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Adult Clinical Case Sessions: Human and Animal
Horm Res 2009;71(suppl 1):144147
DOI: 10.1159/000178059
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
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 ani-
mals 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 fre-
quently studied mouse and rat [1, 2] .
Several human endocrine disorders are also known to
occur as similar, spontaneous endocrinopathies in com-
panion animals, and these animals may serve as models
for the diseases in humans. This review summarizes sev-
eral endocrine diseases in companion animals that are
similar to those in humans.
Growth Hormone (GH) Disorders
GH Deficiency
Pituitary dwarfism due to combined pituitary hor-
mone deficiency (CPHD) is well known as an autosomal,
recessively inherited disorder in German shepherd dogs.
CPHD in these dogs is characterized by underdevelop-
ment of the pituitary gland and a combined deficiency of
GH, thyrotropin, prolactin and gonadotropins, though
adrenocorticotropin secretion is preserved [3] . This ca-
nine disorder is due to a mutation in the gene encoding
for the pituitary transcription factor Lhx3 . Therefore,
Key Words
Dog Cat Animal models Veterinary endocrinology
Background: Several endocrine disorders that affect hu-
mans also occur as endocrinopathies in companion animals.
Spontaneous endocrine disorders in animals may provide
valuable information for their counterparts in human endo-
crinology. For example, the discovery of progesterone-in-
duced growth hormone production in the mammary gland
of dogs may have important consequences for understand-
ing 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 hu-
mans and emphasizes their usefulness as spontaneous ani-
mal models for human endocrine disorders.
Copyright 2009 S. Karger AG, Basel
Companion animals, in particular dogs and cats, share
the same living environment as humans and thus are ex-
posed to similar noxae. In addition, dogs and cats are kept
until old age, which allows accurate observation of the
Published online: January 21, 2009
H.S. Kooistra, MD
Utrecht University, Department of Clinical Sciences of Companion Animals
Yalelaan 8
NL3584 CM Utrecht (The Netherlands)
Tel. +31 30 253 9411, Fax +31 30 251 8126, E-Mail
2009 S. Karger AG, Basel
Accessible online at:
Endocrine Diseases in Animals Horm Res 2009;71(suppl 1):144147 145
this form of pituitary dwarfism in dogs may serve as a
model for CPHD caused by homozygous Lhx3 defects in
humans [4] .
GH Excess
The pathogenesis of GH excess is completely different
in dogs and cats. In cats, as in humans, excessive GH se-
cretion is most often due to a somatotroph pituitary ad-
enoma. 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 character-
ized 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 envi-
ronment. Progesterone-induced production of GH in
the mammary gland is associated with local production
of insulin-like growth factors and their binding pro-
teins. This local system plays an important physiologi-
cal role in the regulation of mammogenesis and in prep-
aration of the mammary gland for lactation [7] . The pro-
gesterone-induced local biosynthesis of GH and the
resulting highly proliferative environment in the mam-
mary gland also play an important role in the develop-
ment 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
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 fibroadeno-
matous 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 cir-
culation in women, though 40% of women with breast
cancer have been reported to have elevated plasma GH
concentrations [12] . Future research is needed to dis-
close the importance of progesterone-induced mamma-
ry GH production in the pathogenesis of breast cancer
in women.
Diabetes Mellitus
With an estimated incidence of 2.45 cases/1,000 cat-
years-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 se-
cretion at the time of diagnosis, relative resistance to ke-
toacidosis, significant but incomplete loss of cells and
deposition of amyloid in the pancreatic islets [13] . The
main pathogenetic mechanisms of type 2 diabetes mel-
litus in humans are impaired insulin secretion and insu-
lin 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, ac-
quired factors such as obesity and physical inactivity
may precipitate the disease by inducing insulin resis-
tance [14] .
Other diseases may also induce insulin resistance and
consequently lead to other specific types of diabetes mel-
litus. In felines, the most common cause of this type of
diabetes mellitus is GH excess due to a functional so-
matotroph pituitary adenoma. Transsphenoidal hypo-
physectomy not only results in remission of acromegaly
but quite often also leads to resolution of the diabetes
mellitus [15] .
Evidence suggests that autoimmune mechanisms af-
fect -cell function in more than 50% of diabetic dogs. In
the rest, diabetes is often precipitated by counter-regula-
tory 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 frequen-
cy 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] . Ex-
cessive 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 intra-
ocular haemorrhage; and other changes attributable to
hypertensive damage in such target organs as the kidney,

Horm Res 2009;71(suppl 1):144147 146
heart or brain. The diagnosis of feline primary hyperal-
dosteronism is based upon the ratio between the plasma
aldosterone concentration and the plasma renin activity
(i.e., an elevated plasma aldosterone:renin ratio) and re-
sults of a suppression test using fludrocortisone acetate
[17] .
In both dogs and cats, approximately 8085% of cases
of chronic endogenous glucocorticoid excess (Cushings
syndrome) are due to a functional corticotroph adenoma
originating from either the anterior lobe or the pars in-
termedia of the pituitary gland (Cushings disease). In the
remaining 1520% of cases, spontaneous hypercorti-
solism is due to a functional adrenocortical adenoma or
carcinoma. In dogs, Cushings syndrome may also occur
due to ectopic adrenocorticotropin secretion or food-de-
pendent hypercortisolism [18, 19] .
Cushings 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 Cushings disease is highly similar be-
tween dogs and humans, with characteristic signs includ-
ing abdominal obesity, weight gain, fatigue, muscle atro-
phy and skin changes. Canine Cushings disease may
therefore serve as an animal model for the human dis-
ease, especially since therapeutic canine hypophysec-
tomy can generate substantial amounts of primary corti-
cotroph pituitary adenoma tissue for in vitro research
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 pseudohyper-
parathyroidism. Pseudohyperparathyroidism or hyper-
calcemia 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 an-
imals may arise through (1) local osteolysis, (2) secretion
of parathyroid hormone-related peptide and (3) produc-
tion of vitamin D.
Hyperthyroidism and Thyroid Tumors
No disease entity comparable to Graves disease in hu-
mans has been observed in dogs and cats. Nevertheless,
hyperthyroidism is very common in old cats. Feline hy-
perthyroidism resembles hyperthyroidism caused by
toxic adenomas in humans (Plummers disease). Studies
in cats indicate that in some cases the disease is due to
mutations in the genes encoding for the thyrotropin re-
ceptor 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 carcino-
ma 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 ex-
tremely rare in cats. Other acquired endocrine deficiency
syndromes such as hypoadrenocorticism and hypopara-
thyroidism 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 auto-
immune-mediated hormone deficiency than dogs.
Endocrine disorders in companion animals have many
similarities to those in their human counterparts. Con-
sequently, companion animals with spontaneous endo-
crinopathies may serve as animal models for the corre-
sponding 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.

Endocrine Diseases in Animals Horm Res 2009;71(suppl 1):144147 147
1 Tan CP, Sano H, Iwaasa H, Pan J, Sailer AW,
Hreniuk DL, Feighner SD, Palyha OC, Pong
SS, Figueroa DJ, Austin CP, Jiang MM, Yu H,
Ito J, Ito M, Guan XM, MacNeil DJ, Kanatani
A, Van der Ploeg LH, Howard AD: Melanin-
concentrating hormone receptor subtypes 1
and 2: species-specific gene expression. Ge-
nomics 2002; 79: 785792.
2 Dackowski WR, Luderer HF, Manavalan P,
Bukanov NO, Russo RJ, Roberts BL, Klinger
KW, Ibraghimov-Beskrovnaya O: Canine
PKD1 is a single-copy gene: genomic organi-
zation and comparative analysis. Genomics
2002; 80: 105112.
3 Kooistra HS, Voorhout G, Mol JA, Rijnberk
A: Combined pituitary hormone deficiency
in German shepherd dogs with dwarfism.
Domest Anim Endocrinol 2000; 19: 177190.
4 Pfaeffle RW, Savage JJ, Hunter CS, Palme C,
Ahlmann M, Kumar P, Bellone J, Schoenau
E, Korsch E, Brmswig JH, Stobbe HM, Blum
WF, Rhodes SJ: Four novel mutations of the
LHX3 gene cause combined pituitary hor-
mone deficiencies with or without limited
neck rotation. J Clin Endocrinol Metab 2007;
92: 19091919.
5 Fracassi F, Gandini G, Diana A, Preziosi R,
Van den Ingh TSGAM, Famigli Bergamini P,
Kooistra HS: Acromegaly due to a somato-
troph adenoma in a dog. Domest Anim En-
docrinol 2007; 32: 4354.
6 Selman PJ, Mol JA, Rutteman GR, van Gar-
deren E, Rijnberk A: Progestin-induced
growth hormone excess in the dog originates
in the mammary gland. Endocrinology 1994;
134: 287292.
7 Mol JA, Selman PJ, Sprang EP, van Neck JW,
Oosterlaken-Dijksterhuis MA: The role of
progestins, insulin-like growth factor (IGF)
and IGF-binding proteins in the normal and
neoplastic mammary gland of the bitch: a re-
view. J Reprod Fertil 1997; 51(suppl):339
8 Mol JA, Lantinga-van Leeuwen IS, van Gar-
deren E, Selman PJ, Oosterlaken-Dijkster-
huis MA, Schalken JA, Rijnberk A: Mam-
mary growth hormone and tumorigenesis
lessons from the dog. Vet Q 1999; 21:
9 Kooistra HS, Den Hertog E, Okkens AC, Mol
JA, Rijnberk A: Pulsatile secretion pattern of
growth hormone during the luteal phase and
mid-anoestrus in beagle bitches. J Reprod
Fertil 2000; 119: 217222.
10 Mol JA, van Garderen E, Selman PJ, Wolfs-
winkel J, Rijnberk A, Rutteman GR: Growth
hormone mRNA in mammary gland tumors
of dogs and cats. J Clin Invest 1995; 95: 2028
11 Mol JA, Henzen-Logmans SC, Hageman P,
Misdorp W, Blankenstein MA, Rijnberk A:
Expression of the gene encoding growth hor-
mone in the human mammary gland. J Clin
Endocrinol Metab 1995; 80: 30943096.
12 Emerman JT, Leahy M, Gout PW, Bruchov-
sky N: Elevated growth hormone levels in
sera from breast cancer patients. Horm
Metab Res 1985; 17: 421424.
13 OBrien TD: Pathogenesis of feline diabetes
mellitus. Mol Cell Endocrinol 2002; 197: 213
14 Slingerland LI, Vasilova VV, Plantinga EA,
Kooistra HS, Beynen AC: Indoor confine-
ment and physical inactivity rather than the
proportion of dry food are risk factors in the
development of feline type 2 diabetes melli-
tus. Vet J 2008; in press.
15 Meij BP, van der Vlugt-Meijer RH , van den
Ingh TS, Rijnberk A: Somatotroph and cor-
ticotroph pituitary adenoma (double adeno-
ma) in a cat with diabetes mellitus and hy-
peradrenocorticism. J Comp Pathol 2004;
130: 209215.
16 Javadi S, Djajadiningrat-Laanen S, Kooistra
HS, Van Dongen AM, Voorhout G, Van Sluijs
FJ, Van den Ingh TSGAM, Boer WH, Rijn-
berk A: Primary hyperaldosteronism, a me-
diator of progressive renal disease in cats.
Domest Anim Endocrinol 2005; 28: 85104.
17 Djajadiningrat-Laanen SC, Galac S, Cam-
melbeeck SE, Van Laar K, Boer P, Kooistra
HS: Urinary aldosterone to creatinine ratio
before and after suppression with oral salt or
fludrocortisone acetate in cats. J Vet Int Med
2008; accepted.
18 Galac S, Kooistra HS, Voorhout G, Van den
Ingh TSGAM, Mol JA, Van Den Berg G, Meij
BP: Hyperadrenocorticism in a dog due to
ectopic secretion of adrenocorticotropic
hormone. Domest Anim Endocrinol 2005;
28: 338348.
19 Galac S, Kars VJ, Voorhout G, Mol JA, Koo-
istra HS: ACTH-independent hyperadreno-
corticism due to food-dependent hypercor-
tisolaemia in a dog: a case report. Vet J 2008;
177: 141143.
20 Verschueren CP, Rutteman GR, Vos JH, Van
Dijk JE, de Bruin TW: Thyrotrophin recep-
tors in normal and neoplastic (primary and
metastatic) canine thyroid tissue. J Endocri-
nol 1992; 132: 461468.