Increased clearance of cortisol by 5 beta-reductase in a subgroup of women with adrenal hyperandrogenism in polycystic ovary syndrome

A. Gambineri, G. Forlani, A. Munarini, F. Tomassoni, G. E. Cognigni, W. Ciampaglia, U. Pagotto, B. R. Walker, R. Pasquali

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: Increased peripheral metabolism of cortisol may explain compensatory ACTH-dependent adrenal steroidogenesis and hence hyperandrogenism in polycystic ovary syndrome (PCOS). Previous studies have described an increased 5 alpha-reduction of cortisol or impaired regeneration of cortisol by 11 beta-HSD1 in PCOS. However, these observations may be confounded by obesity. Moreover, the relationship between alterations in cortisol metabolism and the extent of adrenal androgen hyper-secretion in response to ACTH has not been established. This study aimed to examine the association between cortisol metabolism and ACTH-dependent adrenal hyperandrogenism in PCOS, independently of obesity. Design: We compared 90 PCOS women (age 18-45 yr) stratified by adrenal androgen responses to ACTH(1-24) and 45 controls matched for age and body weight. Methods: PCOS women were stratified as normal responders (NR), intermediate responders (IR), and high responders (HR) to 250 mu g ACTH(1-24): NR (no.=27) had androstenedione and DHEA responses within 2 SD of the mean in controls; IR (no.=43) had DHEA responses > 2 SD above controls; HR (no.=20) had both androstenedione and DHEA responses > 2 SD above controls. Results: All groups were similar for age, body weight, and body fat distribution. Basal testosterone, androstenedione, and 5 alpha-dihydrotestosterone plasma levels were similarly elevated among the 3 groups of PCOS compared with controls, whereas basal DHEA-S was higher in HR (2.8 +/- 1.2 mu g/ml) and IR (2.4 +/- 1.1 mu g/ml) than in NR (1.8 +/- 0.8 mu g/ml) and controls (1.7 +/- 0.6 mu g/ml). The HR group had the lowest basal plasma cortisol levels (101 +/- 36 ng/ml vs IR 135 +/- 42 ng/ml, NR 144 +/- 48 ng/ml, and controls 165 +/- 48 ng/ml; all p<0.01), but the greatest cortisol response to ACTH(1-24) (Delta((60.0))cortisol 173 +/- 60 ng/ml vs IR 136 +/- 51 ng/ml, NR 114 +/- 50 ng/ml, and controls 127 +/- 50 ng/ml; all p<0.01), and the highest urinary excretion of total and 5 beta-reduced cortisol metabolites (eg 5 beta-tetrahydrocortisol/cortisol ratio 25.2 +/- 15.3 vs IR 18.8 +/- 10.7, NR 19.7 +/- 11.4, and controls 17.2 +/- 13.7; all p<0.05). There were no differences in urinary excretion of 5 alpha-reduced cortisol metabolites or in 5 alpha-dihydrotestosterone/testosterone ratio between groups. Conclusions: Adrenal androgen excess in PCOS is associated with increased inactivation of cortisol by 5 beta-reductase that may lower cortisol blood levels and stimulate ACTH-dependent steroidogenesis. (J. Endocrinol. Invest. 32: 210-218, 2009) (C) 2009, Editrice Kurtis

Original languageEnglish
Pages (from-to)210-218
Number of pages9
JournalJournal of Endocrinological Investigation
Volume32
Issue number3
Publication statusPublished - Mar 2009

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