Functional evaluation of the hypothalamic-pituitary-adrenal axis

The regulation of hypothalamic pituitary-adrenal (HPA) axis is controlled by three major factors: stress, circadian rhythm and negative feedback. Hypothalamic CRF binds to CRF receptor on ACTH cells and stimulates synthesis and secretion of ACTH. However, vasopressin binds to V1b receptor and enhances CRF induced ACTH secretion. ACTH stimulate secretion of cortisol and DHEA-S. Cortisol inhibits secretion of CRF and ACTH with negative feedback mechanism. To evaluate the ability of the hypothalamus to secrete CRF, insulin-induced hypoglycemia and metyrapone tests are used. For evaluation of the secretion of pituitary ACTH and adrenal cortisol, a CRF test is useful. Autonomic secretion of ACTH and/or cortisol is evaluated with a dexamethasone suppression test.     

Abnormal pituitary function during melancholia: reduced alpha-melanocyte-stimulating hormone secretion and increased intact ACTH non-suppression.

In order to investigate pituitary alpha-melanocyte-stimulating hormone (alpha-MSH), intact (1-39 structure) adrenocorticotropic hormone (ACTH), and adrenal cortisol secretion, we measured 8 a.m. plasma levels of those hormones before and after administration of 1 mg dexamethasone in 39 depressed inpatients and 10 healthy controls. We found a significantly lower baseline alpha-MSH secretion in melancholic patients as opposed to healthy controls. There were no significant relations between alpha-MSH secretion on the one hand and ACTH or cortisol secretion on the other. Dexamethasone did not affect the 8 a.m. alpha-MSH circulating levels. The post-dexamethasone intact ACTH and cortisol values were significantly higher in melancholics as compared with healthy, minor and simple major depressed subjects. ACTH non-suppression was defined as post-dexamethasone intact ACTH greater than or equal to 12 pg/ml. ACTH non-suppression was found to be more sensitive (70%) and specific (100%) for melancholia than cortisol non-suppression. By means of pathway analysis we have established that cortisol non-suppression during a severe depression is completely determined by an augmented ACTH escape from suppression by dexamethasone. It is concluded that the assay of post-dexamethasone intact ACTH could, in the future, replace post-dexamethasone cortisol determination.     

Cyclical Cushing's disease. A case report.

A 41-year-old man with clinical Cushing's syndrome and intermittent central ACTH hypersecretion for a period of 9 1/2 years follow-up is described. Episodes of biochemical and clinical remission alternated with periods of florid Cushing's disease, characterized by circadian hyperpulsatile ACTH and cortisol secretion. Responses to metyrapone and inhibition of ACTH and cortisol hypersecretion after high dose dexamethasone during active phases of the disease favored a central origin of ACTH hypersecretion, confirmed by simultaneous bilateral venous sampling of the sinus petrosus inferior. Prolonged clinical remission followed near total anterior hypophysectomy. However, on anatomopathological examination of the pituitary neither corticotroph cell hyperplasia nor a microadenoma could be documented. The possibility of a functional ACTH hypersecretion is discussed.     

Different therapeutic efficacy of ketoconazole in patients with Cushing's syndrome

Summary The property of ketoconazole to inhibit adrenal biosynthesis of cortisol was used in a clinical study of 14 patients with Cushing's syndrome (pituitary-dependent Cushing's disease,n=10; adrenocortical adenoma,n=2; adrenocortical carcinoma,n=1; ectopic ACTH syndrome,n=1). Five patients were treated in a short-term manner (1000 mg over 24 h) and nine patients for a longer period (600 mg/die from 1 week up to 12 months). After short-term administration of ketoconazole, serum cortisol levels fell distinctly only in the patient with adrenocortical adenoma, but not at all or only slightly in the other patients, whereas serum levels of progesterone and 11-deoxy-compounds increased markedly in all patients, with the exception of the patient with adrenocortical carcinoma. Plasma ACTH levels increased in the patients with Cushing's disease but not in the patients with tumor. After long-term treatment of three patients with Cushing's disease over 3, 10, and 12 months, the clinical signs of hypercortisolism persisted or were only slightly ameliorated. In these three patients as well as in three other patients with Cushing's disease treated for a shorter period of 1 to 4 weeks, serum and urinary cortisol levels decreased, but were not normalized, whereas plasma ACTH levels increased variably. Only in one patient with Cushing's disease, in the second patient with adrenocortical adenoma, and in the patient with ectopic ACTH syndrome, serum and urinary cortisol levels returned to normal. We concluded from our data, that the antimycotic drug inhibits biosynthesis of cortisol by blocking adrenal 11- and 17-hydroxylase activity. This effect was compensated in part by a rebound increase of pituitary ACTH secretion in most patients with Cushing's disease. Therefore, ketoconazole treatment is above all effective in patients with Cushing's syndrome due to an adrenal tumor or in patients with ectopic ACTH syndrome, who cannot respond with an increased pituitary ACTH secretion.Abbreviations ACTH Adrenocorticotropic hormone - AA Adrenocortical adenoma - AC Adrenocortical carcinoma - B Corticosterone - CRH Corticotropin-releasing hormone - EAS Ectopic ACTH syndrome - PDCD Pituitary-dependent Cushing's disease - P Progesterone - 17OH-P 17-hydroxyprogesterone - RIA Radioimmunoassay - S 11-deoxycortisol - DOC 11-deoxycorticosterone     

The corticotropin-releasing factor stimulation test. An aid in the evaluation of patients with Cushing's syndrome

We investigated the effect of exogenous corticotropin-releasing factor on plasma levels of ACTH and cortisol in 13 patients with ACTH-secreting pituitary adenomas (Cushing's disease) and in 9 patients with other forms of Cushing's syndrome. In all patients with Cushing's disease, ovine corticotropin-releasing factor, given intravenously as a bolus injection (1 microgram per kilogram of body weight), caused a further increase in the already elevated levels of ACTH and cortisol. Successful transphenoidal adenomectomy was followed as early as one week after surgery by normalization or near-normalization of the ACTH and cortisol responses to corticotropin-releasing factor. On the other hand, patients with the ectopic ACTH syndrome, who also had high basal plasma concentrations of ACTH and cortisol, had no ACTH or cortisol responses to corticotropin-releasing factor. This difference in responsiveness between these two patient groups cannot be explained on the basis of different metabolic clearance rates of exogenous corticotropin-releasing factor, as shown by similar disappearance curves of immunoreactive corticotropin-releasing factor from plasma. Patients with Cushing's syndrome of adrenal origin who were hypercortisolemic during testing had undetectable plasma levels of ACTH and no ACTH or cortisol responses to corticotropin-releasing factor. We conclude that stimulation of the pituitary-adrenal axis with corticotropin-releasing factor may be useful in differentiating pituitary from ectopic causes of Cushing's syndrome.     

Interleukin-6 response to isokinetic exercise in elite athletes: relationships to adrenocortical function and to mechanical and myoelectric fatigue

Exercise stimulates the release of interleukin-6 (IL-6). Aims of the study were to: (a) analyse the IL-6 response to exercise in power (n = 7) and endurance athletes (n = 13); (b) determine the effects of the IL-6 production on mechanical and myoelectric fatigue; (c) evaluate the relationship between IL-6 and adrenocortical responses. EMG variables (conduction velocity, mean power frequency, average rectified value), ACTH, cortisol, DHEA, IL-6, myoglobin, and lactate were analysed before and after an isokinetic exercise. The exercise elicited significant mechanical and myoelectric fatigue as well as significant biochemical responses. Power athletes showed IL-6 and lactate responses higher than endurance athletes. The correlation analyses showed that the greater the mechanical fatigue, the greater the increases in lactate and IL-6. No correlations were found between IL-6 and EMG variables. No relationships were found between IL-6 and cortisol, after correction for ACTH levels. In conclusion, the muscular IL-6 production, as inferred by its circulating levels, had no detectable effects on the myoelectric manifestations of fatigue and the cortisol response to exercise was not related to the amount of circulating IL-6, but only to the activation of ACTH secretion.     

Evidence for existence of cortical androgen-stimulating hormone.

An animal model using dexamethosone-suppressed, castrated dogs was developed to test the hypothesis that a pituitary hormone other than ACTH modulates adrenal androgen (AA) secretion. Plasma samples were obtained every 15 min during infusions of saline, synthetic alpha 1-24 corticotropin, porcine 1-39 corticotropin (ACTH), or bovine pituitary gland extract (PE) in a wide range of doses. Androstenedione (A), dehydroepiandrosterone (DHA), and cortisol (F) were quantified by radioimmunoassay. When the ratio of AA levels was related to those of F, in order to correct for ACTH content in the PE, the slopes of the dose-response curves for corticotropin and PE were different at the 0.01 level. For A the dose-response slope for the PE was 0.18 +/- 0.5 SE, whereas that of ACTH was 0.02 +/- 0.01. For the DHA response the slopes were 0.17 +/- 0.04 for the PE and 0.04 +/- 0.03 for ACTH. Related studies showed no increase in AA levels in response to luteinizing hormone-releasing hormone, bovine growth hormone (GH), bovine prolactin, ovine thyroid-stimulating hormone (TSH), or synthetic aqueous arginine vasopressin (AVP). We conclude that a pituitary factor other than ACTH, prolactin, GH, luteinizing hormone, follicle-stimulating hormone, TSH, or AVP may be responsible for the observed increase in AA concentrations.     

Pituitary and adrenal functions during late asthmatic responses

The purpose of the present study was to examine the role of low cortisol levels which were observed during late asthmatic responses (LAR). Selective functions of the adrenals and pituitary glands were studied in three groups of asthmatics who showed LAR, immediate asthmatic responses (IAR), and DAR (dual asthmatic responses). Serial plasma ACTH levels in each group showed no apparent abnormalities when compared with diurnal levels. The cortisol response to ACTH changed within the normal range in all three groups with minor differences. We suggest that low cortisol levels that appear during LAR are not principally due to any dysfunction in the pituitary adrenal system.     

Corticotropin deficiency: a rare cause of hyponatremia mimicking SIADH.

We describe 2 patients presenting with severe chronic hyponatremia in whom clinical and biochemical features strongly suggested the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Both, however, were proven to have a primary pituitary deficiency of corticotropin. Their short synacthen tests were only mildly abnormal but associated with low basal ACTH levels. The diagnosis of ACTH deficiency was made more convincingly by their dramatic response to glucocorticoid replacement therapy. In patients in whom no cause for SIADH can be found, a trial of maintenance cortisol therapy is warranted to exclude this eminently treatable condition.     

The oCRH stimulation test before and after clinical recovery from depression

A substantial body of data suggests that excessive cortisol secretion in depression may result from a dysregulation at several sites within the hypothalamic-pituitary-adrenocortical (HPA) axis. These alterations in regulatory mechanisms are thought to be the result of a hypothalamic 'overdrive' of corticotropin-releasing hormone (CRH). Previous studies have demonstrated a diminished adrenocorticotropin (ACTH) secretory response, as well as a heightened adrenocortical responsiveness after ovine-CRH administration in depressed patients. In the present investigation, we examined pituitary and adrenocortical responsiveness after an ovine-CRH stimulation test before and during clinical recovery in seven depressed patients. Cumulative ACTH responses increased significantly during clinical recovery (P = 0.014). Paradoxically, maximum and peak cortisol responses increased after recovery, suggesting that heightened adrenocortical responsiveness to ACTH during depression may take longer to 'normalize' than abnormal pituitary responsiveness to ovine-CRH stimulation.     

Effect of selection for behavior on pituitary-adrenal axis and proopiomelanocortin gene expression in silver foxes (Vulpes vulpes)

Silver foxes from a commercial population (farm bred or unselected for behavior control) and from populations selected for tame behavior and enhanced aggressiveness towards man have been investigated. Plasma cortisol and adrenocorticotropic hormone (ACTH) levels, pituitary ACTH levels, POMC gene expression in the anterior pituitary, and corticotropin-releasing factor (CRF) gene expression in the hypothalamus were assessed. The results indicate that the males from the tame-behavior group have lower plasma cortisol and ACTH levels and POMC gene expression in the anterior pituitary in response to capture and handling in comparison with unselected ones. Foxes from the aggressive behavior group also have lower POMC expression, although plasma cortisol and ACTH levels remain the same as in unselected ones. The three groups of animals show no significant changes in the ACTH level in the pituitary and CRF expression in the hypothalamus.     

Silent corticotroph adenomas: further clinical and pathological observations

Adrenocorticotroph cell pituitary adenomas immunoreactive for adrenocorticotropic hormone (ACTH) but unassociated with preoperative signs of hypercortisolism constitute between 6% and 43% of all ACTH adenomas. Few large series have been published. At our referral center for pituitary diseases, we have encountered 12 patients with silent ACTH adenomas, none of whom exhibited definite clinical features of hypercortisolism preoperatively. Two patients presented with apoplexy, and in 2 patients preoperative neuroimaging studies mimicked craniopharyngioma. Pathological examination revealed 8 adenomas with variably basophilic cytoplasm (type I, including 1 each with coarse basophilic granules and Crooke's hyaline change) and 4 with predominantly chromophobic cytoplasm (type II). Diffuse versus patchy (30% to 50% of cells) immunostaining best distinguished these 2 types; calcitonin staining was focal or negative in both. Two patients had unexpected postoperative courses consistent with acute cortisol insufficiency; 1 patient suffered from a severe flu-like illness, and the other had dizziness and was found to have a serum cortisol level of < 1.0 microg/dL. Both patients improved after cortisol replacement followed by a slow taper. Another patient developed 2 separate pituitary adenomas, a silent ACTH adenoma followed by a pure prolactinoma resected months later. Clonality studies demonstrated that the 2 tumors had arisen from different clonal populations. These cases offer additional insights into clinical, neuroimaging, histological, and biological features of silent ACTH adenomas. Because 2 of these patients seemed to require postoperative cortisol supplementation that otherwise would not have been given, clinicians should be notified about ACTH immunostaining in adenomas from patients without preoperative diagnoses of Cushing's disease, to optimize postoperative care.     

Dose-dependence of bacterial lipopolysaccharide (LPS) effects on peak response and time course of the immune-endocrine host response in humans

OBJECTIVE AND DESIGN: Dose-dependence of lipopolysaccharide (LPS) effects on peak and time course parameters of the immune-endocrine host response was examined in a placebo-controlled design. SUBJECTS: Data from 42 male volunteers were included. TREATMENT: 0.4 or 0.8 ng LPS/kg body weight were applied at 7.00 p.m. METHODS: Body temperature, heart rate and leukocyte counts were quantified. Plasma levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), adrenocorticotropic hormone (ACTH), cortisol and human growth hormone (hGH) were measured. RESULTS: LPS increased significantly the levels of immune (TNF-alpha, IL-6) and endocrine (ACTH, cortisol) parameters. HGH secretion was advanced without changes in the total amount of hGH released. Dose-dependence of endotoxin's effects was significant for neuroendocrine (cortisol) and physiological (temperature, heart rate) parameters. Examination of time course parameters demonstrated that the higher dose of endotoxin prolonged the increases in temperature, IL-6 and cortisol levels. CONCLUSIONS: Our data show that increases in the dosage of LPS lead to differential peak responses and changed time course patterns of the human host response.     

Influence of sodium balance on ACTH/adrenal corticosteroid dose-response curves in the dog

In order to define short-term ACTH/corticosteroid dose-respone characteristics, we infused ACTH for 1 h at each of five incremental rates into pedigreed male beagle dogs in four different states of sodium balance. Progressive sodium depletion was associated with progressive increased in basal (pre-ACTH) plasma levels of renin, angiotensin II, aldosterone, 18-hydroxycorticosterone (18-OH-B), and 18-hydroxy-11-deoxycorticosterone (18-OH-DOC). Administration of dexamethasone significantly reduced the preinfusion levels of cortisol, aldosterone, 18-OH-B, and 18-OH-DOC. The threshold dose of ACTH required to elicit an aldosterone response during low-sodium intake was similar to that for cortisol, but was higher during normal or high-sodium intake. Steepest portions of the dose-response curves were at lower rates of ACTH infusion for cortisol than for aldosterone, and maximum increment was much greater for cortisol (60-fold) than for aldosterone (12-fold). Whereas the slopes of ACTH/aldosterone and ACTH/18-OH-B dose-response curves were steepened by lower sodium diets, the ACTH/cortisol response was significantly flattened by severe sodium depletion. We conclude that ACTH is a potent and direct-acting short-term regulator of aldosterone secretion, subject to modification by altered sodium balance.     

Proopiomelanocortin-Derived Peptides and Cytokines: Relations in Patients with Acquired Immunodeficiency Syndrome

α-Melanocyte-stimulating hormone (α-MSH), adrenocorticotropic hormone (ACTH), β-endorphin, cortisol, and the cytokines interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNFα) were measured in 80 AIDS patients (group IV CDC) and in healthy hospital personnel. The average plasma α-MSH was significantly greater in AIDS patients than in control subjects; no significant differences between groups were observed in the average concentrations of ACTH, cortisol, and β-endorphin; plasma cytokines were likewise similar in the two groups. Plasma concentrations of α-MSH and ACTH were inversely related in AIDS patients and a similar inverse relation between α-MSH and IL-6 was also observed in these patients. There were positive relations among elevated circulating ACTH, cortisol, IL-6, and high fever in AIDS patients with severe concomitant disease. Plasma α-MSH concentrations within a specific range correlated positively with 6 month survival. Because cytokines can stimulate HIV expression in certain cell types and they are believed to have a role in disease progression in HIV-infected patients, it may be that a potent endogenous modulator of cytokine action such as α-MSH is crucial to survival in these patients.     

Corticotropin releasing hormone increases apparent potency of adrenocorticotropic hormone stimulation of cortisol secretion.

HYPOTHESIS: Corticotropin releasing hormone (CRH) has a regulatory effect on cortisol secretion in addition to its classic effect of stimulating adrenocorticotropic hormone (ACTH) secretion. REVIEW: There is growing evidence of "long-loop" and paracrine adrenal stimulation by CRH. Data from a study of the ovine-corticotropin releasing hormone (oCRH) stimulation test in 13 sexually abused girls and 13 normal controls was used in Montecarlo simulations of the hypothalamic-pituitary-adrenal axis, to get estimates of adrenal sensitivity to ACTH and cortisol elimination kinetics before and after oCRH administration. In both controls and sexually abused girls, ACTH had an apparent greater effect on cortisol secretion after administration of oCRH compared to its effect during the baseline period. This lends support to the hypothesis and suggests that it should be tested experimentally.     

Cortisol insufficiency caused by electroconvulsive therapy? A case report

A 30-year-old woman was treated with a series of electroconvulsive therapy (ECT) due to a personality disorder with depressive symptoms. Three days after the last ECT, anisocoria was noticed. It subsided after 2 days, and attacks of syncope, vertigo, anorexia and weight loss started. These symptoms ceased by administration of cortisone acetate and fluoro-cortisone. During an observation time of five years, repeated attempts to omit the cortico-steroids or reduce the cortisone dose to less than 20 mg/day have resulted in immediate symptoms of cortisol deficiency. Plasma adrenocorticotrophin (ACTH) and cortisol and urinary cortisol were low during cortisol withdrawal. Cortisol response to ACTH stimulation and cortisol and ACTH response to hypoglycemia were normal. The cortisol deficiency was considered to be due to a defect in the central nervous regulation of ACTH secretion. As it occurred in close connection to ECT, it seems likely that the treatment induced a defect, or aggravated a preexisting one, in neural pathways controlling corticotrophin-releasing factor and ACTH secretion.     

Evidence that intravenous administration of interleukin-1 stimulates corticotropin releasing hormone secretion in the median eminence of freely moving rats: estimation by push-pull perfusion.

Utilizing push-pull perfusion, we examined secretory profiles of corticotropin releasing hormone (CRH) in the median eminence (ME) and of plasma adrenocorticotropin (ACTH) in freely moving male rats after intravenous bolus injection of recombinant human interleukin (IL)-1 alpha (1.0 microgram) and 1 beta (1.0 microgram). The ME was perfused with artificial cerebrospinal fluid between 11.00 and 14.00 h, and perfusates and blood samples were collected every 20 min. Administrations at 12.00 h of IL-1 alpha and 1 beta, but not vehicle only, resulted in significant increases in both the plasma ACTH and ME-CRH. The rise in ME-CRH clearly preceded the enhanced ACTH secretion. These in vivo data strongly suggest that IL-1 stimulates ACTH secretion, at least in part, by triggering hypothalamic CRH release. This is the first to characterize the temporal profile of CRH secretion in the ME after intravenous administration of IL-1 to freely moving rats.     

Effect of theophylline on cortisol secretion

Theophylline is thought to improve asthma by increasing intracellular cyclic adenosine 3'-5'-monophosphate (cAMP) levels. It has been demonstrated in experimental animals that elevation of intracellular cAMP in the adrenal cortex causes an increased secretion of cortisol. We studied whether therapeutic doses of theophylline given intravenously and orally to human subjects over 3 days would increase cortisol secretion. A single-blind, 6-day protocol was employed in five normal and five asthmatic volunteers. Adrenal function was monitored by 8 A.M. and 4 P.M. serum cortisol and adrenocorticotropic hormone (ACTH) levels; daily 24-hr urine for urinary-free cortisol (UFF), 17-hydroxysteroids (17-OH), and 17-ketosteroids (17-KS); and alternate-day cortisol secretory rates (FSR) measured by isotope dilution after intravenous 14C-cortisol. Serum theophylline concentration also was monitored. Results in normal and asthmatic subjects were similar. Theophylline caused a significant but transient increase in UFF and 17-OH excretion. Urine volumes also increased significantly, suggesting that the renal effect of theophylline accounted for the increased UFF and 17-OH excretion. FSR increased during the first 24 hr after theophylline in eight of nine cases (p < 0.05 by sign test), mean values increasing from 14.2 to 19.3 mg, but this effect had dissipated by day 3 of theophylline administration. In contrast to these findings, theophylline had no effect on serum cortisol or ACTH or urinary 17-KS. It is likely that serum cortisol and ACTH remained unchanged because the increase in cortisol secretion was offset by a concomitant increase in cortisol clearance. It is concluded that theophylline produces a small, transient increase in cortisol secretion and clearance, and this effect is similar in asthmatic and normal subjects.