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Beyond Adrenal and Ovarian Androgen Generation: Increased Peripheral 5-Reductase Activity in Women with Polycystic Ovary Syndrome

Department of Medicine, Endocrine and Diabetes Unit, University of Würzburg (M.F., N.S., S.B.S., B.A., W.A.), 97080 Würzburg; and Steroid Research Unit, Center of Pediatrics and Adolescent Medicine, Justus Liebig University (S.A.W.), 35392 Giessen, Germany

Address all correspondence and requests for reprints to: Wiebke Arlt, M.D., Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom. E-mail: w.arlt{at}bham.ac.uk.

Hyperandrogenism, a main clinical feature of polycystic ovary syndrome (PCOS), is thought to result from enhanced ovarian and adrenal androgen generation. To investigate the contribution of peripheral steroidogenesis, we used an oral challenge with dehydroepiandrosterone (DHEA) and analyzed its downstream conversion toward androgens in eight women with PCOS (age, 20–32 yr; body mass index, 20–41 kg/m²) and eight healthy women matched for age and body mass index. They underwent frequent serum sampling and urine collection for 8 h on three occasions: at baseline, and after 4 d of dexamethasone (Dex; 4 x 0.5 mg/d), followed by ingestion of 100 mg DHEA or placebo. Dex induced similar significant suppression of circulating steroids in both groups. The oral DHEA challenge led to similar significant increases in the area under the concentration-time curve (0–8 h after Dex) of serum DHEA, DHEA sulfate, androstenedione, and testosterone. However, after oral DHEA, PCOS women had significantly higher increases in serum 5-dihydrotestosterone (P < 0.01), its main metabolite androstanediol glucuronide (P < 0.05), and the 5-reduced urinary androgen metabolite androsterone (P < 0.05). PCOS women also had significantly higher baseline excretion of 5-reduced glucocorticoid (P < 0.01) and mineralocorticoid metabolites (P < 0.05). Taken together, these data indicate enhanced peripheral 5-reductase activity in PCOS. Thus, not only ovary and adrenal, but also liver and peripheral target tissues, significantly contribute to steroid alterations in PCOS.

W.A. is a DFG Heisenberg Senior Clinical Fellow (Ar 310/3-1). Establishment of GC-MS urinary steroid analysis was made possible by DFG Research Grant Re 753/5–1 (to S.A.W.).

Abbreviations: A’dione, 4-Androstene-3,17-dione; ADG, 5-androstane-3,17ß-diol-17-glucuronide; An, androsterone; AUC_{(0–8 h)}, area under the curve (0–8 h); Dex, dexamethasone; DHEA, dehydroepiandrosterone; DHEAS, DHEA sulfate; DHT, 5-dihydrotestosterone; E2, 17ß-estradiol; Et, etiocholanolone; GC-MS, gas chromatographic-mass spectrometric; PCOS, polycystic ovary syndrome; T, testosterone; THA, tetrahydro-11-dehydrocorticosterone; THB, tetrahydrocorticosterone; THE, tetrahydrocortisone; THF, tetrahydrocortisol.

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