Androgens drive microvascular endothelial dysfunction in women with polycystic ovary syndrome: role of the endothelin B receptor

Abstract

Key points Polycystic ovary syndrome (PCOS) is a complex syndrome with cardiovascular risk factors, including obesity and insulin resistance. PCOS is also associated with high androgens, increases the risk of cardiovascular dysfunction in women. Due to the complexity of PCOS, had it has been challenging to isolate specific causes of the cardiovascular dysfunction. Our measure of cardiovascular dysfunction (endothelial dysfunction) was most profound in lean women with PCOS. The endothelin‐1‐induced vasodilation in these PCOS subject, was dependent on the ETBR but was not NO‐dependent. We also demonstrated oestrogen administration improved endothelial function in lean and obese women with PCOS likely because oestrogen increased NO availability. Our studies indicate a primary role for androgens in cardiovascular dysfunction in PCOS. Abstract 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 (ETBR) 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 (%CVCmax) 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 ETBR (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). ETBR 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 ETBR‐stimulated NO production, and is reversed with EE.

The role of androgens in microvascular endothelial dysfunction in polycystic ovary syndrome: does size matter?

“…The findings from Usselman et al . () confirm and expand earlier observations on the important role of hyperandrogenism in contributing to the microvascular endothelial dysfunction in women with PCOS regardless of obesity and IR status. Moreover, treating women with PCOS with either oestrogen or an androgen receptor blocker may be viable treatments for reversing the microvascular endothelial dysfunction in women with PCOS.…”

“…In a recent publication in The Journal of Physiology , Usselman et al . () investigated whether the ET‐B receptor‐mediated microvascular endothelial dysfunction in women with PCOS was related to hyperandrogenism, independent of the effects of obesity and IR. In obese and lean women with and without PCOS, cutaneous microvascular endothelial function was assessed by laser Dopper flowmetry coupled with microdialysis infusions of low‐dose ET‐1 with or without inhibition of ET‐B receptors (BQ‐788) and NO ( l ‐NAME).…”

Blood pressure and hypertension during pregnancy in women with polycystic ovary syndrome: Odense Child Cohort

“…Our data did not allow for a conclusion regarding mechanisms for lower BP in PCOS, but the results could suggest a higher degree of vasodilation in women with PCOS at the beginning of pregnancy. Estrogen displays a vasodilatory function by increasing endothelial nitric oxide synthase and angiotensin converting enzyme 2, acting as a modest antioxidant along with other mechanisms 38,39 . During pregnancy, increased placental estrogen is associated with high levels of sex hormone binding globulin 40 and higher total testosterone 41 .…”

“…Mean BMI in women with PCOS in the present study was 23.3 kg/m 2 , and BMI in women with PCOS and the reference group was comparable. In the present study we did not adjust for BMI, but considered BMI as an intermediary factor and an incorporated part of the PCOS diagnosis, 39 as increased BMI is part of the PCOS feature in most women with PCOS 42 . Additionally, excess weight exacerbates the overall expression of the syndrome 43 and adjusting for BMI would indirectly also adjust for the impact of PCOS.…”

Pathophysiological effects of androgens on the female vascular system

“…The overexposure to androgens is considered the key disruption influencing the clinical features of AE-PCOS. The mechanisms responsible for vascular dysfunction in AE-PCOS are currently unknown, but research also points to the chronic excess androgen milieu [ 38 – 41 ]. The androgenic effects on cardiovascular risk are already apparent in young women with AE-PCOS [ 20 , 21 , 42 – 44 ] and characterized by endothelial dysfunction [ 45 – 48 ].…”