Abstract and Introduction
Abstract
Objectives Insulin-sensitizing drugs (ISDs) have been advocated for the long-term treatment of polycystic ovary syndrome (PCOS). It is therefore important to compare the efficacy and safety of ISDs such as metformin and thiazolidinediones (TZDs) for the treatment of this syndrome.
Methods A meta-analysis to assess the effectiveness and safety of metformin vs TZDs (including pioglitazone and rosiglitazone) in the treatment of PCOS was conducted, using MEDLINE (1966–May 2010) and EMBASE (1988–May 2010) to select randomized controlled trials comparing clinical, hormonal and metabolic results.
Results Ten trials were included. TZDs were superior to metformin in reducing serum levels of free testosterone (P = 0·03) and dehydroepiandrosterone sulfate (DHEA) (P = 0·002) after 3 months treatment. Decreases in triglyceride levels were more pronounced with metformin after 6 months (P < 0·0001). Decreases in body mass index (BMI) were greater with metformin treatment as assessed at 3 and 6 months (P < 0·00001). There were no significant between-group differences concerning improvements in ovulation, pregnancy rate, menstrual patterns or insulin sensitivity, or changes in serum levels of androstenedione, luteinizing hormone, follicle-stimulating hormone, total cholesterol, low-density lipoprotein C or insulin. Metformin caused a significantly higher incidence of side effects such as nausea, diarrhoea and abdominal cramping (P < 0·00001). Significant between-study heterogeneity was detected for several variables assessed.
Conclusions The findings from this meta-analysis do not indicate that metformin is superior to TZD's for the treatment of PCOS or vice versa. Between studies, heterogeneity was a major confounder. A large scale, well-designed, randomized, controlled trial is needed to further address this issue.
Introduction
Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. Its prevalence in otherwise healthy women has generally been reported to be about 6·5%, although one study has reported a prevalence of 12·5% and a prevalence of 50% has been reported in women with type 1 diabetes. It is characterized by oligo-amenorrhoea, clinical and/or biochemical hyperandrogenism, polycystic ovaries and, often, morbid obesity. The syndrome has received significant attention because of its high prevalence and deleterious metabolic, reproductive and cardiovascular consequences.
The pathological mechanisms underlying PCOS are not fully understood. In the past 15–20 years, an increasing body of evidence has accumulated indicating that one of the central pathophysiologies of PCOS is an insulin-resistant state that results in hyperinsulinaemia. Insulin has an important influence on the synthesis of androgens in the ovaries – both directly by binding to the insulin receptor and the insulin-like growth factor (IGF-1) receptor on thecal cells and participating together with luteinizing hormone (LH) in stimulating steroidogenesis and, indirectly, by increasing LH release from the pituitary. On the contrary, insulin acts through the insulin receptor, but not the IGF-1 receptor, to enhance steroidogenesis in cultured human granulosa cells. Hyperinsulinaemia may be responsible both for increased androgen production and, by reducing the synthesis of sex hormone–binding globulin in the liver, for increases in levels of free androgens (testosterone). Thus, correction or reduction of hyperinsulinaemia is associated not only with improvements in the biochemical indicators of endocrinopathy, such as a reduction in the fasting blood insulin level and homoeostasis assessment model of insulin resistance (HOMA-IR) and decreased total cholesterol (TC) and triglycerides (TG), but also, commonly, with restoration of menstrual cycling and ovulation in PCOS.
Two classes of insulin-sensitizing drugs have been used in the treatment of PCOS. These include the biguanide metformin and thiazolidinediones (TZDs) such as pioglitazone and rosiglitazone. Metformin was first used as a treatment for women with PCOS and to investigate the role of insulin resistance in the pathogenesis of the syndrome in 1994. Metformin therapy in PCOS reduces hyperinsulinaemia, insulin resistance, hyperandrogenaemia and systolic blood pressure and facilitates normal menses and ovulation. It has since become a cornerstone of PCOS treatment. Metformin acts by inhibiting gluconeogenesis in the liver, stimulating peripheral uptake of glucose and thus decreasing insulin resistance, reducing lipid uptake or synthesis in the intestines and hepatocytes and decreasing the release of free fatty acids from adipose tissue. A meta-analysis that examined 13 studies involving the use of metformin in 543 women with PCOS demonstrated that the drug efficiently induced ovulation. Other studies have shown that metformin promotes the recovery of menstrual regularity. Some studies have reported that it reduces spontaneous abortion rates; however, one more recent article found no evidence that it is useful in preventing this outcome, and a recent Cochrane Review article states that although metformin improves pregnancy rates, it does not improve live birth rates. TZDs have also been demonstrated to improve insulin sensitivity and reduce androgenaemia in women with PCOS.
Few studies to date have directly compared the efficacies of metformin and TZDs for the treatment of PCOS. In a report involving a comparison between metformin and rosiglitazone, Yilmaz et al. found that both drugs improved ovarian function and reduced hirsutism. In another study of a small sample of young women with PCOS, Jensterle et al. reported that metformin and rosiglitazone were equally effective for improving endothelial function.
No large-scale comparison of metformin vs TZDs for the treatment of PCOS has been performed. A method for combining the results from previous studies that have examined the treatment effects of metformin and TZDs is random-effects meta-analysis. Hence, in an effort to determine which of these agents is safer and more effective for treating PCOS, we performed a systemic review and meta-analysis of the available literature. Comparisons were made between these two classes of agents with respect to clinical, hormonal and metabolic outcomes.