age. If the testes have
Cryptorchidism is diagnosed by inspection and palpation. not descended by eight weeks of age, cryptorchidism may be
Cryptorchid testes may be present in the abdomen, at the diagnosed tentatively. However, testicular descent has been
inguinal ring, or in the inguinal canal. Abdominal testes can- reported to be complete as late as six months of age in some
not be palpated. Those in the inguinal area can sometimes be dogs.49,50 Thus periodic reexaminations should be performed
palpated, but in young animals it is difficult to determine the until six months of age.
position of the testes reliably because of their small size during
the first weeks of life. In addition, the cremaster muscle may Treatment
hold immature testes in the inguinal canal or retract them Human chorionic gonadotropin (hCG) and gonadotropin-
from the scrotum when the animal is exposed to stress during releasing hormone (GnRH) have been tried and reported
physical examination. Cats have large inguinal fat pads which anecdotically to be effective.51–53 The scientific basis for
make inguinal testes extremely difficult to palpate. this form of treatment is not clear, since there is no evidence
that testicular descent is controlled by gonadotropins. As the
Bilateral cryptorchidism in cats can be suspected by the pres- inguinal canal is usually closed in abdominal cryptorchids,
ence of barbs on the penis (fig. 8.5). In dogs rectal palpation success can only be expected in inguinal cryptorchidism.
of the prostate gland may provide evidence for the presence or Testosterone has been tried as a therapy for cryptorchidism
absence of circulating testosterone. Diagnostic imaging of the with little or no success.53 Surgical placement of the retained
inguinal region and the abdomen by ultrasonography or com- testis in the scrotum (orchidopexy) has been shown to impro-
puted tomography (fig. 8.10) often reveals a cryptorchid tes- ve testicular function and may even result in normal fertili-
tis. If palpation and diagnostic imaging are inconclusive, basal ty.54,55 However, it is generally considered to be unethical be-
and GnRH-stimulated plasma testosterone concentrations cause it conceals a congenital abnormality and promotes
may distinguish between animals without testes and those spread of the defect in the population. Surgical removal of the
with one or two cryptorchid testes (chapter 12.5.1). retained testis or castration are frequently advised because this
eliminates the risk of developing testicular neoplasms and pre-
Testicular neoplasia 243
A B
Figure 8.12:
A ten-year-old dachshund with pendulous prepuce and bilaterally symmetrical alopecia (A). These signs were
C caused by a mixed Sertoli cell tumor /seminoma in an ectopic testis in the inguinal area (B, C) and were resolved
after removal of the tumor. Note the small contralateral scrotal testis (B).
cal alopecia (fig. 8.12), atrophy and pigmentation of the skin, may also be caused by other conditions, such as idiopathic or
and signs of feminization such as gynecomastia (fig. 8.13), a immune-mediated thrombocytopenia, myeloproliferative dis-
pendulous prepuce (fig. 8.12), atrophy of the prepuce, and orders, and aplastic anemia. Symptoms and signs of abdominal
atrophy of the contralateral testis, and they may be attractive testicular torsion are nonspecific and other causes of »acute
to other male dogs. There may be blood dyscrasias varying abdomen« must be considered as possible differential diag-
from thrombocytopenia to pancytopenia. In severe cases this noses.
may lead to hemorrhagic diathesis and anemia (fig. 8.14).
Diagnosis
Occasionally dogs with an intra-abdominal testis tumor are Testicular neoplasia in dogs and cats is diagnosed by the find-
presented as an emergency, due to testicular torsion.85,86 ing of a palpable mass in a scrotal or ectopic testis. The con-
Anorexia and lethargy may be accompanied by swelling of the sistency is usually firm and these tumors are rarely found
scrotal and inguinal areas and a stiff gait. Physical examination painful by palpation. In dogs with testicular enlargement due
reveals a painful abdominal mass. It should be added that non- to orchitis or testicular torsion the swelling is mostly soft and
neoplastic abdominal testes may also undergo torsion.87 Scro- painful. In cryptorchid dogs, testicular tumors may not be no-
tal testicular torsion is very rare in dogs.88 ticed unless skin disorders or signs of feminization develop.
Cytological examination of a fine-needle aspiration biopsy
Differential diagnosis may reveal the type of testicular neoplasm (fig. 8.15). Ultra-
Testicular enlargement by tumor should be differentiated sonography of scrotal testes may be used to detect small neo-
from orchitis and testicular torsion. The skin disorders may plasms in the testis that otherwise may be missed by palpation.
mimic other endocrine diseases such as hypothyroidism
(chapter 3.3), hypercortisolism (chapter 4.3), and possibly
growth hormone deficiency (chapter 2.2.2). Blood dyscrasias
Testicular neoplasia 245
A B
Figure 8.15:
Fine-needle aspiration biopsies of canine testes.
(A) Sertoli cell tumor. There is a uniform population of pleomorphic cells. Note the
marked variability in nuclear size. The nuclei are generally round to oval and have
a finely-clumped chromatin pattern with prominent and occasional multiple nu-
cleoli. There are variable degrees of cytoplasmic vacuolization.
(B) Seminoma. Note the marked variations in cell and nuclear size. Nuclei have
coarsely-clumped chromatin and usually contain a single, large, irregularly-
shaped nucleolus. There is often a high mitotic index. Cytoplasm is lightly baso-
philic and granular.
(C) Leydig cell tumor. There is a uniform population of cells with abundant cyto-
plasm and numerous small cytoplasmic vacuoles containing cholesterol C
(May-Grünwald Giemsa stain, x1000).
246 Testes
This technique may also help in the search for the presence of neous hypercorticolism did not differ from that in healthy
an ectopic testis tumor (see also chapter 8.3). dogs, but the response to suprapituitary stimulation tended to
be lower than in healthy dogs.92
Treatment
Testicular tumors are treated by orchidectomy. Removal of Clinical manifestations
the tumor is usually simple, but blood transfusions may be Male infertility ranges from complete absence of libido to the
necessary in patients with severe blood dyscrasias. If both inability to sire offspring in spite of normal mating. Depend-
testes are tumorous, both should be removed. In cases of uni- ing on the cause there may be other signs that are characteris-
lateral testis tumor the contralateral scrotal testis, which may tic of the underlying condition.
be atrophic due to suppression of GnRH secretion by feed-
back of the autonomously hypersecreting tumor, can be left Diagnosis
in place. An ectopic contralateral testis is best removed be- Diagnosis of male infertility is based on a Breeding Soundness
cause of the high incidence of Sertoli cell tumors in nonscro- Evaluation (BSE), which consists of a medical and reproduc-
tal testes. tive history, a complete physical examination, semen collec-
tion for semen analysis, testing for Brucella canis, and ultra-
Prognosis sound examination of the testes, epididymes, and prostate.
The prognosis after surgical removal of the affected testis de- Endocrine testing of the hypothalamic-pituitary-gonadal
pends on the type of tumor but is usually good. Associated axis by a GnRH-stimulation test may be necessary (chap-
skin disorders and signs of feminization are reversible, but ter 12.5.1). Particular attention should be paid to endocrine
8 more severe forms of blood dyscrasia are not amenable to diseases such as hypothyroidism and hypercortisolism. Tes-
treatment and can result in fatal complications. Metastases are ticular biopsy is performed only if the results of all less invas-
uncommon but may occur with all types of testicular tumors. ive methods are inconclusive.
The reported incidence is 1–10 % for Sertoli cell tumors, 3 %
for seminomas, and 2–3 % for Leydig cell tumors.34,59–61,67 Possible results of semen analysis include oligozoospermia
(쏝 200 million sperms in the entire ejaculate, providing that
the ejaculate was collected in a representative way); tera-
tozoospermia (쏝 70 % of sperm cells with normal morphol-
8.5 Male infertility ogy); asthenozoospermia (쏝 50 % progressively forward
motility); leukozoospermia (쏜 2000 white blood cells per µl
Infertility in the male dog or cat may be congenital (thus no in the ejaculate); azoospermia (no sperm observed in the
offspring) or acquired (may have sired offspring). Possible ejaculate); and hemozoospermia (blood seen grossly or in cy-
causes of congenital infertility include an abnormal hypotha- tological smears). More than one abnormality may be present
lamic-pituitary-gonadal axis, chromosomal and /or sexual in a single sample (fig. 8.16).
differentiation abnormalities (see chapter 6), segmental apla-
sia of the ducts, cryptorchidism (chapter 8.3), and defects in Testicular biopsy is indicated in dogs which are persistently
spermatogenesis. Acquired fertility disorders may be caused azoospermic or severely oligospermic. A wedge biopsy is pre-
by testicular hyperthermia due to inflammation or environ- ferred over a percutaneous needle biopsy because specimens
mental factors, testicular neoplasia (chapter 8.4), infections of obtained with needle biopsies contain insufficient tubules in
the reproductive tract, endocrine disorders, exposure to circular cross section to allow detailed histomorphometric
toxins, medication, or may be idiopathic. Idiopathic infertil- analysis of spermatogenesis.93 Testicular biopsy is not entirely
ity is the most common form in men (~ 50 %) and it is as- harmless and should be undertaken with care. However, if
sumed that a large proportion of these have a genetic origin.89 superficial avascular areas are biopsied the method can be
A similar high incidence of idiopathic infertility is suspected considered safe.94 Antisperm antibodies induced by Trucut
in the dog. Endocrine disorders associated with infertility testicular biopsies were found to be transient and nonpredic-
are hypothyroidism and hypercortisolism. Hypothyroidism tive of changes in the total number of morphologically nor-
caused by lymphocytic thyroiditis was shown to be related in mal motile sperm cells.95
incidence to lymphocytic orchitis and reduced fertility in a
colony of beagles.90 However, hypothyroidism induced by 131I Leukozoospermia indicates prostatitis (with or without be-
did not change reproductive function in male dogs.91 nign prostatic hyperplasia), orchitis, epididymitis, and /or uri-
Exogenous glucocorticoid excess in dogs was found to exert nary tract disease. Orchitis and epididymitis are diagnosed by
negative feedback on the secretion of LH by the pituitary, re- ultrasonography and fine needle aspiration biopsy. The latter
sulting in decreased secretion of testosterone by the Leydig method should be used with care. Epididymal aspiration may
cells.11 Basal plasma LH concentration in dogs with sponta- cause hematoma, fibrosis, or sperm granuloma, which could
result in obstruction.96 Diagnosis of infection of the repro-
ductive organs requires bacteriological culture of the ejacu-
late. Mycoplasma and E. coli are the infective organisms cul-
tured most frequently.97
Male infertility 247
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8
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253
9 Calciotropic Hormones
Marianna A. Tryfonidou
Herman A.W. Hazewinkel
Hans S. Kooistra
9.1 Introduction anisms and by calciotropic hormones. Three organs are es-
pecially involved in maintenance of the calcium homeostasis:
Calcium is the most abundant mineral in mammals. It is an es- the gut, the kidney, and the skeleton.
sential structural component of the skeleton and contributes
to many important physiological functions, such as nerve Direct regulation
conduction, muscle contraction, enzyme activity, and blood When calcium is absorbed from the intestine, it tends to raise
coagulation. About half of the circulating calcium is loosely the plasma calcium concentration. Independent of hormonal
bound to plasma proteins (mostly albumin). Ten percent is control some calcium is deposited in bone and less is dissolved
bound to other ions and the remainder comprises the biologi- from the soluble phase into the circulation. In addition, more
cally significant ionically active fraction. It is essential that the calcium is filtered by the glomeruli and excreted. When cal-
concentration of calcium remains constant despite the vari- cium concentration decreases, more calcium enters from the
ations in its intake and excretion. In healthy states the total labile pool into the circulation and less is lost via the kidneys
plasma calcium concentration varies within narrow limits and (fig. 9.2). In both situations endogenous fecal excretion does 9
is fairly constant even under extreme dietary variations not seem to be much influenced.
(fig. 9.1). Calcium homeostasis is maintained by direct mech-
A B
9 Figure 9.3:
The relative calcium fluxes in adult and young growing dogs.
(A) In adult dogs a calcium intake of 100 mg per kg body weight per day covers all losses.
(B) In young dogs calcium metabolism is characterized by high calcium turnover in the skeleton and more efficient absorption; the requirements in absolute amounts de-
pend on the size and growth rate of the dog, and may vary from 50–350 mg/kg body weight.
Figure 9.4:
Influences of calciotropic hormones on calcium metabolism. PTH increases osteoclasia and calcium reabsorption in the renal tubules. Vitamin D metabolites increase
active calcium absorption in the intestine and renal reabsorption; in addition they activate osteoclasia and osteoid and cartilage mineralization. CT decreases osteoclastic
activity and thus increases bone mineralization.
Introduction 255
9
9.1.1.2 PTH synthesis and secretion
The major cell of the parathyroids is the chief cell. It has clear
or slightly eosinophilic cytoplasm, depending on the amounts
of intracellular fat and glycogen (fig. 9.6). The cytoplasm of
active chief cells has a higher density due to the abundance of
Figure 9.7:
Inverse sigmoidal relationship between the extracellular ionized calcium concen-
Figure 9.6: tration and PTH secretion. CaS for PTH indicates the Ca2+ setpoint for PTH secretion,
Histological section of the parathyroid gland of a dog with renal secondary hyper- i.e., the extracellular ionized calcium concentration suppressing the plasma PTH
parathyroidism; note the large pale (= active) chief cells (H&E, x600). concentration to 50 % of its maximum. Also note that there is a nonsuppressible
element to PTH secretion even at very high calcium concentrations.
Figure 9.9:
Osteoclast differentiation and activation. In normal
physiological bone remodeling the osteoblast plays a
central role. Left: The ligand of the receptor activator of
nuclear factor -kb (RANKL) is produced by osteoblasts
and stroma cells and binds to the receptor RANK pres-
ent on osteoclasts. Thereby bone resorption is stimu-
lated. The production of RANKL is under the influence
of the calciotropic hormones PTH and calcitriol. Right:
On the contrary, osteoblasts produce osteoprotegerin
(OPG) that acts as a decoy receptor and blocks the
RANKL binding to RANK. Thereby osteoclast produc-
tion and activation is blocked resulting in inhibition of
bone resorption.
9
9.1.1.3 Regulation of PTH secretion phosphate (cAMP) and possibly other second messengers (see
The ionized fraction of blood calcium is the most important also fig. 1.4) in cells of the main target organs, i.e., kidney and
determinant of PTH secretion. PTH secretion is regulated at bone. In the kidney, PTH enhances reabsorption of calcium
a setpoint that maintains the concentration of plasma ionized from the glomerular filtrate and increases excretion of phos-
calcium within narrow limits. Concentrations below the set- phate. When plasma PTH levels are persistently increased,
point stimulate and those above it inhibit hormone secretion PTH also stimulates the renal production of calcitriol. The ef-
(fig. 9.7).The PTH response to similar reductions in calcium fects of PTH on bone can be either catabolic or anabolic, de-
concentration may be less for slow than for fast reductions in pending on the mode of secretion. High concentrations of
calcium concentration.9 In addition to the ionized calcium PTH cause catabolic actions: osteoblasts shrink and change
concentration, calcitriol (1,25-(OH)2D; a metabolite of vita- their shape, allowing osteoclasts to come into contact with
min D) and phosphate have significant roles in regulating bone-matrix surface and to resorb bone. Osteoclasts are re-
PTH secretion. cruited and activated by local biologically active factors
(figs. 9.8, 9.9) originating from osteoblasts and resolved from
The effects of changes in plasma ionized calcium concen- bone matrix. Thereby, PTH causes the release of calcium and
tration on PTH secretion occur within minutes. The mol- phosphate into the extracellular fluid. Intermittent low doses
ecular mechanism underlying ionized calcium-regulated of PTH cause anabolic actions in bone, with an increase in
PTH secretion involves activation of a cell surface calcium- the number of osteoblasts, the alkaline phosphatase concen-
sensing receptor. In this context it should be mentioned that tration, and collagen synthesis. The plasma PTH concen-
often total (= bound and ionized), rather than ionized, cal- tration in dogs decreases during the first months of life
cium is measured. Therefore one should be aware of factors (fig. 9.10) and thereby parallels bone cell activity during skel-
that may influence the fraction of plasma calcium that is ion- etal growth.
ized. Of these, the circulating albumin concentration is of
greatest relevance, since it is the main calcium-binding pro- Overall, the combination of calcium mobilization from bone
tein. When in patients with hypoalbuminemia a »normal« and retention of calcium by the kidneys causes the plasma cal-
plasma calcium concentration is found, there may actually be cium concentration to rise. In addition, PTH contributes in-
elevated levels of ionized calcium. Acid-base status also in- directly to the maintenance of normocalcemia by stimulating
fluences the protein binding of calcium; alkalosis decreases the formation of calcitriol, which in turn enhances intestinal
and acidosis increases the ionized calcium concentration. calcium and phosphate absorption and calcium reabsorption
and mobilization from bone. The phosphatemic effect of
PTH and calcitriol tends to blunt the hypercalcemic effect of
9.1.1.4 PTH action PTH owing to the formation of calcium phosphate com-
Binding of PTH to a plasma membrane receptor, the PTH / plexes, but this is counteracted by the phosphaturic action of
PTHrP receptor, causes a rise in cyclic 3',5'-adenosine mono- PTH.
258 Calciotropic Hormones
Figure 9.10:
Plasma concentrations (mean ± SEM) of immunoreactive PTH, CT, and
1,25-(OH)2D in growing Great Danes from six to 26 weeks of age. Both PTH and
CT, but not 1,25-(OH)2D, are significantly negatively correlated with age.
Figure 9.11:
9.1.2 Vitamin D In the skin (beige area) of most mammals,11 but not the dog and cat,10 dehydro-
cholesterol (7 DHC) is photosynthesized under the influence of sunlight (UV-B)
9.1.2.1 Vitamin D sources and synthesis into provitamin D3, followed by a temperature-dependent isomerization into vita-
There are two forms of vitamin D: ergocalciferol (vitamin D2) min D3. Other isomers including lumisterol and tachysterol can be formed under
that is naturally occurring in plants and cholecalciferol (vita- prolonged radiation. When synthesized or absorbed with the food, vitamin D is
min D3) that is synthesized by vertebrates. Amphibians, rep- bound to vitamin D-binding proteins (DBP) and transported to the liver for its first
tiles, birds, omnivores, and herbivores synthesize vitamin D3 hydroxylation by 25-hydroxylase into 25-OHD, followed by a second hydroxylation
in the skin under the influence of UV light. However, dogs in the kidney into 24,25-(OH)2D and the biologically most active metabolite,
1,25-(OH)2D by 24- and 1a-hydroxylase, respectively. (Modified from How et al.,
and cats are not capable of synthesizing sufficient vitamin D3 1994.)11
in the skin (fig. 9.11).10 This is due to low levels of 7-dehy-
drocholesterol (7-DHC) in the skin11 caused by high degra-
dation of 7-DHC by a reductase.12 Thus, vitamin D is an es-
sential vitamin for dogs and cats, as they are solely dependent
on dietary resources to meet their vitamin D3 requirement.
Introduction 259
Figure 9.12:
General diagram of vitamin D metabolism and catabol-
ism describing the regulation of the major vitamin D
metabolites. (Modified from Hazewinkel and Tryfoni-
dou, 2002.)102
9.1.2.2 Vitamin D metabolism biologic activity mainly in bone.13,14 The enzymes responsible
Vitamin D must be metabolically activated before it can pro- for the production of 1,25-(OH)2D and 24,25-(OH)2D in the
duce its known physiological actions in target organs. Vitamin kidney are 1a-hydroxylase and 24-hydroxylase, respectively.
D is hydroxylated by 25-hydroxylase in the liver to 25-hydro- The catabolism of both vitamin D metabolites is mediated by
xyvitamin D (25-OHD). The second, most important, step in 24-hydroxylase distributed in various tissues (fig. 9.12).
the bioactivation of vitamin D is the formation of 1,25-dihy-
droxycholecalciferol (1,25-(OH)2D = calcitriol), the biologi-
cally active vitamin D metabolite in target organs related 9.1.2.3 Regulation of vitamin D metabolites
to calcium homeostasis. In addition to calcitriol, another The plasma level of all vitamin D metabolites is a function of
metabolite is produced in the kidney, i.e., 24,25-(OH)2D production and metabolism /catabolism. 25-OHD and
(fig. 9.11). This metabolite was first considered to be a prod- 24,25-(OH)2D circulate in levels of nmol/l, whereas calcitriol
uct in the catabolic pathway of vitamin D with no biological circulates in levels of pmol/l. Plasma levels of 25-OHD reflect
action. However, 24,25-(OH)2D is now considered to have the vitamin D status (e.g., deficiency or intoxication). The
260 Calciotropic Hormones
Figure 9.14:
Intestinal calcium absorption is the sum of passive and active absorption. Passive
paracellular calcium absorption occurs under the influence of the concentration
gradient between the intestinal lumen and the interstitium. Transcellular active
9 absorption is influenced by 1,25-(OH)2D. In the intestinal cell synthesis of alkaline
phosphatase (AP), calcium binding protein (CaBP), and ATP-ase are stimulated
and thereby cellular absorption, transport, and expulsion of calcium.
A B
Figure 9.15:
(A) canine calcitonin (CT) consists of 32 amino acids with a disulfide bridge between the cysteines at positions 1 and 7, and only differing in seven amino acids (*) from
bovine CT.19 (B) Effects of the infusion of 1 mg calcium per kg body weight on plasma ionized calcium and CT concentrations of a healthy dog.
calcitonin (cCT) has been elucidated (fig. 9.15) and this has local Ca2+ and PO43– concentration to a point where HA pre-
allowed the development of a homologous radioimmunoassay cipitation begins.
for CT in the dog.19,20 The circulating concentrations of CT
decrease during the first three months of life in the dog Diphosphonates (not normally present in biological systems
(fig. 9.10). and with phosphate-oxygen replaced by a phosphate-carbon
binding) have the same binding and mineralization inhibiting
During calcium ingestion, the plasma CT concentration is properties as pyrophosphates and are completely stabile in an
raised directly (by calcium) and indirectly (e.g., by gastrin), aqueous biological environment. They are used as a coating of
causing osteoclasts to retract their brush border and to de- implants such as heart valve replacements to prevent their
crease lysosomal enzyme secretion (fig. 9.8). As a conse- mineralization and they are used as a marker of tissue mineral-
quence, the plasma calcium concentration is prevented from ization. By labeling diphosphonates with 99mtechnetium, in-
rising (and therefore the PTH concentration does not fall) creased radionuclide accumulation can be found at skeletal
and thus calcium is routed to the bone and not lost via the sites with increased (physiological or pathological) mineral-
kidneys (fig. 9.4). CT has no direct effects on the intestine or ization (figs. 9.17, 9.18).
the kidney in the dog, but influences the hypothalamic satiety
center and influences 1,25-(OH)2D synthesis (fig. 9.12).21 Osteoblasts covering bone surface, the so-called bone lining
cells, separate multinucleated osteoclasts from bone matrix.
The osteoclasts are able to resorb mineralized bone at their
brush border with the aid of acid phosphatase (fig. 9.8) and
9.1.4 Calciotropic hormones and bone are mainly found in metaphyseal areas, where they shape the
metabolism funnel, as well as on the inner surface of the diaphysis at the
9 endosteal side, where they adapt the medulla to hemopoetic
Functionally the skeleton can be considered as two organs: and mechanical demands (fig. 9.16).
(1) a supporting and protecting framework and (2) a reservoir
of minerals. Each has its own regulatory mechanism with The osteocyte is the most abundant cell type of bone. There
consequences for skeletal integrity, involving the same cellu- are approximately ten times as many osteocytes as osteoblasts,
lar structures. Since most cellular activity occurs during skel- and the number of osteoclasts is only a fraction of the number
etal growth, most derangements of skeletal integrity are ob- of osteoblasts. The osteocytes communicate with neigh-
served in dogs and cats during early life. boring osteocytes and surface osteoblasts by cytoplasmic ex-
tensions running through caniculi. The role of osteocytes can
Growth in width of the long bones starts when the perios- be considered as the mechanosensory cells of bone, and the
teum, surrounding the cartilaginous template, forms primi- caniculi network as the structure that mediates mechanosens-
tive (i.e., woven) bone which organizes itself into highly or- ing. Loading of the bone may cause a flow of interstitial fluid
ganized lamellar bone (fig. 9.16). Growth in length of the through this network which will mechanically activate osteo-
long bones is limited to those places in which cartilage re- cytes as well as ensure transport of cell signaling molecules,
mains during the adolescent life, i.e., the physeal growth explaining the communication between osteocytes and os-
plates (fig. 9.16). The cartilage also extends to the epiphyseal teoblasts.24 In addition, electrical potentials can change the
ends of the long bone, allowing for the proportional growth chemical concentration and composition of this interstitial
of the epiphyses. This proportional growth and longitudinal fluid. Electrical potentials can originate from loading of bone
growth occurs via the process of endochondral ossification crystals (HA) by the piezoelectric effect or can be applied by
(fig. 9.16).22,23 special medical equipment to stimulate fracture healing or
endosseous new bone formation.25 Thus, an increase in pres-
In adulthood, about one quarter of bone is organic material sure on porous bone will cause fluid flow by compression or by
(of which 90 % is collagen) and about three quarters is inor- electrical induction and as a result new bone will be formed
ganic material. The latter is initially a poorly crystallized cal- normalizing the pressure. This is a hormone-independent
cium phosphate and later crystalline hydroxyapatite (HA). For regulatory process of bone formation. The clinical relevance
mineralization of bone, calcium- and phosphate-rich vesicles of this regulatory mechanism is illustrated in fig. 9.19.
are extruded from osteoblasts into the extracellular matrix. In
addition to this cellular regulation of mineralization, physico- In physiological states including growth, osteoblast and osteo-
chemical processes of direct formation of crystalline HA and clast activity is coupled (fig. 9.8). In addition to the hor-
growth of HA crystals play a role in tissue mineralization. Py- mone-independent regulation of bone remodeling, an in-
rophosphate, two phosphate molecules linked through an creasing number of substances is being recognized that
oxygen molecule, inhibits calcium phosphate crystallization influences bone metabolism. One of the most important sig-
in soft tissues and body fluids by binding to the surface of cal- naling pathways of osteoclast differentiation and activation is
cium phosphate and blocking the formation and growth of the receptor activator of nuclear factor -kb (RANK) pathway
HA crystals. Enzymatic degradation of pyrophosphate by al- (fig. 9.9).26
kaline phosphatase, produced by osteoblasts, can raise the
Introduction 263
Figure 9.16:
(A) Schematic representation of the proximal end of a long bone with (1) medul-
lary cavity, (2) diaphysis, (3) periosteum, (4) secondary ossification center (epiphy-
sis), (5) physeal growth plate, (6) epiphyseal cartilage. During longitudinal growth
9
(앖) periosteal bone formation (+) and bone resorption (–) in the medulla and at
metaphyseal sides, maintain the bone’s characteristic form as part of the remodel-
ing process.
(B) The inset shows the process of endochondral ossification: chondrocytes are
orientated in rows and while dividing and enlarging, they move away from their
nutrient vessel. The intercellular substance mineralizes and consequently seals off
the chondrocytes from nutrition, causing death of chondrocytes in their lacunae.
Metaphyseal vessels grow into the empty lacunae, introducing osteoblasts which
Figure 9.17:
cover the mineralized cartilage with osteoid that will be bone after its mineral-
A 2.5-year-old Labrador retriever with lameness of the right front leg for four
ization. Multinucleated chondroclasts remove the remnants of mineralized carti-
months. The radiograph of the right elbow revealed only minor sclerosis at the
lage to complete the process of endochondral ossification. (Modified from Nap et
base of the medial coronoid (arrow). The bone scintigraphy scans, using diphos-
al., 1994.)22
phonates labeled with 99mTc04–, clearly demonstrated increased bone cell activity
in the area of the right medial coronoid, in comparison with the left side. This is in-
dicative for a fragmented coronoid process.
Figure 9.18:
Bone scintigraphy scans, using diphosphonates la-
beled with 99mTc04–, of a 1.5-year-old Labrador re-
triever with shifting lameness and bone pain without
fever, revealing increased bone cell activity in the me-
dullary cavity (arrows) of the left and right ulna, typical
of enostosis.
264 Calciotropic Hormones
9
A B C
Figure 9.19:
The clinical relevance of the hormone-independent processes of bone remodeling is demonstrated with a radiograph of the tibia of a ten-month-old dachshund with
severe varus deformity and thickening of the concave cortex (A). Following corrective osteotomy (B), fixation with a bone plate was performed, which neutralized the
forces acting on the bone. The radiograph after plate removal six months later (C) revealed disuse osteoporosis, i.e., osteoporosis due to lack of external forces.
9.2 Hypoparathyroidism This section will concentrate on the second form. In this
spontaneous disease the few histological studies available have
Hypoparathyroidism is the state of deficient PTH secretion or revealed parathyroid atrophy, i.e., no parathyroid tissue may
action. The latter may be the result of the release of biologi- be found on surgical exploration.27 In addition lymphocytic
cally ineffective hormone or target cell resistance to PTH infiltrations have been found in some cases, suggesting an im-
(pseudohypoparathyroidism), but so far these abnormalities mune mediated cause of the atrophy.28,29
have not been observed in dogs and cats. Thus for the time
being for these species the definition of the disease may be Clinical manifestations
confined to deficient secretion of PTH. As with other endo- In both the dog and the cat spontaneous hypoparathyroidism
crine glands, theoretically a primary form and a secondary is rare. The disease may occur at almost any age but the oc-
form can be distinguished. Secondary hypoparathyroidism is currence appears to be highest in young adults (one to four
encountered in situations of hypercalcemia, which has an in- years of age).
hibitory influence on PTH release (chapter 9.1.1). However,
because of the causative hypercalcemia, the hypofunction will The presenting signs and symptoms are directly attributable to
not become manifest as such. In contrast, primary hypopara- the decreased concentration of extracellular ionized calcium.
thyroidism has serious clinical consequences. The rate of decrease in the plasma calcium concentration is an
important determinant in the development of neuromuscular
Pathogenesis manifestations. For example, signs of hypocalcemic tetany
From a pathogenetic point of view there are two main causes may occur in dogs after bilateral thyroidectomy when calcium
of primary PTH deficiency: (1) neck surgery and (2) idio- values are still higher (e.g., 1.8 mmol/l) than might be found
pathic disease. The former type is especially encountered fol- in cases of spontaneous PTH deficiency, in which a plasma
lowing surgical treatment of hyperthyroidism or primary calcium concentration of 1.3 mmol/l may not be associated
hyperparathyroidism. It may be a transient or a permanent with clinical manifestations of tetany.
hormone deficiency, depending on the viability of the tissue
left in situ at the time of surgery (see also chapter 3.4).
Hypoparathyroidism 265
A B
Figure 9.20:
ECG recordings (leads I, II, and III) of a two-year-old female German shepherd dog with primary hypoparathyroidism (calibration: 1 cm = 1 mV; paper speed 25 mm/s).
(A) On admission (total plasma calcium 1.0 mmol/l) the recordings were disturbed by muscle twitching, and the T waves were deep and wide. (B) During administration
of calcium these ECG changes disappeared; at the time of this recording total plasma calcium had only increased to 1.35 mmol/l. (Courtesy of Drs. J.J. van Nes and A.A.
Stokhof).
9
Neuromuscular signs may include focal muscle twitching, Diagnosis
rear limb cramping, stiff gait, generalized muscle spasms, and In the absence of renal failure, the diagnosis of hypoparathy-
convulsions.30 The onset of these neuromuscular signs is often roidism is virtually certain if hypocalcemia and hyperphos-
during exercise, excitement, or stress. In some cases intense phatemia are found. The diagnosis may be further supported
facial rubbing and licking and biting of the legs may be seen, by measurement of the plasma PTH concentration. An inap-
which can be interpreted as paresthesias due to increased sen- propriately low plasma PTH concentration while there is hy-
sory excitability, known from the disease in humans.31 In ad- pocalcemia confirms the diagnosis, provided that the assay
dition there may be lethargy and anorexia. On the other used is sensitive enough to measure plasma PTH in healthy
hand, once tetany occurs there may be an alarm reaction giv- animals. Commercially available assays for intact human PTH
ing rise to restlessness and panting. have been validated for use in dogs and cats.33–36
9.3 Hyperparathyroidism
Hyperparathyroidism can be primary or secondary. Primary
hyperparathyroidism is the state of autonomous hypersecre-
tion of PTH, most commonly by an adenoma of the chief
cells. Secondary hyperparathyroidism is an adaptive increase
in PTH secretion, unrelated to intrinsic disease of the para-
thyroids. In the latter, the increased PTH secretion is the re-
sult of chronic decreases in the concentration of ionized cal-
cium in plasma. Several conditions may lead to these events,
but in dogs and cats there are only two in which secondary
hyperparathyroidism produces clinically significant manifes-
tations: chronic renal failure (chapter 9.3.2) and calcium defi-
9 ciency during growth (chapter 9.3.3).
Figure 9.21:
9.3.1 Primary hyperparathyroidism
The dog described in the legend of fig. 9.20 was treated initially with 500 µg dihy-
drotachysterol and 2.5 g calcium lactate twice daily. This caused the plasma calci-
Pathogenesis
um concentration to gradually rise until it was within the reference range (zone). A small solitary parathyroid adenoma (fig. 9.22) is the most
When hypercalcemia developed the doses were lowered. The dog did very well for common cause of primary hyperparathyroidism in both
many years on twice daily 100 µg dihydrotachysterol and twice daily 1 g calcium the dog and cat.39,40 At surgery the other glands may appear
lactate as a supplement to a balanced commercial dog food. (Courtesy of Dr. J.J. normal or atrophied. The PTH excess may also be caused
van Nes.) by an adenoma of more than one gland or by one or more
minimally enlarged glands with multiple hyperplastic
nodules.41 Very rarely the is disease caused by a parathyroid
carcinoma.39,42
Figure 9.23:
A nine-year-old male Malinese shepherd dog with emaciation, dehydration, and
weight loss due to primary hyperparathyroidism.
Differential diagnosis
The main problem in the differential diagnosis of primary hy-
Figure 9.22:
perparathyroidism is distinguishing it from other conditions 9
Surgical specimen following unilateral thyroparathyroidectomy associated with hypercalcemia and specifically hypercalcemia
in a nine-year-old male Malinese shepherd dog with primary of malignancy (chapter 9.4). Other causes of hypercalcemia
hyperparathyroidism. Note the parathyroid adenoma originat- such as hypervitaminosis D (chapter 9.5.2), acute renal fail-
ing from the parathyroid tissue at the cranial pole (top) of the ure, and primary hypoadrenocorticism (chapter 4.2.1) pose
thyroid gland. less of a diagnostic problem because of the changes associated
with the primary disease.
The parathyroid glands may be visualized by ultrasonographic surgery in patients who are not suited for surgical interven-
examination as round or oval structures that are anechoic tion.61 The efficacy of percutaneous ethanol injection for
or hypoechoic compared with surrounding thyroid paren- treatment of primary hyperparathyroidism in humans does
chyma, but due to their small size parathyroid glands are not not approach that of surgery, and post-ablation periglandular
routinely seen on ultrasonographic examination.52–54 Parathy- fibrosis can make future surgery or ablation difficult.62 Cal-
roid glands exceeding 4 mm in diameter are highly suspicious cimimetic compounds that stimulate the calcium-sensing re-
for parathyroid pathology. In humans, parathyroid scinti- ceptor on the surface of the chief cells and thereby decrease
graphy using 99mtechnetium-sestamibi has been proven useful PTH secretion may hold promises for the medical treatment
in identifying parathyroid tumors. However, 99mtechnetium- of primary hyperparathyroidism in the near future.
sestamibi scintigraphy has a poor sensitivity and specificity
when used in hypercalcemic dogs for the detection of mor- Surgical removal of a parathyroid adenoma results in a rapid
phological changes of the parathyroid glands.55 decline, i.e., usually within 48 h, in plasma calcium concen-
tration and a rise (if lowered) in plasma phosphate concen-
Definite differentiation between parathyroid and nonparathy- tration (fig. 9.24). When an adenoma is not identified im-
roid causes of hypercalcemia may rely on measurement of the mediately, all four parathyroid glands should be inspected
plasma PTH concentration. As discussed in chapter 9.1, this carefully for the presence of nodular hyperplasia. Macroscopi-
is best performed with the two-site type of assay that measures cally suspected glands are removed, leaving at least one para-
intact PTH and is unaffected by renal function. In the absence thyroid gland in situ. Especially in critically hypercalcemic
of renal failure (see chapter 9.3.2), an elevated PTH level cases, perioperative measures to reduce the hypercalcemia
confirms the diagnosis of primary hyperparathyroidism. But a should be directed at increasing urinary calcium excretion by
plasma PTH concentration within the reference range, oc- volume expansion, i.e., intravenous therapy with isotonic sa-
9 curring in approximately 70 % of dogs with primary hyper- line.
parathyroidism,45 also confirms the diagnosis, as in hypercal-
cemia of nonparathyroid origin PTH concentrations should Following surgical removal of the parathyroid mass(es) or after
be low as a result of the inhibitory effect of the high plasma ethanol or heat ablation, there is a rapid decline in the circu-
calcium concentration on PTH release. A serious diagnostic lating PTH concentration, while the unaffected parathyroids
problem may arise when it is suspected that primary hyper- are still suppressed from the long-term hypercalcemia. This
parathyroidism is complicated by renal failure. together with the elevated bone turnover and thus high
calcium accretion (»bone hunger«) may lead to postoperative
Dogs with hypercortisolism may have elevated plasma PTH hypocalcemia. Therefore plasma calcium concentration
concentrations, which may be associated with abnormalities should be monitored carefully after the treatment (fig. 9.24).
in calcium and phosphate metabolism in these dogs.56 The In order to prevent signs of hypocalcemia, administration of
elevated plasma PTH concentrations in dogs with hypercor- vitamin D and calcium (see chapter 9.2) should be started
tisolism have been reported to reduce significantly with tri- when the plasma calcium concentration declines to the lower
lostane treatment.57 limit of the reference range. If signs of tetany have already oc-
curred, calcium gluconate can be given intravenously and /or
Treatment subcutaneously (see chapter 9.2). The aim is to maintain the
Surgical resection of abnormal parathyroid tissue has long plasma concentration in the lower part of the normal range,
been the treatment of choice. However, dogs with primary so that there is sufficient stimulus for restoration of the func-
hyperparathyroidism have also been treated using per- tion of the remaining parathyroid tissue. It may be necessary
cutaneous ultrasonographically guided techniques of chemi- to continue this substitution for several weeks. Once the
cal ablation (injection of ethanol)58 or radiofrequency heat plasma calcium concentration is stable, withdrawal of the vita-
ablation59. A retrospective study indicated that 45 of 48 para- min D can be attempted gradually by first giving it every
thyroidectomies, 13 of 18 percutaneous ultrasound-guided other day and then increasing the number of days between ad-
ethanol ablation procedures, and 45 of 49 percutaneous ultra- ministrations. When the hypocalcemia does not recur, the
sound-guided heat ablation treatments resulted in control of calcium supplementation can also be lowered gradually. One
hypercalcemia for a median of more than 500 days.60 The re- should be careful not to induce hypercalcemia, as this is now a
sults of another retrospective study indicated, however, that more serious risk than in primary hyperparathyroidism; vita-
ultrasound-guided ethanol ablation had limited effect.46 Dur- min D induces not only hypercalcemia but also a tendency to
ing ultrasound-guided ethanol or heat ablation of a parathy- hyperphosphatemia, which combination much more easily
roid tumor it is often necessary to redirect the needle several leads to nephrocalcinosis than hypercalcemia per se.
times to ablate all abnormal tissue and the operator needs to
go through a learning curve.60 Leakage of the ethanol or ex-
tension of thermal necrosis into the surrounding tissues may
cause damage to structures such as the recurrent laryngeal
nerve. In human medicine the sonographically guided per-
cutaneous injection of ethanol is considered an alternative to
Hyperparathyroidism 269
Figure 9.27:
A five-year-old cat with chronic renal insufficiency. The associated secondary renal
hyperparathyroidism (plasma PTH = 882 ng/l) had caused severe bone demineral-
ization with a so-called »rubber jaw« and the inability to close the mouth.
Figure 9.26:
Demineralization of all bones of the skull and mandible of a
dog with advanced secondary renal hyperparathyroidism. Due
to subperiosteal bone resorption the contours of the bone are
hardly visible. The teeth have maintained a normal density,
causing an increased contrast between teeth and bone. The laboratory findings are usually dominated by the abnor-
malities associated with the renal insufficiency, such as ele-
vated plasma concentrations of urea, creatinine, and phos-
phate. Despite the often low normal plasma calcium
concentrations, PTH secretion increases and gradually causes
the skeletal changes indicated above.
Clinical manifestations
The animal may be presented with the classic signs of renal Treatment
insufficiency, such as anorexia, vomiting, polydipsia, poly- The aim of the treatment is to reduce the plasma PTH con-
uria, and depression, but in some cases these features may be centration below a »toxic« level in order to improve survival
mild or only intermittent. In longstanding cases signs of and quality of life.64,65 The most important step in the preven-
secondary hyperparathyroidism may develop. Although not tion and treatment of renal osteodystrophy is the restriction
common, symptoms of neuromuscular irritability and tetany of dietary phosphorus. Restriction of dietary proteins has
similar to those of hypoparathyroidism may occur. The skel- not been proved to have a beneficial effect.66 The phosphate
etal changes range from mild to severe forms of fibrous restriction may be reinforced by administering aluminum-
osteodystrophy. In older dogs the volume of bone is usually containing antacids that prevent phosphate absorption. In
not affected and the changes are most prominent in the skull cases in which there is a tendency to hypocalcemia this ap-
with loss of teeth and hypoostotic osteodystrophy (fig. 9.26). proach may be extended by supplementation with calcium
As a result of the accelerated bone resorption the mandibles and vitamin D sterols (chapter 9.2). Supplementation with
may become pliable, for which the term »rubber jaw« is used. low daily doses of calcitriol (2.5–5.0 ng/kg, PO, q 24 h) can
The jaws may fail to close properly (fig. 9.27). control renal hyperparathyroidism67 but may induce hypercal-
cemia on the long term. Analogues of calcitriol, such as
When renal insufficiency develops before maturation of the 22-oxacalcitriol, have been experimentally proved to be ef-
skeleton the repair by proliferation of connective tissue may fective in decreasing plasma PTH concentrations without
exceed the rate of bone resorption. This results in an increase causing hypercalcemia.68 Their clinical application needs
in bone volume. This hyperostotic osteodystrophy results in further evaluation.
facial swelling (fig. 9.28).
Hyperparathyroidism 271
Figure 9.28:
9
A seven-month-old male Great Dane with renal insufficiency. In this young dog the secondary renal hyperparathyroidism caused hyperostotic osteo-
dystrophy, which led to facial swelling (A). Lifting of the upper lip (B) revealed that the facial swelling was due to increased volume of the maxilla.
9.3.3 Nutritional secondary thereby its calcium requirement) and the severity of the cal-
cium deficiency, the increased bone resorption will cause
hyperparathyroidism clinical problems within one to three months.69
In growing dogs, especially of the larger breeds, and cats a
substantial amount of calcium is laid down as calcium phos- Clinical manifestations
phates in newly-formed osteoid and cartilage. If insufficient Cancellous bone in the epiphyseal and metaphyseal areas may
calcium is available in the food, the calcium concentration in become so thin that spiculae will collapse, causing compres-
plasma will tend to decrease, initiating hyperparathyroidism. sion fractures. Osteoclasts at the endosteal side of long bones
Since in carnivores nutritional secondary hyperparathyroid- will remove cortical bone to such an extent that the cortex
ism (NSH) is especially seen in animals fed an unbalanced will bend under the influence of body weight and muscle
food mainly based on meat or meat by-products (table 9.1), tone, causing folding (greenstick) fractures and deformed
this entity is also known as the all meat syndrome. skeletal protuberances.
In NSH, PTH production and secretion increase, leading to On presentation, the patient will be alert and have a good hair
increases in calcium reabsorption in the kidney, osteoclasia, coat, and a disproportionally enlarged abdomen due to the
and 1,25-(OH)2D synthesis. The former two effects result in a fact that the growth of the skeleton lags behind that of the soft
rapid normalization of the plasma calcium concentration tissues (fig. 9.29). The animal will be reluctant to walk due to
(fig. 9.4), whereas the latter effect requires a few days but bone pain and pathological fractures. There may be fractures
eventually will lead to an augmentation of the intestinal ab- and abnormal alignment of bones, and bones may be painful
sorption efficiency of calcium and phosphate (fig. 9.14). The upon palpation. In severe cases there may be paresis posterior
circulating phosphate concentration will increase due to aug- due to compression fractures of vertebrae (fig. 9.29). As ex-
mented intestinal phosphate absorption and increased bone plained earlier, plasma calcium concentration is very effec-
resorption with liberation of phosphate. Concomitantly and tively regulated and its measurement does not contribute to
due to the hyperparathyroidism, the tubular maximum for the diagnosis (fig. 9.1). Plasma and urinary concentrations of
phosphate will decrease, causing hyperphosphaturia and pre- phosphate may be elevated. Due to high bone turn-over, the
venting further elevation of the plasma phosphate concen- plasma level of alkaline phosphatase will be increased.
tration. Depending on the growth velocity of the animal (and
272 Calciotropic Hormones
A B
Figure 9.29:
(A) Kitten, three months of age and fed chicken meat almost exclusively, was in good general condition but unable to stand.
(B) The radiograph revealed the disproportionally enlarged abdomen, thin cortices and wide medullae of the long bones, pathological fractures of both femurs, and com-
pression fractures of vertebrae (arrows).
In adult animals the calcium requirement is lower than in thus its effects on intestines and bone cells, is highly increased
9 young growing animals. Nevertheless, very prolonged dietary (fig. 9.4), additional administration of vitamin D is contrain-
calcium deficiency may cause problems that become manifest dicated.
by loosening of teeth due to alveolar resorption.
Prognosis
Diagnosis The prognosis depends on the severity and the extent of patho-
PTH and 1,25-(OH)2D concentrations will be elevated logical fractures. Compression fractures of vertebrae can, but
(fig. 9.13), but these measurements are not readily available. not necessarily, have a bad prognosis. Healed greenstick frac-
The most practical way to make a diagnosis is the combi- tures and bent long bones will not always cause locomotion
nation of a carefully taken history, focused on dietary com- disturbances. Narrowing of the pelvis may cause recurring
position, and radiographs of the affected sites. The most char- constipation although in less severe cases, in which treat-
acteristic features are thin cortices, a wide medullary cavity, ment is begun soon enough, constipation may not remain a
pathological fractures, bending of protuberances (including problem (fig. 9.29).
calcaneus and ischiatic tuberosity), and growth plates of
normal width bordered by a well-mineralized metaphysis
(fig. 9.29). Bone biopsies reveal mineralized osteoid with
massive osteoclasia. 9.4 Hypercalcemia of malignancy
Differential diagnosis Parathyroid hormone-related protein (PTHrP) was initially
Hypervitaminosis A (chapter 9.7) and hypovitaminosis D identified as the protein responsible for humoral hypercalce-
(chapter 9.5.1) should be considered, as well as inborn meta- mia of malignancy (see also chapter 10.1). Later it became ap-
bolic disorders such as osteogenesis imperfecta. In adult dogs, parent that PTH and PTHrP genes have arisen from a com-
renal secondary hyperparathyroidism (chapter 9.3.2) and par- mon ancestral gene and represent two members of a small
odontal diseases should be taken into account. gene family. PTHrP is larger than PTH (139–177 versus
84 amino acids), but shares 70 % sequence homology with
Treatment PTH in the N-terminal region. The posttranslational pro-
In the severe stage of NSH the pathological fractures of the cessing of PTHrP is extremely complex and appears to be
long bones can neither be treated by splinting, since the bone analogous to that of proopiomelanocortin (fig. 4.4), in that it
will break just proximal to the splint, nor by osteosynthesis, is processed into a series of peptides with potentially different
because of the weakened nature of the bones. Therapy is li- functions.70 Peptides containing the first 34 amino acids of
mited to good nursing to prevent additional damage to the both PTH and PTHrP bind with equal affinity to PTH /
skeleton, especially the vertebrae, and food with a normal cal- PTHrP receptor. The PTH / PTHrP receptor is expressed in
cium content (i.e., 1.2 % on a dry matter basis).69 This will many tissues and its transcription is tissue specific. PTH func-
improve skeletal mineralization in three weeks. Extra calcium tions mainly in an endocrine manner to regulate extracellular
as calcium carbonate (50 mg Ca/kg body weight per day) can calcium concentration, whereas PTHrP mainly acts in an
be prescribed during this period. Since the endogenous autocrine or paracrine manner to modulate a range of physio-
1,25-(OH)2D concentration in the plasma (fig. 9.13), and logical and developmental responses.71 PTHrP is synthesized
Hypercalcemia of malignancy 273
Pathogenesis
In principle, malignancy-associated hypercalcemia may arise
through: (1) local osteolysis due to bone metastasis, (2) secre-
Figure 9.30:
9
tion of PTHrP, and (3) production of calcitriol. Other mech-
Perineum of a twelve-year-old female cocker spaniel with a
anisms of humoral hypercalcemia of malignancy include
large adenocarcinoma of the apocrine glands of the anal sac
tumor production of various substances that stimulate bone region, which caused hypercalcemia.
resorption, including cytokines (notably interleukin-1) and
growth factors such as transforming growth factor beta
(TGF-b). An important humoral pathway for hypercalcemia
of malignancy involves the production of soluble forms of re- Clinical manifestations
ceptor activator of nuclear factor-kappa b ligand (RANKL), a Hypercalcemia of malignancy is diagnosed in 57–67 % of hy-
newly discovered member of the tumor necrosis factor super- percalcemic dogs.83,87 In contrast, neoplasia is diagnosed in
family and a critical regulator in bone metabolism, which is only 30 % of hypercalcemic cats. 86 In 10–40 % of dogs with
capable of stimulating the activity of osteoclasts by binding to malignant lymphoma there is hypercalcemia, with a marked
a receptor (RANK) on their surface.80 overrepresentation of boxers.88 Most canine malignant lymph-
omas that are associated with hypercalcemia belong to the
Local osteolysis may be expected especially in hematological T-cell subclass.88 Multiple myeloma is associated with hyper-
malignancies that produce substances that act locally in the calcemia in 15–20 % of cases.79,89
bone marrow to mobilize calcium and phosphate.81 Tumor-
derived PTHrP activates osteoclasts systemically through the Adenocarcinomas of apocrine glands of the anal sac region
RANK / RANKL /osteoprotegerin triad (fig. 9.9), i.e., by occur mainly in older (욷 9 years) dogs. There is some contra-
increasing RANKL expression and decreasing the production dictory information regarding gender predisposition. In the
of osteoprotegerin (OPG), the endogenous RANKL in- early reports the dogs were almost exclusively female.74,90,91 In
hibitor.82 The plasma PTHrP concentrations are elevated in more recent reports on retrospective studies, with the histo-
most hypercalcemic dogs with adenocarcinomas derived from pathology being an important inclusion criterion, the sex dis-
apocrine glands of the anal sac.83,84 In dogs with malignant tribution was about equal.92–94 It has been suggested that this
lymphoma the plasma PTHrP concentration by itself may not change could be a reflection of an increased frequency and ear-
be high enough to cause hypercalcemia and thus other fac- lier age of neutering in recent years.92 The patient groups seem
tors, such as the production of calcitriol, may interact syner- to differ also with regard to the prevalence of hypercalcemia.
gistically or additively. 83–85 In the early case series almost all dogs were hypercalcemic,
whereas in the recent retrospective studies hypercalcemia is re-
In hypercalcemic cats, increased plasma PTHrP concen- ported in about half of the dogs diagnosed with anal sac gland
trations have been found to be associated mainly with malig- carcinoma. Dogs with adenocarcinoma of apocrine glands of
nant lymphoma and carcinomas.35 In squamous cell carcino- the anal sac may be presented for the signs of hypercalcemia or
mas, hypercalcemia of malignancy was most often detected in because of a swelling in the perineum. This swelling has an in-
cases involving the mandible with radiographic evidence of tact overlying skin that is usually not attached to the tumor.
bone lysis.86 Only occasionally they are so large at the time of presentation
that there are problems with defecation (fig. 9.30). When a
274 Calciotropic Hormones
Figure 9.31:
Perineum of a nine-year-old female German pointer with an adenocarcinoma of the apocrine glands
of the right anal sac region. A probe has been introduced into the natural orifice of the anal sac (A).
A The cross-section of the surgical specimen illustrates the intimate relationship between the anal sac
Prognosis
In dogs with malignant lymphoma that is associated with
hypercalcemia, the prognosis for response and survival with ficient vitamin D (table 9.1). Only when extremely deficient
chemotherapy is worse than in dogs with malignant lymph- diets are fed (i.e., only lean meat or only vegetables) vitamin
oma and normocalcemia. This may be related to the fact that D deficiency may develop, and then especially in pups or
hypercalcemia is especially encountered among lymphomas kittens which have not had the chance to store enough vita-
of the T-cell immunophenotype, which have a much less fa- min D in their body fat.69 Hypovitaminosis D in young ani-
vorable prognosis than the B-cell lymphomas.101 mals (rickets) occurs rarely, but may be mentioned by the
owner because it is a classic bone disease. In adult dogs and
In the absence of metastases the prognosis after surgical cats hypovitaminosis D (osteomalacia) does not cause clinically
removal of an adenocarcinoma of the anal sac is excellent. relevant disturbances in bone metabolism. This section will
However, there are often metastases to regional lymph nodes; therefore focus on rickets.
resection of these iliac/ lumbar lymph nodes may have a
positive effect on prognosis. Hypercalcemia, however, is a When there is a low vitamin D intake, insufficient calcitriol is
negative predictor for survival.94 formed. This leads to insufficient calcium and phosphate ab-
sorption from the intestine, low osteoclastic activity, and in-
sufficient renal reabsorption of calcium and phosphate. As a
result, the plasma calcium concentration tends to decrease.
9.5 Vitamin D-related disorders This in turn stimulates the parathyroid glands to hypersecrete
PTH, thereby increasing calcium reabsorption and osteo-
9.5.1 Hypovitaminosis D clastic activity (fig. 9.4) and decreasing the renal tubular
maximum for phosphate (causing hypophosphatemia). Due
Dogs and cats are dependent on the dietary vitamin D con- to hypovitaminosis D, newly formed osteoid is not mineral-
tent to fulfill their requirement.102,103 Prey, home-made diets ized. The mineralized bone is therefore sealed off eventually
containing animal fat, and commercial pet foods contain suf- by nonmineralized osteoid, making it inaccessible to the os-
276 Calciotropic Hormones
9
Figure 9.33:
(A) Young mixbred dog with clearly noticeable bulging metaphyseal
areas of the distal radius and ulna, as well as pronounced palpable
areas near the growth plates of all ribs.
(B) The radiograph of the radius and ulna revealed thin cortices,
wide medullary cavities, and increased width of the growth plates
B
with a mushroom appearance, typical for hypovitaminosis D.
Figure 9.34:
Radiograph of a four-month-old boxer with hyper-
trophic osteodystrophy. A pathognomonic radiolu-
cent area (arrow) parallels the growth plates and is
separated from it by a thin mineralized area. In addi-
tion, the well-mineralized cortex differs considerably
from what is seen in hypovitaminosis D (see for com-
parison fig. 9.33).
teoclasts for resorption and remodeling. The newly-formed The growth plates are extremely wide for the chronological
cartilage will not mineralize and this prevents completion of age of the animal (fig. 9.33).
the cascade of events in endochondral ossification (fig. 9.16).
Diagnosis
Clinical manifestations The plasma concentrations of 25-OHD and 24,25-(OH)2D
The animal is alert, its coat may be in poor condition, and its are very low and the concentration of calcitriol is low to nor-
body conformation may be disproportional due to the fact mal. The radiological abnormalities are quite typical for hy-
that growth of bones lags behind that of the soft tissues. The povitaminosis D (fig. 9.33). A biopsy of the greater tubercle,
animal is reluctant to walk and palpation of the bones causes to obtain cancellous bone and growth plate cartilage without
pain. The legs are bent and the metaphyseal areas of long disturbing growth in length, will reveal osteoid seams cover-
bones and ribs are enlarged (fig. 9.33). The plasma calcium ing poorly-mineralized trabeculae and an extremely wide
concentration is low to normal (fig. 9.1), whereas the phos- growth plate.
phate concentration is low in plasma (쏝 1 mmol/l) and high
in urine (쏜 20 mmol/l), the latter due to the concomitant Differential diagnosis
hyperparathyroidism. This entity can be confused with or be complicated by nutri-
tional secondary hyperparathyroidism, depending on the
On radiographic examination the cortex of the long bones is mineral content of the food. However, the plasma concen-
thin and may be folded or there may be pathological fractures. tration of vitamin D metabolites and the radiological appear-
Vitamin D-related disorders 277
B C
9
Figure 9.35:
Dogs raised on diet supplemented with 100 times more vitamin D than the recommended requirements de-
velop severe disturbances of endochondral ossification without clinical signs of vitamin D intoxication. These
disturbances result in valgus deformation due to radius curvus syndrome (A). The growth plates are irregular,
with focal disorders of endochondral ossification characterized by arrest of chondrocyte apoptosis, retarded
A formation of primary spongiosa, and protrusion of the growing cartilage in the metaphyseal area, with necrosis
in the most severe cases (B). Growing dogs raised on a balanced diet have regular growth plates (C).
ance of growth plates will be different. With regard to the lomas. Hypercalcemia combined with elevated plasma
latter, hypertrophic osteodystrophy (fig. 9.34) and congenital 24,25-(OH)2D has been reported in a dog with granuloma-
disorders such as chondrodysplasia104 have to be considered. tous lymphadenitis106 and in dogs with granulomas due to an-
giostrongylosis.107
Treatment
The dog or cat must be fed a normal food, containing 400 IE Vitamin D intoxication may result from overdosage of vita-
vitamin D per kg, as soon as possible.69 Within four weeks, min D in the treatment of hypoparathyroidism or from in-
mineralization of cortices, growth plates, and callus will occur toxication with cholecalciferol-containing rodenticides.108–110
to such an extent that corrective orthopedic surgery can be Vitamin D intoxication leads to increased formation of
performed if necessary. 25-OHD, augmented calcium and phosphate absorption
from the intestine, and increased calcium and phosphate reab-
Prognosis sorption in the kidneys. The resulting hypercalcemia as well
The prognosis for mineralization of bone and cartilage is as the direct feedback effect of vitamin D on the activity of
good, but functional recovery depends on the severity of the the chief cells in the parathyroid glands (fig. 9.12) causes hy-
skeletal abnormalities. poparathyroidism, which increases the tubular maximum for
phosphate. The elevated plasma concentrations of calcium
and phosphate lead to increased urinary excretion of both
elements. Eventually calcification of soft tissues will occur, in-
9.5.2 Hypervitaminosis D and vitamin D cluding vessel walls and heart valves, as well as kidney tubules
intoxication with renal failure as a consequence.
Hypervitaminosis D usually results from excessive supple- In contrast to vitamin D intoxication, hypervitaminosis D is
mentation of vitamin D in the diet.105 Granulomatous characterized by normocalcemia, normophosphatemia, and
disease in humans is also associated with increased production no clinical signs of soft tissue calcification, but with disturb-
of 1,25-(OH)2D by activated macrophages in the granu- ances of endochondral ossification (fig. 9.35).111 In hyper-
278 Calciotropic Hormones
vitaminosis D effective counterbalance is provided by low osteoporosis in humans, has given promising results in experi-
plasma PTH levels, high calcitonin levels, and the effective- mental settings and in several disease processes in dogs and
ness of 24-hydroxylase, resulting in lower plasma calcitriol cats.100,113,114
levels than in controls.112 Commercially available dry dog
food may exceed by four to 13 times the recommended Prognosis
requirements of vitamin D. It has been shown that a tenfold Neuromuscular disturbances and encephalopathy due to rapid
increased vitamin D intake during growth is sufficiently development of severe hypercalcemia may occur and death
counterregulated by the calciotropic hormones, resulting in may ensue. If there is renal damage, the prognosis is guarded.
maintenance of calcium homeostasis and only minimal In milder cases, treatment can be successful.108
microscopic changes in endochondral ossification.3
Clinical manifestations
The symptoms and signs of vitamin D intoxication may be 9.6 Calcitonin-related
dominated by one or more of the signs of hypercalcemia, such
as polydipsia /polyuria, dehydration, weakness, and ano- disorders
rexia.108 If complicated by renal insufficiency, there may be
vomiting and other signs of azotemia. Routine laboratory in- 9.6.1 Nutritional secondary
vestigations will reveal that calcium and phosphate concen- hypercalcitoninism
trations in plasma and urine are elevated. The circulating con-
centration of PTH is low and that of 25-OHD is high, Supplementation of balanced commercial foods and the use
whereas the plasma calcitriol concentration is low to normal of home-made unbalanced diets are common errors. Es-
9 (except when calcitriol has been administered and is the cause pecially young dogs of large breeds are often given extra
of intoxication). mineral and vitamin mixtures. Studies in giant and miniature
dogs have revealed that in large-breed dogs overfeeding of a
Diagnosis balanced diet or supplementing an otherwise balanced diet
The diagnosis can be made on the basis of the history and the with calcium or vitamin D causes hypercalcitoninism, with
finding of elevated concentrations of calcium and phosphate severe consequences for skeletal development.111,115
in plasma and urine. Especially hypercalcemia of malignancy
(chapter 9.4) and hyperphosphatemia due to primary renal During calcium ingestion, the plasma CT concentration is
disease (chapter 9.3.2) should be ruled out. For the differen- raised directly (by calcium) and indirectly (e.g., by gastrin),
tial diagnosis of hypercalcemia, the reader is referred to causing osteoclasts to retract their brush border (fig. 9.8). As a
chapter 9.3.1. consequence, the plasma calcium concentration is prevented
from rising (and therefore the PTH concentration does not
Treatment fall) and thus calcium is not lost via the kidneys but routed
The aim of the treatment is to minimize nephrocalcinosis by primarily to the bone, ready to be used at a later stage or
increasing renal calcium excretion and by decreasing intesti- added to the mineral content of the bone (fig. 9.4).
nal calcium absorption. In mild cases glucocorticoids can be
prescribed to reduce intestinal absorption and increase renal Chronic high intake of calcium causes C-cell hyperplasia in
excretion of calcium. In addition, a diet without calcium young dogs.4,116 Persistent hypercalcitoninism causes de-
should be given to minimize intestinal calcium absorption. In creased osteoclastic activity and hypermineralization of the
cases with severe hypercalcemia (쏜 4.0 mmol/l), general skeleton. The imbalance of the calciotropic hormones and
weakness, and anorexia, fluid therapy should be given, since the (direct or indirect) effect of calcium on chondrocytes may
dehydration contributes to the increased plasma calcium con- lead to disturbed endochondral ossification. In this situation
centration. Mild volume expansion together with furosemide the chondrocytes do not mature, the intercellular substance
will promote calciuria. The treatment with glucocorticoids, does not mineralize, and the chondrocytes continue to live
furosemide, and the special diet should be continued for at and prevent blood vessels from invading. The disturbed carti-
least one month, since the release of the vitamin D stores in lage maturation is characterized by thickened cartilage and is
body fat may take several weeks. 108 known as osteochondrosis.22,117
Treatment of the hypercalcemia with injections of calcitonin The consequences of decreased osteoclasia with hyper-
in order to reduce calcium release from the bone by osteo- mineralization as well as signs of osteochondrosis may be
clasts has been recommended.108 However, osteoclasia is observed in the same patient in varying gradations. However,
not the main cause of hypercalcemia in hypervitaminosis D. in some cases one of these disturbances may dominate the
In addition, the use of heterologous calcitonin may cause clinical features. Therefore each entity will be discussed
antibody formation and contribute to the feeling of ill- separately.
ness. The use of substances that inhibit bone resorption,
such as the biphosphonates widely used for the treatment of
Calcitonin-related disorders 279
Figure 9.36:
Myelogram of the cervical region of a six-month-old
Great Dane with an uncoordinated gait, pain reaction
upon hyperextension of the neck, and positive crossed
extensor reflexes of the rear limbs. The radiograph re-
veals impingement of the spinal cord at the cranial ori-
fices of the 5th and 6th cervical vertebrae (arrows), typi-
cal of the canine wobbler syndrome.
9.6.1.1 Decreased osteoclasia correction of the diet, glucocorticoid therapy, and avoidance
Chronic excessive calcium intake (with or without a constant of microtrauma caused by pulling on the collar may lead to
ratio to phosphorus) causes hypercalcitoninism, which in- clinical improvement. Surgical decompression is indicated in 9
duces decreased osteoclastic skeletal remodeling (fig. 9.4). young dogs with progressive signs. 118
Especially foramina, which do not widen in proportion to
soft tissue growth, may cause noticeable hindrance to both Prognosis
nervous structures and blood vessels, which may lead to cer- In mild cases improvement will follow after four weeks of
vical spondylomyelopathy and enostosis, respectively. conservative treatment, but the prognosis in more severe cases
with multiple compressions is guarded.
9.6.1.1.1 Cervical spondylomyelopathy
Retarded skeletal remodeling of the spinal canal at the cranial 9.6.1.1.2 Enostosis
vertebral orifice may cause irreversible damage to the spinal In dogs with enostosis (also known as canine panosteitis and
cord. This occurs especially in the cervical region and may eosinophilic panosteitis), a delay in remodeling of the nutri-
give rise to ataxia (uncoordinated gait), thereby being one of tional foramen in the diaphyses of all long bones is present.
the causes of the so-called canine wobbler syndrome. Consequently, edema occurs in the medullary cavity and be-
neath the sensitive periosteum. Later there is extra bone
Diagnosis formation, both in the medullary cavity on organized fibrous
The clinical findings include uncoordinated gait in young tissue and subperiosteally due to the elevation of the perios-
dogs (approximately six months of age) of a giant breed (e.g., teum by the edema (fig. 9.37).119
Great Dane), with pain in response to extension of the neck,
hyperactivity of the reflexes of the pelvic limbs, and positive Diagnosis
crossed extensor reflexes of the pelvic limbs. Radiographs of Dogs of larger breeds not over two years of age develop shift-
the cervical vertebrae may reveal narrowing of the cranial ori- ing lameness of varying severity.120,121 Physical examination
fices of the fourth, fifth, and sixth cervical vertebrae and mye- may reveal an elevated body temperature, severe lameness of
lography will reveal impingement on the spinal cord at these one or more legs, and a painful reaction to deep palpation of
locations (fig 9.36). the long bones. Routine laboratory investigations are incon-
clusive. In the subacute phase (at least three weeks after the
Differential diagnosis start of the initial signs) radiographic examination of long
Discospondylitis, inflammatory (infectious) meningitis, and bones may reveal medullary new bone formation (fig. 9.37).
traumatic or congenital abnormalities should be considered in In the more severe cases there may be noticeable subperito-
young dogs with these neurological signs. Cervical disc pro- neal new bone. Other causes of lameness of one or more legs
trusion and the vertebral instability as seen in older dogs (ap- in these young dogs (including osteochondritis dissecans,
proximately six years of age) of large breeds (e.g., Doberman) fragmented coronoid process, ununited anconeal process)
can give identical clinical signs. can occur solely or together with enostosis and may confuse
the results of the physical examination. Bone scintigraphy
Treatment (figs. 9.17, 9.18) and other imaging techniques may help to
The spinal cord may be so seriously damaged that the lesion is make the diagnosis and differentiate it from other develop-
irreversible and any treatment unsuccessful. In milder cases mental orthopedic disorders.
280 Calciotropic Hormones
Figure 9.37:
(A) Schematic representation of the pathophysiologic mechan-
ism of enostosis. The cortex receives its blood supply from the
periosteal arteries (outer 1/3) and medullary vessels (inner
2/3). A relative delay in remodeling of the nutritional foramen
causes impingement of the nutrient arteries, resulting in
9 edema beneath the sensitive periosteum and the medullary
cavity.
(B) German shepherd dog, nine months of age, suffering from
enostosis with shifting lameness, pain upon palpation of the
long bones, and radiopaque areas due to new bone formation
in the medullary cavity. These confluent dense areas are first
present near the nutritional foramina (arrow) of the long B
bones.
A
9
Figure 9.38:
(A) Deerhound, eight months of age, with bilateral valgus deformation due to radius curvus syndrome,119 with a retained cartilage cone (arrow) in the distal ulnar meta-
physis (B). (C) The radius may push the humerus proximally against the anconeal process, which breaks off in its growth plate, causing an ununited anconeal process.
Diagnosis growth plates of the distal radius or ulna may cause early clo-
There will be bilateral valgus deformity with cranial bowing sure of the affected (part of the) growth plate and conse-
of the radius. Radiographs will demonstrate a cartilage cone quently valgus deformation; mostly this affects only one front
at the distal growth plate of the ulna, together with a curva- leg and no cartilage cone is present.
ture of the radius and a thickened concave cortex (fig. 9.38)
and an abnormal alignment of both the carpus and the elbow Treatment
joint. Due to elbow incongruity, the anconeal process can be Restriction in food and calcium intake alone can lead to nor-
loosened in its growth plate (fig. 9.38).122 malization of the endochondral ossification.69,123 When the
valgus deformity is severe, conservative treatment will not
Differential diagnosis normalize the stance nor will it prevent secondary effects,
Dogs with chondrodysplasia as prescribed in breed standards such as incongruity of the elbow joint, detachment of the an-
(such as the basset hound) or as in inherited disorders (as in coneal process, valgus deformity, and carpal abnormalities.
the Alaskan malamute104) are physically similar in the front Additional corrective surgery will be needed in these cases. 126
legs, but also short in the rear legs. Traumatic injury to the
282 Calciotropic Hormones
B
9 Figure 9.39:
(A) Radiograph of shoulder joint of a seven-month-old Bouvier de Flandres with lameness of both front legs and pain reaction on hyperflexion of the
shoulder joint. There is an indentation of the contour of the subchondral bone at the caudal aspect of the humeral head (arrow), indicating osteo-
chondrosis.
(B) Based on the concomitant clinical manifestations, arthrotomy was performed and revealed osteochondritis dissecans with a cartilage flap. Re-
moval of the flap was followed by curettage of the cartilage defect.
Figure 9.40:
Radiographs of two littermate tomcats (see also fig. 3.9) at eight weeks of age: (A) healthy and (B) congenitally hypothyroid, revealing retarded skeletal growth and
development.
Figure 9.42:
Hypervitaminosis A in a three-year-old cat, which was fed almost exclusively cat
food and raw liver and was referred because of lameness of both front legs and an
inability to groom itself. The radiographs revealed new bone formation without B
bone loss on the vertebrae (A) and around the elbow joint (B), causing ankylosis.
9
Vitamin A (or retinol) is formed in the gut of dogs by the re- 9.8 Puerperal tetany
versible reduction of retinaldehyde originating from carotene.
Cats require retinol (as present in a variety of foodstuffs), since At the peak of lactation, two to three weeks postpartum, hy-
cats lack carotenase in their intestinal mucosa.135 Vitamin A is pocalcemia may occur in bitches and less often in queens.
oxidized in its target cells to retinoic acid. Retinoic acid in- Puerperal tetany occurs mainly in bitches of small breeds with
teracts via nuclear receptors with the genome to regulate cel- large litters. Little is known about the pathogenesis, but
lular growth and differentiation.136 Vitamin A is important for insufficient calcium supply during nursing may be a causative
normal osteoblastic, chondroblastic, and osteoclastic activity. factor. In cats, preparturient hypocalcemia has also been re-
High doses of vitamin A inhibit chondrogenesis in growth ported.139
plates and inhibit collagen synthesis by osteoblasts in both
dogs and cats. Since cats are not able to form retinyl esters in Clinical manifestations
order to excrete the excess of this fat-soluble vitamin, chronic Once the plasma calcium concentration has reached a critical
vitamin A intoxication is more likely to be diagnosed in cats level, the signs may proceed rapidly from restlessness, panting,
than in dogs. and ataxia to tetany with tonic/clonic convulsions and opis-
thotonus. Examination usually reveals an anxious, restless ani-
Hypervitaminosis A in cats is characterized by new bone mal with tachycardia and hyperthermia. In a very severely hy-
formation without osteolysis, starting at the points of inser- pocalcemic (and hypomagnesemic) lactating bitch the typical
tion of ligaments, muscles, and joint capsules, which causes muscle tremors and rigidity were not part of the clinical fea-
narrowing of the intervertebral foramina in the vertebral tures. In this dog the clinical manifestations were dominated
bodies and ankylosis of vertebrae and larger joints. This causes by atony, weakness and paresis.140
pain, lameness, and stiffness (fig. 9.42). The vitamin A con-
centration in plasma or in a liver biopsy (since the liver is the Diagnosis
major organ in vitamin A storage) can support the diag- The diagnosis is usually made by the recognition of the com-
nosis.137,138 Although ankylosis is irreversible, the cat will im- bination of a heavily lactating animal with signs of increased
prove with appropriate analgesia and feeding a low vitamin neuromuscular excitability. Laboratory examination will re-
A-containing food for several weeks. veal hypocalcemia and usually also hypophosphatemia.
Treatment
The condition may be fatal if left untreated. Consequently,
treatment is begun without delay, i.e., without laboratory
confirmation. As in hypocalcemia of primary hypoparathy-
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Figure 10.2:
The amino acid sequence of canine ANP. The disulfide bond is essential for bio-
logical activity.
10
Figure 10.3:
Plasma ANP concentrations (mean ± SEM) in eleven dogs with pericardial effu-
Figure 10.1: sion, as influenced by pericardiocentesis (at time zero). This illustrates that it is not
Role of natriuretic peptides in volume homeostasis. pericardial or atrial pressure but rather atrial stretch that causes ANP release.
앖= increase,앗= decrease (Adapted from Stokhof et al., 1994.)5
trations in cardiac ventricles. ProBNP undergoes posttrans- The half lives of both NT-proANP and NT-proBNP are
lational modification similar to that for proANP, resulting in longer than those of ANP and BNP, respectively. These
BNP and NT-proBNP. Canine NT-proBNP shares only 45 physiologically inactive fragments are also more stable in the
per cent homology with human NT-proBNP. Recently assays laboratory than the active hormones. These characteristics
have been introduced that enable measurements of concen- make measurements of the pro-fragments more suitable for
trations of NT-proBNP in dog plasma.4 clinical assessment of heart disease. Studies in dogs and cats
Erythropoietin 293
10.3 Erythropoietin
Erythropoietin (Epo) is a glycoprotein having a molecular
mass of 34 kD and containing 165 amino acids. About 40 %
of its mass is composed of carbohydrate. It is primarily pro-
duced in interstitial fibroblasts in the kidney. Extrarenal Figure 10.4:
sources account for less than 10 % of the production, for Transverse CT of the thorax at the level of T-7 in a
which the liver is the main site. Epo exhibits a high degree of twelve-year-old male beagle with pituitary-depend-
sequence homology among mammals. Human Epo is 85 % ent hypercortisolism and polycythemia. The right
ventricle is enlarged and there is marked enlarge-
identical to feline and canine Epo.10,11
ment of the right caudal lobar pulmonary artery
(arrow) caused by a thrombus.28
The release of Epo is regulated by classic feedback control. It
is secreted in response to renal tissue hypoxia, whereas hyper-
oxia decreases its production. This includes not only systemic
hypoxia, but also local changes in renal blood flow caused by 10
renal cysts or tumors that compress the surrounding renal par- regenerative anemia secondary to renal failure without caus-
enchyma. Other hormones may influence Epo secretion and ing the profound erythroid hypoplasia that may occur in
thereby erythropoiesis. GH and IGF-I have been reported to rhEpo-treated dogs.19 Unfortunately this does not hold true
decrease Epo secretion from rat kidneys.12 Chronic GH ad- for cats and even with use of rfEpo red-cell aplasia may de-
ministration to dogs causes a dose-related normochromic, velop.20 This has also been reported to occur in cats in which
normocytic, nonregenerative anemia leading to a 10 % decre- fEpo was delivered via gene therapy.21
ment in the hematocrit.13 This can explain why bitches that
develop diabetes mellitus in the luteal phase of the estrous Increased production of Epo may lead to the syndrome of
cycle, i.e., due to progesterone-induced GH excess of mam- polycythemia, termed secondary polycythemia because it is
mary origin (chapter 2.2.4.2), may have low hematocrit secondary to excessive production of Epo or another ery-
values. Glucocorticoids are important in promoting erythro- throid-stimulatory substance. In this syndrome most symp-
poiesis directly in situations of hematological stress, such as in toms and signs can be related to hyperviscosity. They include
coping with hemorrhage or erythrolysis.14,15 Thyroid hor- lethargy, disorientation, tremors, ataxia, episodic weakness,
mone induces Epo gene expression and directly promotes dif- and seizures. The sludging of blood cells may result in throm-
ferentiation and maturation of erythroid cells toward nu- bosis and hemorrhagic diathesis. In most of the reported cases
cleated red blood cells.16 In the absence of thyroid hormone, the underlying cause was a renal carcinoma and its removal re-
such as in primary hypothyroidism, hematocrit values are solved the problems.22,23 Polycythemia has also been observed
usually low (chapter 3.3.1). in dogs with tumors of nonrenal origin, such as a cecal leio-
myosarcoma and a cervical schwannoma.24,25 Nonneoplastic
With progressive loss of renal parenchyma, such as in chronic renal disorders such as pyelonephritis have also been reported
renal insufficiency, a relative deficiency of Epo may develop. to cause secondary polycythemia.26,27 In these cases the ery-
Indeed, in dogs with chronic renal failure, circulating con- throcytosis has been suggested to be the result of circulatory
centrations of Epo have been reported in the low normal disturbances in the kidney, sufficient to cause local tissue hy-
range, despite mild to moderate anemia.17 Recombinant poxia without destruction of the cells responsible for Epo
human Epo (rhEpo) has been used to treat this anemia. In production. Consistent with the previously-mentioned effect
both dogs and cats rhEpo induces a rapid and substantial red of glucocorticoids on erythropoiesis, spontaneous hypercor-
cell response, but in several treated animals the effect was tisolism may also be accompanied by elevated hematocrit
short-lived because of the development of antibodies against values (table 4.3). Polycythemia has been observed in a dog
rhEpo.18 Apparently there is sufficient structural difference with pituitary-dependent hypercortisolism (fig. 10.4).28
between rhEpo and feline Epo (fEpo) or canine Epo (cEpo)
to induce an immune response. The use of rcEpo has been re- In addition to these secondary forms of polycythemia there is
ported to stimulate erythrocyte production in dogs with non- polycythemia vera, in which the circulating concentration of
294 Tissue Hormones and Humoral Manifestations of Cancer
erythropoietin is low and excessive erythropoiesis is caused by macrophages, dendritic cells, and T-regulatory lymphocytes
a population of abnormally replicating erythroid progenitor that are involved in the development and progression of
cells that fail to respond to inhibitory signals. The mechanism cancer. In humans the systemic effects of pro-inflammatory
or cause of this myeloproliferative disorder with character- cytokines such as interleukin-6 (IL-6) and tumor necrosis fac-
istics of malignant transformation remains obscure. tor-a (TNF-a) include fatigue, depression, anorexia, fever,
and hyperalgesia.30–32 This cancer cachexia often results in
Initial treatment consists of temporary alleviation by repeated marked weight loss and particularly loss of muscle mass. The
phlebotomy and replacement of the removed volume by col- latter is due to increased degradation of myofibrillar protein,
loidal and electrolyte solutions.29 especially myosin heavy-chain, and sometimes also decreased
protein synthesis. The enhanced protein degradation is me-
diated by the ubiquitin-dependent proteolytic system, which
can be activated by cytokines such as TNF-a and IL-1.33
10.4 Humoral manifestations
of cancer In addition to anorexia and protein loss, a hypermetabolic
state also plays an important role in cancer cachexia. There is
As discussed in chapter 10.1, a wide range of DNES hyper- increased thermogenesis in brown adipose tissue caused by
plasias and tumors produce peptides causing hormonal syn- uncoupling of mitochondrial respiration from adenosine-
dromes of an »ectopic« nature. Measurements of the particular 5'-triphosphate (ATP) synthesis. There is experimental evi-
hormone can be used as an aid in diagnosis and in following dence that TNF-a can stimulate heat production in cancer
the result of treatment. Many of these tumors can be visual- patients indirectly by promoting the expression of uncoupling
ized with labeled ligands to receptors on the DNES cells. proteins, and also by direct uncoupling of mitochondrial res-
For example, octreotide scintigraphy can visualize somatosta- piration.33
tin-binding sites (see also chapter 5.3.1 and fig. 5.22). Fur-
10 thermore, tumors with somatostatin receptors may respond to
a somatostatin analogue such as octreotide by decreased pep-
Similar to neoplasms in humans, osteosarcomas in dogs in-
crease resting energy expenditure and protein loss.34 The syn-
tide secretion and diminished growth. drome of cancer cachexia has been studied in canine and fe-
line patients by measuring weight loss and changes in body
The secretion of peptides by cancers is not confined to condition. Both weight loss and loss of lean body mass are
the well-known peptide hormones but may also include cy- more prevalent in cancer in cats than in dogs.35,36
tokines. Tumor stroma contains inflammatory cells such as
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metabolism. Philadelphia; Lippincott Williams & Wilkins 2001: atrial natriuretic factor, B-type natriuretic factor, endothelin, and
1605–1611. cardiac troponin-I. J Vet Intern Med 2007;21:238–242.
2. STREWLER GJ. Humoral manifestations of malignancy. In: Kro- 7. OYAMA MA, FOX PR, RUSH JE, ROZANSKI EA, LESSER M.
nenberg HM, Melmed S, Polonsky KS, Larsen PR, eds. Williams Clinical utility of serum N-terminal pro-B-type natriuretic peptide
textbook of endocrinology. Philadelphia; Saunders/Elsevier 2008: concentration for identifying cardiac disease in dogs and assessing
1803–1820. disease severity. J Am Vet Med Assoc 2008;232:1496–1503.
3. RADEMAKER MT, ESPINER EA. The endocrine heart. In: 8. FINE DM, DECLUE AE, REINERO CR. Evaluation of circu-
Becker KL, ed. Principles and practice of endocrinology and lating amino terminal-pro-B-type natriuretic peptide concen-
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1622–1634. heart failure or primary pulmonary disease. J Am Vet Med Assoc
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RA, MARTIN M, STAFFORD-JOHNSON M, SMITH P, 9. CONOLLY DJ, SOARES MAGALHAES RJ, SYME HM, BOS-
LITTLE C, ATTREE S. The diagnostic accuracy of different na- WOOD A, LUIS FUENTES V, CHU L, METCALF M. Circu-
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J Small Anim Pract 2008;49:26–32. Med 2008;22:96–105.
5. STOKHOF AA, OVERDUIN LM, MOL JA, RIJNBERK A. Ef- 10. WEN D, BOISSEL J-PR, TRACY TE, GRUNINGER RH,
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triuretic hormone and arginine vasopressin in dogs with sponta- Erythropoietin structure-function relationships: high degree of
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a common mechanism of action. Exper Hematol 2008;36: GOTA K. Secondary erythrocytosis associated with high plasma
1573–1584. erythropoietin concentrations in a dog with cecal leiomyosarcoma.
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12. SOHMIYA M, KATO Y. Human growth hormone and insulin-
like growth factor-I inhibit erythropoietin secretion from the kid- 25. YAMAUCHI A, OHTA T, OKADA T, MOCHIZUKI M,
neys of adult rats. J Endocrinol 2005;184:199–207. NISHIMURA R, MATSUNAGA S, NAKAYAMA H, DOI K,
SASAKI N. Secondary erythrocytosis associated with schwannoma
13. PRAHALADA S, STABINSKI LG, CHEN HY, MORRISSEY in a dog. J Vet Med Sci 2004;66:1605–1608.
RE, DE BURLET G, HOLDER D, PATRICK DH, PETER CP,
VAN ZWIETEN MJ. Pharmacological and toxicological effects of 26. WATERS DJ, PRUETERS JC. Secondary polycythemia associated
chronic porcine growth hormone administration in dogs. Toxicol with renal disease in the dog: two case reports and review of the lit-
Pathol 1998;26:185–200. erature. J Am Anim Hosp Assoc 1988;24:109–114.
14. BAUER A, TRONCHE F, WESSELY O, KELLENDONK C, 27. KESSLER M. Secondary polycythaemia associated with high
REICHARDT HM, STEINLEIN P, SCHÜTZ G, BEUG H. The plasma erythropoietin concentrations in a dog with a necrotising
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BEUG H, MÜLLNER EW. Different steroids co-regulate long- ism. J Vet Clin Sci 2009;2:42–50.
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failure. J Am Vet Med Assoc 1998;212:521–528. ETTI L, PALLINI R, FERNANDEZ E, MAIRA G. Pyrogenic
cytokine interleukin–6 expression by a chordoid meningioma in
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11 Obesity
Margarethe Hoenig
11.1 Introduction
Obesity is a pandemic in humans and pet animals. This most
common nutritional disorder in cats and dogs occurs when
energy input – food intake – is greater than energy output.
The excess energy leads to deposition of triglycerides in
adipose tissue. The oversupply of high-energy diets to a pet
population now frequently leading a very sedentary lifestyle is
the most likely cause.
pide (Yarvitan®, Janssen), new agents used for the treatment In humans, obesity increases secretion of both insulin and
of canine obesity. Dirlotapide and mitratapide inhibit micro- proinsulin and there is a marked increase in the proinsulin:in-
somal triglyceride transfer protein, which leads to lipid ac- sulin ratio when diabetes mellitus develops (chapter 5.2.1).
cumulation in enterocytes. It has been proposed that this This suggests that proinsulin can be used as an indicator and
change triggers PYY release, which acts as a satiety signal.16 sensitive marker of beta cell dysfunction.23,24 Proinsulin has
been shown to be a marker for insulin resistance, and proin-
sulin levels in humans are related to atherosclerosis and car-
diovascular disease.25 Proinsulin secretion is also increased in
11.2.2 Hormonal and metabolic changes obesity in cats26 but it is not known whether there is a change
in the proinsulin:insulin ratio with the development of dia-
The development of obesity leads to marked alterations in in- betes mellitus and thus whether this ratio might be used as an
sulin secretion and a decrease in insulin action, i.e., an in- indicator of the disease. Changes in proinsulin secretion in
crease in insulin resistance (fig. 11.2). The mechanism by obesity have not been studied in dogs.
which an increase in fat mass causes these changes is not
understood. It appears that insulin resistance precedes changes There are other hormonal changes in obese cats and dogs. As
in insulin secretion, at least in cats.17 A recent study revealed in humans, obese cats and dogs have low adiponectin concen-
that each kg increase in weight led to approximately 30 % loss trations.11,27 Adiponectin is secreted from adipose tissue and
in insulin sensitivity and glucose effectiveness.18 The decrease modulates glucose and lipid metabolism. Its concentration is
in insulin sensitivity is associated with increased lipolysis in inversely related to body mass and positively correlated with
adipose tissue and a rise in the concentration of nonesterified insulin sensitivity.
fatty acids in plasma. It is thought that this rise contributes to
insulin resistance, not only by increasing glucose output from Thyroid hormone changes are also seen in obesity. Thyroid
the liver but also by suppressing insulin-stimulated glucose hormones are involved in regulation of the resting (basal)
transport through the insulin-sensitive glucose transporter metabolic rate, thermogenesis, and lipolysis (chapter 3.1).
GLUT 4. In obese cats, GLUT 4 expression was decreased Free thyroxine (FT4) concentration and the FT4 fraction have
when glycosylated hemoglobin values were still normal.19 been shown to be significantly higher in obese cats than in
11 Changes in the subcellular distribution of GLUT 4 have also lean cats, although usually still within the normal range until
been observed in obese dogs.20 Probably because of increased development of the morbid obesity seen in clinical patients.
secretion of tumor necrosis factor a from large adipocytes, In cats, FT4 has the strongest positive correlation with the
which regulates lipoprotein lipase, fatty acids are not only de- obesity indices body fat, body mass index, girth, nonesterified
posited in fat cells but are also shunted to muscle cells, where fatty acids, and leptin.28 Energy expenditure is lower in obese
they are deposited.17 than in lean cats and increases with administration of triiodo-
thyronine (T3), suggesting that thyroid hormone is partly in-
Obesity also leads to changes in insulin secretion. At a time volved in the low heat production.29 Plasma total thyroxine
when fasting blood glucose concentration is still maintained (TT4) and T3 concentrations were higher in obese than in
within the normal range, the insulin secretion pattern has al- lean dogs, although still within the reference range.30
ready changed in obese cats and dogs compared with lean ani-
mals, primarily due to a large increase in second-phase re- One of the main questions concerning the progression from
lease. The beta cell response is adequate to maintain fasting compensated obesity to diabetes in both cats and humans
levels, but it is not adequate to maintain glucose tolerance in concerns the role of islet amyloid polypeptide (IAPP), also
all cases. In dogs, glucose intolerance was related to the de- called amylin, a hormone cosecreted with insulin. It is the
gree of obesity and was not seen until the dog exceeded its precursor of islet amyloid, which is thought to be formed
ideal body weight by approximately 70 %.21 Glucose toler- when the endoplasmic reticulum is unable to process amylin
ance was still normal in approximately 30 % of obese cats correctly. This leads to the formation of toxic fibrils and
with a similar degree of obesity.17 The obese glucose-intoler- eventually amyloid deposition, with apoptosis of beta cells
ant cats of that study had a significantly higher area under the that exceeds the rate of their regeneration.31 In obese cats the
curve of insulin concentration during the last 30 min of test- secretion of amylin follows the pattern of insulin secretion,
ing and lower glucose clearance when they were lean, com- i.e., there is hyperamylinemia.32 Yet there is no evidence that
pared with the obese cats having normal glucose tolerance. this leads to amyloid formation in obese cats, which suggests
This suggests that abnormalities in insulin action rather than that neither obesity nor hyperamylinemia per se is sufficient
in insulin secretion were already present in the cats when lean to cause amyloidosis in the presence of a normal beta cell
and predisposed them to more severe changes when they be- mass.
came obese. Persistent insulin resistance in cats eventually
leads to a decrease in the total insulin secretory capacity and Compared with lean cats, obese cats have lower expression of
overt diabetes mellitus. At that time insulin secretion is low peroxisome proliferator-activated receptors (PPARs), which
and erratic.22 Similar data are not available for dogs. are transcription factors involved in carbohydrate, lipid, and
protein metabolism, and in cell differentiation.8 PPARa is in-
Pathophysiology 299
Figure 11.2:
Known hormonal and metabolic changes in obese
dogs and cats.
volved in adipocyte mitochondrial biogenesis and the up- higher or not different from that in lean dogs and the high
regulation of genes involved in fatty acid oxidation. The low density lipoprotein (HDL) fraction, which represents cho- 11
expression suggests that fat cells of obese cats are less meta- lesterol, has been reported to be either increased or de-
bolically active than those of lean cats. PPARg is highly creased.40,41 As in humans, hypertension and atherosclerosis
expressed in adipose tissue and is involved in adipocyte differ- have been reported in obese dogs on a high fat diet, suggest-
entiation.33 It is activated by fatty acids and thiazolidine- ing that the dyslipidemia of obesity is more detrimental in
diones, drugs which increases insulin sensitivity in many dogs than in cats.42 In newly obese cats, plasma cholesterol
species, including cats.34 The low PPARg concentration seen is increased by increased HDL cholesterol.37 A significant
in obese cats supports the finding of marked insulin resistance. decrease in HDL cholesterol is seen in long-term obesity in
Information about PPAR expression in obese dogs is lacking, cats.38 However, in contrast to humans, dogs and cats have
although it has been shown that the PPARa agonist, fenofi- much higher concentrations of HDL than LDL cholesterol
brate, lowers serum concentrations of triglyceride and choles- and the former remains high in spite of any decrease with
terol.35 obesity.
Obesity is characterized in both dogs and cats by marked al- The type of fat deposition has received great attention in
terations in lipid metabolism and lipoproteins. There is an in- human medicine because visceral fat (the android type of fat
crease in the plasma concentration of nonesterified fatty acids deposition) is thought to play a primary role in causing insulin
(NEFAs), which is thought to increase VLDL synthesis.35–38 resistance. Visceral fat is resistant to the antilipolytic effects of
Plasma triglycerides are increased, a change mostly due to an insulin and it leads to many of the metabolic abnormalities in
increase in the very low density lipoprotein (VLDL) fraction. obese humans, such as reduced hepatic insulin extraction, in-
Overproduction of VLDL in cats was associated with an in- creased gluconeogenesis, and perturbed lipid metabolism.43
creased number of large and medium-sized VLDL particles,38 However, abdominal fat deposition in cats is equally divided
which have been associated with cardiovascular disease in hu- between subcutaneous and intra-abdominal, regardless of
mans.39 Overproduction of VLDL has also been associated diet.11 In insulin-resistant obese dogs fed a high-fat diet, ab-
with decreased expression of PPARa. Atherogenesis and cor- dominal subcutaneous fat increased more than visceral fat,44
onary artery disease are not features of feline obesity or dia- which argues against a primary role of visceral fat deposition
betes mellitus, and diabetic cats are not prone to high blood in the change of insulin sensitivity in both species.
pressure or such complications as hypertensive retinopathy or
proteinuria. Diagnosis
There are subjective as well as objective methods to assess
There have been conflicting findings concerning cholesterol. body composition. A nine-point body condition scoring sys-
In obese dogs, plasma cholesterol has been found to be either tem is probably the most frequently used method in private
300 Obesity
practice, but has the drawback of being subjective.45,46 It is voluntary food intake than a diet with either moderate pro-
also difficult to score animals that have lost weight recently or tein / high fiber content or high protein /moderate fiber con-
have long hair. In cats, a body condition score of 1–3 indicates tent.51 Because different fiber types and protein sources were
an animal that is underfed and whose ribs are easily visible (1) used for all three diets in that study, it is not clear what effect
or have minimal fat covering and are easily palpated (3). The can be ascribed to protein or to fiber. Energy restriction
ideal body condition is 5, which indicates a well-propor- should proceed slowly in order to avoid the development of
tioned cat in which a waist is easily observed. Overfed cats are hepatic lipidosis, especially in cats. A 1–1.5 % weight loss per
scored 7–9, depending on the amount of fat: 7 if the ribs are week has been reported to be safe. The value of added sub-
not easily palpated and 9 if they cannot be palpated at all be- stances such as conjugated linoleic acid or carnitine needs to
cause of heavy deposits of fat. In dogs, 1–3 indicates an be examined in well-controlled studies. Several commercial
underfed animal: 1 if there is loss of muscle and fat mass and 3 weight-loss diets are available to dog and cat owners. These
if the ribs are easily palpated. A score of 4 or 5 indicates an diets provide the necessary nutrients despite reduced caloric
ideal body condition: the ribs are palpable and have some fat intake. There are also several computer programs that can
covering, the waist is easily noted, and the abdominal tuck is help owners to design a weight-loss program for their pet.
evident. Scores of 6–9 indicate that a dog is overfed: 6 if the Owners of intact cats need to be aware that neutering de-
ribs are difficult to palpate, 9 if they cannot be palpated, there creases energy requirements52 and increases appetite (see also
is no observable waist or abdominal tuck, and there are fat de- chapter 8.2).53
posits over the entire body.
Many pet owners find it easier to increase energy expenditure
There are also objective methods to judge obesity in dogs and in a dog than in a cat, because dogs can be walked and many
cats; some require specialized equipment, others do not. dogs enjoy other activities such as swimming. Indoor cats are
Body mass index (BMI) is well known from human medicine, more limited in activity but owners can also encourage exer-
where it is widely used to assess adiposity. It has also been cal- cise by providing toys and by placing small amounts of food
culated in cats according to the following formula: BMI = around the house rather than providing it in one dish.
body weight (kg)/body length (m) × height (m), where
height is the distance from the point of the shoulder through Recently, dirlotapide (Slentrol®, Pfizer) was approved by the
11 the point of the elbow to the proximal boundary of the meta- Federal Drug Administration in the United States for the
carpal pad and length is the distance from the point of the treatment of obesity in dogs and mitratapide (Yarvitan®,
shoulder to the tuber ischium.47 BMI correlates well with Janssen Animal Health, Belgium) was approved by the Euro-
other indices of obesity, but only within well-defined popu- pean Commission. These drugs decrease intestinal absorption
lations, because of the great variation in size of the general pet of fat by inhibition of microsomal triglyceride transfer pro-
population. tein. The accumulation of lipids in enterocytes is thought to
increase peptide YY concentrations in plasma, resulting in
Obesity assessed by measuring the body circumference or satiety (chapter 11.2.1). The dose of dirlotapide is titrated in-
girth immediately caudal to the last rib correlates well with dividually within a range of 0.01–0.2 ml/kg.16 Mitratapide
measurements of body fat by dual energy x-ray absorptio- solution is provided in bottles of three sizes to facilitate ad-
metry (DEXA).48 Girth and BMI measurements require ministration of the dose in the food according to the dog’s
no specialized equipment. Highly sophisticated assessment weight. Treatment is given for three weeks and then in-
of adiposity is possible with DEXA and magnetic resonance terrupted for two weeks to evaluate the dog’s nutritional
imaging (MRI). MRI can provide exact quantification of requirements. The diet is adjusted accordingly and mitrata-
specific adipose depots within the body.11,44 pide is resumed for an additional three weeks. There is no
similar drug for use in cats at present.
Treatment
Assuming that obesity is primary and not secondary to a Prognosis
disease such as hypothyroidism or hypercortisolism, the aim In order for the treatment of obesity to be successful, it is im-
of treatment is to decrease energy input and increase energy portant for the veterinarian and the owner to recognize that
output. This is accomplished through management of diet obesity is a disease and will have detrimental consequences for
and lifestyle,49 and recently therapeutic intervention has also the pet if left untreated. The veterinarian needs to monitor
become available for dogs. The diet should be high in protein, and record indices of obesity at check-ups and provide
which increases loss of fat mass and preserves lean body mass achievable milestones for the owner during the course of the
in both dogs and cats.11,50 Recently it was shown that a diet weight loss. Exercise is an important part of any program and
high in fiber and high in protein led to greater reduction in will benefit both pet and owner.
References 301
References
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Protocols and
Algorithms
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305
Performance If Uosm remains low throughout the first test, the owner re-
Immediately after collection of the zero blood sample from ceives a second set of tubes and a dropper bottle of desmo-
the jugular vein, four releasing hormones are injected via a pressin (DDAVP). The owner administers one drop of des-
catheter in the cephalic vein within 30 seconds, in the follow- mopressin in the conjunctival sac three times daily for four
ing order and doses: 1 µg CRH/kg, 1 µg GHRH/kg, 10 µg days and on the fourth day repeats the collection of the eleven
GnRH/kg, and 10 µg TRH/kg. Blood samples are collected urine samples at 2 h intervals.
at the times given for the CRH test (chapter 12.1.1) for
measurement of ACTH, cortisol, GH, PRL, TSH, and Interpretation
LH.2,12 Marked fluctuations in Uosm and any values higher than
1000 mOsm/kg indicate good renal concentrating ability,
Interpretation showing the polyuria to be the result of variations in water in-
The results are compared with those in healthy control dogs take, i.e., primary polydipsia. If Uosm remains low and the
(fig. 2.14). Only the LH response is lower in the combined measurements are repeated after desmopressin administration,
test than when its releasing hormone GnRH is administered central diabetes insipidus is indicated by prompt cessation of
alone.2 the polyuria and polydipsia and the increase in Uosm from
low values to 쏜 1000 mOsm/kg. If Uosm does not exceed
1000 mOsm/kg after desmopressin, central diabetes insipidus
is unlikely and there is either primary polydipsia or (func-
12.1.4 Sample handling tional) nephrogenic diabetes insipidus.
Performance Performance
Urine samples are collected at home while water is available Following 12 h of fasting, water is withheld and then plasma
ad libitum. The owner is provided with written instructions and urine osmolality (Posm and Uosm) are measured every 2 h,
and eleven small labeled tubes in a suitable box for mailing or hourly if the polyuria is severe. When the loss of body
to the laboratory. Urine is collected at 2 h intervals during weight, measured at each interval, approaches 5 % of initial
the day and at 4 h intervals during the night for a period body weight, the test is stopped. When Posm 욷 310 mOsm/kg
of 24 hours and the samples are sent to the laboratory for and there is 쏝 5 % increase in Uosm between consecutive col-
measurement of Uosm. lections but Uosm is still 쏝 1000 mOsm/kg, 2–4 µg of the va-
Thyroid 307
Comments
12.2.3 Vasopressin measurements during The biological activities of rhTSH and bovine TSH (bTSH),
hypertonic saline infusion which was used in the past, are similar.20 Maximal stimulation
of the thyroid is achieved with 100 µg or even 50 µg rhTSH
Indication per dog. 21 Higher doses do not increase the T4 response and
Suspicion of deficient vasopressin release or inappropriate va- responses to a fixed dose do not vary with body weight.18,20
sopressin secretion. One ampule of the highly purified recombinant form of
human TSH contains 1100 µg of lyophilized rhTSH, of
Performance which less than 1/10 is needed per dog. Fortunately, the recon-
The euhydrated and fasted animal is infused for 2 h via the stituted rhTSH can be stored at 4 oC for 4 weeks and at –20
jugular vein with 20 % NaCl solution at a rate of 0.03 ml/kg oC for at least eight weeks without loss of biological activity,
body weight per minute. Samples for plasma VP (Pvp) and allowing for several TSH-stimulation tests per ampule.22
Posm are obtained at 20 min intervals. Because there is the
risk of inducing critical hypertonicity in a severely polyuric In secondary hypothyroidism it may be necessary to admin-
animal, Posm should be measured in the samples immediately ister rhTSH on three consecutive days to produce an increase
and when it reaches ~ 350 mOsm/kg the hypertonic saline in plasma T4 concentration.
infusion should be stopped.
Interpretation
The slope of the regression line for Posm and Pvp is used as 12.3.2 TRH-stimulation test
a measure of the sensitivity of the osmoregulatory system.
In the nomogram developed by Biewenga et al., the 90 % Indication
range for sensitivity was 0.24–2.47 pmol/ml per mOsm/kg.17 Suspicion of deficient TSH secretion. The test is a com-
The 90 % range for the threshold of the system was 276– ponent of the combined anterior pituitary function test
309 mOsm/kg. See also fig. 2.31, fig. 2.34, and fig. 2.35. (chapter 12.1.3) but can also be used to test for the paradoxi-
308 Protocols for Function Tests
cal GH response that may occur in pituitary hyperplasia due If treatment for adrenocortical insufficiency is already being
to primary hypothyroidism (chapter 3.3.1). given, the morning dose of cortisone is postponed on the test
day until the test is completed. This is not necessary if de-
Performance xamethasone is used rather than cortisone, because dexame-
TRH is administered intravenously in a dose of 10 µg per kg thasone is not measured in cortisol assays. Glucocorticoid
body weight and blood is collected at –15, 0, 5, 10, 20, 30, treatment for more than three days can by itself result in a sub-
and 45 min. For sample handling see chapter 12.1.4. normal response via induction of secondary hypocortisolism
(chapters 4.2.2, 4.3.6).
Interpretation
In healthy dogs the maximum plasma TSH concentration Interpretation
(mean ± SEM; 1.26 ± 0.22 µg/l) occurs at 10 min after in- In healthy dogs, plasma cortisol concentration rises to
jection.12 A low basal plasma TSH concentration and lack 270–690 nmol/l after ACTH. In primary adrenocortical in-
of increase after TRH administration is consistent with sec- sufficiency it usually increases 쏝 50 nmol/l above the low
ondary hypothyroidism, as occurs after hypophysectomy.23 basal value. In secondary adrenocortical insufficiency plasma
However, in spontaneous primary hypothyroidism basal TSH cortisol is low and, depending on the severity and duration of
concentration may also be below the upper limit of the refer- the insufficiency, the increase after ACTH is subnormal or
ence range, and may not be increased by TRH (chap- absent.
ter 3.3.1).19,24
Comment
In contrast to healthy dogs, those with primary hypo- Differentiation between primary and secondary adreno-
thyroidism respond to TRH administration by an increase cortical insufficiency can be confirmed by measuring plasma
in plasma GH concentration (mean ± SEM at 10 min: ACTH, which is extremely high in primary hypoadrenocor-
11.9 ± 3.5 µg/l), as a result of the development of thyrosoma- ticism and below the level of detection in secondary hypoad-
totroph pituitary cells (chapter 3.3.1).25 renocorticism. In healthy dogs the reference range for the
cortisol/ACTH ratio (CAR), with cortisol in nmol/l and
Comment ACTH in pmol/l, has been reported to be 1–26.30
Studies have been undertaken to determine whether the
plasma T4 response to TRH might be helpful in the diagnosis
12 of primary hypothyroidism. However, contrary to expec-
tations, there is often no significant increase in plasma T4 after 12.4.2 Low-dose dexamethasone
TRH administration in healthy dogs.26 Although the low and suppression test (iv-LDDST)
variable responses to TRH make it of no value for identifying
dogs with hypothyroidism,27 a definite increase in T4 after Principle
TRH might exclude hypothyroidism. The sensitivity of the hypothalamic-pituitary-adrenocortical
axis to suppression by glucocorticoids is tested by administer-
ing a low dose of a potent glucocorticoid that causes suppres-
sion in healthy animals but not in those with hypercortisol-
12.4 Adrenal cortex ism.
Performance Interpretation
Synthetic ACTH (cosyntropin or tetracosactrin) is adminis- In dogs the finding of plasma cortisol 쏜 40 nmol/l at 8 h
tered intravenously and blood is collected immediately before after dexamethasone confirms hypercortisolism with a pre-
and at 60 min after the injection for measurement of plasma dictive value of a positive test result of 0.92 (confidence inter-
cortisol. It was customary in the past to administer the full val, CI: 0.85–0.96), and a predictive value of a negative test
contents of a vial (0.25 mg) of synthetic ACTH, but the high result of 0.59 (CI: 0.43–0.73).31 The measurements at 0 and
cost prompted re-evaluation of the dose and 5 µg/kg was 4 h are not needed for the diagnosis per se but may be useful
found to be sufficient for maximal adrenocortical stimu- in the differential diagnosis. A high value at 8 h after a lower
lation.28,29 value at 4 h indicates escape from the suppression by dexame-
thasone.32 If the values at either 4 h and/or 8 h are at least
Adrenal cortex 309
Comment
The stress of disease and hospitalization can cause false-posi-
tive results.34 Stress from other procedures such as ultraso-
nography performed during the test may also override the
suppressive effect of dexamethasone.35 Long-term anticon- Figure 12.1:
vulsant treatment with phenobarbital does not affect the re- Box with cushion lining for sending three urine samples to the laboratory for cor-
tisol assay. The tubes should be no more than half filled, so that the stopper is not
sults.36,37 expelled by freezing. The fourth tube contains the dexamethasone tablets for the
suppression test.
Performance Performance
Blood for cortisol assay is collected immediately before and The owner is provided with three tubes for urine samples and
3–4 h after intravenous administration of 0.1 mg dexametha- a one with dexamethasone tablets, in a cushioned box for
sone per kg body weight. mailing the urine tubes to the laboratory (fig. 12.1). The
owner collects morning urine samples at home at the same
Interpretation time (e.g., 7 A.M.) on three consecutive days, after taking the
A decrease in plasma cortisol of 쏜 50 % in this test indicates dog for its last walk at the same time (e.g., 11 P.M.) on the
that the hypercortisolism is pituitary dependent. A decrease of preceding evening. After collecting the second urine sample,
쏝 50 % indicates that the hypercortisolism is ACTH inde- the owner gives the three oral doses of dexamethasone
pendent (primarily adrenocortical tumor, chapter 4.3.2), or (0.1 mg per kg body weight) at 8 h intervals. An example of
pituitary dependent but dexamethasone resistant (chap- the instruction sheet for the owner is given as an annex to this
ter 4.3.1), or due to ectopic ACTH excess (chapter 4.3.4). chapter, together with directions for collecting urine at home
from cats.
310 Protocols for Function Tests
Interpretation empty its bladder and the third urine sample is collected at
In our laboratory the basal UCCR in healthy pet dogs is 16.00 h for measurement of UCCR.
0.3–8.3 × 10–6 39 and in healthy cats it is 8.0–42.0 × 10–6.40
The reference values of the laboratory performing the assays Interpretation
should be used. The mean of the two basal UCCR values is In seven healthy pet dogs the UCCR at 16.00 h was 쏝 1.0 ×
calculated and values exceeding the upper limit in healthy 10–6.48 In dogs with mild pituitary-dependent hypercortisol-
dogs or cats provides the diagnosis of hypercortisolism. If the ism the UCCR following dexamethasone was 쏜 1.0 × 10–6.49
UCCR of the third urine sample is 쏝 50 % of the mean of
the first two the hypercortisolism is pituitary-dependent. For Comments
the interpretation of post-dexamethasone UCCRs 쏜 50 % The bioavailability of dexamethasone is lower after oral ad-
of the mean basal values, see chapter 12.4.3. ministration than after intravenous administration, but the
oral dose of 0.01 mg dexamethasone per kg body weight is
Comments still sufficient to suppress the system in healthy pet dogs. This
Stress (including hospitalization) during or prior to the urine lower exposure to dexamethasone may give the o-LDDST a
collection should be avoided as much as possible, for it higher discriminatory power than the iv-LDDST, in addition
readily activates the pituitary-adrenocortical axis and thus to which the test is done at home, without the stresses of a
elevates cortisol excretion. The urine samples should be col- hospital visit and an invasive test procedure.49
lected by the owner at home under conditions free of
stress.41–43 The high sensitivity of the UCCR not only reveals In both the iv and the oral LDDST the dosage of dexametha-
stress responses but also increased cortisol production associ- sone is critical. For the studies of the o-LDDST mentioned
ated with diseases such as malignant lymphoma and hyper- above dexamethasone was triturated with lactose and micro-
thyroidism.40,44 From studies in such populations it has been crystalline cellulose was used as a diluent. Capsules were pre-
concluded that the UCCR has high sensitivity but lacks spe- pared with the following doses: 0.25, 0.1, 0.05, 0.01, 0.005,
cificity.45 However, in the appropriate populations – animals and 0.001 mg dexamethasone. This series of capsules facili-
suspected of hypercortisolism – the specificity of the LDDST tated dosage with an accuracy of 0.1–0.2 kg body weight.
and the UCCR is similar (0.73 and 0.77, respectively). More
importantly, the predictive value of a positive UCCR (0.88;
CI 0.80–0.93) and that of a negative UCCR (0.98; CI
12 0.88–1.00) compare well with these variables for the LDDST 12.5 Ovary and Testis
(chapter 12.4.2).31
12.5.1 GnRH-stimulation test
The UCCR is also very useful for monitoring the result of
treatment following hypophysectomy or adrenalectomy as Indication
well as treatment with o,p'-DDD.46,47 The replacement glu- (1) Suspicion of decreased secretory capacity of gonadotroph
cocorticoid and /or mineralocorticoid should be omitted the cells. (2) Search for functional ovarian or testicular tissue, as in
night before the urine sample is collected and resumed di- bitches with primary anestrus due to hermaphroditism50 or
rectly after it is collected. Both complete adrenocortical ab- incomplete ovariectomy. (3) Detection of hormonal abnor-
lation and hypophysectomy result in UCCRs 쏝 2.0 × 10–6. malities in the pituitary-gonadal axis in cases of infertility.
(4) Suspicion of anorchism or cryptorchidism in male dogs.
Performance
12.4.5 Urinary corticoid:creatinine ratios Blood is collected before and after intravenous administration
of 0.1 ml GnRH/kg body weight (Fertagyl® or Receptal®),
with low-dose suppression test in EDTA- or heparin-coated tubes (see also chapter 12.1.4)
(UCCR + o-LDDST) for measurement of LH, FSH, progesterone, estradiol, and /or
testosterone. The sampling scheme depends on the hormones
Indication of interest. For LH and FSH, blood is collected at –40, 0, 5,
Dogs in which results of the UCCR and /or the iv-LDDST 10, 20, 30, and 60 min. For progesterone one basal sample
have been inconclusive or negative but in which there is still (–40 or 0 min) suffices. For estradiol, blood is collected at
suspicion of hypercortisolism. –40, 0, 60, and 120 min. For testosterone, blood is collected
at 0, 60, and 90 min.
Performance
The owner collects urine on two consecutive mornings at Interpretation
8.00 h for measurement of the UCCR, without changing the Plasma progesterone 쏜 3 nmol/l indicates the presence of lu-
feeding regimen. After collection of the second urine sample, teal (ovarian) tissue but values 쏝 3 nmol/l do not exclude it.
the owner administers 0.01 mg dexamethasone per kg body
weight orally. The dog is walked at 12.00 h and 14.00 h to
Ovary and Testis 311
Figure 12.3:
Mean LH (blue) and testosterone (red) responses to GnRH (0.1 ml Fertagyl® per
kg body weight) in six healthy male dogs. (Adapted from Knol et al., 1993.)55
Please collect a sample during the dog’s first morning uri- 08.00 hours tablet(s)
nation on three successive days. Take the dog out to uri-
nate fairly late in the evening before each sample so that 16.00 hours tablet(s)
the morning sample is from urine produced during the
night. Make the collection at about the same time each 24.00 hours tablet(s)
morning.
Hence the third morning urine sample will be collected
Place the urine sample in the tube numbered 1, 2 or 3, re- about 8 hours after the last tablet(s). The tablets can be
spectively. Fill the tube only half-full (below the mark) and given with or without food (e.g., in a small piece of meat).
then place it in the freezer or freezer compartment of the It is likely that the dog will drink more and urinate more
refrigerator until all three samples can be mailed or than usual for about a day following the tablets.
brought to the laboratory. The tubes can be filled to less
than the mark, but please do not fill them above the mark For cats, urine is collected by replacing the litter box for
because this can cause the stopper to be forced out when the night with one containing aquarium gravel that has
the urine is frozen. The samples should not be allowed to been washed with tap water and dried. The gravel does not
remain unrefrigerated for more than a day, and so should absorb cortisol from the urine, as litter does. The next
not be mailed just before the weekend. morning the urine is taken up with a syringe or pipette and
poured into the tube through gauze. In place of aquarium
Using the first two samples to measure cortisol production, gravel, there is also a litter specifically designed for urine
we can then examine the control of the adrenal cortex in collection in cats.58
12
References
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MOL JA, DUCHATEAU L, VAN HAM LML, KOOISTRA HS. KOOISTRA HS. Pulsatile secretion pattern of growth hormone in
Adenohypophyseal function in bitches treated with medroxypro- dogs with pituitary-dependent hyperadrenocorticism. Domest
gesterone acetate. Domest Anim Endocrinol 2007;32:63–78. Anim Endocrinol 2003;24:59–68.
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BERK A. Assessment of a combined anterior pituitary function test gestin treatment in the dog. I. Effects on growth hormone, insulin-
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315
13 Treatment Protocols
The preceding chapters have covered diagnostic procedures 쎱 Immediately following removal of the pituitary gland:
and modes of treatment for endocrine disturbances in dogs – Hydrocortisone, 1 mg/kg every 6 h.
and cats. This chapter adds treatment protocols requiring – Desmopressin, 1 drop (~ 5 µg) in the conjunctival sac
further elaboration. every 8 h.
쎱 Analgesia with 0.3 µg buprenorphine per kg body weight
It concludes with the instructions for owners for dogs being every 8 h, as required.
treated for hypercortisolism with o,p'-DDD. These instruc- 쎱 Antibiotic therapy consists of intravenous administration
tions have proved to be very useful to owners in carrying out of 20 mg amoxycillin /clavulanic acid per kg body weight
this somewhat complicated protocol. every 8 h.
At hospital discharge enough time is taken to inform the tion of circulating volume and the consequent increase in
owner, with written instructions, on initial and lifelong glomerular filtration results in adequate kaliuresis, even if the
medications. The owner is instructed to double the dose of infused fluid contains some potassium.
cortisone during every period of moderate to severe stress,
such as that caused by significant illness or severe excitement Hypocortisolism is corrected by adding hydrocortisone
and anxiety, and to continue this for the duration of the stress. acetate (5 mg/kg) or prednisolone succinate (1 mg/kg) or de-
The owner must also be provided with injectable hydrocorti- xamethasone phosphate (0.2 mg/kg) to the initial intravenous
sone and syringes and needles if traveling with the dog, in the or intraosseous dose of fluid. Thereafter, hydrocortisone
event that the cortisone cannot be given orally for any reason. (1 mg/kg) or prednisolone (0.5 mg/kg) is administered sub-
cutaneously every 6 h.
Monitoring for possible recurrence of hypercortisolism is
achieved by measuring UCCR in morning urine samples The hypoaldosteronism is corrected by subcutaneous admin-
collected at home (chapter 12.4) at two and eight weeks after istration of desoxycorticosterone pivalate (Percorten® V) in a
hypophysectomy and every six months thereafter. The even- dose of 2 mg/kg every three weeks or desoxycorticosterone
ing dose of cortisone is omitted prior to each sample and the acetate in oil in a dose of 0.1 mg/kg once daily. If neither of
morning dose is delayed until after the sample is collected. these mineralocorticoids is available but hydrocortisone is
available for glucocorticoid replacement, the dose of hydro-
Follow-up examinations are made at eight weeks after hypo- cortisone can be doubled to make use of its slight intrinsic
physectomy and then once yearly for the remainder of the mineralocorticoid activity (lacking in prednisolone and de-
dog’s life. Each follow-up consists of physical examination, xamethasone). However, this should be changed as soon as
routine biochemistry, and measurement of plasma thyroxine.4 possible to the orally administered mineralocorticoid fludro-
cortisone with supplemental salt (see below).
Maintenance therapy
13.2 Adrenal cortex The following oral maintenance medication is divided into at
least two portions per day:
13.2.1 Primary hypoadrenocorticism 쎱 Glucocorticoid: Cortisone acetate in a daily dose of
electrolyte disturbances. After the initial resuscitation by in- dose of 0.1 g/kg body weight per day. It may provoke vo-
travenous or intraosseous administration of fluid (see below) miting of the meal and the salt can then be given with the
in a dose of 100 ml/kg, the infusion is continued to provide drinking water or as tablets.
the equivalent of 10–15 % of body weight during the first
4–8 h and 100 ml/kg/24 h thereafter. This is accompanied by
monitoring of physical cardiovascular variables, urine pro-
duction, and central venous pressure. The fluid therapy de- 13.2.2 Treatment of hypercortisolism
creases hyperkalemia by (1) dilution, (2) movement of potas- with trilostane
sium into cells with restoration of metabolic acidosis, and (3)
increased renal excretion of potassium. Plasma potassium Hans S. Kooistra
should be monitored closely, for hypokalemia can develop
during this phase. Treatment with trilostane is started at 2 mg/kg daily in one or
two portions given with food. The dose is subsequently ad-
Traditionally, 0.9 % NaCl has been used for initial fluid ther- justed according to the clinical response and the results of
apy because it provides the needed water and sodium but ACTH-stimulation tests. In addition, the efficacy of treatment
no potassium to exacerbate the hyperkalemia (see also is monitored by clinical signs and measurements of plasma
chapter 4.1.6). However, raising plasma sodium concen- sodium, potassium, urea, creatinine, liver enzymes, and
tration too rapidly in patients with severe hyponatremia may ACTH.5
cause neurological disorders and thus fluid with a lower so-
dium concentration may be preferable. Furthermore, restora-
Endocrine pancreas 317
The maximal lowering of plasma cortisol concentration oc- 쎱 Radiographs, abdominal ultrasonography, TLI, cPLI if in-
curs between 2 and 6 h after oral administration of trilostane.6 dicated.
Hence treatment is evaluated by ACTH-stimulation tests per- 쎱 Cessation of diabetogenic drugs.
formed 2–3 h after a dose, the first test approximately two 쎱 Start intermediate-acting insulin (lente insulin; Caninsu-
weeks after the start of the treatment. Adjustment of the dose lin®, Vetsulin®, both Intervet/Schering Plough):
is determined as follows: – dogs: 0.25–0.5 IU/kg BID
쎱 If clinical manifestations of hypercortisolism such as poly- – cats: 1–2 IU/cat BID.
uria and polydipsia have ceased and the post-ACTH 쎱 Treatment may be started in the hospital for one to two
plasma cortisol concentration is 40–150 nmol/l, the dose days. Blood glucose is measured three to four times daily
of trilostane is left unchanged. and the dose of insulin is decreased if blood glucose is
쎱 If clinical manifestations of hypercortisolism have not de- 쏝 5 mmol/l. Treatment may also be started without hos-
creased or ceased but the post-ACTH plasma cortisol pitalization.
concentration is 40–150 nmol/l, the dose of trilostane is 쎱 Begin treatment of concurrent problems (e.g., urinary
increased slightly or given in two portions daily rather tract infection, stomatitis/gingivitis).
than one portion. 쎱 Castration if intact bitch. Consider administration of a
쎱 If clinical manifestations of hypercortisolism have not progesterone receptor blocker such as aglepristone if the
ceased and the post-ACTH plasma cortisol concentration bitch cannot undergo surgery or has recently received
is 쏜 150 nmol/l, the daily dose of trilostane is increased progestins.
by ~ 1 mg/kg. 쎱 Prescribe dietary management:
쎱 If clinical manifestations of hypercortisolism have ceased – dogs: high-fiber diet
but the post-ACTH plasma cortisol concentration is – cats: high-protein, low-carbohydrate diet, provided
150–250 nmol/l, the dose of trilostane is not changed but that dietary management of another disease does not
the dog is monitored closely for signs of possible recur- have priority
rence of hypercortisolism. – if overweight, aim for 1 % weight loss per week
쎱 If clinical manifestations of hypercortisolism have ceased – give food just before insulin administration.
and the dog’s condition is considered satisfactory but 쎱 Instruct the owner (duration at least 1 hour).
the post-ACTH plasma cortisol concentration is 쎱 Give the owner written instructions.
쏝 40 nmol/l, the dose of trilostane is a) not changed if
plasma cortisol was increased by ACTH, or b) decreased Reevaluation one week after diagnosis
by ~ 1 mg/kg if there was no response to ACTH. The dog 쎱 Owner gives food and insulin at home and then brings pa-
is monitored closely for signs of hypocortisolism and re- tient to the clinic as soon as possible.
examined at monthly intervals. 쎱 History, physical examination, body weight. 13
쎱 If there are signs suggesting adrenocortical insufficiency, 쎱 Measure blood glucose concentration every 1–2 h for the
such as lethargy and anorexia, trilostane treatment is remainder of the day.
stopped immediately and an ACTH-stimulation test is 쎱 Measure blood fructosamine.
performed. If necessary, intravenous fluid and cortico- 쎱 Adjust insulin dose if required: in dogs increase by
steroids are started (see chapter 13.2.1). 10–25 %, in cats by 0.5 1.0 IU/injection.
쎱 After Somogyi reaction or overt hypoglycemia, reduce
Follow-up examinations are repeated at intervals of two to dose by at least 50 %.
three weeks and the dose is adjusted as required until the
response is satisfactory. The dog is then reexamined one Reevaluation three weeks after diagnosis
month later and at intervals of three to six months thereafter. 쎱 Repeat history, physical examination, body weight, blood
glucose curve (BGC), fructosamine, and dose adjustment,
as after one week.
쎱 Introduce owner to home monitoring (HM) and instruct
13.3 Endocrine pancreas on all relevant technical aspects (duration at least 0.5 h)
쎱 Owner measures fasting blood glucose twice weekly and
13.3.1 Treatment of diabetes mellitus performs a BGC once per month.
in dogs and cats
Reevaluation six to eight weeks after diagnosis
Claudia E. Reusch 쎱 Repeat history, physical examination, body weight, BGC,
fructosamine, and dose adjustment, as after one week.
Initial presentation BGC may not be required if animal appears to be doing
쎱 Diagnosis of diabetes mellitus (hyperglycemia, glucosuria, well, blood glucose measured close to the time of insulin
elevated fructosamine). administration is 5–10 mmol/l, and fructosamine is
쎱 Laboratory evaluation (routine hematology, blood bio- 350–450 µmol/l.
chemistry, urinalysis, urine culture). 쎱 If owner performs HM, check his / her technique.
318 Treatment Protocols
쎱 Test for underlying disease (hypercortisolism, hyperso- is adjusted according to plasma sodium concentration and
matotropism) if there are suggestive symptoms and /or fluid balance. Fluid balance is monitored closely; with a cen-
signs. tral venous catheter and a urine catheter in place.
Potassium supplementation
Reevaluation ten to twelve weeks after diagnosis The potassium deficit can be severe even though plasma po-
쎱 Repeat all measures as at six to eight weeks. tassium is normal or even elevated. The lack of insulin con-
tributes to the loss of intracellular potassium, aggravated by
Continuing reevaluations every four months vomiting, osmotic diuresis, and secondary hyperaldosteron-
쎱 Repeat all measures as at six to eight weeks. ism due to the hypovolemia. Consequently, potassium must
쎱 Urine culture at least once yearly. be supplemented in virtually all patients with diabetic ke-
toacidosis. The initial dose depends on the pretreatment
Goals of therapy plasma potassium concentration (table 13.1). Plasma potas-
쎱 Resolution of polyuria, polydipsia, and polyphagia and sium is measured again after 2 h of fluid therapy, since it is
return to normal body weight. rapidly lowered by dilution and osmotic diuresis. In addition,
쎱 Maintenance of blood glucose between 15 mmol/l at the potassium shifts from the extracellular to the intracellular
time of insulin administration and 5 mmol/l at the nadir. space with correction of the metabolic acidosis. The cotrans-
쎱 Maintenance of fructosamine at 350–450 µmol/l, al- port of potassium with glucose is amplified by insulin therapy
though fructosamine is the least important variable for and if hypokalemia is severe, plasma potassium should be cor-
evaluation of metabolic control. rected to near normal before insulin therapy is started. Intra-
venous administration of potassium should not exceed
0.5 mmol/kg/h, to avoid cardiac arrhythmias.
13.3.2 Management of diabetic Phosphate supplementation
ketoacidosis Hypophosphatemia can develop during the first few days of
treatment, especially if there is no food intake after initial
Joris H. Robben treatment. Phosphate should be supplemented if plasma phos-
Claudia E. Reusch phate is 쏝 0.5 mmol/l in dogs or 쏝 0.8 mmol/l in cats. It is
supplemented by continuous intravenous infusion at a rate of
The clinical manifestations of diabetic ketoacidosis depend on 0.03–0.06 mmol/kg/h for 6 h. Higher infusion rates, up to
the stage at the time of presentation and usually include vo- 0.12 mmol/kg/h, are sometimes necessary. The duration of
13 miting, polyuria, lethargy, and weight loss. The animals are infusion is determined by measuring plasma phosphate every
often severely hypovolemic and may be presented in a state of 6 h. Simultaneous supplementation of potassium should be
sopor or stupor, or even in coma. Laboratory findings include reduced if potassium phosphate is used for the infusion.
hyperglycemia (sometimes severe), metabolic acidosis, ke-
tonemia, and ketonuria. The fluid loss via osmotic diuresis, Bicarbonate supplementation
vomiting, and hyperventilation is usually equivalent to In most cases, correction of hypovolemia will also restore the
10–12 % of body weight. acid-base balance quickly, so that administration of bicarbon-
ate to correct metabolic acidosis is often unnecessary and can
Diabetic ketoacidosis is one of the most complex metabolic even be detrimental. Hence bicarbonate supplementation
emergencies and its treatment is demanding. It requires 24 h
surveillance with frequent reevaluation of physical and lab-
oratory variables and appropriate adjustments of therapy.
Treatment consists of fluid therapy, electrolyte supplemen-
tation, correction of acid-base balance, and correction of the
hyperglycemia. Table 13.1: Potassium supplementation in diabetic ketoacidosis
Table 13.1: treated with 0.9 % NaCl*
Fluid therapy Plasma potassium mmol KCl added Maximum rate
Hypovolemia and shock should be treated as soon as possible (mmol/l) per liter of 0.9 % NaCl (ml/kg/h)
with intravenous fluid (30–90 ml/h). Dehydration is usually
3.6–5.0 20 24
resolved within 12–24 h. This requires (1) maintenance fluid
(~ 2 ml/kg/h), (2) correction of the fluid deficit (= amount of 3.1–3.5 30 16
dehydration), and (3) replacement of losses due to vomiting 2.6–3.0 40 11
and polyuria. Fluid therapy is started with a solution having a 2.1–2.5 60 8
sodium concentration of 140 mmol/l or slightly higher
쏝 2.0 80 6
(154 mmol/l; NaCl 0.9 %), depending on the plasma sodium
concentration and the state of hydration. The type of solution * If any other crystalloid solution is used, its potassium content must be taken into account.
Endocrine pancreas 319
should be considered only if blood gasses can be measured blood glucose concentration measured hourly for 6–8 h
during treatment, the initial pH is 쏝 7.1, and there is con- after injection, to determine the duration of action.
comitant renal failure. The bicarbonate deficit in mmol can
be calculated by: Continuous rate infusion
쎱 First administer regular insulin at a rate of 0.05 IU/kg/h
NaHCO3 = 0.3 × body weight (kg) × (24 – [bicarbonate (cat) or 0.1 IU/kg/h (dog) by means of a syringe pump.
(mmol/l)]). For this purpose, add the dose for 0.5 IU/kg to 50 ml of
0.9 % NaCl in a syringe or the dose for 5 IU/kg to a
The initial dose is one-fourth to one-half the calculated bi- 500 ml flask or bag of 0.9 % NaCl. Administer at a rate of
carbonate deficit, administered over ~ 6 h. Acid-base balance 5 ml/h in cats or 10 ml/h in dogs. Adding 2 ml of plasma
is determined at least every 3 h. to 50 ml of 0.9 % NaCl solution before adding insulin
prevents adhesion of insulin to the synthetic material of
Insulin and glucose therapy the syringe and tubing. Alternatively, fill the syringe and
Insulin therapy should be postponed for 2–4 h in patients tubing with insulin-containing solution, discard the
with severe diabetic ketoacidosis, hypovolemic shock, dehy- solution after 1 h, and then refill the system with a fresh
dration, hypokalemia (쏝 3.5 mmol/l), and hyperglycemia. insulin-containing solution.
The patient is first stabilized by administering intravenous 쎱 The continuous rate infusion of glucose is started if blood
fluids and potassium, which often lowers blood glucose by di- glucose falls below 15 mmol/l (see step 5 of the intermit-
lution, diuresis, and improved uptake of glucose in peripheral tent technique), while adjustments are being made in the
tissues. continuous rate infusion of regular insulin (table 13.2).
Add the appropriate amount of 50 % glucose to the main-
Regular crystalline insulin can be administered intermittently tenance fluid to make a 5 % solution. Alternatively, 20 %
or as a continuous rate infusion. The goal in either case is to glucose can be administered via a dedicated syringe pump
reduce the hyperglycemia in a controlled manner, reduce os- and a central line at one-fourth the maintenance rate,
motic diuresis, and improve acid-base status. which simplifies adjustments in glucose administration.
Aim at a blood glucose concentration of 9–12 mmol/l.
Intermittent, intramuscular (IM) technique 쎱 After the patient is stable and rehydrated, regular insulin
Start regular insulin if blood glucose is 쏜 15 mmol/l: can be administered SC three to four times /day (see steps
쎱 Administer 2 IU of regular insulin IM per cat or dog 6 and 7 of the intermittent technique).
쏝 10 kg, and 0.25 IU/kg IM in dogs 쏜 10 kg. Ideally,
the blood glucose concentration should be decreased by After the patient has been stabilized, its condition improved,
3 mmol/l/h, to avoid large shifts in osmolality which can and it has begun to eat, treatment with longer-acting insulin 13
have detrimental neurological effects. can be initiated.
쎱 Measure blood glucose after 1 h.
쎱 If blood glucose is still 쏜 15 mmol/l, administer 1 IU of
13.3.3 Treatment of hypoglycemia 쎱 The patient must be fed as soon as possible after stabiliz-
ation, if necessary by force feeding or enteral tube feeding.
Joris H. Robben Parenteral feeding should be considered if the enteral
route is not available.
쎱 Patients with severe, acute symptoms and signs related to 쎱 Diazepam (1 mg/kg) or propofol (2–6 mg/kg) can be
hypoglycemia should be treated immediately. Time given to effect if the patient still has seizures after normal-
required for measurement of blood glucose should never ization of the blood glucose concentration. These anti-
postpone emergency treatment, for the longer the period convulsants have a relatively short half-life, so the neuro-
of hypoglycemia, the greater the risk of irreversible brain logical status of the patient can be examined shortly after
damage. stopping the medication.
쎱 If intravenous injection is not possible (e.g., because the 쎱 In animals with refractory or persistent hypoglycemia due
patient is having seizures), apply glucose syrup to the oral to insulin overdosage or an insulin-secreting pancreatic
mucosa. Do not pour syrup into the patient’s mouth, for it tumor, the counterregulatory hormone glucagon can be
may be aspirated. administered. Start with a 50 ng/kg bolus followed by a
쎱 Serious neurological symptoms such as seizures should continuous rate infusion at an initial rate of 5–10 ng/kg/
decrease within 1–2 min after giving glucose. If they do min. Adjustment of the dose is based on measurements of
not, administer diazepam rectally (1 mg/kg), but continue blood glucose.
trying to raise blood glucose concentration via the oral 쎱 Hyperglycemia may stimulate insulin release from an in-
mucosa. sulin-secreting pancreatic tumor (insulinoma), resulting in
쎱 As soon as intravenous injection is possible, slowly rebound hypoglycemia. Consequently, it is probably
(5–10 min) administer a bolus of glucose: 6–12 ml of better to avoid high blood glucose concentrations in pa-
20 % glucose or 2.5–5 ml of 50 % glucose for a cat or tients with a tentative diagnosis of insulinoma. Even nor-
small dog, and 20–35 ml of 20 % glucose or 8–15 ml of mal blood glucose concentrations may not be needed to
50 % glucose for a large dog. If blood glucose decreases control symptoms: 2.8–3.5 mmol/l is often sufficient, be-
15–30 min after the bolus, immediately start a continuous cause insulinoma patients have adapted to a chronic hypo-
rate infusion of 2.5–5 % glucose at 1.5 to two times the glycemic state.
maintenance rate. 쎱 Dexamethasone (0.5–1 mg/kg added to intravenous fluids
쎱 Continuous rate infusion of 20 % or 50 % glucose should and administered over 6 h) or diazoxide (5–30 mg/kg
be via a central venous catheter, because these hyperos- BID) can also be considered to control hypoglycemia.
molar solutions can cause phlebitis if administered in pe- Both drugs have a slow onset of action and should be
ripheral vessels. The rate of continuous infusion is ad- given as soon as possible. If the patient is unable or unwill-
13 justed by serial measurements of blood glucose every ing to swallow, diazoxide capsules can be opened and the
20–60 min. If blood glucose falls below the reference powder can be dissolved in water and administered by gas-
range, the infusion rate is increased by 25–50 %. If blood tric tube.
glucose is very low, an additional bolus must be given.
The target of treatment is a normal blood glucose concen-
tration, not hyperglycemia.
In your dog excessive amounts of the hormone cortisol are The initial treatment of your dog consists of: tablets
produced by adrenocortical tissue. The treatment with of o,p'-DDD (= Lysodren® or Mitotane®) times
o,p'-DDD aims at complete destruction of all adrenocor- daily for in total 25 days. The o,p'-DDD is given daily for
tical tissue (including adrenocortical tumor tissue). The the first five days and then every other day. For good ab-
requirement for the hormones normally produced by ad- sorption and to prevent vomiting, the tablets should always
renocortical tissue is then provided by lifelong adminis- be given with food.
tration of replacement hormone tablets. It is very import-
ant that the instructions for the replacement hormone be For the first two days only o,p'-DDD is given. On the third
followed carefully and completely, for deficiency of these day the replacement of the adrenocortical hormones is
hormones can result in a life-threatening crisis. begun with the addition of cortisone, fludrocortisone, and
ordinary salt. To allow a more gradual change from the ex-
cessive hormone production, the dose of cortisone is kept
higher than the normal requirement for the first week after
o,p'-DDD therapy.
Endocrine pancreas 321
During the first two months your dog receives as replace- A deficiency in replacement medications can lead to a life-
ment therapy: threatening crisis and emergency treatment may be
required. It is far better to contact the veterinarian before a
Cortisone acetate: × daily tablets of mg crisis occurs. The first warning is often loss of appetite.
Many dogs with the disease have an excessive appetite, and a
Fludrocortisone acetate: × daily tablets decrease in appetite is an expected sign of recovery. How-
of mg ever, an almost complete refusal to eat should be recognized
as a warning. You should stop o,p'-DDD immediately, con-
NaCl (salt): × daily gram tinue the replacement medications, and obtain the veterin-
arian’s advice promptly.
Follow-up
Special circumstances in replacement therapy
The first follow-up examination is at one month after the
beginning of o,p'-DDD therapy. At this time the dose of It is extremely important to give the replacement medi-
cortisone is usually reduced by half. Results of blood cations without interruption. Yet there may be situations
examination will be used to determine whether the doses in which your dog cannot or will not take anything orally
of fludrocortisone and salt need to be adjusted. After this, or cannot retain the medications because of vomiting. If
follow-up examinations are usually made once every six for any reason your dog cannot take or retain the tablets
months. Their purpose is to be certain that the replace- and salt for two times in succession, injectable medications
ment doses of fludrocortisone and salt are correct. Some- should be started. This also applies if your dog must be
times, in spite of the destructive action of o,p'-DDD on fasted before being brought to the veterinarian for treat-
adrenocortical tissue, symptoms of the disease reappear. ment that requires anesthesia.
This can occur after several months or even after four to
five years. It is then necessary to repeat the treatment with 쎱 The cortisone tablets are replaced by subcutaneous in-
o,p'-DDD. jections of hydrocortisone acetate (50 mg/ml) in a dose
of ml twice daily. The hydrocortisone injec-
The first signs of recovery are often already apparent dur- tions are continued until the dog can again swallow and
ing the o,p'-DDD therapy. The excessive thirst and hunger retain the cortisone tablets.
diminish and the dog’s endurance increases. The recovery
of the coat takes longer, but once this begins, after about 쎱 The fludrocortisone tablets and salt are replaced
two months, a very thick coat usually develops. The re- by subcutaneous injections of desoxycorticosterone
covery of the skin and coat may be preceded by a short acetate (DOCA, 1 mg/ml) in a dose of ml 13
period of excessive scaling and some itching. This can be once daily or of desoxycorticosterone pivalate in a
relieved by a treatment with shampoo once or twice a dosage of ml once every three weeks. If neither
week. DOCA nor DOC pivalate (chapter 13.2.1) is available,
you should double the dose of hydrocortisone. The salt
is not needed when DOC injections are used. The
Complications
DOC injections are continued until the dog can again
With the above treatment instructions, most dogs recover swallow and also retain the fludrocortisone and salt.
without complications, but there can be complications as-
sociated with the o,p'-DDD or the replacement therapy. If If you take your dog on vacation or on a trip away from
you notify the veterinarian in time, the problems can home for more than one or two days, also take the inject-
usually be resolved without difficulty. able medications, syringes, and needles, and this instruc-
tion sheet, for not all veterinarians may have these medi-
In the beginning of treatment there may be mild side ef- cations at hand. If you leave the dog in the care of someone
fects from o,p'-DDD, such as nausea, incoordination, or else, also make provision for the possible need for the in-
slight disorientation. These signs usually disappear if jections, even if you have not yet had to use them yourself.
administration is continued but simply spread out more
over the day. If the dog refuses to eat or eats almost noth- In cases of anesthesia, severe physical stress, or injury, the
ing, stop the o,p'-DDD completely, but be sure to con- dose of cortisone should be doubled for one or two days.
tinue the replacement medications, and notify the veterin- With these exceptions, the dose of cortisone remains un-
arian. changed for life, while the dose of fludrocortisone and salt
may have to be adjusted by the veterinarian.
322 Treatment Protocols
References
1. HANSON JM, MOL JA, MEIJ BP. Peri-operative plasma profile of 4. HANSON JM, VAN ’T HOOFD MM, VOORHOUT G,
adrencorticotropic hormone predicts recurrence after transsphenoi- TESKE E, KOOISTRA HS, MEIJ BP. Efficacy of transsphenoidal
dal hypophysectomy for the treatment of pituitary-dependent hy- hypophysectomy in treatment of dogs with pituitary-dependent hy-
peradrenocorticism in dogs. In: Thesis J.M. Hanson, Utrecht Uni- peradrenocorticism. J Vet Int Med 2005;19:687–694.
versity 2007:131–145.
5. GALAC S, BUIJTELS JJCWM, MOL JA, KOOISTRA HA. Ef-
2. HARA Y, MASUDA H, TAODA T, HASEGAWA D, FUJITA Y, fects of trilostane treatment on the pituitary-adrenocortical and
NEZY Y, TAGAWA M. Prophylactic efficacy of desmopressin renin-aldosterone axis in dogs with pituitary-dependent hypercor-
acetate for diabetes insipidus after hypophysectomy in the dog. J Vet tisolism. Vet J 2008; doi:10.1016/j.tvjl.208.10.007.
Med Sci 2003;65:17–22.
6. NEIGER R, HURLEY K. 24 hour cortisol values in dogs with hy-
3. MEIJ BP, VOORHOUT G, VAN DEN INGH TSGAM, HAZE- peradrenocorticism on trilostane. Proceed British Small Anim Vet
WINKEL HAW, TESKE E, RIJNBERK A. Results of transsphe- Assoc Congress, Birmingham, 2001:549.
noidal hypophysectomy in 52 dogs with pituitary-dependent hy-
peradrenocorticism. Vet Surg 1998;27:246–261. 7. RIJNBERK A, BELSHAW BE. O,p'-DDD treatment of canine
hyperadrenocorticism: an alternative protocol. In: Kirk RW, Bon-
agura JD eds, Current Veterinary Therapy XI. Philadelphia: WB
Saunders Co 1992:345–349.
13
Algorithms 323
14 Algorithms
Hans S. Kooistra
Ad Rijnberk
In these step-by-step procedures for problem solving the em- secretion of ACTH and subsequently cortisol excess.2 As
phasis is on associated symptoms and signs that may point to parathyroid tumors are usually very small and a malignancy
an endocrine disturbance. The history and physical examin- causing hypercalcemia may not have been detected by phy-
ation are aimed at the detection of endocrine disease, and the sical examination (section 9.3), measurement of plasma
use of a standard form for these steps may be helpful.1 When calcium and phosphate should always be included in the lab-
suspicion of an endocrine disturbance arises, it can be tested oratory profile for PU/ PD. Polycythemia and hyperaldoste-
by specific examinations. ronism may also cause PU/ PD in dogs.3,4
If the history and physical examination do not reveal clues If the routine laboratory examinations reveal no abnor-
suggesting an endocrine disturbance, the next step is labora- mal values suggesting the cause of the PU/ PD, abdominal
tory examination of urine and blood. If the routine labora- ultrasonography, serial measurements of urine osmolality
tory examinations reveal no abnormal values, diagnostic (chapter 12.2.1), the modified water deprivation test (chap-
imaging and work-up at specialist level may be required. ter 12.2.2), and vasopressin measurements during hypertonic
saline infusion (chapter 12.2.3) may be required.
rhea. The first step is to carefully evaluate food intake. Some References
owners feed strictly according to the recommendations of the
manufacturer or seller of the food, not taking account of 1. RIJNBERK A, KOOISTRA HS. Endocrine glands. In: Rijnberk
energy expenditure. A, Van Sluijs FJ, eds. Medical history and physical examination in
companion animals. Edinburgh, Saunders Elsevier 2009:207–212.
Large and widespread malignancies such as malignant lymp-
2. ROTHUIZEN J, BIEWENGA WJ, MOL JA. Chronic glucocor-
homa increase energy demand, as do cardiac abnormalities ticoid excess and impaired osmoregulation of vasopressin release in
that result in tachycardia. However, in patients with these dis- dogs with hepatic encephalopathy. Domest Anim Endocrinol
orders weight loss is rarely seen as the primary problem and in 1995;12:13–24.
most of them the appetite is poor.
3. VAN VONDEREN IK, MEYER HP, KRAUS JS, KOOISTRA
HS. Polyuria and polydipsia and disturbed vasopressin release in
2 dogs with secondary polycythemia. J Vet Intern Med 1997;11:
300–303.
14
Algorithms 325
14
Figure 14.1
326 Algorithms
14
Figure 14.2a
Algorithms 327
14
Figure 14.2b
328 Algorithms
14
Figure 14.3a
Algorithms 329
14
Figure 14.3b
330 Algorithms
14
Figure 14.3c
Algorithms 331
14
Figure 14.3d
332 Algorithms
14
Figure 14.4
Index 333
Index
Growth plate 262, 263, 272, 276 adrenocortical tumor 125 transdermal methimazole 78 Hypoprolactinemia 70
Growth-hormone responsive aminoglutethimide 125 T-S ratio 75 Hypothalamic-hypophyseal portal
dermatosis 24 diagnostic imaging 120 Hypertonic saline infusion 43 system 13
Gubernaculum testis 240 diagnosis 116 Hyperviscosity 293 Hypothalamic-pituitary-thyroid
Gynecomastia 244 differentiation 118 Hypervitaminosis A 272, 284, axis 59
food-dependent 131 284 Hypothalamus 13
H ketoconazole 124 Hypervitaminosis D 267, 277 Hypothermia 68
HDDST see High-dose dexa- nonsuppressible 126 Hypervolemia 39 Hypothyroidism 23, 60, 63, 64,
methasone supression test (of ) PI origin 117 Hypoadrenocorticism 103, 104, 65, 71, 160, 161, 221, 246, 283
Hepatic pituitary-dependent 116 105, 108, 109, 174 99mTcO – uptake 70
4
lipidosis 300 recurrence 316 acute crisis 108 acquired juvenile 60
steatosis 160 treatment 316 atypical primary 104 acquired primary 65
Hepatoencephalopathy 39, 323 treatment (at the pituitary breed predisposition 105 antibodies to Tg 70
Hermaphroditism 189, 221, 310 level) 120 (in) cats 105 central 64, 71
pseudohermaphroditism treatment (at the adrenal level) client instruction and clinical manifestations 64
189, 195 123 follow-up 108 congenital 23
true hermaphroditism 189, trilostane 316 clinical manifestations 107 diagnosis 68
190 Hyperfunction 9 diagnosis 107, 110, 111 differential diagnosis 68
Herpesvirus 228 secondary 9 ECG 106 ECG 68
High-dose dexamethasone Hyperglycemia 159, 160, 172, emergency treatment 316 hyperlipidemia 68
suppression test 117, 309 180 hypotonic dehydration 105 iatrogenic 64
Histone 6 stress 162, 168, 171 iatrogenic 105 iodine deficiency 60
History and physical examination Hyperglycemic hyperosmolar iatrogenic secondary 132 locomotor disturbances 68
10 syndrome 162, 172, 173 maintenance medication 316 nonregenerative anemia 68
Home monitoring (diabetes Hyperkalemia 107, 265, 316 primary 103, 267 pathogenesis 64
mellitus) 166 Hyperlipidemia 160, 163 relative 110 pituitary enlargement 70
Hormone-receptor complex 5 Hypernatremia 315 secondary 109 primary 64
Hormones 3, 4, 5, 9, 10, 11 (in) pituitary apoplexy 33 (and) stress 109 secondary 24, 64
action, metabolism, and Hyperosmolality 172, 173 treatment 108, 110, 111 sulfonamides 60
elimination 5 Hyperparathyroidism 266 Hypoaldosteronism tertiary 64, 71
anabolic 158 chemical ablation 268 hyperreninemic 104 thyroiditis 60
antibodies to 11 nutritional 271 primary 107 treatment 71
catabolic 158 primary 266 Hypocalcemia 256, 265, 268, ultrasonography 70
chemical nature 3 radiofrequency heat ablation 284 (in) young animals 60
concentrations in plasma 10 268 Hypocortisolism 107, 109, 110 Hypotonicity syndrome 44
endocrine 2 renal 270, 270 correction 316 Hypovitaminosis D 272, 275
excess 9 secondary 266, 269, 271 primary 107 Hypovolemia 316, 318
exocrine 3 surgery 268 Hypofunction 8
free 4 Hyperphosphatemia 265, 278 Hypogenitalism 237 I
ketogenic 159 Hypersomatotropism 160, 168 Hypoglycemia 163, 165, 171, IAPP see Islet amyloid polypeptide
paracrine 2, 3 Hypertension 299 172, 173, 174, 179, 265, 317 Iatrogenic hypercorticism 132
peptide 5 Hyperthyroidism 73, 81, 160, insulin-like growth Iatrotropic threshold 42
protein-bound 4 169 factor 178 IGF-1 see also Insulin-like growth
resistance 10 apathetic 73 juvenile 179 factor
steroid 5 (in) cats 73, 74 symptoms 173 (in) diagnosis of acromegaly
storage, release, and transport (in) dogs 81 treatment 320 27
4 thyroid storm 74 Hypogonadism (in) dwarfism 23
urinary excretion 10 Hyperthyroidism, feline 73 hypergonadotropic 237 low caloric intake 23
Human chorionic gonadotropin 99mTcO – uptake 75 hypogonadotropic 237 (and) nutritional condition
4
242 antithyroid drugs 78 Hypokalemia 130, 135, 136, 27
Hydrocortisone 315, 316 biochemical abnormalities 173 (in) response to treatment 27
Hyperaldosteronism 39, 134, 74 Hypoluteoidism 221, 228 IGF-binding proteins 19
135, 137 clinical manifestations 73 Hypomagnesemia 173 Incidentaloma 125
(in) cats 135 diagnosis 74 Hyponatremia 44, 107, 108, 173 Incretins 157
diagnosis 137 differential diagnosis 74 Hypoparathyroidism 264, 277 Infertility 190, 194, 221, 246
medical treatment 138 ethanol injection 79 primary 264 Inhibin 236
polyuria 135 heat ablation 79 secondary 264 Insulin 155, 156, 160, 319
primary 135 parathyroid damage 77 Hypophosphatemia 173, 267, action 158, 159, 165
renal insufficiency 137 pertechnetate scintigrams 274, 275, 284 adhesion prevention 319
secondary 134 76 Hypophysectomy 120, 315 administered intermittently
surgical treatment 138 plasma TSH 75 cryohypophysectomy 27 319
Hypercalcemia 256, 267, 268, postoperative complication immediate postoperative antibodies 160
273, 277, 278 76 treatment 315 continuous rate infusion 319
(of) malignancy 267, 272 preoperative treatment 76 maintenance therapy 315 deficiency 160
Hypercalcitoninism 278 prognosis 79 pituitary tumor 34 efficacy 165
Hypercortisolism 39, 111, 116, radioiodine therapy 78 Hypophysiotropic hormones 16 lente-type 170
117, 120, 124, 125, 126, 160, radioiodine uptake 75 Hypophysiotropic regulation 17 preparations 164
162, 163, 168, 221, 246, 268, relapse 78 Hypophysis receptor 158
283 T3-suppression test 75 anatomy 13 resistance 160, 161, 164, 165,
ACTH-independent 111 thyroidectomy 76 Hypopituitarism 24, 32 167, 208
336 Index
secretion 156, 157 Low-sodium diet 42 Multiple endocrine neoplasia Osteochondritis dissecans 279,
sensitivity 160 Luteal phase 211, 215 117, 140 282
structure 156 Luteinization 207 Myxedema 65 Osteochondrosis 278, 280
synthesis 156 Luteinizing hormone 204, 230, Osteoclasia 278, 283
therapy 163 236 N Osteoclasts 256, 257, 262
Insulin-like growth factor 19, Luteolysis 217 Na+K+-ATPase 68, 102, 114 Osteocytes 262
178, 208 Lymphoma 273 Natriuretic peptides 135, 291 Osteodystrophy 270, 277
Insulin-like peptide 3 (Insl3) 241 atrial natriuretic peptide 291 Osteomalacia 275
Insulinoma 174 M brain natriuretic peptide 291 Osteoporosis 264, 283
diagnosis 175 Macula densa 101 pro-fragments 292 Osteoprotegerin 257, 273
diagnostic imaging 175 Male pseudohermaphroditism Nephrocalcinosis 266, 268, 274, Ovarian cysts 219
treatment 176 196 278 Ovarian tumors 219
Insulin-receptor substrate (IRS) Malignant lymphoma 273 Nephrogenic diabetes insipidus Ovariectomy 218, 222, 310
molecules 158 Mammary gland 20, 208 41 incomplete 219
Interestrous interval 204, 210, expression of the GH gene diagnosis 41 Ovariohysterectomy 227
211, 215, 218, 221, 222 23 treatment 42 Ovary 187, 203, 207
Interleukin-1 110 fibroepithelial hyperplasia Nerve terminals 16 Oviducts 188
Intersexuality 189 27 Neuroendocrine 13 Ovotestes 190, 191, 193
Intracrine 2, 3 pseudopregnancy 30 diffuse neuroendocrine system Ovulation 207, 207, 213
Introns 6, 7 Mammary growth hormone 291 Oxytocin 35, 219
Iodide 57 excess 27 Neuroglycopenia 173 maternal behavior 35
Iodide symporter 57 (in) cats 27 Neurohypophyseal hormones milk ejection 35
Iodine deficiency 60 diagnosis 29 35 myometrial contractions 35
Iodothyronine 57 (in) dogs 28 Neurohypophysis 14, 35, 40
Islet amyloid polypeptide 157, prognosis 30 Neuropathy 161, 168 P
298 treatment 29 Neuropeptide Y 297 Pancreas 155
Islets of Langerhans 155 Mammary tumor 222, 223 Neurophysin 35 Pancreatic carcinoma 160
Masculinization 195, 196, 198 Neurotransmitter 3, 16 Pancreatic polypeptide 155
J Median eminence 14, 16 Neuter status 311 Pancreatitis 168
Juxtaglomerular cells 101 Medroxyprogesterone acetate Nonesterified fatty acids 299 Panosteitis 279
29, 223 Nonthyroidal illness 68 Paradoxical secretion 16
K Medullary thyroid carcinomas Noradrenaline 139 Parafollicular cells 261
Karyotype 222 81 Norepinephrine 93, 139 Paragangliomas 140
Karyotyping 191 Melanocyte 97 Normetanephrine 139 Paraneoplastic endocrine
Ketoacidosis 160, 163 a-MSH 97 Normetanephrine–creatinine syndromes 291
hypokalemia in 318 eumelanin 97 ratio 141 Parathyroid glands 255, 267, 275
Ketoconazole 124 pheomelanin 97 Nuclear factor-kappa B 101 anatomy 255
Ketone bodies 163, 172, 174 Melanotroph 118 Nucleosomes 6 location 255
Ketonuria 172 adenoma 118 Parathyroid hormone 255
Kidney function 36 Melatonin 215 O Parathyroid hormone-related
Klinefelter’s syndrome 191 Messenger RNA 6 o,p'-DDD 123, 127 protein 272
Metanephrine 139 client information 320 Parathyroid hyperplasia 266
L Metergoline 210 hormone substitution 128 Parathyroid tumor 266, 268
Laboratory testing 10 Metestrus 204, 208 inappetence 128 Parturition 212
Lactogenesis 21 Methimazole 57, 78 owner compliance 128 induction 219
Lactotrophs 16 Methylprednisolone 133 recurrences 128 Pathological fractures 271, 276
Lactotropin 18 Micro RNAs 7 Obesity 160, 167, 297 Pendrin 57
LDDST see also Low-dose dexa- Mineralization 262, 278 amylin 298 Penis 189
methasone suppression test Mineralocorticoid 99 appetite 297 Peptide YY 297
predictive value 308 deficiency 106 breed prevalence 297 Perchlorate 57, 63
Leptin 160, 167, 297 regulation 99 cholesterol in plasma 299 Peroxisome proliferator-activated
Leukozoospermia 246 Mineralocorticoid excess 134 gender 297 receptors 298
Leydig cells 188, 191 clinical manifestations 135 insulin resistance 298 Persistent estrus 191, 219, 228
tumor 243 diagnosis 137 insulin secretion 298 Persistent Müllerian duct
Lhx4 21 laboratory findings 137 lipid metabolism 299 syndrome 196
Libido 246 subtype classification 138 neutering 297, 300 Phagolysosome 57
LIF-receptor gene 21 Mitochondrial respiration 294 prognosis 300 Phenoxybenzamine 142
Ligand-receptor interaction 5 uncoupling 294 proinsulin 298 Pheochromocytes 139
Lipase Mitratapide 300 thyroid hormone 298 Pheochromocytoma 140
hormone-sensitive 158 Modified water deprivation test treatment 298, 300 clinical manifestations 140
lipoprotein 158 306 Octreotide 177, 180 diagnosis 140
Lipolysis 102 Monoiodotyrosine 57 scintigraphy 294 diagnostic imaging 140
Lipoprotein Monorchism 242 Oligozoospermia 246 extra-adrenal 140
HDL 299 Mosaicism 190 Oocytes 207 fine-needle aspiration 141
LDL 299 Mucometra 227 Oophoritis 221 surgery 142
VLDL 299 Müllerian ducts 188, 196 Orchitis 246 urinary normetanephrine
Lipotoxicity 160, 167 Müllerian inhibiting substance Os clitoris 194 141
Low-dose dexamethasone 188 Osmoreceptor 43 Pheromones 3
suppression test 116, 308, Multiple endocrine deficiencies Ossification centers 62 Phlebotomy 294
309 64 Osteoblasts 256, 257, 262 Phosphorylation 8
Index 337
Physical inactivity 167 Prednisolone 131, 316 RANK 262, 273 Spermatogenesis 235
Pinocytosis 57, 59 Prednisone 131 RANKL 257, 273 spermatids 235
Pit-1 21 Pregnancy 212, 215, 217 Rathke’s pouch 14 spermatocytes 235
dependent cell lines 14 prolonged 223 Receptors 5, 9 spermatogonia 235
Pituitary 13, 18, 21, 111 termination 217 aberrant 9 spermatozoa 235
adenoma 111, 117 Pregnenolone 94 intracellular 5 Spironolactone 138
anterior lobe 13, 13, 14 Preovulatory FSH surge 207 membrane 5 Splicing 7
carcinoma 116 Preovulatory LH surge 204, Refractometry 306 Split heat 220, 228
CT 33 207 Renal disease 41 SRY gene 187, 189, 194
cysts 23 Preprohormones 8 failure 269 Start codon 7
dwarfism 21 Preproinsulin 156 familial 41 Steroid hormones 3
growth hormone 18 Proestrus 206 juvenile onset 41 Steroidogenesis 94
invasive adenoma 116 Progenitor cells 14 Renin 101 Streptozotocin 177
mass 32 Progestagens/Progestins 160, regulation 100 Stress 97, 110, 132, 141
ontogenesis 14 162, 221, 222, 223, 226 Renin-angiotensin system 99 Sulfonylureas 169
pars distalis 14 Progesterone 94, 162, 207, 208, Retinoids 3 Superfecundation 217
pars intermedia 13, 14, 117 210, 212, 214, 217, 218, 220, Retinol 284 Superfetation 217
posterior lobe 13, 14, 35 221, 226, 229 Rickets 275 Syndrome of inappropriate
somatotrophs 18 plasma concentration 323 RNA 7 antidiuresis 44
stalk damage 41 progesterone-receptor tRNA 7
tumor 37 antagonist 30, 217, 225 Rubber jaw 270 T
vascularization 14 Prognathia 26 T3, reverse 57
Pituitary apoplexy 32 Prognathism 28 S TATA box 6
Pituitary dwarfism 22, 23 Prohormones 3 Sample handling 306 Teratozoospermia 246
Pituitary reserve capacity 32 Proinsulin 156, 175, 298 Schmidt’s syndrome 64 Testes 187, 235
Pituitary tumor 31, 34 Prolactin 16, 20, 208, 210, 212, Scrotum 189, 241 descent 239
adenoma 31 215, 217, 218 Seminiferous tubules 235 development 193
carcinoma 31 luteotropic factor 20 Seminoma 243 differentiation 194, 196
diagnostic imaging 33 pseudopregnancy 30 Serotonin antagonist neoplasms 243
hormone deficiency 31 pulses 20 (in) pseudopregnancy 31 regulation 236
hormone substitution 34 releasing hormone 16 Sertoli cell tumor 243 torsion 244
hypophysectomy 34 Prolactinoma 31 Sertoli cells 188, 235 Testosterone 189, 191, 198, 222,
invasive adenoma 31 Proligestone 223 Sex determination 236, 237, 283
mass effects 32 Promoter 6 molecular events 188 Tetany 264, 265
medical therapy 34 Pro-opiomelanocortin 14, 96 Sex reversal syndrome 192 puerperal 284
radiation therapy 34 Prop-1 21 Sexual differentiation 187 Thiazolidinediones 169, 299
suprasellar expansion 32 Propofol 320 chromosomal sex 190 Thiocyanate 57, 63
Pituitary-dependent hyper- Propylthiouracil 57 gonadal sex 187, 192 Thirst osmoreceptors 36
cortisolism 120, 123, 126 Prostaglandin 134 phenotypic sex 187, 189, Thrombocytopenia 244
bilateral adrenalectomy 123 Prostaglandin F2a 212, 217, 195 Thyrocyte 57
diagnosis 118 219, 228 SIAD 44 Thyroglobulin 55, 57
medical treatment 123 Prostate 189 clinical manifestations 44 autoantibodies 64
o,p'-DDD 123 Pseudohermaphroditism 221 diagnosis 45 Thyroglossal duct 55, 61
radiotherapy 123 Pseudohyperparathyroidism pathogenesis 44 Thyroid 55, 59, 60, 61, 76, 79,
treatment 120 273 treatment 45 261
trilostane 123 Pseudohypoparathyroidism Sick euthyroid syndrome 68 accessory tissue 61
Polycythemia 39, 174, 293 264 Signal peptide 7 cancer 79
Polydipsia, primary 37, 40, 42 Pseudopregnancy 30, 208, 214, Silencers 6 dysgenesis 61
diagnosis 43 215, 218, 223 Skeletal growth 257 embryology 55
fluctuations in Uosm 42 PTH 255, 278 (and) prepubertal gonadectomy follicle 55
oropharyngeal signals 42 action 257 283 hyperplasia 60
satiation of thirst 42 assay 265, 268 Skeletal maturation 62 morphology 55
treatment 43 deficiency 264 delayed 62 scintiscan 76, 77
Polyglandular deficiency excess 266 Skeletal remodeling 279 Thyroid hormone 55, 58, 59,
syndrome 64, 105 resistance 256, 269 Skeleton 262 62, 64
Polyhormonal 9 secretion 255, 256 Skin atrophy 323 3,5,3'-L-triiodothyronine 55
Polypeptide hormones 3 synthesis 255 Sodium channels 102 action 59
Polyphagia 162, 168 PTH/PTHrP receptor 257, Sodium chloride 316 antibodies 64
Polyuria 37, 38, 162, 163, 168, 272 Somatomammotropic hormones binding globulin 58
267, 274, 278 Puberty 204, 213 14 chemical structure 56
algorithm 323 Puerperal tetany 265 Somatostatin 18, 155, 158 defective synthesis 62
diagnostic imaging 44 Pyometra 39, 217, 226, 227 analogues 27, 294 deficiency 283
dry food 44 receptor 123, 176, 180 deiodination 58
glucocorticoid excess 38 R receptor scintigraphy 175 free T4 58
POMC 118 Radiation therapy Somatotroph 16 intrathyroidal regulation 59
unprocessed 118 pituitary tumor 34 adenoma 25, 116 L-thyroxine 55
Portal system 139 side effects 34 Somatotropin 18 peroxidase 57
Posttranslational processing 7 Radioiodine treatment 78 Somogyi effect 165, 317 receptor 59
PPARa agonist 299 Radius curvus syndrome 277, Sorbitol 161 total thyroxine 58
PP-cells 155 280 SOX9 187, 194 transporters 58
338 Index