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Metformin Therapy For The Management Of Infertility in Women With Polycystic Ovary Syndrome | Royal College of Obstetricians and Gynaecologists

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Metformin Therapy For The Management Of Infertility in Women With PolycysticOvary Syndrome

SAC Opinion Paper

01/12/2008 - 01:00

SAC Opinion Paper No. 13

This paper can be downloaded as a pdf file below:

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Scientific Advisory CommitteeOpinion Paper 13

December 2008

SAC Opinion Paper 13 1 of 4

METFORMIN THERAPY FOR THE MANAGEMENT OF INFERTILITYIN 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

4050% 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 1015% of slim and 2040% 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,


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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 5003000 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 perday. 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 hasshown 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

particular, the use of metformin either alone or in combination with drugs to induce ovulation such as



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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 isnot 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

syndrome (PCOS). Hum Reprod2004;19:417.

2. Legro RS, Castracane VD, Kauffman RP. Detecting insulin resistance in polycystic ovary

syndrome: purposes and pitfalls. Obstet Gynecol Surv 2004;59:14154.

3. Balen AH, Anderson R. Impact of obesity on female reproductive health: British Fertility

Society, Policy and Practice Guidelines. Hum Fertil2007;10:195206.4. Kayshap S, Wells GA, Rosenwaks Z. Insulin-sensitizing agents as primary therapy for patients

with polycystic ovary syndrome. Hum Reprod2004;11:247483.5. 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 Metabol2002;87:56974.7. 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 Reprod2006;21:809.8. 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. BMJ2006;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;356:55166.

10. Tang T, Glanville J, Orsi N, Barth JH, Balen AH. The use of metformin for women with

PCOS undergoing IVF treatment. Hum Reprod2006; 21:141625.11. Tang T, Lord JM, Norman RJ, Balen AH. Insulin-sensitising drugs (metformin, troglitazone,

rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome. Cochrane

Database Syst Rev 2008 Cochrane Database Syst Rev 2003(2):CD003053. DOI:

10.1002/14651858.CD003053.



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12. Diabetes Prevention Program Research Group. Reduction in the incidence of Type 2 diabetes

with lifestyle intervention or metformin. N Engl J Med2002;346:393403.13. Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on

infertility treatment related to polycystic ovary syndrome. Hum Reprod2008; 23:46277.

The review process will commence in December 2011Unless otherwise indicated

This opinion paper was produced on behalf of the Royal College of Obstetricians and Gynaecologists by:Professor AH Balen FRCOG, Leeds

and peer reviewed by:

Professor R Fleming, Honorary Professor of Reproductive Medicine, University Department of Obstetrics and Gynaecology, RoyalInfirmary, Glasgow; Professor S Franks FRCOG, London; Dr SD Keay FRCOG, Coventry; Dr T McFarlane FRCOG, Manchester;Professor N Sattar, Department of Pathological Biochemistry, Glasgow Royal Infirmary, Glasgow.

The Scientific Advisory lead peer reviewers were: Professor R Anderson FRCOG, Vice Chair; Professor S Thornton FRCOG, Chair.

The final version is the responsibility of the Scientific Advisory Committee of the RCOG.


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