METFORMIN THERAPY FOR THE MANAGEMENT OF INFERTILITY IN WOMEN WITH POLYCYSTIC OVARY SYNDROME

1. Introduction

The key clinical features of polycystic ovary syndrome (PCOS) are hyperandrogenism (hirsutism,
acne, alopecia) and menstrual irregularity with associated anovulatory infertility.1 The consensus
definition of PCOS recognises obesity as an association and not a diagnostic criterion1 as only
40–50% of women with PCOS are overweight. Ovarian hyperandrogenism is driven primarily by
luteinising hormone (LH) in slim women, while in the overweight insulin may augment the effects of LH.1 Women with polycystic ovaries are more insulin resistant than weight-matched women with normal ovaries. Insulin resistance is seen in 10–15% of slim and 20–40% of obese women with PCOS and women with PCOS are at increased risk of developing type 2 diabetes.2

2. Insulin resistance

Insulin resistance is defined as a reduced glucose response to a given amount of insulin and usually
results from faults within the insulin receptor and post-receptor signalling. As a result circulating
insulin levels rise. Insulin resistance does not affect all actions of insulin and, in the ovary, high levels
of circulating insulin are thought to contribute both to excess androgen production and to anovulation. Insulin resistance can be measured by a number of expensive and complex tests but in clinical practice it is not necessary to measure it routinely; it is more important to check for impaired glucose tolerance.2 Simple screening tests include an assessment of body mass index (BMI) and waist circumference. If the fasting blood glucose is less than 5.2 mmol/l the risk of impaired glucose tolerance is low. The 2-hour standard 75 g oral glucose tolerance test (OGTT) may be conducted in those at high risk (BMI greater than 30 kg/m2 in white women or greater than 25 kg/m2 in women from South Asia, who have a greater degree of insulin resistance at a lower body weight).1,2

3. Metformin therapy for PCOS

Obesity has a profound effect on both natural and assisted conception, influencing the chance of
becoming pregnant and the likelihood of a healthy pregnancy.3 Increasing obesity is associated with
greater insulin resistance. Metformin inhibits the production of hepatic glucose, enhances insulin
sensitivity at the cellular level and also appears to have direct effects on ovarian function. It is logical
to consider, therefore, that insulin lowering and insulin sensitising treatments such as metformin and
the thiazolidinediones (rosiglitazone, pioglitazone) should improve the symptoms and reproductive
outcome for women with PCOS.4 Most of the initial studies of metformin in the management of PCOS were observational. Initial systematic reviews, in which the majority of studies had a small sample size and did not include a power calculation for the proposed effect, suggested that metformin when compared with placebo, had a significant effect on lowering serum androgen levels and restoring menstrual cyclicity and was effective in achieving ovulation either alone or when combined with clomifene.5 Subsequent larger randomised trials, however, have not substantiated these early positive findings. Furthermore, while some studies suggested that metformin therapy may achieve weight reduction,6 the large randomized controlled trials
and systematic reviews have failed to confirm this.5,7,11

Metformin appears to be less effective in those who are significantly obese (BMI greater than 35 kg/m2),6,7
although there is no agreement on predictors for response or the appropriate dose and whether dose
should be adjusted for body weight or other factors. Doses of between 500–3000 mg/day have been used
and the most common dose regimens are 500 mg three times daily or 850 mg twice a day. Long-acting
preparations are associated with fewer gastrointestinal adverse effects. Metformin appears to be safe in pregnancy, although usual advice is to discontinue once a pregnancy occurs. There is no firm evidence that metformin reduces the risk of either miscarriage or gestational diabetes.

The largest prospective randomised, double blind, placebo-controlled study trial to evaluate the combined effects of lifestyle modification and metformin (850 mg twice daily) studied 143 anovulatory women in the UK with a mean BMI of 38 kg/m.27 All subjects had an individualised assessment by a dietician in order to set a realistic goal that could be sustained with an average reduction of energy intake of 500 kcal per
day. As a result, both the metformin-treated and placebo groups managed to lose weight but the amount of weight reduction did not differ between the two groups. An increase in menstrual cyclicity was observed in those who lost weight, but again did not differ between the two arms of the study.7
In a Dutch trial, 228 women with PCOS were treated either with clomifene citrate (CC) plus metformin
or CC plus placebo.8 There were no significant differences in either rates of ovulation (64% versus
72%), continuing pregnancy (40% versus 46%) or rate of spontaneous miscarriage (12% versus 11%).
A significantly larger proportion of women in the metformin group discontinued treatment because of
adverse effects (16% versus 5%). The US Pregnancy in Polycystic Ovary Syndrome (PPCOS) trial9 enrolled 676 women for six cycles or 30 weeks, randomised to three treatment arms (metformin 1000 mg twice daily plus placebo, clomifene citrate plus placebo or metformin plus clomifene citrate). Overall, live birth rates were 7% (5/208), 23% (47/209) and 27% (56/209), respectively, with the metformin alone group being significantly lower than the other two groups. Miscarriage rates tended to be higher in the metformin alone group (40% versus 23% and 26%, respectively). Thus, it was concluded that as
first-line therapy for the treatment of women who are anovulatory and infertile with PCOS, metformin
alone was significantly less effective than clomifene citrate alone and that the addition of metformin to
clomifene citrate produced no significant benefit.9 Subgroup analysis of women with a BMI greater than
35 kg/m2 and in those with clomifene resistance did, however, suggest a potential benefit from the
combined use of metformin with clomifene citrate.9
It has been suggested that co-treatment with metformin may improve the response to exogenous
gonadotropins or the outcome of assisted reproduction therapy. Indeed, the largest study to date has shown an increase in continuing pregnancy rates in women with polycystic ovaries and a mean BMI of 28 kg/m2 treated with metformin (850 mg twice daily) for only 4 weeks during an IVF cycle.10 In this study, 101 women were randomised to receive metformin or placebo. Both the clinical pregnancy rates beyond 12 weeks of gestation per cycle started (39% versus 16%; P = 0.023) and per embryo transfer (44% versus 19%; P = 0.022) were significantly higher in those treated with metformin. Furthermore, a significant decrease in the incidence of severe ovarian hyperstimulation syndrome was observed (4% versus 20%; p=0.023) despite the higher pregnancy rate in the metformin arm of the study.10 These results are promising but further studies are required to confirm these observations before the place of metformin in assisted reproductive techniques can be clearly assessed.
The updated Cochrane review concluded that the benefit of using therapy to lower insulin levels such as metformin is limited in terms of improvement in reproductive outcome and metabolic parameters.11 In
SAC Opinion Paper 13 2 of 4 particular, the use of metformin either alone or in combination with drugs to induce ovulation such as clomifene citrate did not increase the chance of having a livebirth. Furthermore, despite evidence of a reduction in development of diabetes in a high risk non-PCOS population12 the long-term use of metformin in reducing the risk of developing metabolic syndrome is questionable.11 Lifestyle advice with
appropriate attention to diet and exercise has to be the mainstay for young women with PCOS.

4. Opinion

While initial studies appeared to be promising, more recent large randomised controlled trials have not
observed beneficial effects of metformin either as first-line therapy or combined with clomifene citrate
for the treatment of the anovulatory woman with PCOS. Most work has been undertaken in the
management of anovulatory infertility and there are no good data from randomised controlled trials on
the use of metformin in the management of other manifestations of PCOS. It is clear that the first aim
for women with PCOS who are overweight is to make lifestyle changes with a combination of diet and
exercise in order to lose weight and improve ovarian function. The European Society for Human
Reproduction and Embryology and American Society for Reproductive Medicine consensus on infertility
treatment for PCOS concluded that there is no clear role for insulin sensitising and insulin lowering drugs
in the management of PCOS, and should be restricted to those patients with glucose intolerance or type
2 diabetes rather than those with just insulin resistance.13 Therefore, on current evidence metformin is not a first line treatment of choice in the management of PCOS.

References

1. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003
consensus on diagnostic criteria and long-term health risks related to polycystic ovary
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2. Legro RS, Castracane VD, Kauffman RP. Detecting insulin resistance in polycystic ovary syndrome: purposes and pitfalls. Obstet Gynecol Surv 2004;59:141–54.

3. Balen AH, Anderson R. Impact of obesity on female reproductive health: British Fertility
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4. Kayshap S, Wells GA, Rosenwaks Z. Insulin-sensitizing agents as primary therapy for patients
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5. Lord JM, Flight IH, Norman RJ. Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, d-chiro-inositol) for polycystic ovary syndrome. Cochrane Database Syst Rev 2003;(2):CD003053 [DOI:10.1002/14651858. CD003053].

6. Fleming R, Hopkinson Z, Wallace A, Greer I, Sattar N. Ovarian function and metabolic factors in women with oligomenorrhoea treated with metformin in a randomized double blind placebo-controlled trial. J Clin Endocrinol Metabol 2002;87:569–74.

7. Tang T, Glanville J, Hayden CJ, White D, Barth JH, Balen AH. Combined life-style modification and metformin in obese patients with polycystic ovary syndrome (PCOS). A randomised, placebo-controlled, double-blind multi-centre study. Hum Reprod 2006;21:80–9.

8. Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, van der Veen F. Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial. BMJ 2006;24:332(7556):1485.

9. Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, et al. Cooperative
Multicenter Reproductive Medicine Network. Clomiphene, metformin, or both for infertility
in the polycystic ovary syndrome. N Engl J Med. 2007;356:551–66.

10. Tang T, Glanville J, Orsi N, Barth JH, Balen AH. The use of metformin for women with PCOS undergoing IVF treatment. Hum Reprod 2006; 21:1416–25.

11. Lord JM, Flight IHK, Norman RJ. Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome. Cochrane Database Syst Rev 2008;(4):CD003053. SAC Opinion Paper 13 3 of 4

12. Diabetes Prevention Program Research Group. Reduction in the incidence of Type 2 diabetes
with lifestyle intervention or metformin. N Engl J Med 2002;346:393–403.

13. Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on
infertility treatment related to polycystic ovary syndrome. Hum Reprod 2008; 23:462–77.