Long-term Metformin in PCOS Benefits Women of All Weights

Metformin improves menstrual cycle regularity and lowers body mass index (BMI), testosterone, and luteinizing hormone (LH) within 6 months of treatment in women with polycystic ovary syndrome (PCOS) who are normal weight or overweight, new results show.

The study is one of the few to examine the long-term effects of metformin, which was given daily for 2 years, although researchers found that most benefits emerged after 6 months, with over 40% of patients achieving normal menstruation by this point.

The trial is also the first to evaluate metformin in all subgroups of women with PCOS, as most prior studies have looked at patients who are obese and/or hyperandrogenic (androgen excess), say the authors led by Po-Kai Yang, MD, from the National Taiwan University Hospital, Taipei City. The study was published online January 9 in the Journal of Clinical Endocrinology & Metabolism.

They found that there are differences in treatment response to metformin between different BMI/testosterone subgroups — of which there were four — which could help in patient selection for treatment.

For menstrual regularity — the primary endpoint — the normal weight, excess testosterone subgroup had the most significant sevenfold improvement from baseline, whereas the overweight, normal testosterone subgroup had the longest duration of improvement and the highest rate of normal menses after treatment (achieved by > 60% vs baseline).

The reason for the difference in menstrual response between BMI/testosterone phenotypes is unknown, "but probably relates to the different pathophysiological mechanisms displayed over the spectrum of clinical manifestations in PCOS," the researchers say.

New Look at Metformin Effects in All Women With PCOS

The authors conducted the study because they felt there was a need to evaluate the effects of metformin on the menstrual cycle in all women with PCOS. "In particular, attention should be paid to the nonobese, normal androgenic phenotype for being underrepresented in past studies," they point out.

They add that BMI and testosterone have been considered separate prognostic markers in the treatment of PCOS. Considering the two variables together, and their effect on response to metformin, is novel.

With regard to BMI, lean women with PCOS often have elevated LH, while obese women with PCOS have a greater tendency for insulin resistance. Testosterone is thought to be a determinant of menstrual regularity.

Metformin is an insulin sensitizer, and in women with PCOS it has been shown to have beneficial effects on hyperinsulinemia, hyperandrogenemia, ovarian steroidogenesis, menstrual cycles, blood pressure, and pregnancy rates, the authors note.

They compared the response, including the proportion of patients with regular menstruation during treatment (the primary outcome), as well as hormonal, metabolic, and anthropometric profiles, in 119 overweight and normal weight women with PCOS (Rotterdam criteria) treated with daily metformin over 2 years

Daily Metformin for 2 Years, But Most Benefit Seen in First 6 Months

Patients started on 500 mg/day of metformin in the first month, followed by 1000 mg/day in the second month, and 1500 mg/day from the third to 24th month. (A decrease to 1000 mg/day was allowed in those with intolerable gastrointestinal side effects.)

The efficacy of menstrual cycle restoration was then assessed according to baseline BMI and testosterone status. Patients were stratified into four subgroups: normal weight, normal testosterone (n = 49); normal weight, elevated testosterone (n = 23); overweight, normal testosterone (n = 27); and overweight, elevated testosterone (n = 20).

At baseline, the proportions of patients with hyperandrogenism/anovulation, hyperandrogenism/polycystic ovarian morphology, anovulation/polycystic ovarian morphology, and all three were 17.6%, 12.6%, 20.2%, and 49.6%, respectively.

Overall, 47 patients were overweight, and 72 were normal weight. The proportion of patients with normal menstrual cycles was higher in the overweight than normal weight subgroup.

At 6 months, the proportion of women with normal menses was 47% of normal weight, normal testosterone patients; 43% of normal weight, elevated testosterone patients; 42% of overweight, normal testosterone patients; and 42% of overweight, elevated testosterone patients.

Those categorized as normal weight, elevated testosterone (who had the lowest rate of normal menses at study entry) showed the most improvement by 6 months (odds ratio 7.21, normal menses vs baseline).

Those categorized as overweight, normal testosterone at baseline showed continued improvement to 12 months and had the highest proportion of patients with normal menstrual cycles (63%) after 2 years of treatment.

Metformin and Other Outcomes According to Subgroup

There were significant differences between the normal weight and overweight subgroups during the first 3 months with respect to other outcomes, but further changes were rare after 6 months.

By month 24, BMI, testosterone, free androgen index, LH level, and LH/follicle stimulating hormone ratio were all significantly lower in overweight and normal weight patients treated with metformin compared with baseline.

And they stress that, overall, the first 6 months of metformin use seemed most significant with respect to changes in BMI, testosterone, and LH levels.

The study was limited by the fact that there was no control group and a high dropout rate as time went on: 94% and 95% of patients completed follow-up at months 3 and 6, but this decreased to 68% by 12 months and 37% by 2 years.

Further studies are needed to investigate the factors that determine the treatment efficacy of metformin in different phenotypic subgroups of women with PCOS, the researchers conclude.

The authors have reported no relevant financial relationships.

J Clin Endocrinol Metab. Published online January 9, 2018. Full article

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