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

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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 5α-reduction of cortisol or impaired regeneration of cortisol by 11β-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 ACTH1–24 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 ug ACTH1–24: 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 5α-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 μg/ml) and IR (2.4±1.1 μg/ml) than in NR (1.8±0.8 μg/ml) and controls (1.7±0.6 μg/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 ACTH1–24 (Δ(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 5β-reduced cortisol metabolites (eg 5β-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 5α-reduced cortisol metabolites or in 5α-dihydrotestosterone/testosterone ratio between groups. Conclusions: Adrenal androgen excess in PCOS is associated with increased inactivation of cortisol by 5β-reductase that may lower cortisol blood levels and stimulate ACTH-dependent steroidogenesis.

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Authors and Affiliations

  1. Division of Endocrinology, Department of Internal Medicine, and Centre for Applied Biomedical Research (C.R.B.A.), S. Orsola-Malpighi Hospital, University Alma Mater Studiorum of Bologna, Via Mas-sarenti 9, 40138, Bologna, Italy

    A. Gambineri, G. Forlani, A. Munarini, F. Tomassoni, U. Pagotto & R. Pasquali MD

  2. Day-Surgery Center, Gynepro Medical, Bologna, Italy

    G. E. Cognigni & W. Ciampaglia

  3. Endocrinology Unit, Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK

    B. R. Walker

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  1. A. Gambineri
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  2. G. Forlani
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  3. A. Munarini
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  9. R. Pasquali MD
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Correspondence to R. Pasquali MD.

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Gambineri, A., Forlani, G., Munarini, A. et al. Increased clearance of cortisol by 5β-reductase in a subgroup of women with adrenal hyperandrogenism in polycystic ovary syndrome. J Endocrinol Invest 32, 210–218 (2009). https://doi.org/10.1007/BF03346454

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