Polycystic ovary syndrome: The long-term metabolic risks

Metformin and weight loss

What is the status of metformin and weight loss?
Weight loss leads to greater improvements in overall health, increased fecundity, and improved pregnancy outcome. In spite of the advantages, most patients with PCOS have difficulty losing weight and often regain lost weight over time. Many investigators have raised the question as to whether treatment with insulin-sensitizing drugs contributes to weight loss, compared with diet or a lifestyle modification program.

A systematic search of the literature for randomized controlled trials in women of reproductive age that assessed the effect of insulin-sensitizing drugs on weight loss compared with placebo and diet and/or a lifestyle modification program, revealed 14 trials in the literature, including two in women with PCOS.⁵ Treatment with metformin showed a statistically significant decrease in body mass index compared with placebo, with some indication of greater effect with high-dose metformin (>1,500 mg/day) and longer duration of therapy (>8 weeks).

Clearly, a structured lifestyle modification program to achieve weight loss should still be the first-line treatment in obese women with or without PCOS. Further adequately powered studies are necessary to confirm such findings.² As new weight loss drugs become available, they should also be considered for treatment of obesity in women with PCOS.

Metformin and anovulation

What is the status of metformin and the treatment of anovulation?
While metformin may offer limited assistance with weight loss, especially when combined with diet and lifestyle therapy, and weight loss generally improves ovulation in overweight women with PCOS, there is no evidence that metformin is a powerful ovulatory drug.⁶ However, results of a meta-analysis that included 17 studies totaling more than 1,600 women with PCOS, showed that metformin did improve ovulation, especially in non-clomiphene–resistant women.⁷ Metformin alone did not increase the odds of pregnancy, but in combination with clomiphene, pregnancy was increased. The combination of metformin and clomiphene was especially beneficial in clomiphene-resistant women.

It is important to note that, in women with PCOS, treatment with metformin alone, and in combination with clomiphene, helps to reduce the number of multiple pregnancies, compared with treatment with clomiphine alone.⁹

Metformin and early pregnancy loss

What is the status of metformin and the treatment of early pregnancy loss?
While there is mixed evidence as to metformin’s effect on early pregnancy loss, the strongest evidence to date does not indicate a beneficial effect. In a large, randomized, prospective study of 626 infertile women with PCOS, the rate of pregnancy loss was similar between the clomiphene only and clomiphene plus metformin groups, and there was a slight trend for an increase in pregnancy loss in the metformin alone group.⁹

In a comprehensive review of the literature, Mathur and colleagues concludes that, while some studies have found improvements or no difference in the rates of early pregnancy loss with metformin (alone or in combination with clomiphene), there are “no conclusive data to support a beneficial effect of metformin on pregnancy loss.”⁶

Metformin and pregnancy outcomes

What is the status of metformin and improving pregnancy outcomes?
In a meta-analysis of eight studies of women with PCOS or DM exposed to metformin during the first trimester of pregnancy with major fetal malformations as the primary outcome, the authors concluded there was no evidence of an increased risk with metformin.⁸

While it is logical to say that metformin could even be beneficial during pregnancy, given its effect of reducing the risk of developing gestational diabetes, there is inadequate evidence to support the use of metformin during pregnancy at this time.^6,8

In the next installment: The authors address several questions about current opinion and future considerations: “What is the current opinion concerning how important circulating LH/FSH ratios are to the diagnosis of PCOS?” “Are there any new tests on the horizon that will make the diagnosis of PCOS easier?” “My patient has excessive hair growth and acne and only wants cosmetic results. Other than traditional therapy with oral contraceptives, what medical treatment options does she have?” “We hear a lot about weight loss improving the clinical effects of PCOS. Are there any specific dietary approaches that are more successful than others in PCOS?”

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