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

Smith PE. Hypophysectomy and a replacement therapy in the rat. Am J Anat 1930; 45:205.

Collip JB, Anderson EM, Thomson DL. The adrenocorticotropic hormone of the anterior lobe. Lancet 1933; 2:347.

Li CH, Beschwind II, Cole RD, et al. Amino acid sequence of a corticotropin. Nature 1955; 176:687.

Lee TH, Lerner AB, Buettner-Janusch U. Isolation and structure of human corticotropin (ACTH). J Am Chem Soc 1959; 81:6084.

Eipper BA, Mains RE. Structure and biosynthesis of pro-adrenocorticotropin/endorphin and related peptides. Endocr Rev 1980; 1:1.

Satoh H, Mori S. Subregional assignment of the proopiomelanocortin gene (POMC) to human chromosome band 2p23.3 by fluorescence in situ hybridization. Cytogenet Cell Genet 1997; 76:221.

Chang AC, Cochet M, Cohen SN. Structural organization of human genomic DNA encoding the proopiomelanocortin peptide. Proc Natl Acad Sci U S A 1980; 77:4890.

Marcinkiewicz M, Day R, Seidah NG, Chretien M. Ontogeny of the prohormone convertases PC1 and PC2 in the mouse hypophysis and their colocalization with corticotropin and a-melanotropin. Proc Natl Acad Sci U S A 1993; 90:4922.

Li CH, Barafi L, Chretien M, Chung D. Isolation and structure of b-LPH from sheep pituitary glands. Nature 1965; 208:1093.

Comuzzie AG, Hixson JE, Almasy L, et al. A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2. Nat Genet 1997; 15:273.

Krude H, Biebermann H, Luck W, et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 1998; 19:155.

Mountjoy KG, Robbins LS, Mortrud MT, Cone RD. The cloning of a family of genes that encode the melanocortin receptors. Science 1992; 257:1248.

Magenis RE, Smith, L, Nadeau JH, et al. Mapping of the ACTH, MSH, and neural (MC3 and MC4) melanocortin receptors in the mouse and human. Mammalian Genome 1994; 5:503.

Shima S, Mitsunaga M, Nakao T, et al. Effect of ACTH on cholesterol dynamics in rat adrenal tissue. Endocrinology 1972; 98:808.

Brody RI, Black VH. Differential ACTH response of immunodetectable HMG CoA reductase and cytochromes P450 (17 alpha) and P450 (21) in guinea pig adrenal outer zone cell types, zona glomerulosa and zona fasciculata. Endocr Res 1991; 17:195.

Frohman LA. Diseases of the anterior pituitary. In: Felig P, Baxter JD, Broadu AE, Frohman LA, eds. Endocrinology and Metabolism, 2nd ed. New York: McGraw-Hill 1987:247.

Gallagher TF, Yoshida K, Roffwarg HD, et al. ACTH and cortisol secretory patterns in man. J Clin Endocrinol Metab 1973; 36:1058.

Krieger DT, Allen W. Relationship of bioassayable and immunoassayable plasma ACTH and cortisol concentration in animal subjects and in patients with Cushing’ disease. J Clin Endocrinol Metab 1975; 10:675.

Horrocks PM, Jones AF, Ratcliffe WA, et al. Patterns of ACTH and cortisol pulsatility over twenty-four hours in normal males and females. Clin Endocrinol (Oxf) 1990; 32:127.

Schurmeyer TH. On the relationship between ACTH and cortisol secretion. Horm Metab Res Suppl 1987; 16:6.

Keller-Wood ME, Dallman MF. Corticosteroid inhibition of ACTH secretion. Endocr Rev 1984; 5:1.

Reincke M, Lehmann R, Karl M, et al. Severe illness. Neuroendocrinology. Ann NY Acad Sci 1995; 771:556.

Grice JE, Jackson RV, Hockings GI, et al. Adrenocorticotropin hyperresponse to the corticotropin-releasing hormone-mediated stimulus of naloxone in patients with myotonic dystrophy. J Clin Endocrinol Metab 1995; 80:179.

Crofford LJ, Engleberg NC, Demitrack MA. Neurohormonal perturbations in fibromyalgia. Baillieres Clin Rheumatol 1996; 10:365.

Munck A, Guyre PM, Holbrook, NJ. Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocr Rev 1984; 5:25.

Sack RL, Lewy AJ, Blood ML, et al. Circadian rhythm abnormalities in totally blind people: incidence and clinical significance. J Clin Endocrinol Metab 1992; 75:127.

Krieger DT. Rhythms of ACTH and corticosteroid secretion in health and disease and their experimental modification. J Steroid Biochem 1975; 6:785.

Luboshitzky R. Endocrine activity during sleep. J Pediatr Endocrinol Metab 2000; 13:13.

Banky Z, Molnar J, Csernus V, Halasz B. Further studies on circadian rhythms after local pharmacological destruction of the serotoninergic innervation of the rat suprachiasmatic region before the onset of the corticosterone rhythm. Brain Res 1988; 445:222.

Desir D, Van Cauter E, Fang VS, et al. Effects of “jetlag” on hormonal patterns. I. Procedures, variations in total plasma proteins, and disruption of adrenocorticotropin cortisol periodicity. J Clin Endocrinol Metab 1981; 52:628.

Levin N, Shinsako J, Dallman M. Corticosterone acts on the brain to inhibit adrenalectomy-induced adrenocorticotropin secretion. Endocrinology 1988; 122:694.

Reul JHM, de Kloet ER. Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation. Endocrinology 1985; 117:2505.

Ratka A, Sutanta W, Bloemers M, de Kloet ER. On the role of brain mineral-ocorticoid (Type I) and glucocorticoid (Type II) receptors in neuroendocrine regulation. Neuroendocrinology 1989; 50:117.

Dallman MF, Akana SF, Levin N, et al. Corticosteroids and the control of function in the hypothalamo–pituitary–adrenal (HPA) axis. Ann NY Acad Sci 1994; 746:22.

Magiakou MA, Mastorakos G, Rabin D, et al. Hypothalamic corticotropin-releasing hormone suppression during the postpartum period: implications for the increase in psychiatric manifestations at this time. J Clin Endocrinol Metab 1996; 81:1912.

Zhang Y, Proneca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372:425.

Licinio J, Mantzoros C, Negrao AB, et al. Human leptin levels are pulsatile and inversely related to pituitary-adrenal function. Nat Med 1997; 3:575.

Heiman ML, Ahima RS, Craft LS, et al. Leptin inhibition of the hypothalamic– pituitary–adrenal axis in response to stress. Endocrinology 1997; 138:3859.

Bornstein SR, Uhlmann K, Haidan A, et al. Evidence for a novel peripheral action of leptin as a metabolic signal to the adrenal gland: leptin inhibits cortisol release directly. Diabetes 1997; 46:1235.

Flier JS. Clinical review 94: What’ in a name? In search of leptin’ physiologic role. J Clin Endocrinol Metab 1998; 83:1407.

Orth DN, Jackson RV, DeCherney GS, et al. Effect of synthetic ovine corticotropin releasing factor: dose response of plasma ACTH and cortisol. J Clin Invest 1983; 71:587.

Vale W, Spiess J, Rivier C, Rivier J. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and b-endorphin. Science 1981; 213:1394.

Castro MG, Morrison E, Perone MJ, et al. Corticotrophin-releasing hormone receptor type 1: generation and characterization of polyclonal antipeptide antibodies and their localization in pituitary cells and cortical neurones in vitro. J Neuroendocrinol 1996; 8:521.

Webster EL, Lewis DB, Torpy DJ, et al. In vivo and in vitro characterization of antalarmin, a nonpeptide corticotropin-releasing hormone (CRH) receptor antagonist: suppression of pituitary ACTH release and peripheral inflammation. Endocrinology 1996; 137:5747.

DeBold CR, Sheldon WR, DeCherney GS, et al. Arginine vasopressin potentiates adrenocorticotropin release induced by ovine corticotropin-releasing factor. J Clin Invest 1984; 73:533.

Al-Damluji S, Perry L, Tolin S, et al. Alpha-adrenergic stimulation of corticotrophin secretion by a specific central mechanism in man. Neuroendocrinology 1987; 45:68.

Chrousos GP, Gold PW. The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 1992; 267:1244.

Jackson RV, Grice JE, Hockings GI, Torpy DJ. Naloxone-induced ACTH release: mechanism of action in humans. Clin Endocrinol (Oxf) 1995; 43:423.

Torpy DJ, Grice JE, Hockings GI, et al. Alprazolam blocks the naloxone-stimulated hypothalamo–pituitary–adrenal axis in man. J Clin Endocrinol Metab 1993; 76:388.

Papanicolaou DA, Wilder RL, Manolagas SC, Chrousos GP. The pathophysiologic roles of interleukin-6 in human disease. Ann Intern Med 1998; 128:127.

Chrousos GP. The hypothalamic–pituitary–adrenal axis and immune-mediated inflammation. N Engl J Med 1995; 332:1351.

Nicholson WE, Davis DR, Sherrell BJ, Orth DN. Rapid radioimmunoassay for corticotropin in unextracted human plasma. Clin Chem 1984; 30:259.

Findling JW, Engeland WC, Raff H. The use of immunoradiometric assay for the measurement of ACTH in human plasma. Trends Endocrinol Metab 1990; 1:283.

Oldfield EH, Doppman JL, Nieman LK, et al. Petrosal sinus sampling with and without corticotropin releasing hormone for the differential diagnosis of Cushing’ syndrome. N Engl J Med 1991; 325:897.

Longui CA, Vottero A, Harris AG, Chrousos GP. Plasma cortisol responses after intramuscular corticotropin 1-24 in healthy men. Metabolism 1998; 47:1419.

Hockings GI, Strakosch CR, Jackson RV. Secondary adrenocortical deficiency: avoiding potentially fatal pitfalls in diagnosis and treatment. Med J Aust 1997; 166:400.

Thaler LM, Blevins L Jr. The low dose (1 µg) adrenocorticotropin stimulation test in the evaluation of patients with suspected central adrenal insufficiency. J Clin Endocrinol Metab 1998; 83:2726.

Streeten DH, Anderson GH Jr, Bonaventura MM. The potential for serious consequences from misinterpreting normal responses to the rapid adrenocorticotropin test. J Clin Endocrinol Metab 1996; 81:285.

Schulte HM, Chrousos GP, Avgerinos P, et al. The corticotropin releasing hormone test: a possible aid in the evaluation of patients with adrenal insufficiency. J Clin Endocrinol Metab 1984; 58:1064.

Avgerinos PC, Nieman LK, Oldfield EH, Cutler GB Jr. A comparison of the overnight and the standard metyrapone test for the differential diagnosis of adrenocorticotrophin-dependent Cushing’ syndrome. Clin Endocrinol (Oxf) 1996; 45:483.

Weber A, Topperi J, Harvey RD, et al. Adrenocorticotropin receptor gene mutations in familial glucocorticoid deficiency: relationships with clinical features in four families. J Clin Endocrinol Metab 1995; 80:65.

Heinrichs C, Tsigos C, Deschepper J, et al. Familial adrenocorticotropin unresponsiveness associated with alacrima and achalasia: biochemical and molecular studies in two siblings with clinical heterogeneity. Eur J Pediatr 1995; 154:191.

Negesser SK, van Seters AP, Kievit J, et al. Long-term results of total adrenalectomy for Cushing’ disease. World J Surg 2000; 24:108.

Jennings AS, Liddle GW, Orth DN. Results of treating childhood Cushing’ disease with pituitary irradiation. N Engl J Med 1977; 297:957.

Karl M, von Wichert G, Kempter E, et al. Nelson’ syndrome associated with a somatic frame mutation in the glucocorticoid receptor gene. J Clin Endocrinol Metab 1996; 81:124.

Newell-Price J, Trainer P, Besser M, Grossman A. The diagnosis and differential diagnosis of Cushing’ syndrome and pseudo-Cushing’ states. Endocr Rev 1998; 19:647.

Orth DN. Cushing’ syndrome. N Engl J Med 1995; 332:791.

Shigemasa C, Kouchi T, Veta Y, et al. Evaluation of thyroid function in patients with isolated ACTH deficiency. Am J Med Sci 1992; 304:279.

Sugiura M, Hashimoto A, Shizawa M, et al. Heterogeneity of anterior pituitary cell antibodies detected in insulin dependent diabetes mellitus and ACTH deficiency. Diabetes Res 1980; 3:11.

Nussey SS, Soo SC, Gibson S, et al. Isolated congenital ACTH deficiency. A cleavage enzyme defect? Clin Endocrinol (Oxf) 1993; 39:381.

Hiroi N, Yakushiji F, Shimojo M, et al. Human ACTH hypersensitivity syndrome associated with abnormalities of the ACTH receptor gene. Clin Endocrinol (Oxf) 1998; 48:129.

Nishihara E, Kimura H, Ishimaru T, et al. A case of adrenal insufficiency due to acquired hypothalamic CRH deficiency. Endocr J 1997; 44:121.

Gomez MT, Magiakou MA, Mastorakos G, Chrousos GP. The pituitary corticotroph is not the rate limiting step in the postoperative recovery of the hypothalamic–pituitary–adrenal axis in patients with Cushing syndrome. J Clin Endocrinol Metab 1993; 77:173.

Graber RL, Ney RL, Nicholson WE, et al. Natural history of pituitary-adrenal recovery following long-term suppression with corticosteroids. J Clin Endocrinol Metab 1965; 25:11.



  1. Execelent data my friend, afiliados elite I just didn’t know what you published, excellent share. afiliados elite

  2. short term car insurance uk I like this weblog very much, Its a real nice position to read and receive information. “Inflation is the one form of taxation that can be imposed without legislation.” by Milton Friedman.

  3. Execelent details my friend, como ganar dinero por internet en peru I just didn’t know what you published, excellent share. como ganar dinero por internet en colombia

  4. You actually make it seem so easy with your presentation but I find this topic to be actually something that I think I would never understand. It seems too complex and extremely broad for me. I’m looking forward for your next post, I will try to get the hang of it!

  5. Thanks for post this information,
    It was really helpful to solve my confusion,

    General and Cosmetic Dentistry

  6. dich vu seo Good Day how are you, this would be one of three sentences Backlinker would post


  8. I can see you happen to be an expert at your field! I am launching a internet site soon, and your details will be very useful for me.. Thanks for all your help and wishing you all the success.

  9. http://generictadalafilcialis.com/ generic cialis from india generic cialis price generic cialis cheap
    daily cialis generic

  10. http://generictadalafilcialis.com/ cialis generic buy generic cialis paroxetine forum cialis generic pills
    spam viagra cialis generic levitra

  11. http://genericviagrasildenafil.com/ soft buy viagra sildenafil sample free herbal buy viagra
    lowest price viagra

  12. http://buycialisg.com generic cialis any good buy Cialis online generic cialis soft
    best price for generic cialis

  13. comment5, http://prednisonerxph.com/ order prednisone, 296829, http://amoxilrxph.com/ amoxicillin 500mg, 8-OOO, http://tadalafilrxpharm.com/ buy Tadalafil, pxpew,

  14. comment5, Tadalafil, [url=”http://tadalafilrxpharm.com/”]Tadalafil[/url], http://tadalafilrxpharm.com/ Tadalafil, uxplc, order Cialis, [url=”http://ordercialisdrugstore.com/”]order Cialis[/url], http://ordercialisdrugstore.com/ order Cialis, 92277, buy amoxil online, [url=”http://amoxilrxph.com/”]buy amoxil online[/url], http://amoxilrxph.com/ buy amoxil online, 8-O,

  15. comment3, viagra prix, [url=”http://viagrafrancepharmacie.com/”]viagra prix[/url], http://viagrafrancepharmacie.com/ viagra prix, vncxq, Viagra cialis generico, [url=”http://viagraitaliafarmacia.com/”]Viagra cialis generico[/url], http://viagraitaliafarmacia.com/ Viagra cialis generico, 447734, Cialis Enter Here, [url=”http://www.cialisonlinepharmacies.com/”]Cialis Enter Here[/url], http://www.cialisonlinepharmacies.com/ Cialis Enter Here, vucyxm, azithromycin price, [url=”http://zithromaxonlinepharmacies.com”]azithromycin price[/url], http://zithromaxonlinepharmacies.com azithromycin price, %[[,

  16. comment6, Buy Generic Cialis, [url=”http://cialisaps.com/”]Buy Generic Cialis[/url], http://cialisaps.com/ Buy Generic Cialis, %[, amoxil online, [url=”http://amoxilfst.com/”]amoxil online[/url], http://amoxilfst.com/ amoxil online, 592, Buy Doxycycline Here, [url=”http://doxycyclineaps.com/”]Buy Doxycycline Here[/url], http://doxycyclineaps.com/ Buy Doxycycline Here, xeqsh,

  17. comment5, Buy Ambien Online, [url=”http://buyambienonlinerew.com/”]Buy Ambien Online[/url], http://buyambienonlinerew.com/ Buy Ambien Online, eev, Generic Valium, [url=”http://genericvaliumrew.com/”]Generic Valium[/url], http://genericvaliumrew.com/ Generic Valium, limdst, Buy Xanax, [url=”http://buyxanaxrew.com/”]Buy Xanax[/url], http://buyxanaxrew.com/ Buy Xanax, 8[[[,

  18. comment2, Buy Valium, [url=”http://buyvaliumrew.com/”]Buy Valium[/url], http://buyvaliumrew.com/ Buy Valium, =-), Generic Xanax, [url=”http://genericxanaxrew.com/”]Generic Xanax[/url], http://genericxanaxrew.com/ Generic Xanax, 4180, Cialis Price, [url=”http://cialispricerew.com/”]Cialis Price[/url], http://cialispricerew.com/ Cialis Price, 8015, Generic Valium, [url=”http://genericvaliumrew.com/”]Generic Valium[/url], http://genericvaliumrew.com/ Generic Valium, =),

  19. comment6, cialis, [url=”http://cialisgeneriquepharmaciefr.com/”]cialis[/url], http://cialisgeneriquepharmaciefr.com/ cialis, gkw,

  20. comment5, Cialis, [url=”http://genericcialiscanadarx.com/”]Cialis[/url], http://genericcialiscanadarx.com/ Cialis, 843,

  21. comment1, Cialis, [url=”http://buycialiscanadarx.com/”]Cialis[/url], http://buycialiscanadarx.com/ Cialis, 735,

  22. comment5, Stress, [url=”http://buyxanaxdgstore.com/”]Stress[/url], http://buyxanaxdgstore.com/ Stress, :-O,

  23. comment6, Viagra Online, [url=”http://buyviagracanadarx.com/”]Viagra Online[/url], http://buyviagracanadarx.com/ Viagra Online, kyjw, Valium, [url=”http://bestpriceval.com/”]Valium[/url], http://bestpriceval.com/ Valium, >:P, Cialis, [url=”http://buycialiscanadarx.com/”]Cialis[/url], http://buycialiscanadarx.com/ Cialis, =(((,

  24. comment6, Xanax lowest price, [url=”http://www.bestpricex.com/”]Xanax lowest price[/url], http://www.bestpricex.com/ Xanax lowest price, uwweim, Cialis Online, [url=”http://ordercialisonlinerx.com/”]Cialis Online[/url], http://ordercialisonlinerx.com/ Cialis Online, 469, No Fax Payday, [url=”http://nofaxpaydayloansnfpl.com/”]No Fax Payday[/url], http://nofaxpaydayloansnfpl.com/ No Fax Payday, 394,

  25. http://ussafepharm.com/ generic cialis 20mg generic Cialis generic cialis 20mg
    buy generic cialis london

  26. http://ussafepharm.com/ cialis generic cheapest buy cialis no prescription generic cialis effectiveness
    generic cialis overnight delivery

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google+ photo

You are commenting using your Google+ account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )


Connecting to %s

%d bloggers like this: