Growth Hormone & IGF Research 13 (2003) S158–S164

www.elsevier.com/locate/ghir

Endocrine diseases in dogs and cats: similarities and differences

with endocrine diseases in humans
Ad Rijnberk *, Hans S. Kooistra, Jan A. Mol
Department of Clinical Sciences of Companion Animals, Utrecht University, P.O. Box 80.154, 3508 TD Utrecht, The Netherlands

Abstract

Over several millennia, humans have created hundreds of dog and cat breeds by selective breeding, including fixation of mutant
genes. The domestic dog is unique in the extent of its variation in height, weight and shape as well as its behavior. It is primarily the
relatively long persistence of high levels of growth hormone (GH) release at a young age that accounts for the large body size in
giant breeds of dogs. Several of the endocrine diseases of humans are also known to occur as similar entities in dogs and cats. With
some variations, this is true for conditions such as diabetes mellitus and the hypofunction syndromes of the thyroid and adrenal
cortex. Also, the hyperfunction syndromes of hypercortisolism and hyperparathyroidism in dogs and cats have many similarities
with their human counterparts. The exception seems to be GravesÕ disease. This condition, which is due to production of thyroid-
stimulating hormone (TSH)-receptor antibodies, has not been observed in dogs and cats. The very common form of hyperthy-
roidism in cats is due to toxic adenomas. In the 1980s it was discovered that in dogs exogenous progestins and endogenous
progesterone can induce GH excess. This GH excess originates form the mammary gland and may give rise to acromegaly and
insulin resistance. GH production by the mammary gland is not unique to the dog. It has become clear that cats and humans also
express the GH gene in the mammary gland. There is increasing evidence that this locally produced GH not only plays a role in the
morphologic changes of the mammary gland associated with the ovarian cycle and gestation, but that it is also involved in the
development of breast cancer. In dogs, induction of mammary GH production by progestin administration allows for treatment of
GH deficiency.
Ó 2003 Elsevier Science Ltd. All rights reserved.

Keywords: Dog; Cat; Endocrine disease; Acromegaly; Dwarfism; Mammary growth hormone; Progestagens

1. Introduction parts than with those of the frequently studied mouse

Companion animals, and particularly dogs and cats,
maintain a close relationship with humans. By sharing
the same living environment, humans and pets are ex-
posed to similar noxae. Furthermore, dogs and cats are
kept until old age, which permits accurate observation
of the development of diseases and the process of aging.
This makes these animals of great interest in compara-
tive medicine. Recently, the importance of companion
animals in comparative medicine has been underscored
by the observation that, in general, canine genes have a
higher degree of homology with their human counter-
*
Corresponding author. Tel.: +31-30-693-2156; fax: +31-30-251-
8126.
E-mail address: A.Rijnberk@vet.uu.nl (A. Rijnberk).
and rat [1,2].
This review begins with an introduction to some en-
docrine phenomena that contribute to the variations in
size and shape of dogs and cats of different breeds. Then,
there is a brief section on examples of endocrine diseases
in dogs and cats similar to those in humans. The review
will concentrate on conditions due to excessive and de-
ficient secretion of growth hormone (GH).
2. Size and shape
Selection and mixing within the wolf gene pool over
many millennia have yielded several hundred dog
breeds. The domestic dog is unique among mammalian
species in the extent of its variation in height, weight and
shape as well as in its behavior. Human interference in

1096-6374/$ - see front matter Ó 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S1096-6374(03)00076-5
 A. Rijnberk et al. / Growth Hormone & IGF Research 13 (2003) S158–S164
the genetic make-up by selective breeding with fixation
of mutant genes has led to extreme variations in size as
exemplified by the Chihuahua and the St. Bernard.
Adult dogs at the opposite ends of the scale may differ
nearly 100-fold in weight. Within each breed, key traits
are inherited within extremely narrow limits.
In cats the situation is different. Cats spread from
Egypt to the Middle East and then to Europe around
1000 AD, where initially they made a transition from a
sacred animal to an animal blamed for almost every-
thing, including shipwrecks and the spread of disease.
Later the cat recovered its popularity because of its
ability to control the rodent population. However, it is
only in the 20th century that cats have been widely ac-
cepted as household pets. Consequently, selective
breeding of cats is a relatively recent phenomenon.
Breeders have mainly concentrated on producing par-
ticular coats and specific facial features that are attractive
to humans (i.e., pedomorphic shape) [3,4]. Representa-
tives of different cat breeds do not differ greatly in size.
In the 1930s, the medical anatomist Charles R.
Stockard was the first to study a possible endocrine basis
for differences in the size and shape of dogs of different
breeds. This hypothesis was based upon the similarities
between some endocrine diseases known in humans and
some characteristics of dog breeds. For example, pos-
ture, voice, large size and skin overgrowth in breeds such
as the St. Bernard dog and the bloodhound made the
investigators think of acromegaly. In their attempt to
substantiate the hypothesis morphologically, they found
no correlation between pituitary size and the type of
dog, but histological examination of the anterior pitui-
tary lobe of large dogs revealed an abundance of aci-
dophilic cells [5].
The first biochemical data to support an endocrine
basis for differences in body size among dog breeds were
provided in the 1980s [6]. In a study of adult dogs of
different breeds, circulating concentrations of insulin-
like growth factor I (IGF-I) correlated with body size.
Also, among genetic subgroups within one breed (i.e.,
standard, miniature and toy poodles), IGF-I levels
paralleled body size; whereas, basal and clonidine-
stimulated plasma concentrations of GH levels were
similar among dogs of different sizes [7].
From these studies, the impression was that the main
determinant for differences in body size was IGF-I. This
changed in the 1990s when young dogs were studied
longitudinally. Basal plasma GH concentrations in
Great Dane pups initially were found to be high and
then appeared to decline to the low levels of adulthood
at about 6 months of age. In miniature poodle pups,
basal GH levels were low and did not change with time
[8,9]. In accordance with the results of the just men-
tioned studies, plasma IGF-I concentrations in the
Great Dane pups were higher than those in the minia-
ture poodles.
S159
Fig. 1. Basal plasma GH concentrations (means
SEM, n ¼ 6) of
beagles (m) and Great Danes (d) from 6 to 24 weeks of age (modified
and reprinted, with permission, from Favier et al. [10]).
When the plasma GH concentrations of Great Danes
pups were compared with those of pups of a medium-
sized breed (beagles), it appeared that basal concentra-
tions in the beagles were high until the age of 7 weeks;
whereas, in the Great Danes the basal plasma GH levels
remained at high levels until after 24 weeks of age
(Fig. 1). Thus, it seems that it is primarily the persistence
of high GH release for relatively longer periods at a
young age that determines large body size (J. Endocrinol.
170 (2001) 479–484).
3. Endocrine diseases
Most endocrine diseases that are common in humans
are also known to occur in both dogs and cats, albeit
with some differences in incidence, pathogenesis and
clinical features. Some characteristics of these classic
endocrine diseases in dogs and cats are summarized here.
Diabetes mellitus is a common endocrine disorder in
dogs and cats, with an incidence of approximately 0.5%.
In both these species, the occurrence of diabetes mellitus
is extremely rare in young animals. The pathogenesis of
diabetes mellitus in middle-aged and older animals dif-
fers considerably between the two species. In dogs, there
is evidence suggesting that autoimmune mechanisms
may affect b-cell function. The disease is often precipi-
tated by counter-regulatory hormone excess, such as
hypercortisolism and excess GH secretion. In cats, dia-
betes mellitus bears close resemblance to human type 2
diabetes mellitus, including the occurrence of islet am-
yloidosis [11,12].
Primary hypothyroidism is common in dogs and ex-
tremely rare in cats. Other acquired endocrine deficiency
syndromes such as hypoadrenocorticism and hypo-
parathyroidism are not uncommon in dogs but are
S160 A. Rijnberk et al. / Growth Hormone & IGF Research 13 (2003) S158–S164
infrequent in cats. Pathogenetically, these conditions are
considered to be the end stage of progressive autoim-
mune destruction, associated with a high incidence of
circulating autoantibodies [13,14]. Cats seem to be much
less prone to autoimmune-mediated hormone deficiency
than are dogs.
The hyperfunction syndromes hypercortisolism and
hyperparathyroidism in companion animals have many
similarities with those in their human counterparts.
Notably, the incidence of both pituitary-dependent hy-
peradrenocorticism and hyperadrenocorticism due to
adrenocortical tumor is much higher in dogs than in
humans. In cats, these conditions are as rare as they are
in humans. In canine pituitary-dependent hyperadren-
ocorticism, the size of the corticotrophic adenoma cor-
relates with the degree of resistance to dexamethasone
and the plasma levels of adrenocorticotrophic hormone
(ACTH) precursors [15,16]. In both dogs and cats, pi-
tuitary-dependent hyperadrenocorticism can be treated
by hypophysectomy [17,18]. In addition, there are
medicinal options such as partial or complete destruc-
tion of the adrenal cortices with o,p0 -DDD (2,40 -
dichlorodiphenyldichloroethane or mitotane), to which
dogs are very sensitive, [19,20] as well as by blocking
adrenocortical steroid synthesis [21].
No disease entity comparable to GravesÕ disease in
human (i.e., a condition due to TSH-receptor antibod-
ies) has been observed in dogs or cats [22]. Nevertheless,
hyperthyroidism is very common in old cats. The feline
disease resembles hyperthyroidism caused by toxic ad-
enomas in humans; though, so far no mutations have
been found in the extracellular or transmembrane part
of the gene encoding the thyrotropin receptor [23]. Re-
sults of recent studies in cats indicate that in some cases
the disease is due to mutations in the Gsa gene [24].
In dogs, thyroid neoplasia accounts for about 2% of
all canine tumors. Over 85% of the canine thyroid
Fig. 2. Female crossbred rough-coated Belgian shepherd dog at the age of 3 years photographed in the ownerÕs garden (a) and at the age of 6 years in
the clinic after several years of oestrus prevention with 2–3 yearly injections with medroxyprogesterone-acetate (MPA): coarsening of the physical
features and a thick haircoat (b) (reprinted, with permission, from A. Rijnberk, Clinical Endocrinology of Dogs and Cats, Kluwer Academic
Publishers, Dordrecht/Boston, 1996).
tumors detected clinically are rather large (diameter > 3
cm) malignant solid masses. Among domestic animals,
thyroid cancer in the dog, and particularly the follicular
type, most closely resembles human (follicular) carci-
noma in terms of the clinical behavior and also in the
pattern of circulating thyroglobulin levels and in the
conservation of thyrotropin receptors in primary tumors
[25,26]. In 10–15% of cases (small) thyroid tumors give
rise to the syndrome of hyperthyroidism [27].
3.1. GH excess
The pathogenesis of GH excess is completely different
in cats and dogs. In cats, like in humans, excessive GH
secretion is caused by an adenoma in the pituitary gland.
This may lead to acromegalic changes such as coarsen-
ing of the facial features, but in most cases the devel-
opment of insulin resistance as a result of the GH excess
poses most problems. Pituitary adenomas in cats are
usually diagnosed only after the cat is presented with
insulin-resistant diabetes mellitus [28]. In contrast, only
one case of a somatotrophic adenoma has been reported
in dogs [29].
In the 1970s and 1980s, studies showed that admin-
istration of progestins to dogs could lead to physical
changes reminiscent of acromegaly (Figs. 2 and 3). The
associated increases in plasma GH concentrations de-
clined upon withdrawal of the progestins [30,31]. Similar
changes may be seen in middle-aged and elderly dogs
during the natural increase in progesterone production
that occurs in the luteal phase of the estrous cycle
(metestrus). These changes are reversed with a decline in
the progesterone concentration. Such a decrease is most
pronounced after ovariectomy [32].
In the search for the mechanism underlying this
progestin-induced excess of GH secretion, we found
that supra-pituitary stimulation had only minimal or no
 A. Rijnberk et al. / Growth Hormone & IGF Research 13 (2003) S158–S164
Fig. 3. Same dog as in Fig. 2 after a clip: heavy trunk, heavy limbs and thick skin folds in the neck area (a). Mouth of the dog with maxillar and
mandibular prognathia and widened interdental spaces (b) (reprinted, with permission, from A. Rijnberk, Clinical Endocrinology of Dogs and Cats,
Kluwer Academic Publishers, Dordrecht/Boston, 1996).
effect on plasma GH concentrations. Furthermore,
administration of an analogue of somatostatin had no
effect on the progestin-induced increases in GH
concentration in plasma. Thus, we concluded that
progestin-induced excess GH secretion in dogs has
characteristics mimicking autonomous secretion [33].
This autonomy could not be attributed to neoplastic
transformation at the pituitary level because no pitui-
tary tumors have been found in affected dogs. More-
over, the reversibility of the GH excess upon cessation
of progestin exposure was not consistent with the pos-
sibility of autonomous production of GH by a tumor,
either eutopic or ectopic. The pituitary was excluded as
a source of the GH excess when hypophysectomy was
found not to influence the high (progestin-induced)
plasma concentrations of GH [34]. Consequently, we
tested the hypothesis that the progestin-induced GH
excess could originate from a non-neoplastic extrapi-
tuitary site.
3.2. Mammary GH
Analysis of the GH content of various tissue homo-
genates has revealed that the highest GH immunoreac-
tivity is in extracts of the mammary gland. The
concentration of GH in blood collected from the mam-
mary vein of dogs that had undergone ovariohysterec-
tomy and were treated with progestin was three times
higher than that of blood from the mammary artery. In
addition, complete mammectomy caused an immediate
decline in plasma GH concentrations below the upper
limit of the reference range. Immunohistochemical ex-
amination showed that the progestin-induced GH excess
originated from foci of the hyperplastic ductular epi-
thelium of the mammary gland [34]. The gene encoding
GH in the mammary gland is identical to the pituitary
GH gene [35]. The progestin-induced expression of GH
in mammary tissue is most probably a direct effect of
S161
activated progesterone receptors on the GH gene pro-
moter [36].
Local production of GH in the mammary gland is as-
sociated with local production of IGFs and their binding
proteins (IGFBPs). Thus, during metestrus, under the
influence of progesterone, the mammary gland becomes a
proliferative environment. This local system plays an
important physiological role in the regulation of mam-
mogenesis and in preparation of the mammary gland for
lactation [37]. Studies have shown that mammary GH and
growth factors also reach the systemic circulation in
healthy bitches in metestrus [33,38]. Mammary GH is
systemically released to the extent that acromegaly and
insulin resistance may develop in a small number of el-
derly bitches. High GH concentrations are present in
mammary excretions, particularly prior to parturition
and in colostrum, which may exceed maternal plasma GH
concentrations by up to 100–1000 times. Colostral GH is
probably not absorbed from the gastrointestinal tract in
the blood of the newborn, and it may play a role in gas-
trointestinal development of the neonate [39].
The production of GH by the mammary gland is not
unique to the dog. It has also been demonstrated in cats.
The highest levels of expression have been found in cats
with progestin-induced fibroadenomatous hyperplasia
of the mammary gland [35]. So far, there is no evidence
that GH produced in the mammary gland reaches the
systemic circulation in cats [40]. Furthermore, GH is
also expressed in the human mammary gland. The gene
encoding GH in the human mammary gland is identical
to the gene encoding GH in the pituitary gland [41]. It is
not known whether in vivo mammary GH production in
women is dependent on progesterone, and there are no
recent reports on the possible systemic consequences of
the expression of mammary GH. However, there was
one reported observation in the 1980s that 40% of
patients with breast cancer had elevated plasma GH
concentrations [42].
S162 A. Rijnberk et al. / Growth Hormone & IGF Research 13 (2003) S158–S164
3.3. Mammary GH and breast cancer
Since the 1970s, progestins have been known to
promote the development of mammary tumors in dogs.
It is beyond the scope of this review to discuss in detail
the mediating role of progestin-induced mammary GH
in tumorigenesis. For our purposes, it is sufficient to
note that in dogs GH is not only expressed in healthy
mammary tissue but also in the cells of mammary neo-
plasias [35,43], and this GH expression is mostly local-
ized along with nuclear progesterone receptors [44]. This
finding, together with the fact that growth hormone
receptor (GHR) is expressed in several benign and ma-
lignant mammary tumor cell types, [45] indicates that
the conditions are present for the progestin-induced
autocrine/paracrine action of GH in most canine
mammary tumors.
There is increasing evidence that the local mammary
progesterone/GH/GHR-axis is operational not only in
dogs but also in human breast cancer. GH expression has
been demonstrated in neoplastic human mammary tissue
[41]. In vitro studies in human breast cancer cell lines and
explants have revealed that progesterone promotes GH
expression [46,47]. GHR expression in human breast
cancer correlates positively with progesterone-receptor
expression [48]. These findings, in combination with the
fact that human GH promotes GHR-mediated mam-
mary carcinoma cell proliferation in an autocrine/para-
crine manner [49,50], also indicate that the progesterone/
GH/GHR-axis is involved in the development of breast
cancer in humans. This insight helps explain epidemio-
logic observations indicating that progestin administra-
tion is a risk factor in development of breast cancer
[51,52].
4. GH deficiency
GH deficiency is primarily known to occur in Ger-
man shepherd dogs as an autosomal recessive inherited
condition characterized by profound dwarfism with re-
tention of puppy hairs and lack of primary guard hairs.
Basal plasma concentrations of GH and IGF-I, pro-
lactin, thyrotropin and luteinizing hormone (LH) are
low. Results of a combined anterior pituitary function
test employing four releasing hormones consistently
showed no response by GH, TSH and prolactin, while
there was a minor response by LH and follicle-stimu-
lating hormone (FSH). The response of ACTH was not
impaired [53,54].
In humans and mice, combined GH, TSH and pro-
lactin deficiency has been related to mutations in the
gene encoding for transcription factor Pit-1 [55]. This
contrasts with the endocrine phenotype of the German
shepherd dogs, which also included gonadotropin in-
sufficiency. Indeed, sequence analysis of genomic DNA
from German shepherd dwarfs did not reveal a disease-
causing mutation in the Pit-1 gene [56]. The phenotype
of the German shepherd dwarfs closely resembled that
of humans and mice with mutations in the Prophet of
Pit 1 (Prop1) gene [56]. However, in the dwarf dogs, no
Prop1 abnormalities have been found [57]. Recently, the
lim homeodomain gene LHX4 was also excluded as a
candidate gene for pituitary dwarfism in German shep-
herd dogs [58].
As canine GH is not available for therapeutic treat-
ment of dwarfism in dogs, induction of mammary GH
has been used. Injections of medroxyprogesterone ace-
tate at 3–6-week intervals caused plasma concentrations
of GH and IGF-I to increase to within the reference
ranges, which was associated with growth in height and
development of a complete coat of adult hair [59].
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