Principles and Practice of Endocrinology and Metabolism



Synthesis and Processing of Proopiomelanocortin
Functions of Adrenocorticotropin

Regulation of Adrenocorticotropin Secretion

Mechanism of Control of ACTH Secretion

Measurement of Adrenocorticotropin

Basal Plasma ACTH Concentrations: Clinical Applications
Dynamic Testing of Adrenocorticotropin Secretory Function
Clinical Manifestations of Disorders of Adrenocorticotropin Excess
Clinical Manifestations of Adrenocorticotropin Deficiency
Chapter References

The existence of an adrenocorticotropic factor was predicted by classic pituitary ablation/pituitary extract replacement experiments.1,2 Ovine and human adrenocorticotropin hormone (ACTH) were later isolated and sequenced.3,4 ACTH, a 39 amino acid peptide secreted by the corticotropes (located centrally in the anterior pituitary gland), stimulates adrenocortical steroid synthesis. Measurement of this peptide, formerly difficult, is now reliable and practical, although ACTH measurements are most useful when autonomous secretion or pathologic suppression of ACTH release is suspected. ACTH release is stimulated by the hypothalamic secretion of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP)—in response to stress and the circadian rhythm—and inhibited by negative feedback from circulating cortisol. A number of acquired or inherited disorders of ACTH secretion may be manifested by hypercortisolism, adrenal insufficiency, or hyperpigmentation.
When ACTH is synthesized in the anterior pituitary gland by the corticotropes, it is derived from a much larger precursor, a 241 amino acid peptide, proopiomelanocortin (POMC)5 (Fig. 14-1). The human POMC 8-Kb gene is located on chromosome 2p23.3, consisting of a 400 to 700 bp promoter, three exons, and two introns.6,7 The main regulators of POMC transcription are CRH and glucocorticoids. CRH increases POMC transcription through a cyclic adenosine monophosphate–mediated mechanism, whereas glucocorticoids inhibit transcription. In the pituitary, pro-hormone convertase 1 (PC1) cleaves POMC into ACTH and two other large polypeptides, N-terminal peptide and b-lipotropin.8 The roles of these large peptides, which are cosecreted in equimolar amounts to ACTH, are unknown. b-lipotropin was so named because of a mild lipolytic activity9 that has doubtful relevance in humans. Formerly, b-lipotropin was measured by some investigators as a substitute for ACTH. In the brain, ACTH is cleaved by prohormone convertase 2 (PC2), yielding a-melanocyte-stimulating hormone (a-MSH) and corticotropin-like intermediate lobe peptide (CLIP), which are also produced in the human fetal pituitary intermediate lobe. These peptides are not produced in the adult, where the intermediate lobe is no longer present. Although MSH sequences (a-MSH, b-MSH, g-MSH) are contained within POMC fragments, ACTH itself has melanotropic action, increasing melanin synthesis, and may itself lead to pigmentation in hypersecretory states. No MSH peptides are released from the anterior pituitary in humans, nor are these peptides found in human blood. MSH activity in human blood results from MSH sequences contained within ACTH and possibly within b-lipotropin and the N-terminal fragment of POMC.

FIGURE 14-1. Processing of human proopiomel-anocortin (POMC). The processing proceeds in stages, yielding a variety of forms of secreted peptides; N-terminal peptide, adrenocorticotropic hormone (ACTH), and b-lipotropin are the principal circulating forms. Approximately 40% of ACTH has a posttranslational addition of a phosphate moiety. (g-MSH, gamma-melanocyte-stimulating-hormone; LPH, lipotropin; CHO, carbohydrate; PO4, phosphate.)

Animal studies have revealed a role for a-MSH in the regulation of food intake, acting through the brain melanocortin-4 receptor. Studies in Mexican-Americans have shown an association between inheritance of the POMC region of chromosome 2, serum leptin concentration, and obesity.10 POMC gene mutations can result in a monogenic disorder of early-onset obesity, adrenal insufficiency, and red hair.11
The primary action of ACTH is to promote steroidogenesis—that is, to enhance the synthesis and secretion of glucocorticoids, mineralocorticoids, and weak androgenic steroids of the adrenal cortex. However, the main physiologic controller of aldosterone release is the renin-angiotensin system (see Chap. 17). The N-terminal 18 amino acids are capable of cortisol release but are subject to rapid degradation; hence, the N-terminal 24 amino acids are used clinically to stimulate ACTH release (cosyntropin). ACTH acts on a specific 297-amino acid cell surface receptor that belongs to the Gs-protein–coupled 7-transmembrane superfamily of receptors. The ACTH receptor (also known as the melanocortin-2 receptor) gene is located at chromosome 18p11.1.12,13 The ACTH receptor acts via a cyclic adenosine monophosphate–dependent second messenger pathway to increase adrenal lipoprotein uptake from plasma and increase the transcription rates of genes for enzymes involved in steroidogenesis. Increased low-density lipoprotein uptake is facilitated by an increase in cell-surface low-density lipoprotein receptors. In contrast, ACTH has a smaller effect on zona fasciculata hydroxymethylglutaryl-coenzyme A reductase levels and hence cholesterol synthesis.14,15 Acutely, ACTH increases the activity of the rate-limiting enzyme of adrenal steroidogenesis, the P450SCC enzyme that catalyzes the conversion of cholesterol to D5-pregnenolone. Chronically, ACTH increases the activity of other adrenal enzymes involved in steroidogenesis. ACTH also stimulates protein synthesis, resulting in adrenal hypertrophy and hyperplasia. The activity of phenylethanolamine-N-methyltransferase, the enzyme that catalyzes epinephrine production (see Chap. 85), is dependent on cortisol, and hence ACTH levels. ACTH has a trophic effect on tyrosine hydroxylase activity, the enzyme responsible for catalyzing the rate-limiting step in catecholamine biosynthesis, and increases the rate of melanin synthesis in melanocytes, which leads to skin pigmentation.
The anterior pituitary contains ~600 µg of ACTH.16 ACTH, which is released on a pulsatile basis with peaks at ~30-minute intervals,17 is subject to intravascular enzymatic degradation with a plasma disappearance half-life of 7 to 12 minutes.18 Cortisol pulses follow those of ACTH by ~30 minutes, although not all cortisol peaks follow those of ACTH.19 The relationship between increasing levels of ACTH and consequent cortisol secretion is defined by a sigmoidal curve.20 Very high levels of ACTH do not further increase plasma cortisol concentrations, although the duration of a cortisol secretory burst continues to increase.21
Under some circumstances, the relation between ACTH and cortisol secretion is disturbed. In chronic stress, such as critical illness, a greater cortisol release occurs for an additional given ACTH stimulus because of adrenal hypertrophy and altered adrenal enzyme activities, which favor production of cortisol over that of adrenal androgens.22 Elevated ACTH levels after appropriate stimuli, with blunted or normal cortisol responses, are seen in myotonic dystrophy,23 a multisystem genetic disorder, and fibro-myalgia,24 an idiopathic pain syndrome. In these cases, the primary defect is thought to lie in ACTH regulation rather than an altered ACTH bioactivity or adrenal hyporesponsiveness.
Regulation of ACTH release is subject to three themes: stress, the circadian rhythm, and glucocorticoid negative feedback. Stress, defined as a threat to homeostasis, derives from such factors as sepsis, trauma, or emotion. In response to stress, ACTH release is greatly increased; consequently, the secretion of cortisol, the principal glucocorticoid in humans, can increase five-fold. The principal functions of cortisol during stress are to restrain the immune system, by reducing production of potentially damaging cytokines25; augment the effects of catecholamines on the vascular system; mobilize glucose and fatty acids for metabolic use; and sharpen cognition to allow appropriate behavioral responses. During starvation, cortisol acts to increase hepatic glucose production for use as energy.
ACTH secretion follows a light-entrained circadian rhythm with peak cortisol blood levels attained at ~6:00 a.m. to 8:00 a.m. and the lowest concentrations at approximately midnight.26,27 and 27a In animals, the circadian rhythm is based on serotonergic pathways arising from the suprachiasmatic nucleus,28 although the mechanism—or indeed the function—of circadian ACTH release in humans is unknown. In humans, severe disturbances of circadian ACTH release following transmeridian travel require several days to be reentrained29 (see Chap. 6).
Normally, glucocorticoid negative feedback controls ACTH release; however, stress and circadian factors make ACTH release less susceptible to feedback inhibition. At physiologic levels of cortisol, the brain, rather than the pituitary, is the main site of feedback inhibition.30 Cortisol acts at two types of receptors in the hypothalamus and hippocampus to inhibit CRH release; these are type-1 (mineralocorticoid) and type-2 (classic glucocorticoid) receptors. The high affinity type-1 receptors are thought to mediate suppression of CRH release in response to basal conditions, whereas type-2 receptors mediate stress-level cortisol inhibition.31,32 Both rapid and delayed feedback of glucocorticoids on ACTH secretion are observed. Rapid feedback is responsive to the rate of change in glucocorticoid concentrations; delayed feedback responds to absolute circulating glucocorticoid levels.33
The progressive rise in plasma ACTH, which occurs during pregnancy, is associated with increased total and free cortisol (two- to three-fold). This may be due to stimulation of the maternal pituitary corticotropes by placental CRH.34 Transiently reduced central CRH secretion and relative hypocortisolism in the postpartum period may contribute to the mood and autoimmune phenomena observed at this time.
Leptin is a peptide hormone produced by adipocytes. It was isolated after studies of the leptin-deficient ob/ob (obese) mouse.35 Leptin acts on specific neuropeptide/neurotransmitter pathways of the central nervous system and through these modulatory effects inhibits appetite. Starvation is associated with low leptin levels and hypercortisolism. Moreover, plasma leptin and cortisol have an inversely related circadian rhythm.36 These findings suggest a close relationship between the hypothalamic–pituitary–adrenal (HPA) axis and leptin. Leptin inhibits ACTH secretion by inhibiting CRH synthesis.37 Leptin also inhibits adrenocortical enzyme activity.38 Hence, low leptin levels may account for the physiologic hypercortisolism of starvation, allowing stimulation of fuel catabolism and liberating amino acids and glucose39 (see Chap. 186).
As previously stated, pituitary ACTH secretion is subject to regulation by the hypothalamic hormones, principally CRH and AVP (Fig. 14-2).40 These hypophysiotropic factors are secreted into the hypothalamic-pituitary portal circulation at the median eminence from neurons arising in the parvicellular portion of the hypothalamic paraventricular nucleus. CRH, a 41 amino acid peptide discovered in 1981,41 is regarded as the main proximate regulator of ACTH secretion, acting via the CRH-R1 receptor.42,43 The effects of CRH and AVP are synergistic with respect to ACTH release.44 Both CRH and AVP have been used to stimulate ACTH release in clinical studies.

FIGURE 14-2. Neuroendocrine regulation of the hypothalamic–pituitary–adrenal (HPA) axis in humans. The circadian rhythm, stress, and feedback inhibition from circulating cortisol are the major regulators of HPA axis function. The two major secretagogues controlling adrenocorticotropin hormone (ACTH) release are corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). Noradrenergic input from the brainstem comprises a major stimulatory path to CRH release and links the HPA axis and the sympathetic nervous system.

The hypophysiotropic peptides are themselves regulated by a host of neurotransmitter pathways. Research into the role and importance of these pathways in humans has relied on indirect studies of pharmacologic agents through measurement of ACTH and cortisol release. In vitro studies of hypothalamic organ systems and animal preparations have allowed further insights. Importantly, CRH secretion is stimulated by noradrenergic neurons arising in the brainstem.45 These are themselves innervated by CRH neurons, which provide a reverberating feedback loop to link the two great effectors of the stress response (the HPA axis and the sympathetic nervous system)46 and are under tonic inhibition by central opioid pathways.47 Other neurotransmitter systems that stimulate the CRH neuron include acetylcholine, serotonin, and neuropeptide Y. CRH secretion and central noradrenergic nuclei are inhibited by the gamma amino butyric acid/benzodiazepine system.48 Other neurotransmitter systems with inhibitory effects on the CRH neuron include substance P and arcuate nucleus-derived POMC.
A major regulator of ACTH release is the immune system. Cytokines—produced in inflammatory sites with a time course favoring consecutive release of TNF-a, interleukin-1, and interleukin-6 (IL-6)—are potent releasers of ACTH and cortisol. Acutely, IL-6 may act principally at the brain and hypothalamus to indirectly cause release of ACTH, although the pituitary and adrenal can also be stimulated directly.49 In this regard, IL-6 in particular may be considered a hormone that is the major link between the immune system and the HPA axis. The result is a classic feedback loop between IL-6 and the HPA axis, in which cytokines stimulate the axis and cortisol suppresses the immune system and release of cytokines.50
Traditional radioimmunoassays rely on a single-site antibody that measures both intact ACTH and abnormal ACTH, or POMC fragments, such as may be secreted from ectopic ACTH-secreting tumors. The highest correlation between the radioimmunoassay and bioassay of ACTH is found with “midportion” assays (i.e., assays using antisera that cross-react with the mid-portion of the ACTH molecule). These antisera bridge the sites of proteolytic cleavage of ACTH in the 15-amino acid to 18-amino acid portion, thus binding to the portion of the molecule responsible for the steroidogenic activity.51
Greater sensitivity and specificity have been reported for the two-site immunoradiometric assay. Two different antibodies are used, each directed to a different portion of the ACTH molecule. For ACTH to be detected in this assay, each site must be bound to its respective antibody. The detection limit is as low as 2 to 3 pg/mL of plasma, making it possible to measure ACTH without extraction, even in samples with suppressed ACTH levels. Nonetheless, these immunoradiometric assays may fail to detect aberrant large molecular mass forms of ACTH, resulting in misleadingly low levels.52 Detection of large molecular mass forms of ACTH is usually indicative of ectopic (extrapituitary) ACTH production.
Samples for the measurement of ACTH must be collected and immediately placed on ice for plasma separation within a short period. Plasma must be stored frozen until assay. This is necessary to prevent catabolism of ACTH by circulating peptidases. Mishandling of samples for clinical ACTH measurement leads to falsely low ACTH levels.
In many circumstances, because the levels of plasma or urinary cortisol are directly related to those of ACTH and can be measured more economically, cortisol levels can be used as an indirect index of ACTH activity. However, there are several circumstances in which the measurement of ACTH is invaluable. These include the differential diagnosis of ACTH-dependent or independent Cushing syndrome (see Chap. 75); measurement of ACTH in the inferior petrosal sinuses for definitive diagnosis of pituitary Cushing syndrome; the differential diagnosis of adrenal insufficiency; and the monitoring of Nelson syndrome. Typical plasma ACTH concentrations found in pituitary-adrenal disorders are shown in Figure 14-3. Substantial overlap exists between the ACTH values in ectopic Cushing and pituitary-dependent Cushing syndrome; hence, ACTH can not be used to differentiate these disorders, although ACTH levels >2000 pg/mL, in the setting of hypercortisolism, are virtually pathognomic of ectopic Cushing syndrome. Very high ACTH values are also seen in Nelson syndrome. Even in severe, untreated primary adrenal insufficiency, plasma ACTH rarely exceeds 2000 pg/mL. Low or undetectable plasma ACTH values occur in patients with hypopituitarism during or after exogenous corticosteroid administration and in patients with cortisol-secreting tumors (e.g., adrenal adenoma).

FIGURE 14-3. Plasma adrenocorticotropic hormone (ACTH) concentrations in pituitary-adrenal disorders, as determined with an assay using an N-terminal ACTH antiserum. Patients with treated Cushing disease had previous bilateral adrenalectomy, no history of pituitary irradiation, and were taking replacement doses of corticosteroids. Patients with Nelson syndrome had the classic features, except visual field defects were not present in all cases.

Measurement of plasma ACTH in samples obtained simultaneously from the inferior petrosal sinuses and peripheral plasma forms the basis of the currently most definitive test for differentiation of pituitary and ectopic sources of ACTH in ACTH-dependent Cushing syndrome. Ratios of >2:1 before CRH injection and >3:1 after CRH injection indicate pituitary Cushing syndrome.53 The test is generally only necessary in selected cases of ACTH-dependent Cushing syndrome that have eluded diagnosis through less invasive testing.
In adrenal insufficiency, ACTH concentrations can be used to distinguish pituitary from adrenal causes. Inappropriately low or low-normal ACTH levels in the setting of adrenocortical deficiency are indicative of ACTH deficiency that is due to pituitary or hypothalamic disease. High ACTH levels in this setting are seen in primary adrenal insufficiency.
In states of possible autonomous ACTH hypersecretion, dexamethasone is used to inhibit ACTH secretion, and the plasma cortisol concentration or urinary cortisol excretion can be used to estimate ACTH secretory function (see Chap. 74). This technique is used in the diagnosis and differential diagnosis of Cushing syndrome and has been used to demonstrate hypercortisolism in melancholic depression.
Many stimuli have been used to stimulate ACTH secretion for clinical diagnostic purposes. Indications include Cushing syndrome and hypoadrenalism. The most frequently used test of HPA reserve is the cosyntropin stimulation test. This test is based on the rationale that if adrenal cortisol reserves are normal, the hypothalamic CRH and pituitary ACTH reserves must also be normal. Typically 250-µg ACTH (1–24) is administered intravenously and cortisol levels measured at baseline, 30 minutes, and 60 minutes. If plasma cortisol levels rise above 19 µg/dL at 30 (or 60) minutes, this is interpreted as a normal adrenal response. Peak cortisol levels of 16 µg/dL at 60 minutes occur after intramuscular cosyntropin.54 In general, this is used to demonstrate both pituitary ACTH-secretory integrity and normal adrenal-cortisol secretory function, because adrenal atrophy develops rapidly in states of ACTH deficiency. An abnormal cosyntropin test is highly specific for adrenal insufficiency. In cases of pituitary or hypothalamic damage, in which sufficient time may not have passed to allow adrenal atrophy from ACTH deprivation, the cosyntropin test is normal.
However, glucocorticoid deficiency crises have occurred in individuals with a normal cosyntropin test, especially in patients with central hypoadrenalism (pituitary or hypothalamic causes) who may be mistakenly diagnosed as normal in as many as 40% of cases.55 Low sensitivity of the 250-µg cosyntropin test has led to studies using a lower, more physiologic, 1-µg dose, which produces cortisol responses in normal subjects comparable to those obtained with 250-µg cosyntropin and appears more reliable in the diagnosis of central adrenal insufficiency.56 A safe, reliable single test for assessing the functional reserve of the HPA axis57 is still not available. Therefore, good clinical judgment is needed to select the correct test, or combination of tests, to determine whether there is an abnormality of HPA axis function.
Insulin-induced hypoglycemia involves the intravenous injection of 0.15 IU/kg insulin into a fasting subject. Hypoglycemia induces a profound and sustained hypercortisolism (cortisol >19 µg/dL). Careful medical supervision is essential, and the test is contraindicated in patients older than age 60 or in those who have had myocardial ischemia or epilepsy. This test, because of vast accumulated experience, is often regarded as the gold standard against which other tests of HPA axis reserve are compared.
The CRH test (see Chap. 74, Chap. 75 and Chap. 76) involves the intravenous injection of CRH (1 µg/kg) with measurement of ACTH and cortisol at –1, 15, 30, 45, and 60 minutes. The test directly measures corticotrope function and offers the potential to separate pituitary from hypothalamic causes of ACTH deficiency, because pituitary lesions produce an attenuated ACTH/cortisol response to CRH.58 Peak cortisol levels are similar to those observed in the ACTH stimulation test. Metyrapone inhibits the 11-hydroxylase enzyme, thereby inhibiting cortisol synthesis and leading to high levels of its immediate precursor, 11-deoxycortisol, which is stimulated by a lack of cortisol feedback and consequent ACTH hypersecretion (see Chap. 74). This test is used in the differential diagnosis of ACTH-dependent Cushing syndrome; patients with ectopic Cushing syndrome are less sensitive to glucocorticoid feedback, so the 11-deoxycortisol response is lower than in pituitary Cushing syndrome59 (see Chap. 74, Chap. 75 and Chap. 219).
Hyperpigmentation is common when ACTH levels exceed 300 pg/mL (Fig. 14-4). The highest ACTH levels are seen in Addison disease, Nelson syndrome, and ectopic ACTH secretion. Clinically, the hyperpigmentation is found particularly in areas of increased pressure (elbows, knuckles, knees) and is accentuated in areas of normal pigmentation (areolae, genitalia, palmar creases). Surfaces (such as the mucosal) that are not normally pigmented may exhibit hyperpigmentation. Scars acquired after the onset of ACTH excess also may exhibit hyperpigmentation (see Chap. 76).

FIGURE 14-4. Pigmented lunulae in a patient with the paraneoplastic adrenocorticotropic hormone (ACTH) syndrome who developed severe hyperpigmentation of rapid onset 3 months previously. More commonly, pigmentation of the nails related to excess ACTH is longitudinal rather than transverse, as in this patient. (For other examples of hyperpigmentation related to excess ACTH, see Chap. 76 and Chap. 219.)

Most cases of primary adrenal insufficiency are due to autoimmunity; infiltration or infection of the adrenal gland; or, rarely, X-linked adrenoleukodystrophy. Each of these may be associated with specific clinical features such as other immune disorders (type II autoimmune polyglandular syndrome), infectious manifestations, or neurologic disease, respectively.
Congenital resistance to ACTH may occur in isolated familial glucocorticoid deficiency, an autosomal recessive disorder that is due to a mutation of the ACTH receptor.60 Affected children have hypoglycemic episodes, hyperpigmentation, and failure to thrive. Mineralocorticoid production is normal, and there is no cortisol response to exogenous ACTH. Patients with the Allgrove syndrome (ACTH resistance, achalasia, and alacrima) have ACTH resistance but lack mutations in the gene for the ACTH receptor.61
Nelson syndrome entails the development of an invasive ACTH-secreting macroadenoma after bilateral adrenalectomy to alleviate the hypercortisolism of pituitary ACTH-dependent Cushing syndrome.62 Severe pigmentation occurs, and ACTH levels may be used as a tumor marker, particularly after pituitary surgery has made the identification of a pituitary tumor on magnetic resonance imaging unreliable. The development of Nelson syndrome could be prevented in children by presurgical pituitary irradiation.63 Nelson syndrome is not a universal concomitant of bilateral adrenalectomy; an association between the development of Nelson syndrome and the presence of a glucocorticoid receptor mutation has been found.64 Because bilateral adrenalectomy is now rarely performed in pituitary corticotropinoma cases, Nelson syndrome is correspondingly rare.
Autonomous excess secretion of ACTH produces hypercortisolism and Cushing syndrome.65,66 The source of ACTH is generally a pituitary adenoma, although 10% to 20% of cases are due to an ectopic neuroendocrine tumor, most commonly a bronchial carcinoid. Clinical features of Cushing syndrome include centripetal obesity, muscle weakness, osteoporosis, skin thinning with bruising and striae, glucose intolerance, hirsutism, and hypertension. The presence of hyperpigmentation in the context of Cushing syndrome tends to suggest ectopic paraneoplastic ACTH production, in which the ACTH levels are often very high (see Chap. 219).
A number of pituitary pathologies can lead to ACTH deficiency, including pituitary tumor, autoimmune lymphocytic hypophysitis (often postpartum), and granulomatous infiltration. Pituitary hormone deficiencies occasionally develop without apparent cause, although the most common cause in adults is a pituitary tumor, or treatment with surgery or irradiation.
ACTH deficiency is generally a late manifestation of pituitary disease, following growth hormone deficiency (poor growth in children), gonadotropin deficiency (loss of menses in women, loss of libido in men), and hypothyroidism (see Chap. 45) that is generally mild in pituitary disease but may be symptomatic with fatigue and cold intolerance.
ACTH deficiency produces hypoadrenalism. Loss of pigmentation may be apparent, particularly in children. Hypoadrenalism commonly causes fatigue and hypotension, which is often postural. Hyponatremia may be evident because glucocorticoids contribute to the maintenance of renal free water excretion; symptomatic hypoglycemia can occur. Mineralocorticoid production is regulated chiefly by angiotensin II and the potassium ion, thus mineralocorticoid deficiency does not develop in states of ACTH deficiency.
Isolated ACTH deficiency is rare, because pituitary pathologies such as tumor, radiation, or autoimmune disease typically spare the corticotropes until deficiencies of growth hormone, gonadotropins, and, finally, thyroid-stimulating hormone emerge. However, most cases of isolated ACTH deficiencies are likely to be autoimmune because of an association with other autoimmune disorders67 or antipituitary antibodies.68 Congenital ACTH deficiency that is due to a defect in POMC cleavage has been described.69 Undetectable ACTH levels, normal cortisol levels, and increased cortisol secretory sensitivity to ACTH have been reported in a single patient. Two point mutations of the ACTH receptor gene were detected, suggesting the existence of an ACTH hypersensitivity syndrome.70 Acquired isolated CRH deficiency has also been suggested, based on a lack of ACTH response to insulin hypoglycemia but a normal response to exogenous CRH.71 The CRH stimulation test will probably not allow sufficiently accurate separation of pituitary or hypothalamic causes of ACTH deficiency58 to be used as a gold standard test, but it may be useful along with other tests to assist clinical decision making.
A transient functional deficiency of ACTH release occurs after prolonged supraphysiologic glucocorticoid exposure, such as occurs in response to treatment with antiinflammatory doses of glucocorticoids or to correction of Cushing syndrome. Rapid restoration of ACTH release with CRH infusion suggests that the defect may be due predominantly to reduced CRH secretion.72 This functional deficiency may last for as many as 2 years before normal HPA axis dynamics are restored, although a 6- to 9-month recovery course is often observed.73

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