Download Endocrine Diseases in Animals

Adult Clinical Case Sessions: Human and Animal
HORMONE
RESEARCH
Horm Res 2009;71(suppl 1):144–147
DOI: 10.1159/000178059
Published online: January 21, 2009
Endocrine Diseases in Animals
H.S. Kooistra S. Galac J.J.C.W.M. Buijtels B.P. Meij
Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University,
Utrecht, The Netherlands
Abstract
Background: Several endocrine disorders that affect humans also occur as endocrinopathies in companion animals.
Spontaneous endocrine disorders in animals may provide
valuable information for their counterparts in human endocrinology. For example, the discovery of progesterone-induced growth hormone production in the mammary gland
of dogs may have important consequences for understanding the pathogenesis of breast cancer in women. In addition,
the majority of diabetic cats have a type of diabetes mellitus
that closely resembles type 2 diabetes mellitus in humans
and therefore may serve as an animal model for this disease
in humans. This review describes several endocrine diseases
in companion animals that are quite similar to those in humans and emphasizes their usefulness as spontaneous animal models for human endocrine disorders.
Copyright © 2009 S. Karger AG, Basel
Introduction
Companion animals, in particular dogs and cats, share
the same living environment as humans and thus are exposed to similar noxae. In addition, dogs and cats are kept
until old age, which allows accurate observation of the
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development of diseases and the process of aging. As in
humans, the canine (2004) and feline (2007) genomes
have been sequenced and are available for study, making
these animals of great interest in comparative medicine.
Further underscoring the importance of companion animals in comparative medicine is the observation that, in
general, canine genes have a higher degree of homology
with their human counterparts than do those of the frequently studied mouse and rat [1, 2].
Several human endocrine disorders are also known to
occur as similar, spontaneous endocrinopathies in companion animals, and these animals may serve as models
for the diseases in humans. This review summarizes several endocrine diseases in companion animals that are
similar to those in humans.
Growth Hormone (GH) Disorders
GH Deficiency
Pituitary dwarfism due to combined pituitary hormone deficiency (CPHD) is well known as an autosomal,
recessively inherited disorder in German shepherd dogs.
CPHD in these dogs is characterized by underdevelopment of the pituitary gland and a combined deficiency of
GH, thyrotropin, prolactin and gonadotropins, though
adrenocorticotropin secretion is preserved [3]. This canine disorder is due to a mutation in the gene encoding
for the pituitary transcription factor Lhx3. Therefore,
H.S. Kooistra, MD
Utrecht University, Department of Clinical Sciences of Companion Animals
Yalelaan 8
NL–3584 CM Utrecht (The Netherlands)
Tel. +31 30 253 9411, Fax +31 30 251 8126, E-Mail [email protected]
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Key Words
Dog ⴢ Cat ⴢ Animal models ⴢ Veterinary endocrinology
GH Excess
The pathogenesis of GH excess is completely different
in dogs and cats. In cats, as in humans, excessive GH secretion is most often due to a somatotroph pituitary adenoma. In dogs, GH excess due to a pituitary tumor is a
rare event [5]. More often, canine acromegaly is due to
progesterone-induced GH production in the mammary
gland [6].
The estrous cycle of the domestic bitch is characterized by a follicular phase and spontaneous ovulations
followed by a luteal phase (i.e., metestrus has an average
duration of about 2 months, irrespective of pregnancy).
A non-seasonal anestrus, with a duration that may last
from 2 to 10 months, follows each estrous cycle. During
metestrus, under the influence of progesterone, the
mammary gland becomes a highly proliferative environment. Progesterone-induced production of GH in
the mammary gland is associated with local production
of insulin-like growth factors and their binding proteins. This local system plays an important physiological role in the regulation of mammogenesis and in preparation of the mammary gland for lactation [7]. The progesterone-induced local biosynthesis of GH and the
resulting highly proliferative environment in the mammary gland also play an important role in the development and/or progression of mammary tumors in dogs
[8]. Studies show that in the dog mammary-derived GH
and insulin-like growth factors also reach the systemic
circulation [6, 9]. Mammary GH is systemically released
to the extent that acromegaly and insulin resistance may
develop.
The production of GH by the mammary gland is not
unique to the dog. It has also been demonstrated in cats
as well as humans. The highest levels of expression have
been found in cats with progestin-induced fibroadenomatous hyperplasia of the mammary gland [10]. So far,
there is no evidence that GH produced in the mammary
gland reaches the systemic circulation in cats. While
GH is expressed in the human mammary gland [11], it
is not known if mammary GH reaches the systemic circulation in women, though 40% of women with breast
cancer have been reported to have elevated plasma GH
concentrations [12]. Future research is needed to disclose the importance of progesterone-induced mammary GH production in the pathogenesis of breast cancer
in women.
Endocrine Diseases in Animals
Diabetes Mellitus
With an estimated incidence of 2.45 cases/1,000 catyears-of-risk, diabetes mellitus is a common disease in
cats. Most diabetic cats have a type of diabetes mellitus
that closely resembles human type 2 diabetes mellitus.
Feline and human type 2 diabetes mellitus share several
clinical and pathological characteristics, such as onset in
midlife or later, variable but at least residual insulin secretion at the time of diagnosis, relative resistance to ketoacidosis, significant but incomplete loss of ␤ cells and
deposition of amyloid in the pancreatic islets [13]. The
main pathogenetic mechanisms of type 2 diabetes mellitus in humans are impaired insulin secretion and insulin resistance, both of which may have a genetic etiology.
Genetic predisposition also seems to play a role in feline
diabetes mellitus. Analogous to the situation in humans,
in cats genetically predisposed to diabetes mellitus, acquired factors such as obesity and physical inactivity
may precipitate the disease by inducing insulin resistance [14].
Other diseases may also induce insulin resistance and
consequently lead to other specific types of diabetes mellitus. In felines, the most common cause of this type of
diabetes mellitus is GH excess due to a functional somatotroph pituitary adenoma. Transsphenoidal hypophysectomy not only results in remission of acromegaly
but quite often also leads to resolution of the diabetes
mellitus [15].
Evidence suggests that autoimmune mechanisms affect ␤-cell function in more than 50% of diabetic dogs. In
the rest, diabetes is often precipitated by counter-regulatory hormone excess, such as progesterone-induced GH
excess or hypercortisolism.
Primary Hyperaldosteronism in Cats
Feline primary hyperaldosteronism was first reported
in 1983 and has been diagnosed with increasing frequency ever since. Currently it is considered to be the most
common adrenocortical disorder in cats. As in humans,
the condition may be due to adrenocortical neoplasia or
idiopathic bilateral adrenocortical hyperplasia [16]. Excessive secretion of aldosterone may result in systemic
arterial hypertension and potassium depletion. Signs
may include hypokalemic paroxysmal flaccid paresis;
acute blindness due to retinal detachment and/or intraocular haemorrhage; and other changes attributable to
hypertensive damage in such target organs as the kidney,
Horm Res 2009;71(suppl 1):144–147
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this form of pituitary dwarfism in dogs may serve as a
model for CPHD caused by homozygous Lhx3 defects in
humans [4].
heart or brain. The diagnosis of feline primary hyperaldosteronism is based upon the ratio between the plasma
aldosterone concentration and the plasma renin activity
(i.e., an elevated plasma aldosterone:renin ratio) and results of a suppression test using fludrocortisone acetate
[17].
Hypercortisolism
In both dogs and cats, approximately 80–85% of cases
of chronic endogenous glucocorticoid excess (Cushing’s
syndrome) are due to a functional corticotroph adenoma
originating from either the anterior lobe or the pars intermedia of the pituitary gland (Cushing’s disease). In the
remaining 15–20% of cases, spontaneous hypercortisolism is due to a functional adrenocortical adenoma or
carcinoma. In dogs, Cushing’s syndrome may also occur
due to ectopic adrenocorticotropin secretion or food-dependent hypercortisolism [18, 19].
Cushing’s disease is a very frequent endocrinologic
disorder in dogs, in contrast to the situation in humans
and cats where it is more rare. Nonetheless, the clinical
presentation of Cushing’s disease is highly similar between dogs and humans, with characteristic signs including abdominal obesity, weight gain, fatigue, muscle atrophy and skin changes. Canine Cushing’s disease may
therefore serve as an animal model for the human disease, especially since therapeutic canine hypophysectomy can generate substantial amounts of primary corticotroph pituitary adenoma tissue for in vitro research
purposes.
Hyperthyroidism and Thyroid Tumors
No disease entity comparable to Graves’ disease in humans has been observed in dogs and cats. Nevertheless,
hyperthyroidism is very common in old cats. Feline hyperthyroidism resembles hyperthyroidism caused by
toxic adenomas in humans (Plummer’s disease). Studies
in cats indicate that in some cases the disease is due to
mutations in the genes encoding for the thyrotropin receptor or Gs␣.
More than 85% of canine thyroid tumors are rather
large malignant solid masses. Among domestic animals,
thyroid cancer in the dog – particularly the follicular
type – most closely resembles human follicular carcinoma in terms of clinical behavior, the pattern of circulating
thyroglobulin levels and conservation of thyrotropin
receptors in primary tumors [20].
Immune-Mediated Endocrine Deficiency Syndromes
Primary hypothyroidism is common in dogs but extremely rare in cats. Other acquired endocrine deficiency
syndromes such as hypoadrenocorticism and hypoparathyroidism are not uncommon in dogs but infrequent in
cats. Pathogenetically, these conditions are considered to
be the end stage of progressive autoimmune destruction
and are associated with a high incidence of circulating
antibodies. Cats seem to be much less prone to autoimmune-mediated hormone deficiency than dogs.
Conclusions
Disorders of calcium metabolism are also well known
in companion animal endocrinology. Hypercalcemia
may be due to primary hyperparathyroidism in dogs and
cats, but more often the disorder is due to pseudohyperparathyroidism. Pseudohyperparathyroidism or hypercalcemia of malignancy was first described in canine and
feline malignant lymphoma in the 1970s. In addition, the
condition is associated with other malignant tumors.
Malignancy-associated hypercalcemia in companion animals may arise through (1) local osteolysis, (2) secretion
of parathyroid hormone-related peptide and (3) production of vitamin D.
146
Horm Res 2009;71(suppl 1):144–147
Endocrine disorders in companion animals have many
similarities to those in their human counterparts. Consequently, companion animals with spontaneous endocrinopathies may serve as animal models for the corresponding diseases in humans.
Disclosure Statement
H.S.K. declares no conflict of interest. S.G. declares no conflict
of interest. J.J.C.W.M.B. declares no conflict of interest. B.P.M.
declares no conflict of interest.
Kooistra/Galac/Buijtels/Meij
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Hypercalcemia
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Endocrine Diseases in Animals
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