Metformin in Polycystic Ovarian Syndrome and Infertility

Does Metformin Affect the Ovarian Response to Gonadotropins for In Vitro Fertilization Treatment in Patients With Polycystic Ovary Syndrome and Reduced Ovarian Reserve? A Randomized Controlled Trial

Palomba S, Falbo A, Di Cello A, Cappiello F, Tolino A, Zullo F
Fertil Steril. 2011;96:1128-1133

Background

Polycystic ovary syndrome (PCOS) is the most common endocrine finding in women with oligo-anovulation. The intercycle interval is typically more than 35 days, most patients have some clinical or laboratory evidence for hyperandrogenism, and polycystic ovaries appear on ultrasonography. Patients with the syndrome are often infertile, usually as a result of infrequent ovulation.

In most cases, pregnancy can be achieved by restoring regular ovulation, but some patients require more advanced assisted reproductive technology. In such cases, stimulation is not always easy. Patients may react slowly to stimulation, and if one is impatient and keeps increasing the dose of the medications, the risk for ovarian hyperstimulation syndrome (OHSS) is high. Other patients have an explosive response from the onset of stimulation, which also puts them at high risk for OHSS.

Metformin is often prescribed as adjuvant therapy during assisted reproductive technology to correct underlying metabolic problems. This everyday practice, however, is not supported by the evidence, despite some reports that metformin may improve response to stimulation.^[1,2] It has been found to reduce the risk for OHSS, and therefore it may improve the outcomes of in vitro fertilization.^[3] However, it can withhold the response to gonadotropins, an undesirable effect for low-responder patients. The aim of this study was to assess how metformin affects the response to stimulation in low-responder women with PCOS who undergo in vitro fertilization.

Study Summary

The study is a randomized, placebo-controlled trial. The diagnosis of PCOS was established using the Rotterdam criteria. Patients were identified as low responders if they were either of advanced reproductive age (> 35 years) or had an elevated baseline follicle-stimulating hormone (FSH) level (> 10 IU/L). The trial was terminated early, after 88 patients were enrolled, because of an observed negative effect of metformin during a scheduled interim analysis. All patients followed the same treatment protocol. In addition to gonadotropins, patients took either metformin or a similar-looking placebo. Baseline characteristics were well-matched. A trend for more cycle cancellations because of low response in the metformin group was observed (hazard ratio [HR], 1.52; 95% confidence interval [CI], 0.96-2.21). The risk for poor response was also higher in the metformin group (HR, 1.63; 95% CI, 1.08-2.41). In the metformin group, more gonadotropin was used, fewer follicles were recruited, fewer eggs were collected, and the peak estradiol level was lower. Implantation, pregnancy, and delivery rates were similar.

Viewpoint

Disturbance of glucose metabolism often accompanies PCOS. The risk for diabetes is increased several-fold, and many women with PCOS are diagnosed with impaired glucose tolerance or insulin resistance. Most patients with PCOS have elevated baseline and stimulated insulin levels. Insulin serves as a growth factor at the level of the ovary and increases theca cell androgen synthesis. Androgens produced by the theca cells serve as the precursor for estradiol synthesis but increase granulosa cell FSH sensitivity and have local paracrine effects. High local levels of androgen interfere with the normal process of folliculogenesis. The increased sensitivity of granulosa cells to FSH explains why some patients hyperrespond to stimulation. Metformin use is associated with a reduction in insulin secretion and a normalization of the intraovarian paracrine milieu. This may explain why the risk for hyperresponse, and therefore OHSS, is reduced with its use.

Several studies have evaluated the benefit of androgens in poor responders undergoing controlled ovarian hyperstimulation. An androgen effect can be achieved by dehydroepiandrosterone sulfate or testosterone administration before stimulation, or by using luteinizing hormone or aromatase inhibitors at the onset of controlled ovarian hyperstimulation. These results are promising, but further studies are awaited to confirm the preliminary findings.^[4] In a low-responder patient with PCOS, however, metformin may lower intraovarian androgen to a level that adversely affects stimulation. This effect could explain the findings of this randomized trial.

Patients with PCOS need to be tested for metabolic problems. If abnormalities of glucose metabolism are found, lifestyle changes should be recommended; if such changes are ineffective, metformin should be used. However, it should not be administered routinely to patients to improve their chances of conception during fertility treatment unless they are considered to be at high risk for OHSS.

Abstract

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