Sean K. Cunningham

The overnight single-dose metyrapone test is a simple and reliable index of the hypothalamic-pituitary-adrenal axis

OBJECTIVES The ACTH stimulation test examines adrenal responsiveness but may not examine the entire hypothalamic‐pituitary‐adrenal (HPA) axis and requires parenteral administration. The cortisol response to hypoglycaemia provides an index of activity of the entire HPA axis but is demanding for patients and medical staff. The aim of the present study was to examine the performance of the overnight single‐dose metyrapone test as it provides a simple alternative test for HPA axis function.

Cardiovascular risk markers in obstructive sleep apnoea syndrome and correlation with obesity

Background: High C-reactive protein (CRP) and homocysteine levels are risk factors for cardiovascular disease. Some, but not all, previous studies have reported increased levels of CRP and homocysteine in patients with obstructive sleep apnoea syndrome (OSAS). A study was undertaken to investigate the levels of these factors in carefully selected patients with OSAS and matched normal controls. Methods: CRP and homocysteine levels were measured in 110 subjects following polysomnography (PSG). Non-OSAS patients (group 1) were compared with two patient groups (mild/moderate OSAS (group 2) and severe OSAS (group 3)) group-matched for body mass index (BMI), and a fourth group of patients with severe OSAS who were more obese (group 4). All were free of other disease and similar in age, smoking habits and cholesterol levels. 50 suitable patients were commenced on continuous positive airway pressure (CPAP) treatment after PSG and 49 were reassessed 6 weeks later. Results: CRP levels were similar in groups 1, 2 and 3 (median (interquartile range (IQR)) 1.11 (0.76–2.11) mg/l vs 1.82 (1.20–3.71) mg/l vs 2.20 (1.16–3.59) mg/l; pu200a=u200a0.727, Kruskal-Wallis test), but were significantly higher in group 4 than in the other groups (5.36 (2.42–9.17) mg/l, p<0.05 by individual group comparisons). In multivariate analysis of all subjects, BMI was an independent predictor for CRP levels (βu200a=u200a0.221; pu200a=u200a0.006) but apnoea-hypopnoea index and other measures of OSAS were not. There was no difference in homocysteine levels between all four groups (pu200a=u200a0.1). CPAP did not alter CRP (2.29 (1.32–4.10) vs 2.84 (1.13–5.40) mg/l; pu200a=u200a0.145) or homocysteine levels (8.49 (3.66) vs 9.90 (4.72) μmol/l; pu200a=u200a0.381). Conclusion: CRP and homocysteine levels are not associated with OSAS severity in men but CRP is independently associated with obesity.

THE OVERNIGHT DEXAMETHASONE TEST IS A WORTHWHILE SCREENING PROCEDURE

The overnight low‐dose dexamethasone test is a convenient screening procedure for Cushings syndrome. Claims that the test is associated with a high incidence of ‘false positives’, rendering it of little value particularly in obese and hospital in‐patients, have been investigated in the present study. The data from 100 consecutive subjects undergoing overnight low‐dose dexamethasone tests to examine for the possibility of Cushings syndrome, were reviewed. Cushings syndrome was identified in four patients, normal suppression of cortisol values occurred in 84 patients and 12 patients exhibited false positive results. Differences in body weights, body mass indices or in‐patient status did not distinguish between those subjects with normal suppression of plasma cortisol and those subjects who yielded false positive results. These data indicate that the simple overnight dexamethasone test substituted for the more cumbersome traditional 48‐h dexamethasone test in 84 of 96 patients who did not have Cushings syndrome. Thus the overnight test provides a useful screening procedure but a small percentage of patients, approximately 12.5%, will require additional procedures to exclude Cushings syndrome.

The Relationship between Sex Steroids and Sex-Hormone-Binding Globulin in Plasma in Physiological and Pathological Conditions

Physiological and many pathological changes in plasma sex-hormone-binding globulin (SHBG) levels have been attributed to the opposing effects of androgens which lower, and oestrogens which elevate, levels. We examined four clinical situations in which changes in SHBG levels may not be explained by sex steroid alterations. (1) Dexamethasone caused an increase in SHBG levels in hyperandrogenaemic hirsute women whether or not androgens were suppressed. (2) In male patients with untreated isolated gonadotrophin deficiency there was a highly significant correlation between SHBG levels and age, but there was no relationship between the levels of SHBG and those of plasma testosterone, androstenedione or DHEAS. (3) Two 46-XY siblings, phenotypic female subjects with complete androgen insensitivity, demonstrated a marked decline in SHBG levels between the ages of 9–13 and 12–16 years. (4) SHBG was suppressed in obese oligomenorrhoeic women while plasma concentrations of testosterone, androstenedione and oestradiol were normal and that of oestrone was elevated; however, the testosterone: SHBG ratio, an index of free testosterone, was elevated. These observations indicate that the decline in SHBG levels which normally occurs in men during the second decade of life is independent of androgen activity and is under the influence of as yet unidentified factors. Glucocorticoids in small doses increase SHBG levels independently of sex steroid alterations while elevated free testosterone concentration may contribute to suppression of SHBG in obesity.

ADRENAL ABNORMALITIES IN IDIOPATHIC HIRSUTISM

The possibility that abnormal adrenal androgen production may be present in patients with idiopathic hirsutism was examined. Plasma testosterone, dihydrotestosterone and androstenedione levels were elevated in hirsute patients. In response to exogenous α1–24 ACTH the increments in plasma androstenedione, dehydroepiandrosterone (DHA) and cortisol were significantly greater in hirsute patients than in normal subjects. The testosterone response was exaggerated following endogenous stimulation induced by metyrapone. Treatment with dexamethasone, 0.5 mg each night for 3 months, corrected both the androgen excess and the exaggerated androgen responses but not the excessive cortisol response to stimulation. These observations indicate adrenal abnormalities in idiopathic hirsutism. The dissociation of cortisol and adrenal androgen responsiveness following dexamethasone suggests that the abnormalities observed may be due to excessive adrenal androgen production stimulated by a dexamethasone‐suppressible factor other than ACTH. Excess adrenal androgen production may be the primary disorder leading to the development of idiopathic hirsutism.

The effect of prolactin, human chorionic gonadotropin, insulin and insulin-like growth factor 1 on adrenal steroidogenesis in isolated guinea-pig adrenal cells

The controlling mechanism for adrenal androgen production has not been elucidated. The presence of receptors for prolactin, human chorionic gonadotropin (hCG), insulin and insulin-like growth factor 1 (IGF-1) in the adrenal cortex raises the possibility of their involvement in the control of adrenal steroidogenesis. This study was undertaken to investigate the effects of prolactin, hCG, insulin and IGF-1 in the presence and absence of ACTH on cortisol and androgen production using isolated guinea-pig adrenal cells. hCG 10(-7) and 10(-6) M significantly increased cortisol (P < 0.05) production. hCG 10(-6) M significantly increased androstenedione (A4) (P < 0.05) production. In the presence of ACTH, 10(-12) M, hCG 10(-6) M significantly increased the cortisol (P < 0.01) and A4 (P < 0.01) responses. Although the mean cortisol and A4 response to ACTH 10(-9) M was reduced in the presence of hCG 10(-6) M, this was not statistically significant. Prolactin 10(-8) M increased cortisol (P < 0.01), A4, and dehydroepiandrosterone (P < 0.05) production. In the presence of ACTH 10(-12) M, prolactin 10(-8) M increased the cortisol and A4 (P < 0.05) responses. However, the maximally ACTH-stimulated cortisol and A4 responses were not significantly altered in the presence of prolactin 10(-8) M. Insulin 10(-11)-10(-8) M and IGF-1 10(-10)-10(-7) M resulted in no significant increase in cortisol, A4 or dehydroepiandrosterone production. This study suggests that prolactin and hCG could play a role in modulation of adrenal steroidogenesis, particularly when ACTH levels are low. However, there was no evidence that prolactin or hCG is the specific cortical androgen stimulating hormone.

Dissociation of adrenal androgen and cortisol secretion in Cushing's syndrome

OBJECTIVES While ACTH may modulate adrenal androgen production, there is evidence that other factors are required. Cushings disease and ectopic ACTH secretion provide a little utilized opportunity to examine adrenal androgen levels in conditions of ACTH excess. We have compared plasma cortisol values with plasma levels of androstenedione, dehydroeplandrosterone (DHEA), DHEA‐sulphate (DHEAS), testosterone and an Index of free testosterone, the testosterone/sex hormone binding globulin ratio, prior to treatment in patients with Cushings syndrome.

Altered androstenedione and estrone dynamics associated with abnormal hormonal profiles in amenorrheic subjects with weight loss or obesity

The present study was designed for exploration of hormonal disturbances underlying common forms of amenorrhea. Polycystic ovary syndrome (PCO) patients and obese amenorrheic subjects had significantly elevated estrone (E1) levels, elevated luteinizing hormone/follicle-stimulating hormone ratios, and an exaggerated luteinizing hormone response to luteinizing hormone-releasing hormone. However, androstenedione (delta 4A), the precursor of E1, was elevated only in PCO. Thus, the E1/delta 4A ratio, which provides an indirect index of aromatase activity in extraglandular sites, was raised in obese subjects as a group but not in PCO subjects. These findings suggest that elevated E1 levels, which give rise to abnormal gonadotropin secretion, arise from increased available androgens in PCO but from an increased effect of aromatase (present in adipose tissue) in obese subjects. Measurement of androgens and the E1/delta 4A ratio provides insights into the relative contributions of hyperandrogenemia and enhanced aromatase activity to the genesis of amenorrhea in these groups. In patients with suppressed estradiol levels associated with hyperprolactinemia or weight loss, follicle-stimulating hormone levels were suppressed, while luteinizing hormone was not elevated. Prolactin excess explains these findings in hyperprolactinemia. Plasma E1 levels and the E1/delta 4A ratio were suppressed in patients with weight loss, possibly as a consequence of reduced adiposity. This finding suggests that hypothesis that a minimum level of E1, dependent upon adequate adiposity, is critical for the normal mature function of the hypothalamic-pituitary-ovarian axis. Abnormal E1/delta 4A ratios, high in obesity-associated amenorrhea and suppressed in weight loss-associated amenorrhea, may provide specific markers for these groups of patients.

The role of plasma renin activity in evaluating the adequacy of mineralocorticoid replacement in primary adrenal insufficiency

BACKGROUNDu2003Elevation of plasma renin activity (PRA) is a feature of mineralocorticoid deficiency in patients with primary adrenal insufficiency. This study was designed to assess the usefulness of PRA as an index of adequacy of fludrocortisone (FC) replacement in patients with primary adrenal failure, paying particular attention to the variability in PRA levels during FC and glucocorticoid treatment.

Effects of pro-opiomelanocortin-derived peptides on adrenal steroidogenesis in guinea-pig adrenal cells in vitro

The specific control of adrenal androgen secretion is unclear. This study was undertaken to investigate the effects of peptides derived from the ACTH precursor molecule pro-opiomelanocortin (POMC) on cortisol and androgen production using isolated guinea-pig adrenal cells. ACTH 10(-13)-10(-9)M, stimulated steroid production in a dose dependent manner, reaching a maximum of 12, 10 and 7 times basal levels for cortisol, androstenedione (A4) and dehydroepiandrosterone (DHEA), respectively, measured by specific radioimmunoassays. beta-Lipotropin (beta-LPH), 10(-10)-10(-8) M, also stimulated steroid production, reaching 6, 5 and 5 times basal levels of cortisol, A4 and DHEA, respectively. The N-terminal 16K fragment, gamma 3- and beta-MSH stimulated steroid production which reached statistical significance (P < 0.05) only in the case of cortisol. Joining peptide, alpha-, beta- and gamma-endorphin resulted in no significant change in steroid production. Met- and leu-enkephalin resulted in significant inhibition of DHEA production. POMC-derived peptides altered the steroid response to ACTH. beta-LPH and 16K fragment significantly increased the cortisol and A4 responses to a low concentration of ACTH. beta-LPH reduced the maximum cortisol and A4 responses to a high concentration of ACTH. This study suggests that beta-LPH may have a role in modulation of adrenal steroidogenesis but yielded no evidence to support a role for POMC-derived peptides in preferential stimulation of adrenal androgen production in guinea-pig adrenal cells.