Vol. 21, No. 12 December 1999
Refereed Peer Review
FOCAL POINT 5 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.
The Hypothalamic– Pituitary–Adrenal Axis and Pathophysiology of Hyperadrenocorticism
University of Pennsylvania
s Hypothalamic nuclei synthesize corticotropin-releasing hormone, whereas corticotropin is secreted by the pituitary gland. s Tumors of either the anterior or intermediate pituitary lobes are a much more common cause of HAC than are adrenal tumors. s Pituitary-dependent HAC may result from a pituitary tumor or a primary central nervous system defect, such as depletion of the neurotransmitter dopamine. s There are three likely causes of pituitary-dependent HAC in dogs.
Carole A. Zerbe, DVM, PhD
ABSTRACT: The hypothalamic–pituitary–adrenal axis consists of the hypothalamus and corticotropin-releasing hormone, the pituitary and corticotropin, and the adrenal cortex and glucocorticoid production. The clinical syndrome of hyperadrenocorticism results from glucocorticoid excess. This steroid excess, in turn, may result from an adrenal tumor or more commonly from a pituitary tumor causing excessive corticotropin and consequently glucocorticoid excess. In dogs, such a pituitary tumor may arise from either the anterior or intermediate lobes, suggesting that there are multiple causes for hyperadrenocorticism in this species.
yperadrenocorticism (HAC; most often referring to Cushing’s syndrome) 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 evaluate 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 nonhormonal 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-
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been proven to be a more potent or equipotent secretogogue for ACTH release Hypothalamus in some species (sheep and cattle), but it does not diCRH rectly stimulate ACTH release from canine anterior piAnterior tuitary cells in culture,8–11 as Negative pituitary it does in feline PD cells in feedback culture.11a ACTH The hypothalamus also Adrenal has axons that terminate in the intermediate pituitary lobe (pars intermedia [PI]), CORTISOL directly on the cells themselves. Most of these nerves Figure 1—The hypothalamic–pituitary–adrenal axis. Note that anterior pituitary corticotropin (ACTH) secretion is originate in the hypothastimulated by hypothalamic corticotropin-releasing hormone lamic arcuate nucleus and release dopamine (a neuro(CRH) and negatively regulated by glucocorticoids. transmitter that inhibits the synthesis and release of intermediate lobe pituitary NEUROAMINES hormones). There are also CRH-containing fibers in Hypothalamus the intermediate lobe, and ? CRH may have a role in ca(NEUROAMINES) nine PI lobe ACTH secretion.12 Intermediate No pituitary negative The Pituitary and feedback Corticotropin ACTH The pituitary receives inAdrenal put from the hypothalamus The Hypothalamus and via releasing or inhibiting Corticotropin-Releasing hormones and the hypothalCORTISOL Hormone amohypophyseal portal sysThe hypothalamus is part Figure 2—Proposed pars intermedia (PI) hypothalamic–pitu- tem. In dogs, ACTH is conof 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 B cells. 13 The canine pitusize CRH, which is then negative feedback of PI ACTH secretion or of dopamine. itary has a well-developed transported down the nerve intermediate lobe that is unique: It has two types of axons to the median eminence, where the nerve cells cells, A and B, both of which process the ACTH preterminate in the portal capillary bed. Once released, cursor protein proopiomelanocortin (POMC). POMC CRH travels via the hypothalamohypophyseal portal is processed into α-melanocyte–stimulating hormone blood to the anterior pituitary (pars distalis [PD]), (α-MSH) by A cells and ACTH by B cells. This mechwhere it stimulates release of ACTH from the cortianism is especially notable in dogs because pituitary tucotroph. mors leading to Cushing’s syndrome can arise in both Another hypothalamic peptide, arginine vasopressin the anterior and intermediate lobes.14 Additionally, PI (also known as antidiuretic hormone), may also be released 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.
ation of HAC. Anatomically, the HPA axis consists of the hypothalamus, pituitary, and adrenal cortex; physiologically, it consists of hormones of stimulation and negative feedback. The hormones that stimulate synthesis and secretion of other hormones include corticotropin-releasing hormone (CRH) and ACTH; the glucocorticoid cortisol in turn negatively regulates these hormones. This cycle of stimulation and negative feedback represents the classically defined anterior pituitary lobe HPA axis (Figure 1). In dogs, however, the intermediate pituitary lobe HPA axis, in which the intermediate (rather than the anterior) pituitary lobe is the source of pituitary ACTH, should also be considered (Figure 2). Although this source of ACTH does not appear to be important under normal physiologic conditions, its role in certain pathologic conditions is significant.
HPA AXIS s PARAVENTRICULAR NUCLEI s ARGININE VASOPRESSIN s A AND B CELLS
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TABLE I Comparison of the Causes of Cushing’s Syndrome among Dogs, Cats, Horses, and Humans Species Dogs Cats Horses Humans Usual Pituitary Lesion PD adenoma PD adenoma PI adenoma PD adenoma Less Common Pituitary Lesion(s) PI adenoma, corticotroph hyperplasia Corticotroph hyperplasia PI hyperplasia Corticotroph hyperplasia AT AT — Ectopic ACTH production, AT, AIMBAD Other Causes
ACTH = corticotropin; AIMBAD = corticotropin-independent massive bilateral adrenal disease; AT = adrenal tumor; PD = pars distalis (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 pituitary 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 reticularis of the adrenal cortex; it also maintains the integrity 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 operates 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 hormones (e.g., progestogens, mineralocorticoids) as well as estrogens and androgens. These hormones can be secreted 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 endogenous (spontaneous HAC) origin. Spontaneous
HAC, which most commonly results from overproduction 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 bilateral 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 increased.) Another syndrome, Conn’s, occurs when mineralocorticoids are secreted in excess.17 Excessive secretion 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 spontaneous 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 pituitary lobe of origin of hypersecretion of ACTH and its related peptides (Table I).19 In humans, Cushing’s syndrome is usually associated with a microadenoma or occasionally 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 hyperplasia 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 suggested that canine PI tumors involving A cells do not respond to glucocorticoid feedback (dexamethasone negative feedback), whereas PI tumors involving B cells do
CUSHING’S SYNDROME s CONN’S SYNDROME s INTERMEDIATE LOBE TUMORS
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s tor fac s th e ow on Gr rm Ho
rm on es ow th fac tor s
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 excess, 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 associated with hyperplasia and likely result from a genetic event that alters a cell (dark nucleus, top right) that is the target for promotion 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 response to dexamethasone.22 Whether PI tumors associated with HAC in dogs arise from different cellular subsets within this tissue or whether such tumors maintain 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 sectioning of the pituitary for histopathology, accounting for the lower percentage of pituitary tumors in some studies. In other cases, however, hyperplasia rather than tumor of PD and/or PI cells may be found.14,26 Additionally, 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 abnormality (e.g., excessive stimulation of PD or PI corticotrophs by such hypothalamic factors as CRH or such neurotransmitters as serotonin, norepinephrine, and epinephrine) or a primary pituitary tumor. Adrenalectomy, untreated Addison’s disease, and chronic CRH administration 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 major 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 hypothalamic 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 hyperplastic 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 syndrome in dogs. As in other species, the canine PI is negatively regulated by dopamine and reduced dopamine concentrations have been found in the median eminence 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 result, rather than a cause, of glucocorticoid excess.31 An earlier study was unable to document dopamine depletion from the hypothalamus of dogs with PDH or receiving steroid treatment.32 A role for dopamine depletion in the cause of canine PDH was supported by a recent study in which chronic administration of a dopamine antagonist resulted in enhanced ACTH release in response to CRH challenge.33 Of interest is the fact that
CORTICOTROPH HYPERPLASIA s NEUROTRANSMITTERS s DOPAMINE
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this CRH-stimulated ACTH release was not Comparison of Possible Subtypes of blocked by administration of glucocorticoids; in Pituitary-Dependent Hyperadrenocorticism in Dogs other words, chronic dopamine depletion in norPituitary Origin mal dogs was able to unmask a CRH-responsive Type (Frequency) Theoretic Diagnostic Results ACTH release that was not under the negative feedback effect of steroids. I PD (70%) Dexamethasone suppression; Development of a pituitary tumor, however, may ↑ACTH levels not be entirely the result of hypothalamic hypersecretion of CRH or dopamine depletion. Rather, II A cell PI (?) No dexamethasone suppression; it may result from a primary pituitary abnormality. ↑ACTH levels; ↑α-MSH levels For example, most ACTH-secreting pituitary adenomas in humans are monoclonal (i.e., they arise III B cell PI (?) No dexamethasone suppression; from a single cell).34 However, although pituitary ↑ACTH levels; ? α-MSH levels adenomas are monoclonal, somatic mutations that α-MSH = α-melanocyte–stimulating hormone; have been identified in other malignancies are usu- ACTH = corticotropin;pars intermedia. PD = pars distalis; PI = ally absent and the molecular events leading to pituitary tumorigenesis remain unknown.35 Approximately half of cortisol-secreting ATs are beIn a recently proposed model of pituitary tumorigennign; the rest are malignant. Tumors are usually unilatesis (Figure 3), both a hypothalamic (hormonal stimueral but may be bilateral.40 Functioning ATs secrete exlation theory) and a primary pituitary defect theory of 35 cessive cortisol independent of pituitary regulation. tumorigenesis are integrated. In this model, hyperplaThis cortisol activates the negative feedback pathway sia develops as a result of excessive hormonal stimulasuppressing hypothalamic CRH and pituitary ACTH. tion, inhibitory hormone depletion, or growth factor As plasma ACTH concentrations decrease, the uninexcess. This increased proliferation of pituicytes predisvolved and contralateral adrenal cortex atrophies. poses the cells to mutation and subsequent adenoma Hyperadrenocorticism caused by noncortisol steformation. However, most pituitary adenomas are not roid–secreting ATs is common in ferrets and rare in cats. associated with hyperplasia and probably result from a In ferrets, which may have bilateral or unilateral dissingle genetic event that alters a cell.35 ease, the contralateral adrenal cortex does not atrophy In summary, canine PDH may result from hyperplasand the steroid hormones secreted are androgens and tic or adenomatous changes of three different cell types: estrogens, not glucocorticoids. ATs that gave rise to exthe classic anterior pituitary corticotroph, A cells of the cessive secretion of the steroid hormone aldosterone intermediate lobe, or B cells of the intermediate lobe were associated with Conn’s syndrome in one cat,17 (Table II). Because the cells secreting POMC-related whereas another cat had clinical signs that were consispeptides from the PD and PI are regulated differently, tent with Cushing’s syndrome but produced excessive it is likely that there are multiple causes for developamounts of the steroid hormone progesterone rather ment of canine PDH. The clonality of canine pituitary than cortisol.17,18 tumors has not been determined. Pituitary-dependent HAC is rare in cats (there are Rare Forms of Hyperadrenocorticism only 48 reported cases),2 and its pathophysiology has Mixed forms of HAC with concurrent pituitary tunot been studied. Although cats, like horses and dogs, mors and ATs have been reported.41 Ectopic secretion have a well-developed PI lobe, I am unaware of any PI of ACTH has been reported in humans6 but not dogs lobe tumors in cats that have been associated with 5,14 or cats. Bilateral adrenocortical (ACTH-independent) HAC as they have been in dogs and horses. Cushing’s syndrome, although very rare, has also been documented in humans42 but not dogs or cats. Adrenal Tumors Adrenal tumors giving rise to HAC are adrenocortiREFERENCES cal in origin and may be benign adenomas or malig1. Feldman EC, Nelson RW: Hyperadrenocorticism (Cushnant adenocarcinomas.36–39 Ferrets are the only species ing’s syndrome), in: Canine and Feline Endocrinology and Rein which ATs are more common than is PDH; in this production. Philadelphia, WB Saunders Co, 1996, pp 3 species, the tumor does not hypersecrete cortisol. In 187–265. most other species, the incidence of ATs as a cause of 2. Duesberg C, Peterson ME: Adrenal disorders in cats. Vet Clin North Am Small Anim Pract 27:321–347, 1997. HAC is about 10% to 15% (Table I).
PITUITARY TUMORIGENESIS s PITUICYTES s ADENOMA s ADENOCARCINOMA
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About the Author
Dr. Zerbe is affiliated with the Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.