V 20TH ANNIVERSARY
12 December 1999
CE Refereed Peer Review
FOCAL POINT
★ Understanding the
hypothalamic–pituitary–adrenal
axis and the pathophysiology
of hyperadrenocorticism (HAC)
is crucial to understanding
the hormonal tests used for
diagnosis and differentiation
of this disorder.
KEY FACTS
■ Hypothalamic nuclei synthesize
corticotropin-releasing hormone,
whereas corticotropin is secreted
by the pituitary gland.
■ Tumors of either the anterior or
intermediate pituitary lobes are a
much more common cause of
HAC than are adrenal tumors.
■ Pituitary-dependent HAC may
result from a pituitary tumor or a
primary central nervous system
defect, such as depletion of the
neurotransmitter dopamine.
■ There are three likely causes of
pituitary-dependent HAC in dogs.
Vol. 21, No.
The Hypothalamic–
Pituitary–Adrenal Axis
and Pathophysiology of
Hyperadrenocorticism
University of Pennsylvania
Carole A. Zerbe, DVM, PhD
ABSTRACT: The hypothalamic–pituitary–adrenal axis consists of the hypothalamus and corti-
cotropin-releasing hormone, the pituitary and corticotropin, and the adrenal cortex and gluco-
corticoid production. The clinical syndrome of hyperadrenocorticism results from glucocorti-
coid excess. This steroid excess, in turn, may result from an adrenal tumor or more
commonly from a pituitary tumor causing excessive corticotropin and consequently glucocor-
ticoid excess. In dogs, such a pituitary tumor may arise from either the anterior or intermedi-
ate lobes, suggesting that there are multiple causes for hyperadrenocorticism in this species.
H
yperadrenocorticism (HAC; most often referring to Cushing’s syn-
drome) is a very common, spontaneous endocrinopathy in middle-aged
to geriatric dogs. It occurs less commonly in cats, ferrets, horses, and
humans, and there has been one report of HAC in a dolphin.1–7 It is most often
a clinical syndrome of glucocorticoid excess, which may result from an adrenal
or pituitary tumor that is causing excessive corticotropin (ACTH) secretion and
consequently hypersecretion of glucocorticoid.
This article, the first in a series focusing on HAC and hormonal tests to evalu-
ate the disorder in cats and dogs, addresses the anatomy and physiology of the
hypothalamic–pituitary–adrenal (HPA) axis and the pathophysiology of HAC.
Future articles will discuss tests used to confirm HAC (i.e., screening tests) and
those used to distinguish pituitary-dependent HAC (PDH) from adrenal tumor
(AT; i.e., differentiating tests). The clinical syndrome of HAC itself and nonhor-
monal evaluations (e.g., complete blood count, biochemistry, radiography) of
HAC are not discussed; readers are referred elsewhere for information on these
important topics.1,2,7
HYPOTHALAMIC–PITUITARY–ADRENAL AXIS
Understanding the HPA axis is crucial to understanding the testing and evalu-
Compendium December 1999 20TH ANNIVERSARY Small Animal/Exotics

ation of HAC. Anatomical- been proven to be a more

ly, the HPA axis consists of NEUROAMINES potent or equipotent secre-
the hypothalamus, pituitary, togogue for ACTH release
and adrenal cortex; physio- Hypothalamus in some species (sheep and
logically, it consists of hor- cattle), but it does not di-
CRH
mones of stimulation and rectly stimulate ACTH re-
negative feedback. The hor- lease from canine anterior pi-
Anterior
mones that stimulate syn- Negative tuitary cells in culture,8–11 as
thesis and secretion of other pituitary it does in feline PD cells in
feedback
hormones include cortico- ACTH culture.11a
tropin-releasing hormone The hypothalamus also
(CRH) and ACTH; the glu- Adrenal has axons that terminate in
cocorticoid cortisol in turn the intermediate pituitary
negatively regulates these lobe (pars intermedia [PI]),
hormones. This cycle of stim- CORTISOL directly on the cells them-
ulation and negative feedback Figure 1—The hypothalamic–pituitary–adrenal axis. Note
selves. Most of these nerves
represents the classically de- that anterior pituitary corticotropin (ACTH) secretion is originate in the hypotha-
fined anterior pituitary lobe stimulated by hypothalamic corticotropin-releasing hormone lamic arcuate nucleus and
HPA axis (Figure 1). In dogs, (CRH) and negatively regulated by glucocorticoids. release dopamine (a neuro-
however, the intermediate pi- transmitter that inhibits the
tuitary lobe HPA axis, in synthesis and release of in-
which the intermediate (ra- termediate lobe pituitary
ther than the anterior) pitu-
NEUROAMINES hormones). There are also
itary lobe is the source of pi- CRH-containing fibers in
Hypothalamus
tuitary ACTH, should also ? the intermediate lobe, and
be considered (Figure 2). Al- (NEUROAMINES) CRH may have a role in ca-
though this source of ACTH nine PI lobe ACTH secre-
does not appear to be im- Intermediate tion.12
portant under normal physi- No
negative pituitary
ologic conditions, its role in The Pituitary and
certain pathologic condi- feedback ACTH Corticotropin
tions is significant. The pituitary receives in-
Adrenal put from the hypothalamus
The Hypothalamus and via releasing or inhibiting
Corticotropin-Releasing hormones and the hypothal-
Hormone CORTISOL amohypophyseal portal sys-
The hypothalamus is part Figure 2—Proposed pars intermedia (PI) hypothalamic–pitu- tem. In dogs, ACTH is con-
of the brain and consists of itary–adrenal axis. Note that the PI lobe is under tonic nega- tained in both the anterior
collections of nerve cell bod- tive regulation by neuroamines (dopamine). Corticotropin- pituitary corticotroph and a
ies called nuclei. The par- releasing hormone may stimulate PI corticotropin (ACTH) subset of the intermediate
aventricular nuclei synthe- secretion, but glucocorticoids are not likely involved with pituitary lobe cells known as
size CRH, which is then negative feedback of PI ACTH secretion or of dopamine. B cells. 13 The canine pitu-
transported down the nerve itary has a well-developed
axons to the median eminence, where the nerve cells intermediate lobe that is unique: It has two types of
terminate in the portal capillary bed. Once released, cells, A and B, both of which process the ACTH pre-
CRH travels via the hypothalamohypophyseal portal cursor protein proopiomelanocortin (POMC). POMC
blood to the anterior pituitary (pars distalis [PD]), is processed into α-melanocyte–stimulating hormone
where it stimulates release of ACTH from the corti- (α-MSH) by A cells and ACTH by B cells. This mech-
cotroph. anism is especially notable in dogs because pituitary tu-
Another hypothalamic peptide, arginine vasopressin mors leading to Cushing’s syndrome can arise in both
(also known as antidiuretic hormone), may also be re- the anterior and intermediate lobes.14 Additionally, PI
leased into the median eminence and influence ACTH tumors are thought to arise from both A and B cells
release. Compared with CRH, arginine vasopressin has and may be differently regulated.

HPA AXIS ■ PARAVENTRICULAR NUCLEI ■ ARGININE VASOPRESSIN ■ A AND B CELLS

Small Animal/Exotics 20TH ANNIVERSARY Compendium December 1999

TABLE I
Comparison of the Causes of Cushing’s Syndrome among Dogs, Cats, Horses, and Humans
Species Usual Pituitary Lesion Less Common Pituitary Lesion(s) Other Causes

Dogs PD adenoma PI adenoma, corticotroph hyperplasia AT

Cats PD adenoma Corticotroph hyperplasia AT

Horses PI adenoma PI hyperplasia —

Humans PD adenoma Corticotroph hyperplasia Ectopic ACTH production,

AT, AIMBAD
ACTH = corticotropin; AIMBAD = corticotropin-independent massive bilateral adrenal disease; AT = adrenal tumor; PD = pars distal-
is (anterior pituitary lobe); PI = pars intermedia (intermediate pituitary lobe).

The canine PI contains twice as much biologically
active ACTH as does the anterior lobe. 13 It is not
known whether this ACTH plays a physiologic role in
normal dogs, but it is probably important in some pitu-
itary tumors. Regulation of ACTH secretion from the
PI lobe is not well understood, but both A and B cells
of the PI are under tonic negative regulation by the
neuroamine dopamine (Figure 2).15,16 A and B cells do
not seem to be negatively regulated by glucocorticoids,
but B-cell stimulation by CRH may occur.16
The Adrenal Cortex and Glucocorticoids
Corticotropin stimulates the synthesis and secretion
of cortisol from the zona fasciculata and the zona retic-
ularis of the adrenal cortex; it also maintains the in-
tegrity of the adrenal cortex. Excess ACTH causes
adrenocortical hyperplasia and hypertrophy. These
pathologies can sometimes be nodular and asymmetric.
Glucocorticoids play an important role in ACTH
regulation through their negative feedback effects on
both CRH and ACTH. This feedback pathway oper-
ates normally in dogs with ATs, suppressing ACTH
and CRH secretion and thus causing the uninvolved
adrenocortical tissue to atrophy. In contrast, dogs and
cats with ACTH-secreting pituitary tumors experience
bilateral adrenal hyperplasia and hypertrophy.
The adrenal cortex may also secrete other steroid hor-
mones (e.g., progestogens, mineralocorticoids) as well
as estrogens and androgens. These hormones can be se-
creted normally or as a result of AT formation (see the
Adrenal Tumor section).
PATHOPHYSIOLOGY OF
HYPERADRENOCORTICISM
Hyperadrenocorticism may result from steroid excess
of exogenous (iatrogenic Cushing’s syndrome) or en-
dogenous (spontaneous HAC) origin. Spontaneous
HAC, which most commonly results from overproduc-
tion of ACTH and its related peptides, is referred to as
pituitary-dependent hyperadrenocorticism; however, it
may also result from overproduction of cortisol by an
AT, a condition referred to as adrenal-dependent disease.
The term hyperadrenocorticism is also used to refer to
other syndromes of adrenocortical hyperfunctioning. In
ferrets, for example, HAC results from unilateral or bi-
lateral ATs that secrete androgens and/or estrogens.3
(This syndrome, which has not been given a name other
than HAC, is appropriately not referred to as Cushing’s
syndrome because serum glucocorticoids are not in-
creased.) Another syndrome, Conn’s, occurs when min-
eralocorticoids are secreted in excess.17 Excessive secre-
tion of progesterone by an AT was recently reported in a
cat with clinical signs of Cushing’s syndrome.18 Thus
HAC does not always refer to Cushing’s syndrome.
Pituitary-Dependent Disease
In all species (except ferrets) known to develop spon-
taneous HAC, the pituitary-dependent form is most
common, usually accounting for more than 85% of
cases.1–3,5,6 There are, however, differences in the pitu-
itary lobe of origin of hypersecretion of ACTH and its
related peptides (Table I).19 In humans, Cushing’s syn-
drome is usually associated with a microadenoma or oc-
casionally hyperplasia of the PD corticotrophs, whereas
tumors in horses arise exclusively from the PI lobe.5,6,20
In contrast, PDH in dogs can result from tumor or hy-
perplasia of the PD or PI.14 The existence of possible PI
lobe origin tumors in humans remains controversial.21
About 30% of dogs with PDH have intermediate lobe
tumors.14 Presumably, these tumors may arise from either
of two distinct parenchymal cells of the PI.13 It is also sug-
gested that canine PI tumors involving A cells do not re-
spond to glucocorticoid feedback (dexamethasone nega-
tive feedback), whereas PI tumors involving B cells do

CUSHING’S SYNDROME ■ CONN’S SYNDROME ■ INTERMEDIATE LOBE TUMORS

Compendium December 1999 20TH ANNIVERSARY Small Animal/Exotics

Mutation

Gr
ow
es

th
tor

Ho
on

fac s
rm
fac
rm

tor
Carcinoma

on
Ho

th

s
e
ow
Clonal
Gr

expansion
Hormones

Mutation Growth
factors

Hyperplasia Adenoma

Figure 3—Proposed model of pituitary tumorigenesis. This integrated approach incorporates both the hormonal stimulation the-
ory and the intrinsic pituitary defect theory of tumorigenesis. Animal models and patients with hypophysiotrophic hormone ex-
cess, suppressive hormone insufficiency, or growth factor excess develop hyperplasia (green arrows); the increased proliferation
predisposes the cells to mutation (dark nuclei) and subsequent adenoma formation. Most human pituitary adenomas are not asso-
ciated with hyperplasia and likely result from a genetic event that alters a cell (dark nucleus, top right) that is the target for promo-
tion by hormones or growth factors (gold arrows). (Modified from Asa SL, Ezzat S: The cytogenesis and pathogenesis of pituitary
adenomas. Endocr Rev 19:818, 1998; with permission.)

show suppressed plasma cortisol concentrations in re-
sponse to dexamethasone.22 Whether PI tumors associ-
ated with HAC in dogs arise from different cellular
subsets within this tissue or whether such tumors main-
tain the same regulatory responses as normal PI cells is
unknown.
Neoplastic tissue is not present in all dogs or humans
with PDH. The reported incidence of pituitary tumors
in dogs with PDH ranges from 20% to 100%.14,23–26 It is
likely that microadenomas were missed during section-
ing of the pituitary for histopathology, accounting for
the lower percentage of pituitary tumors in some stud-
ies. In other cases, however, hyperplasia rather than tu-
mor of PD and/or PI cells may be found.14,26 Addition-
ally, concurrent tumors of both PI and PD lobes or
tumors of undetermined lobe origin are noted. These
histologic abnormalities suggest that PDH may result
from either a primary central nervous system abnormal-
ity (e.g., excessive stimulation of PD or PI corticotrophs
by such hypothalamic factors as CRH or such neuro-
transmitters as serotonin, norepinephrine, and epi-
nephrine) or a primary pituitary tumor. Adrenalectomy,
untreated Addison’s disease, and chronic CRH adminis-
tration in rats or humans (all of which lead to increased
CRH levels) result in pituitary corticotroph hyperplasia
and microadenomatous formation.27–29 CRH is the ma-
jor stimulatory hormone regulating ACTH release from
canine PD cells and has been shown to stimulate
ACTH and α-MSH secretion from canine PI cells in
vitro.16 Additionally, CRH-containing fibers have been
demonstrated in the canine PI.12 Thus excessive hy-
pothalamic CRH could lead to corticotroph hyperplasia
and possibly tumor formation.
Hypothalamic depletion of such neurotransmitters as
dopamine or γ-aminobutyric acid could also lead to hy-
perplastic or adenomatous changes in pituitary cells. For
example, dopamine depletion has been documented in
horses that develop Cushing’s syndrome.5 Hypothalamic
dopamine depletion may also result in Cushing’s syn-
drome in dogs. As in other species, the canine PI is neg-
atively regulated by dopamine and reduced dopamine
concentrations have been found in the median emi-
nence of dogs with spontaneous HAC.16,30,31 However,
dopamine concentrations were also reduced in normal
dogs treated with dexamethasone, suggesting that the
reduced dopamine concentrations may have been a re-
sult, rather than a cause, of glucocorticoid excess.31 An
earlier study was unable to document dopamine deple-
tion from the hypothalamus of dogs with PDH or re-
ceiving steroid treatment.32 A role for dopamine deple-
tion in the cause of canine PDH was supported by a
recent study in which chronic administration of a dop-
amine antagonist resulted in enhanced ACTH release in
response to CRH challenge.33 Of interest is the fact that

CORTICOTROPH HYPERPLASIA ■ NEUROTRANSMITTERS ■ DOPAMINE

Compendium December 1999 20TH ANNIVERSARY
this CRH-stimulated ACTH release was not
blocked by administration of glucocorticoids; in
other words, chronic dopamine depletion in nor-
mal dogs was able to unmask a CRH-responsive
ACTH release that was not under the negative
feedback effect of steroids.
Development of a pituitary tumor, however, may
not be entirely the result of hypothalamic hyper-
secretion of CRH or dopamine depletion. Rather,
it may result from a primary pituitary abnormality.
For example, most ACTH-secreting pituitary ade-
nomas in humans are monoclonal (i.e., they arise
from a single cell).34 However, although pituitary
adenomas are monoclonal, somatic mutations that
have been identified in other malignancies are usu- ACTH PD = pars distalis; PI = pars intermedia.
ally absent and the molecular events leading to pi-
tuitary tumorigenesis remain unknown.35
In a recently proposed model of pituitary tumorigen-
esis (Figure 3), both a hypothalamic (hormonal stimu-
lation theory) and a primary pituitary defect theory of
35
tumorigenesis are integrated. In this model, hyperpla-
sia develops as a result of excessive hormonal stimula-
tion, inhibitory hormone depletion, or growth factor
excess. This increased proliferation of pituicytes predis-
poses the cells to mutation and subsequent adenoma
formation. However, most pituitary adenomas are not
associated with hyperplasia and probably result from a
single genetic event that alters a cell.35
In summary, canine PDH may result from hyperplas-
tic or adenomatous changes of three different cell types:
the classic anterior pituitary corticotroph, A cells of the
intermediate lobe, or B cells of the intermediate lobe
(Table II). Because the cells secreting POMC-related
peptides from the PD and PI are regulated differently,
it is likely that there are multiple causes for develop-
ment of canine PDH. The clonality of canine pituitary
tumors has not been determined.
Pituitary-dependent HAC is rare in cats (there are
only 48 reported cases),2 and its pathophysiology has
not been studied. Although cats, like horses and dogs,
have a well-developed PI lobe, I am unaware of any PI
lobe tumors in cats that have been associated with
5,14
HAC as they have been in dogs and horses.
Adrenal Tumors
Adrenal tumors giving rise to HAC are adrenocorti-
cal in origin and may be benign adenomas or malig-
nant adenocarcinomas.36–39 Ferrets are the only species
in which ATs are more common than is PDH; in this
3 production. Philadelphia, WB Saunders Co, 1996, pp
species, the tumor does not hypersecrete cortisol. In
most other species, the incidence of ATs as a cause of
HAC is about 10% to 15% (Table I).
PITUITARY TUMORIGENESIS ■ PITUICYTES ■ ADENOMA ■ ADENOCARCINOMA
Small Animal/Exotics
TABLE II
Comparison of Possible Subtypes of
Pituitary-Dependent Hyperadrenocorticism in Dogs
Pituitary Origin
Type (Frequency) Theoretic Diagnostic Results
I PD (70%) Dexamethasone suppression;
↑ACTH levels
II A cell PI (?) No dexamethasone suppression;
↑ACTH levels; ↑α-MSH levels
III B cell PI (?) No dexamethasone suppression;
↑ACTH levels; ? α-MSH levels
= corticotropin; α-MSH = α-melanocyte–stimulating hormone;
Approximately half of cortisol-secreting ATs are be-
nign; the rest are malignant. Tumors are usually unilat-
eral but may be bilateral.40 Functioning ATs secrete ex-
cessive cortisol independent of pituitary regulation.
This cortisol activates the negative feedback pathway
suppressing hypothalamic CRH and pituitary ACTH.
As plasma ACTH concentrations decrease, the unin-
volved and contralateral adrenal cortex atrophies.
Hyperadrenocorticism caused by noncortisol ste-
roid–secreting ATs is common in ferrets and rare in cats.
In ferrets, which may have bilateral or unilateral dis-
ease, the contralateral adrenal cortex does not atrophy
and the steroid hormones secreted are androgens and
estrogens, not glucocorticoids. ATs that gave rise to ex-
cessive secretion of the steroid hormone aldosterone
were associated with Conn’s syndrome in one cat,17
whereas another cat had clinical signs that were consis-
tent with Cushing’s syndrome but produced excessive
amounts of the steroid hormone progesterone rather
than cortisol.17,18
Rare Forms of Hyperadrenocorticism
Mixed forms of HAC with concurrent pituitary tu-
mors and ATs have been reported.41 Ectopic secretion
of ACTH has been reported in humans6 but not dogs
or cats. Bilateral adrenocortical (ACTH-independent)
Cushing’s syndrome, although very rare, has also been
documented in humans42 but not dogs or cats.
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41. Greco DS, Peterson ME, Davidson AP, et al: Concurrent pi-
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