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Treatment of WHO 2: Insulin Sensitizers
Introduction
Affecting 12%–18% of women, depending on diagnostic criteria and population studied, polycystic ovary syndrome (PCOS) is prevalent and underrecognized with serious health impacts for affected women and their families. PCOS is the principal cause of anovulatory female infertility and increases the risk of pregnancy complications, such as miscarriage, fetal anomalies, preeclampsia, and gestational diabetes. PCOS is also associated with a range of metabolic features, which include obesity, metabolic syndrome, type 2 diabetes, and cardiovascular risk factors. PCOS is underpinned by insulin resistance. Obesity, more common in PCOS, increases the prevalence and severity of PCOS by exacerbating insulin resistance. Insulin resistance with compensatory hyperinsulinemia affects up to 85% of women with PCOS. Hyperinsulinemia leads to higher ovarian androgen biosynthesis and decreased hepatic sex hormone binding globulin (SHBG) synthesis. The increased local ovarian androgen production augmented by hyperinsulinemia causes premature follicular atresia and anovulation with insulin having reproductive hormonal effects. The contribution of insulin resistance to anovulation in PCOS has led to the introduction of insulin-sensitizing agents as a pharmacological therapy to potentially induce ovulation and enhance fertility. Of the insulin-sensitizing agents, metformin has been most widely studied in women with PCOS since 1994 and has the most reassuring safety profile (1). Metformin is a biguanide, used as an oral antihyperglycemic agent for the prevention and management of type 2 diabetes and is available in two formulations: immediate and extended release (2).
Overview of Existing Evidence
A recent search of the literature revealed that there were more than 150 randomized controlled trials and systematic reviews addressing the use of metformin for various indications of PCOS (2). In this setting, opinions about metformin use in PCOS are often based on small, poor-quality studies, many of which are inappropriate for use in clinical decision making. Evidence-based guidelines that synthesize this evidence and use a clinical judgment process to provide recommendations for the use of metformin in women with PCOS include the rigorously developed PCOS Australian Alliance evidence-based guideline for assessment and management of PCOS and the U.S. Endocrine Society guideline. Effect sizes and measures of heterogeneity provided here are from exemplar systematic review evidence included in the PCOS Australian Alliance; however, the discussion incorporates the broad body of evidence.
Metformin has been shown to be better than placebo for ovulation rate and pregnancy rate in women with PCOS; however, there was significant statistical heterogeneity in much of the analyses. In women with PCOS and with a BMI ≤30 kg/m2 (p = 0.00071); with a BMI ≥30 kg/m2 (p = 0.0073), and in women who were clomiphene citrate sensitive or had unknown clomiphene citrate sensitivity (p = 0.000019), metformin was better than placebo for ovulation rate. There was no benefit of metformin over placebo in women with PCOS who were clomiphene citrate resistant. Metformin maintained superiority over placebo when all women were combined; however, there was significant statistical heterogeneity in this group (I2= 69%) and in those with a BMI ≤30 kg/m2 (I2= 88%). Metformin outperformed placebo for pregnancy rate in women with PCOS and a BMI ≤30 kg/m2 (p = 0.000017) with little statistical heterogeneity (I2 = 40%), but no difference was noted in those with BMI ≥30 kg/m2, in clomiphene citrate naïve women, women who were clomiphene citrate resistant, or women who were clomiphene citrate sensitive or had unknown clomiphene citrate sensitivity. Combined analyses of all women demonstrated a benefit of metformin over placebo (p < 0.00001) without statistical heterogeneity for pregnancy rate.
Based on limited data that extended to study live birth rates, no difference between metformin and placebo for live birth rate or miscarriage rate has been noted. Metformin induced more minor gastrointestinal-related adverse events compared to placebo (p < 0.00001) with little statistical heterogeneity (I2 = 25%) (3
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