Metformin in polycystic ovary syndrome (PCOS)

• women with polycystic ovary syndrome (PCOS) have markedly decreased insulin sensitivity - there is therefore an increased rate of both impaired glucose intolerance and frank diabetes in women with PCOS. There is also an increased incidence of insulin resistance and body mass index in women with PCOS
• Moghetti et al (1) undertook a double-blind trial comparing the effects of metformin with placebo in women with PCOS. This trial revealed that:
  • metformin significantly improved the frequency of menstruation, increased insulin sensitivity and reduced serum testosterone and insulin
  • there was no significant difference in BMI between the two groups
• there is evidence that metformin used alone or combined with clomifene is effective for improving ovulation rates in women with polycystic ovary syndrome
  • a systematic review and meta-analysis was undertaken (2,3)
    • 15 randomised controlled trials were included
    • the duration of trials ranged from 4-44 weeks - median 10 weeks
    • metformin improved ovulation rate (46% metformin; 24% placebo) at median 10 weeks; NNT 5 (4 to 8)
    • metformin reduced systolic blood pressure (weighted mean difference -9mmHg, 95% CI -15 to -3), and reduced diastolic blood pressure (weighted mean difference - 6mmHg, CI-10 to -2)
    • metformin plus clomifene improved ovulation and clinical pregnancy rates more than clomifene alone
      • ovulation rate at median 10 weeks (76% metformin + clomifene; 42% clomifene alone); NNT 4 (2 to 17)
      • clinical pregnancy rate at median 10 weeks (32% metformin + clomifene; 7% clomifene alone); NNT 5 (3 to 8)
        
        
• however, there is no evidence that metformin improves live birth rates whether it is used alone or in combination with clomiphene, or when compared with clomiphene (4)
  
  
• a further systematic review concluded (5):
  • clomiphene alone is superior to metformin alone regarding live birth rate and ovulation. The combination (clomifene + metformin) is superior to clomifene alone as a primary method for ovulation induction and to achieve pregnancy in PCOS. However, when addressing live birth rate, no statistically significant difference could be demonstrated. Because of the side effects profile and contraindications of metformin, the authors stated that metformin should not be indicated as a primary ovulation induction agent in women with PCOS.

Note - the latest European Society of Human Reproduction and Embryology (ESHRE) guidance on PCOS advises that a shared-decision making approach should be used, considering the following: (6)

Metformin generally has the same efficacy as active lifestyle intervention.

Its use may be associated with low B12 levels.

Side-effects are usually self-limiting and may be minimised by starting at a low dose or using an extended release preparation.

Reference:

1. Moghetti P, Castello R, Negri C et al (2000). Metformin effects on clinical features, endocrine and metabolic profiles and insulin sensitivity in polycystic ovary syndrome. J Clin Endocrinology Metab, 85 (1), 139-46.
2. Lord JM et al. Metformin in polycystic ovary syndrome: systemic review and meta-analysis. BMJ 2003;327:951-6.
3. Lord JM et al. Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome. Cochrane Database Syst Rev 2003; (3):CD003053
4. Morley LC, Tang T, Yasmin E, et al. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev. 2017 Nov 29;11:CD003053
5. Siebert TI et al. Is metformin indicated as primary ovulation induction agent in women with PCOS? A systematic review and meta-analysis.Gynecol Obstet Invest. 2012;73(4):304-13.
6. International Evidence-based Guideline for the assessment and management of polycystic ovary syndrome 2023; ESHRE 2023