Metformin’s action on the polycystic ovary syndrome

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The polycystic ovary syndrome (PCOS) is a common endocrinopathy, affecting at least 5 to 15% of reproductive-aged women [98]. The revised diagnostic criteria of PCOS associated menstrual disturbance and/or hyperandrogenism and/or polycystic ovary on ultrasound [99]. It is now recognized that insulin resistance is a common but not an imperative feature in PCOS. As a consequence, insulin sensitizers have been proposed as a pharmaceutical option in overweight women with PCOS and insulin resistance. Recently, a meta-analysis of 31 clinical trials demonstrated that metformin treatment may increase ovulation, improve menstrual cyclicity, and reduce serum androgen levels in these patients [98]. These beneficial effects of metformin are based on alleviation of insulin excess acting upon ovary and through direct ovarian effects. Insulin was shown to directly stimulate several steroidogenic enzymes in the ovary, such as CYP17, 3β-HSD and StAR protein. By improving insulin sensitivity, metformin reduces CYP17 activity [100]. Furthermore, metformin suppresses androstenedione production by a direct effect on ovarian theca cells and decreases FSH-stimulated 3β-HSD, StAR, CYP11A1 and aromatase activities in both rat granulosa cells and women with PCOS (with reduction of basal and of FSH-stimulated progesterone and estradiol levels as a consequence) [100]. The molecular pathways whereby metformin acts directly on the ovary remain elusive. Recently, it has been demonstrated that metformin treatment increased AMPK activity in rat granulosa cells, leading to subsequent reduction of steroid synthesis [101]. However, it is still unclear whether this effect is AMPK-dependent or not. Pharmacogenetics aspects of metformin action have to be taken into account in the effect of the drug on PCOS. Indeed, data from the Pregnancy in PCOS (PP-COS) trial indicated that a polymorphism in LKB1 gene is associated with a significant decreased chance of ovulation in PCOS patients treated with metformin [102]. Interestingly, metformin has been shown to reduce the risks of abortion in women with PCOS at high risk of pregnancy and neonatal complications by increasing some factors needed for implantation and pregnancy safekeeping, such as IGFBP-1 and glycodelin levels, or uterine artery blood flow [100]. By contrast, metformin reduces factors increasing the abortion risk, such as endometrial androgens receptor expression, plasminogen activator inhibitor-1 (PAI-1) levels and plasmatic endothelin-I (ET-1). Most of theses effects are probably mediated by the metformin-induced improvement in insulin sensitivity. From a clinical point of view, metformin administration should be considered as initial intervention in (overweight or obese) PCOS patients especially when oral contraception is contraindicated or when insulin resistance was present.