Endothelin-1 (ET-1) is an indicator of endothelial injury and dysfunction and is elevated in women with androgen excess polycystic ovary syndrome (AE-PCOS). The endothelin B receptor (ET_B R) subtype mediates vasodilatation, but is blunted in women with PCOS. We hypothesized that androgen drives endothelial dysfunction in AE-PCOS women and oestradiol (EE) administration reverses these effects. We assessed microvascular endothelial function in women with (7 lean and 7 obese) and without AE-PCOS (controls, 6 lean, 7 obese). Only obese AE-PCOS women were insulin resistant (IR). We evaluated cutaneous vascular conductance (%CVC_max ) with laser Doppler flowmetry during low dose intradermal microdialysis ET-1 perfusions (1, 3, 4, 5 and 7 pmol) with either lactated Ringer solution alone, or with ET_B R (BQ-788), or nitric oxide (NO) inhibition (l-NAME). Log[ET-1]-%maxCVC dose-response curves demonstrated reduced vasodilatory responses to ET-1 in lean AE-PCOS (logED₅₀ , 0.59 ± 0.08) versus lean controls (logED₅₀ , 0.49 ± 0.09, P < 0.05), but not compared to obese AE-PCOS (logED₅₀ , 0.65 ± 0.09). ET_B R inhibition decreased ET-1-induced vasodilatation in AE-PCOS women (logED₅₀ , 0.64 ± 0. 22, P < 0.05). This was mechanistically observed at the cellular level, with ET-1-induced, DAF-FM-measurable endothelial cell NO production, which was abrogated by dihydrotestosterone in an androgen receptor-dependent manner. EE augmented the cutaneous vasodilating response to ET-1(logED₅₀ 0.29 ± 0.21, 0.47 ± 0.09, P < 0.05 for lean and obese, respectively). Androgens drive endothelial dysfunction in lean and obese AE-PCOS. We propose that the attenuated ET-1-induced vasodilatation in AE-PCOS is a consequence of androgen receptor-mediated, suppressed ET_B R-stimulated NO production, and is reversed with EE.

Frances E. Steele

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