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

Abstract

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/m(2)) 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 alpha-dihydrotestosterone (P < 0.01), its main metabolite androstanediol glucuronide (P < 0.05), and the 5 alpha-reduced urinary androgen metabolite androsterone (P < 0.05). PCOS women also had significantly higher baseline excretion of 5 alpha-reduced glucocorticoid (P < 0.01) and mineralocorticoid metabolites (P < 0.05). Taken together, these data indicate enhanced peripheral 5 alpha-reductase activity in PCOS. Thus, not only ovary and adrenal, but also liver and peripheral target tissues, significantly contribute to steroid alterations in PCOS.

Mild Cutaneous Manifestation in Two Young Women with Extraordinary Hyperandrogenemia

“…The absence of correlation between acne severity and other clinical markers of androgenicity in women suggests that in most cases factors other than hyperandrogenemia are necessary for development of acne [14, 15, 16, 17]. Our cases further support the concept that, in addition to circulating androgens, local in situ androgen production in target tissues and the end-organ ‘sensitivity’ to androgens may also play important roles in the pathogenesis of androgen-dependent dermatoses.…”

Insulin enhances ACTH-stimulated androgen and glucocorticoid metabolism in hyperandrogenic women

“…Previous studies compared these ratios in PCOS and healthy women (19)(20)(21)(22)(23)(24), although none of them assessed the effects of hyperinsulinaemia on these features. As a whole, these studies suggest an increased activity of 5a-reductase in PCOS women.…”

Reproductive Steroid Regulation of Mood and Behavior

“…Similarly, women with PMDD demonstrate altered metabolism of progesterone to ALLO (152), although women with PMDD had an elevated ALLO/progesterone ratio at baseline, and women with PMDD and controls showed the same pattern of results following progesterone administration (152). The concept of altered steroidogenesis conferring vulnerability to reproductive-related illness is supported by research in polycystic ovarian syndrome, which is characterized by enhanced peripheral 5α-reductase activity and results in hyperandrogenism (90) and attendant behavioral symptoms, including depression and anxiety (64). Steroid synthesis may be similarly altered in PMDD such that mood symptoms result from decreased enzymatic conversion of progesterone to ALLO by 5α-reductase and 3α-hydroxysteroid dehydrogenase (3α-HSD) (Fig.…”