Examining the Evidence
Q.Is rosiglitazone superior to metformin for women with PCOS?
<huc>A.</huc>Maybe. Rosiglitazone outperformed metformin in this small sample of obese women with polycystic ovary syndrome (PCOS). On average, it improved unbound testosterone, 2-hour glucose and 2-hour insulin levels, and the daily urinary progestin-to-estrogen ratio. Ovulation increased on both drugs, alone and in combination, but 5 of 16 women showed no evidence of ovulation after 6 months.
Insulin resistance is central to the anovulation and hyperandrogenism of many women with PCOS, and insulin-sensitizing drugs are increasingly used for chronic treatment, especially to ameliorate the metabolic sequelae of type 2 diabetes and cardiovascular disease. In the diabetes world, combining insulin-sensitizing drugs of different classes yields superior results, compared with monotherapy.
On this basis, Legro and colleagues conducted a pilot study to compare the effects of metformin and rosiglitazone, alone and in combination, on ovulation, androgens, and endometrial histology in women with PCOS. Women were randomized to metformin or rosiglitazone monotherapy for 12 weeks, followed by 12 weeks of combination therapy.
Researchers used urinary pregnanediol-3-glucuronide to detect ovulation, and did periodic endometrial biopsies.
Duration of study was insufficient
Metformin may take as long as 6 months to exert an optimal effect on ovulation, and thiazolidinediones (including rosiglitazone) may require 3 to 4 months to improve insulin sensitivity. Therefore, neither drug was given for a sufficient duration to assess its individual effects.
In this study, the number of subjects was small (5 women completed the metformin arm, and 9 women the rosiglitazone arm), and the groups differed greatly at baseline, with the metformin group being heavier and the rosiglitazone group being more hirsute and having higher serum testosterone and insulin levels. These baseline differences make comparison of the 2 groups after 3 months of monotherapy difficult, because the seeming improvements in testosterone and insulin in the rosiglitazone group may have been due to regression to the mean rather than a true effect of the drug.
Both drugs improved ovulation. Combining the 2 drugs did not add further benefit, but lack of benefit may have been the result of the brief duration of combined therapy (12 weeks).
Both drugs tended to normalize endometrial histology in the women who had simple hyperplasia at baseline. The number of women was small, but the finding is buttressed by 2 earlier studies in PCOS showing that metformin improves uterine vascularity and circulating glycodelin, a marker of endometrial function.1,2
No change to clinical practice—yet
As a pilot study, the trial was not meant to change clinical practice—nor should it. The future trial resulting from this pilot study should incorporate longer durations of treatment and yield more answers.
1. Jakubowicz DJ, Seppala M, Jakubowicz S, et al. Insulin reduction with metformin increases luteal phase serum glycodelin and insulin-like growth factor-binding protein 1 concentrations and enhances uterine vascularity and blood flow in the polycystic ovary syndrome. J Clin Endocrinol Metab. 2001;86:1126-1133.
2. Palomba S, Russo T, Orio F, Jr, et al. Uterine effects of metformin administration in anovulatory women with polycystic ovary syndrome. Hum Reprod. 2006;21:457-465.