The Pituitary- Adrenal Axis and Pa Tho Physiology of Hyperadrenocorticism

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20TH ANNIVERSARYVol. 21, No. 12December 1999

Refereed Peer Review

FOCAL POINTKEY FACTS

Understanding thehypothalamic–pituitary–adrenalaxis and the pathophysiologyof hyperadrenocorticism (HAC)is crucial to understandingthe hormonal tests used fordiagnosis and differentiationof this disorder.

The Hypothalamic–Pituitary–Adrenal Axisand 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 morecommonly 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.

yperadrenocorticism (HAC; most often referring to Cushing

’

s syn-drome) is a very common, spontaneous endocrinopathy in middle-agedto geriatric dogs. It occurs less commonly in cats, ferrets, horses, andhumans, and there has been one report of HAC in a dolphin.

–

It is most oftena clinical syndrome of glucocorticoid excess, which may result from an adrenalor pituitary tumor that is causing excessive corticotropin (ACTH) secretion andconsequently 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 thehypothalamic

–

pituitary

–

adrenal (HPA) axis and the pathophysiology of HAC.Future articles will discuss tests used to confirm HAC (i.e., screening tests) andthose 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 theseimportant topics.

1,2,7

HYPOTHALAMIC–PITUITARY–ADRENAL AXIS

Understanding the HPA axis is crucial to understanding the testing and evalu-

Hypothalamic nuclei synthesizecorticotropin-releasing hormone,whereas corticotropin is secretedby the pituitary gland.

Tumors of either the anterior orintermediate pituitary lobes are amuch more common cause ofHAC than are adrenal tumors.

Pituitary-dependent HAC mayresult from a pituitary tumor or aprimary central nervous systemdefect, such as depletion of theneurotransmitter dopamine.

There are three likely causes ofpituitary-dependent HAC in dogs.

ation of HAC. Anatomical-ly, the HPA axis consists of the hypothalamus, pituitary,and adrenal cortex; physio-logically, it consists of hor-mones of stimulation andnegative feedback. The hor-mones that stimulate syn-thesis and secretion of otherhormones include cortico-tropin-releasing hormone(CRH) and ACTH; the glu-cocorticoid cortisol in turnnegatively regulates thesehormones. This cycle of stim-ulationand negative feedback represents the classically de-fined anterior pituitary lobeHPA axis (Figure 1). In dogs,however, the intermediate pi-tuitarylobe HPA axis, in which the intermediate (ra-ther than the anterior) pitu-itary lobe is the source of pi-tuitary ACTH, should alsobe considered (Figure 2). Al-thoughthis source of ACTHdoes not appear to be im-portant under normal physi-ologic conditions, its role incertain pathologic condi-tions is significant.

The Hypothalamus andCorticotropin-ReleasingHormone

The hypothalamus is partof the brain and consists of collections of nerve cell bod-iescalled

nuclei

. The par-aventricular nuclei synthe-size CRH, which is thentransported down the nerveaxons to the median eminence, where the nerve cellsterminate in the portal capillary bed. Once released,CRH travels via the hypothalamohypophyseal portalblood to the anterior pituitary (pars distalis [PD]), where it stimulates release of ACTH from the corti-cotroph. Another hypothalamic peptide, arginine vasopressin(also known as

antidiuretic hormone

), may also be re-leased into the median eminence and influence ACTHrelease. Compared with CRH, arginine vasopressin hasbeen proven to be a morepotent or equipotent secre-togogue for ACTH releasein some species (sheep andcattle), but it does not di-rectly stimulate ACTH re-lease from canine anterior pi-tuitarycells in culture,

–

asit does in feline PD cells inculture.

11a

The hypothalamus alsohas axons that terminate inthe intermediate pituitary lobe (pars intermedia [PI]),directly on the cells them-selves. Most of these nervesoriginate in the hypotha-lamic arcuate nucleus andrelease dopamine (a neuro-transmitter that inhibits thesynthesis and release of in-termediate lobe pituitary hormones). There are alsoCRH-containing fibers inthe intermediate lobe, andCRH may have a role in ca-nine PI lobe ACTH secre-tion.

The Pituitary andCorticotropin

The pituitary receives in-put from the hypothalamusvia releasing or inhibitinghormones and the hypothal-amohypophyseal portal sys-tem. In dogs, ACTH is con-tained in both the anteriorpituitary corticotroph and asubset of the intermediatepituitary lobe cells known as

B cells

The canine pitu-itary has a well-developedintermediate lobe that is unique: It has two types of cells, A and B, both of which process the ACTH pre-cursor protein proopiomelanocortin (POMC). POMCis processed into

-melanocyte

–

stimulating hormone(

-MSH) by A cells and ACTH by B cells. This mech-anism is especially notable in dogs because pituitary tu-mors leading to Cushing

’

s syndrome can arise in boththe anterior and intermediate lobes.

Additionally, PItumors are thought to arise from both A and B cellsand may be differently regulated.

Compendium

December 199920TH ANNIVERSARYSmall Animal/Exotics

HPA AXIS

PARAVENTRICULAR NUCLEI

ARGININE VASOPRESSIN

A AND B CELLS

HypothalamusNEUROAMINESCRHACTHCORTISOLNegativefeedbackAnteriorpituitaryAdrenal

Figure 1

—

The hypothalamic

–

pituitary

–

adrenal axis. Notethat anterior pituitary corticotropin

(ACTH)

secretion isstimulated by hypothalamic corticotropin-releasing hormone

(CRH)

and negatively regulated by glucocorticoids.

HypothalamusNEUROAMINES(NEUROAMINES)ACTHCORTISOLNonegativefeedbackIntermediatepituitaryAdrenal?

Figure 2

—

Proposed pars intermedia (PI) hypothalamic

–

pitu-itary

–

adrenal axis. Note that the PI lobe is under tonic nega-tive regulation by neuroamines (dopamine). Corticotropin-releasing hormone may stimulate PI corticotropin

(ACTH)

secretion, but glucocorticoids are not likely involved withnegative feedback of PI ACTH secretion or of dopamine.

The canine PI contains twice as much biologically active ACTH as does the anterior lobe.

It is notknown whether this ACTH plays a physiologic role innormal dogs, but it is probably important in some pitu-itary tumors. Regulation of ACTH secretion from thePI lobe is not well understood, but both A and B cellsof the PI are under tonic negative regulation by theneuroamine dopamine (Figure 2).

15,16

A and B cells donot seem to be negatively regulated by glucocorticoids,but B-cell stimulation by CRH may occur.

The Adrenal Cortex and Glucocorticoids

Corticotropin stimulates the synthesis and secretionof 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 causesadrenocortical hyperplasia and hypertrophy. Thesepathologies can sometimes be nodular and asymmetric.Glucocorticoids play an important role in ACTHregulation through their negative feedback effects onboth CRH and ACTH. This feedback pathway oper-ates normally in dogs with ATs, suppressing ACTHand CRH secretion and thus causing the uninvolvedadrenocortical tissue to atrophy. In contrast, dogs andcats with ACTH-secreting pituitary tumors experiencebilateral adrenal hyperplasia and hypertrophy.The adrenal cortex may also secrete other steroid hor-mones (e.g., progestogens, mineralocorticoids) as wellas estrogens and androgens. These hormones can be se-creted normally or as a result of AT formation (see the Adrenal Tumor section).

PATHOPHYSIOLOGY OFHYPERADRENOCORTICISM

Hyperadrenocorticism may result from steroid excessof exogenous (iatrogenic Cushing

’

s syndrome) or en-dogenous (spontaneous HAC) origin. SpontaneousHAC, which most commonly results from overproduc-tion of ACTH and its related peptides, is referred to as

pituitary-dependent hyperadrenocorticism

; however, itmay 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 toother syndromes of adrenocortical hyperfunctioning. Inferrets, for example, HAC results from unilateral or bi-lateral ATs that secrete androgens and/or estrogens.

(This syndrome, which has not been given a name otherthan HAC, is appropriately not referred to as Cushing

’

ssyndrome because serum glucocorticoids are not in-creased.) Another syndrome, Conn

’

s, occurs when min-eralocorticoids are secreted in excess.

Excessive secre-tion of progesterone by an AT was recently reported in acat with clinical signs of Cushing

’

s syndrome.

ThusHAC 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 mostcommon, usually accounting for more than 85% of cases.

–

3,5,6

There are, however, differences in the pitu-itary lobe of origin of hypersecretion of ACTH and itsrelated peptides (Table I).

In humans, Cushing

’

s syn-drome is usually associated with a microadenoma or oc-casionally hyperplasia of the PD corticotrophs, whereastumors 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.

The existence of possible PIlobe origin tumors in humans remains controversial.

About 30% of dogs with PDH have intermediate lobetumors.

Presumably, these tumors may arise from eitherof two distinct parenchymal cells of the PI.

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

Small Animal/Exotics20TH ANNIVERSARY

Compendium

December 1999

CUSHING

’

S SYNDROME

CONN

’

S SYNDROME

INTERMEDIATE LOBE TUMORS

TABLE IComparison of the Causes of Cushing

’

s Syndrome among Dogs, Cats, Horses, and Humans

SpeciesUsual Pituitary LesionLess Common Pituitary Lesion(s)Other Causes

DogsPD adenomaPI adenoma, corticotroph hyperplasiaATCatsPD adenomaCorticotroph hyperplasiaATHorsesPI adenomaPI hyperplasia

—

HumansPD adenomaCorticotroph hyperplasiaEctopic ACTH production, AT, AIMBAD

ACTH

= corticotropin;

AIMBAD

= corticotropin-independent massive bilateral adrenal disease;

= adrenal tumor;

= pars distal-is (anterior pituitary lobe);

= pars intermedia (intermediate pituitary lobe).

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