Lord, J. M., Flight, I. H., & Norman, R. J. (2003). Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ (Clinical Research Ed.), 327(7421), 951-953. https://doi.org/10.1136/bmj.327.7421.951
Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ. 2003;327(7421):951-953. doi:10.1136/bmj.327.7421.951
Lord, Jonathan M., et al. "Metformin in polycystic ovary syndrome: systematic review and meta-analysis." BMJ (Clinical Research Ed.), vol. 327, no. 7421, 2003, pp. 951-953.
Metformin raised ovulation rates in PCOS in a 13-trial review
Metformin raised the odds of ovulation versus placebo or no treatment in a 2003 review of 13 randomized trials. The trials enrolled 543 women with polycystic ovary syndrome (PCOS). 46 out of 100 women taking metformin alone ovulated, against 24 out of 100 on placebo.
Ovulation in PCOS: Metformin alone, 46 in 100; Placebo, 24 in 100. Source: Lord JM et al., 2003, PMID 14576245.Study at a glance, systematic review and meta-analysis of 543 women with polycystic ovary syndrome: Metformin raised ovulation rates in women with PCOS across 13 trials. Source: Lord JM et al., 2003, PMID 14576245.
Key Findings
Metformin versus placebo or no treatment, ovulation: odds ratio 3.88 (95% confidence interval 2.25 to 6.69). Ovulation occurred in 46% on metformin alone and 24% on placebo.
Metformin plus clomifene versus clomifene alone, ovulation: odds ratio 4.41 (2.37 to 8.22); 76% versus 42%. The analysis was robust only in women previously resistant to clomifene.
Clinical pregnancy, three trials of metformin plus clomifene versus clomifene alone: odds ratio 4.40 (1.96 to 9.85). Five trials of metformin versus placebo showed no evidence of benefit: 2.76 (0.85 to 8.98).
Metformin lowered fasting insulin, blood pressure and low density lipoprotein cholesterol. The review found no evidence of an effect on body mass index or waist:hip ratio.
Nausea or vomiting was more common on metformin: odds ratio 3.84 (1.07 to 13.81). Other gastrointestinal disturbance: 4.40 (1.82 to 10.66). No trial reported serious adverse events.
Interpretation
This review and meta-analysis pooled 13 randomized trials of women with PCOS. Most had insulin resistance and did not ovulate on their own. Metformin raised ovulation rates against placebo. Metformin also raised ovulation rates when added to clomifene. Adding metformin to clomifene raised pregnancy rates too. Metformin lowered fasting insulin, blood pressure, and LDL cholesterol. The authors note that long term safety data in young women, and safety data in early pregnancy, are limited. The findings support larger trials of metformin's role in PCOS care, alongside lifestyle changes.
RRM Context
Restorative reproductive medicine asks why ovulation fails. The authors describe PCOS as a condition marked by insulin resistance. PCOS is now called polyendocrine metabolic ovarian syndrome (PMOS). The drop in fasting insulin fits that picture. The authors advise using metformin alongside lifestyle improvements. They report that other studies found higher ovulation rates with lifestyle improvements.
Our editorial summary of this paper, not the article's abstract.
Abstract
Objective
To assess the effectiveness of metformin in improving clinical and biochemical features of polycystic ovary syndrome.
Design
Systematic review and meta-analysis.
Data Sources
Randomised controlled trials that investigated the effect of metformin compared with either placebo or no treatment, or compared with an ovulation induction agent.
Study Selection
13 trials were included for analysis, including 543 women with polycystic ovary syndrome that was defined by using biochemical or ultrasound evidence.
Main Outcome Measures
Pregnancy and ovulation rates. Secondary outcomes of clinical and biochemical features of polycystic ovary syndrome.
Results
Meta-analysis showed that metformin is effective in achieving ovulation in women with polycystic ovary syndrome, with odds ratios of 3.88 (95% confidence interval 2.25 to 6.69) for metformin compared with placebo and 4.41 (2.37 to 8.22) for metformin and clomifene compared with clomifene alone. An analysis of pregnancy rates shows a significant treatment effect for metformin and clomifene (odds ratio 4.40, 1.96 to 9.85). Metformin has an effect in reducing fasting insulin concentrations, blood pressure, and low density lipoprotein cholesterol. We found no evidence of any effect on body mass index or waist:hip ratio. Metformin was associated with a higher incidence of nausea, vomiting, and other gastrointestinal disturbance.
Conclusions
Metformin is an effective treatment for anovulation in women with polycystic ovary syndrome. Its choice as a first line agent seems justified, and there is some evidence of benefit on variables of the metabolic syndrome. No data are available regarding the safety of metformin in long term use in young women and only limited data on its safety in early pregnancy. It should be used as an adjuvant to general lifestyle improvements and not as a replacement for increased exercise and improved diet.
