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

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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
Issue number3
Publication statusPublished - Mar 2009

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