BMJ  2003;327:951 (25 October), doi:10.1136/bmj.327.7421.951

Paper

Metformin in polycystic ovary syndrome: systematic review and meta-analysis

¹ Department of Endocrinology and Metabolism, Peninsula Medical School, South West Centre for Reproductive Medicine, Derriford Hospital, Plymouth, Devon, PL6 8DH, ² Consumer Science Program, Commonwealth Scientific and Industrial Research Organisation, Health Sciences and Nutrition, PO Box 10041, Adelaide, SA 5000, Australia, ³ Reproductive Medicine Unit, Department of Obstetrics and Gynaecology, University of Adelaide, Queen Elizabeth Hospital, Woodville Road, Woodville, SA 5005, Australia

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.

Selection of studies 13 trials were included for analysis, including 543 women with polycystic ovary syndrome that was defined by using biochemical or ultrasound evidence.

Main outcome measure 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.

Introduction

Polycystic ovary syndrome is characterised by anovulation, infertility, and hyperandrogenism, with clinical manifestations of irregular menstrual cycles, hirsutism, and acne. The condition affects an estimated 5-10% of women of reproductive age,^{1 2} although this varies depending on the diagnostic criteria used.³ One of the commonest presenting complaints of women with polycystic ovary syndrome is anovulatory infertility. They also have increased prevalence of cardiovascular risk factors similar to that seen in the metabolic syndrome (which, like polycystic ovary syndrome, is characterised by insulin resistance⁴). By the age of 40, up to 40% will have type 2 diabetes or impaired glucose tolerance.⁵ Polycystic ovary syndrome is therefore an important health concern and may represent a major health issue affecting young women today.

The use of metformin for women with polycystic ovary syndrome has aroused a tremendous amount of interest. Several detailed literature reviews report large numbers of trials, although most of these are uncontrolled, have small numbers of participants, and have no allocation concealment.^6-11 This review aims to answer the question whether metformin is effective in treating women with polycystic ovary syndrome, by amalgamating the trials whose methods are of the highest quality so that meta-analysis can produce valid results.

Methods

We included randomised controlled trials of metformin compared with placebo, no treatment, or ovulation inducing agents in women with polycystic ovary syndrome. We included trials only if polycystic ovary syndrome was defined by using biochemical or ultrasound evidence. We also included studies of metformin in conjunction with an ovulation inducing agent compared with placebo, no treatment, or an ovulation inducing agent.

We searched the trials register of the Cochrane menstrual disorders and subfertility group in December 2002, the Cochrane central register of controlled trials (Cochrane Library, Issue 4, 2002), Medline (January 1966 to December 2002), and Embase (January 1985 to December 2002). We also handsearched the reference sections of all the randomised controlled trials obtained.

One reviewer screened the titles and abstracts of the randomised controlled trials that we identified. Full text articles were obtained for those trials that fulfilled the inclusion criteria or for which insufficient information was given. The methods section was then sent to another reviewer after all information had been removed that could identify the authors, the publisher, or the results of the study. Both reviewers independently assessed whether the studies met the inclusion criteria; disagreements were resolved by discussion and final arbitration by RJN and the Cochrane editorial base. We sought further information from the authors where papers contained insufficient information to make a decision about eligibility or quality.

We performed statistical analyses according to the statistical guidelines for reviewers in the Cochrane menstrual disorders and subfertility group. We undertook sensitivity analyses to examine the stability of the results in relation to quality of allocation concealment, blinding, obesity, length of treatment over two months, dose of metformin, and ethnic group. Data from crossover trials were used only from the first phase (before crossover).

Description of studies
Twenty randomised controlled trials met the initial eligibility criteria. We excluded seven studies, leaving 13 to be included in the analysis, of which 10 were double blind,^12-21 two were single blind,^{22 23} and one we presumed to be unblinded.²⁴

The diagnosis of polycystic ovary syndrome broadly followed the consensus criteria from the National Institutes of Health of anovulation and hyperandrogenaemia, with exclusion of other endocrinopathies, in all but three trials that used ultrasound criteria.^{12 17 24} All of the included trials required oligomenorrhoea or proved anovulation, and all of these trials excluded other endocrinopathies.

Results

Clinical outcomes
Clinical pregnancy rate
Care is needed in interpreting pregnancy rates as no trial had pregnancy as a primary outcome measure, and only six of the trials had tubal disease or male factor infertility, or both, as exclusion criteria.^{14 15 17 20 21 24} Six of the nine trials reporting pregnancy rates were of less than four months' duration.^{14 22 17 21 20 12}

The clinical pregnancy rate reported by five trials comparing metformin with placebo did not show evidence of benefit (odds ratio 2.76, 95% confidence interval 0.85 to 8.98, P = 0.09).^{12 14 17 21 22} We found no significant heterogeneity, but the funnel plot was asymmetrical, which raised the possibility of publication bias. In the three trials comparing clomifene with metformin compared with clomifene alone, we found a significant effect for metformin with clomifene (4.40, 1.96 to 9.85, P = 0.0003).^{14 15 24} We detected no heterogeneity.

Ovulation rate
Overall, as figure 1 shows, a significant effect of metformin compared with placebo on ovulation became obvious (3.88, 2.25 to 6.69, P < 0.0001). We detected no significant heterogeneity. The funnel plot was limited as only seven trials were included, but no bias was evident. The two trials with the lowest weight (total weight 11.8%) are the two that did not show a significant effect.

View larger version (32K): [in this window] [in a new window]   Fig 1 Metformin compared with placebo or no treatment—ovulation rate

 

Figure 2 shows that the effect for metformin and clomifene compared with clomifene alone was also significant (4.41, 2.37 to 8.22, P < 0.0001) based on the results of three trials. However, we detected significant heterogeneity. Two of the trials used participants who were known to have been resistant to clomifene previously, and consequently the ovulation rate in their placebo and clomifene arms was relatively low (17.5%).^{14 15} These two trials showed a significant effect for metformin and clomifene compared with clomifene and placebo (9.34, 3.97 to 21.97, P < 0.00001), without any heterogeneity. In contrast the third trial, where participants were not selected on the basis of being resistant to clomifene, had a high ovulation rate in their placebo and clomifene arm (64%).²⁴ This trial did not show evidence of benefit for metformin compared with clomifene in our analysis when odds ratios were used, although it did in the original report.

View larger version (28K): [in this window] [in a new window]   Fig 2 Metformin combined with clomifene compared with clomifene alone—ovulation rate

 

Weight
We found no evidence of effect from metformin on body weight or body mass index. Only one trial reported waist circumference.¹⁸ We found no evidence of an effect by metformin on waist circumference, nor on waist:hip ratio, as reported by seven trials with minimal heterogeneity.^{12 13 14 16 22 18 21}

Blood pressure
Two trials comparing metformin with placebo reported blood pressure.^{16 22} Analysis showed a significant reduction for metformin in both systolic blood pressure (weighted mean difference -9.07, 95% confidence interval -14.98 to -3.15, P = 0.003) and diastolic blood pressure (-5.69, -9.66 to -1.73, P = 0.005). We detected no heterogeneity between the two trials, but the total number of participants was only 47.

Adverse events
Only one trial reported miscarriage rates and multiple pregnancy rates.²⁰ Neither reached significance.

Four trials included details about side effects that are suitable for analysis (fig 3).^{12 16 17 21} One trial used metformin for six weeks,¹² wheras the others used it for 12 weeks or more. Metformin caused a significantly higher incidence of nausea or vomiting (odds ratio 3.84, 95% confidence interval 1.07 to 13.81, P = 0.05,) and other gastrointestinal disturbance (4.40, 1.82 to 10.66, P = 0.003). We detected no heterogeneity in the results. One trial reported that most of their dropouts were because of gastrointestinal disturbance.¹² No trial reported any serious adverse events.

View larger version (24K): [in this window] [in a new window]   Fig 3 Metformin compared with placebo or no treatment—side effects

 

Biochemical outcomes
Insulin
Metformin had a significant effect in reducing fasting insulin concentrations with a weighted mean difference of -5.37 (-8.11 to -2.63, P = 0.0001) (fig 4). Overall nine trials were included in the analysis, and all had wide confidence intervals.^{12 13 14 16 17 18 20 21 22} Significant heterogeneity was attributable to the large treatment effect seen in two trials.^{13 22} When these trials were excluded, the significance remained without significant heterogeneity, which implies a genuine effect of treatment. The funnel plot implies publication bias, although the symmetry is improved when the two trials are excluded from the analysis.

View larger version (26K): [in this window] [in a new window]   Fig 4 Metformin compared with placebo or no treatment—fasting insulin

 

Lipids
Effects on serum concentrations of cholesterol and lipids were reported by three trials with a total of 98 participants. ^{12 16 17} Total cholesterol showed no evidence of a significant treatment effect with metformin, but low density lipoprotein cholesterol was significantly reduced in the metformin group, with a weighted mean difference of -0.44 (-0.79 to -0.08, P = 0.02). We detected no significant heterogeneity, although none of the trials showed a significant treatment effect of their own. We found no evidence of an effect on high density lipoprotein cholesterol from metformin. We also found no evidence of an effect on triglyceride concentrations.

Discussion

Metformin is effective in achieving ovulation in women with polycystic ovary syndrome. Meta-analysis is valid only if the included participants of all the different studies represent the same overall population. We included only studies of women who have clearly defined polycystic ovary syndrome. The baseline characteristics of the participants from all the trials are similar and represent a population of women with hyperandrogenic anovulation who are mostly over-weight and have insulin resistance. We believe that this population is well recognised worldwide and that the results of this meta-analysis are applicable to this whole group of women. We found a reasonable number of trials with good methods, and we found no evidence of significant publication bias.

Limitations
This review has some limitations. Differences between trial populations have resulted in heterogeneity in some of the analyses as discussed above. Several of the results are constrained by small numbers and wide standard deviations, which limits confidence in drawing conclusions. Although sensitivity analyses using various variables did not alter the conclusions fundamentally, some of the planned analyses were constrained owing to the limited number of trials available. Another concern is that the trials were of varying duration, and meta-analysis will imply that treatment effect is similar in all trials whatever their length of treatment and follow up. However, metformin has its effect relatively quickly,^{13 20-23} and analysis shows no correlation between length of trial and proportion ovulating with metformin alone among the included trials (r = 0.39, P = 0.39). Conversely the correlation between trial length and proportion ovulating with placebo is significant (r = 0.83, P = 0.02), and analysis of trials of varying length will therefore tend to produce a conservative estimate of the treatment effect for metformin compared with placebo.

Strengths
The meta-analysis shows that metformin is effective in achieving ovulation in women with polycystic ovary syndrome. Ovulation was achieved in 46% of those who received metformin alone (compared with 24% who received placebo), with a number needed to treat (NNT) of 4.4. Where metformin and clomifene were compared with clomifene alone, ovulation occurred in 76% of women receiving metformin and clomifene, compared with 42% of those receiving clomifene alone. The number needed to treat is 3.0, with a range of 1.6 in the trial with the lowest rate of ovulation with clomifene alone (the participants were selected as having been previously resistant to clomifene) to 8.6 in a trial in which the participants' previous sensitivity to clomifene was unknown.

These data seem robust with no evidence of major publication bias. Although the combination of metformin with clomifene results in higher ovulation rates, analysis is robust only in those participants who were known to be resistant to clomifene previously. Other reviews have described ovulation rates of 40-85% with clomifene alone, although resistance to clomifene is more prevalent in women who are overweight, which is a common situation in women with polycystic ovary syndrome.^{25 26} A known adverse effect of clomifene alone is an increase in rates of multiple pregnancies,²⁷ but as yet no data imply that this also applies to the combination of metformin with clomifene.

Pregnancy rates are harder to interpret in the meta-analysis, and no trial had live birth rate as a defined outcome measure. We found evidence of effect for metformin with clomifene, but few trials had pregnancy as a defined outcome measure, few controlled for other causes of infertility, and the possibility of publication bias limits confidence in this analysis.

Possible recommendations
Polycystic ovary syndrome is known to be characterised by insulin resistance. Insulin resistance is thought to be a key factor in the development of the metabolic syndrome that is associated with an increased risk of cardiovascular disease.²⁸ If metformin were to improve the variables associated with the metabolic syndrome in women with polycystic ovary syndrome, then in theory it might be expected to reduce the risk of adverse cardiovascular events. If this were to be true then clinically it would be logical to use metformin as a first line agent. The meta-analysis confirms that metformin does significantly reduce fasting insulin and therefore by implication insulin resistance.

Other reported variables of the metabolic syndrome include blood pressure and concentrations of cholesterol and triglycerides. Interpretation of blood pressure is limited by having only 47 participants to analyse, but systolic and diastolic blood pressure were significantly reduced by metformin. Total concentrations of cholesterol, high density lipoprotein cholesterol and triglycerides were all unaffected by metformin, but we found a significant if small reduction in low density lipoprotein cholesterol on the basis of data from 97 participants. Although modest, we believe that these benefits in variables known to be associated with adverse cardiovascular risk are further evidence to justify recommending the use of metformin as a first line treatment for anovulation in women with polycystic ovary syndrome.

What is already known on this topic Polycystic ovary syndrome is characterised by insulin resistance and worsened by obesity Many trials have reported the use of metformin in polycystic ovary syndrome, but most are observational and involve small numbers of participants Previous reviews have reached different conclusions about the effectiveness of metformin in treating polycystic ovary syndrome What this study adds This is the first systematic review and meta-analysis of randomised controlled trials in the use of metformin in treating polycystic ovary syndrome Where metformin is used as a sole agent, ovulation is achieved in 46% of recipients compared with 24% in the placebo arm (NNT = 4.4) Where metformin and clomifene are used in combination, 76% of recipients ovulate compared with 42% receiving clomifene alone (NNT = 3.0) Metformin has small but beneficial effects on aspects of the metabolic syndrome There is no evidence that metformin causes weight loss Equal or better ovulation rates than those achieved by metformin have been described by using lifestyle interventions to achieve weight loss

Contraindications
Metformin was associated with side effects in the form of nausea, vomiting, and gastrointestinal disturbance. Although no serious adverse events were reported, these side effects limited participation levels in some trials. We found no literature about the safety of long term use of metformin in young women, and no conclusion can be drawn from this review as the longest trial followed up participants for only six months. Metformin is contraindicated in the presence of even mild renal impairment because of a danger of lactic acidosis, and it is associated with decreased absorption of vitamin B12. Experience of metformin in pregnancy has been limited, and, although there is currently no evidence that it is teratogenic,²⁹ caution is necessary until its safety in the first trimester has been evaluated more fully.

The overall ovulation rate achieved by metformin or metformin and clomifene was 57%. Other studies have shown greater ovulation rates with lifestyle improvements that included increased exercise and weight loss.³⁰ We found no evidence that metformin has an effect on either reducing body mass index or altering the waist:hip ratio. Patients need to be aware that it is not a "weight loss" drug. Metformin should therefore always be used as an adjuvant to general lifestyle improvements and not as a replacement for increased exercise and improved diet. Figure 5 gives suggestions on how to induce ovulation in women with polycystic ovary syndrome.^31-35

View larger version (49K): [in this window] [in a new window]   Fig 5 Suggested algorithm for the management of ovulation induction in women with polycystic ovary syndrome

 

---

This review is an edited version of that published as a Cochrane review in the Cochrane Library 2003, Issue 3 (www.cochranelibrary.net). Cochrane reviews are regularly updated as new evidence emerges and in response to comments and criticisms, and the Cochrane Library should be consulted for the most recent version of the review.

We thank the corresponding authors of trials who took time to respond to our requests for further data, some of whom took the trouble to perform repeat analyses for us. We would also like to thank the Cochrane Menstrual Disorders and Subfertility review group in Auckland, New Zealand, and in particular their co-ordinator Michelle Proctor, for all their help and support. We are also grateful to Andy Vail of the UK Cochrane Centre for statistical advice.

Contributors: JML was responsible for the primary literature search, initial assessment of trials and quality analysis, data collection, analysis, and the initial draft of the full review. He acts as guarantor. IHKF was responsible for developing the protocol, checking the literature search, undertaking secondary assessment of trials and quality analysis (blinded), reviewing data collection and analysis, and revising the first draft of the full review. RJN was responsible for developing protocol and was the final arbiter to resolve differences in quality assessment between other reviewers. He contributed to finalising the review and the content and is the Cochrane expert.

Funding: Reproductive Medicine Unit, University of Adelaide.

Competing interests: None declared.

References

1. Hull MGR. Epidemiology of infertility and polycystic ovarian disease: endocrinological and demographic studies. Gyn Endocrinol 1987;1: 233-45.
2. Polson DW, Adams J, Wadsworth J, Franks S. Polycystic ovaries—a common finding in normal women. Lancet 1988;1: 870-2.[CrossRef][Web of Science][Medline]
3. Michelmore KF, Balen AH, Dunger DB, Vessey MP. Polycystic ovaries and associated clinical and biochemical features in young women. Clin Endocrinol Oxf 1999;51: 779-86.[CrossRef][Medline]
4. Reaven G. Syndrome X: 10 years after. Drugs 1999;58(suppl 1): S19-82.
5. Legro RS. Diabetes prevalence and risk factors in polycystic ovary syndrome. Obstet Gynecol Clin North Am 2001;28: 99-109.[CrossRef][Web of Science][Medline]
6. Costello MF, Eden JA. A systematic review of the reproductive system effects of metformin in patients with polycystic ovary syndrome. Fertil Steril 2003;79: 1-13.[CrossRef][Web of Science][Medline]
7. Harborne L, Fleming R, Lyall H, Norman J, Sattar N. Descriptive review of the evidence for the use of metformin in polycystic ovary syndrome. Lancet 2003;361: 1894-901.[CrossRef][Web of Science][Medline]
8. Homburg R. Should patients with polycystic ovarian syndrome be treated with metformin? A note of cautious optimism. Hum Reprod 2002;17: 853-6.[Abstract/Free Full Text]
9. Nestler JE, Stovall D, Akhter N, Iuorno MJ, Jakubowicz DJ. Strategies for the use of insulin-sensitizing drugs to treat infertility in women with polycystic ovary syndrome. Fertil Steril 2002;77: 209-15.[CrossRef][Web of Science][Medline]
10. Seli E, Duleba AJ. Should patients with polycystic ovarian syndrome be treated with metformin? Hum Reprod 2002;17: 2230-6.[Abstract/Free Full Text]
11. Stadtmauer LA, Wong BC, Oehninger S. Should patients with polycystic ovary syndrome be treated with metformin?: Benefits of insulin sensitizing drugs in polycystic ovary syndrome--beyond ovulation induction. Hum Reprod 2002;17: 3016-26.[Abstract/Free Full Text]
12. Fleming R, Hopkinson ZE, Wallace AM, Greer IA, Sattar N. Ovarian function and metabolic factors in women with oligomenorrhea treated with metformin in a randomized double blind placebo-controlled trial. J Clin Endocrinol Metab 2002;87: 569-74.[Abstract/Free Full Text]
13. Jakubowicz DJ, Seppala M, Jakubowicz S, Rodriguez-Armas O, Rivas-Santiago A, Koistinen H, et al. Insulin reduction with metformin increases luteal phase serum glycodelin and insulin-like growth factor-binding protein 1 concentrations and enhances uterine vascularity and blood flow in the polycystic ovary syndrome. J Clin Endocrinol Metab 2001;86: 1126-33.[Abstract/Free Full Text]
14. Kocak M, Caliskan E, Simsir C, Haberal A. Metformin therapy improves ovulatory rates, cervical scores, and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome. Fertil Steril 2002;77: 101-6.[Web of Science][Medline]
15. Malkawi HY, Qublan HS. The effect of metformin plus clomiphene citrate on ovulation and pregnancy rates in clomiphene-resistant women with polycystic ovary syndrome. Saudi Med J 2002;23: 663-6.[Web of Science][Medline]
16. Moghetti P, Castello R, Negri C, Tosi F, Perrone F, Caputo M. et al. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab 2000;85: 139-46.[Abstract/Free Full Text]
17. Ng EHY, Wat NMS, Ho PC. Effects of metformin on ovulation rate, hormonal and metabolic profiles in women with clomiphene-resistant polycystic ovaries: A randomized, double-blinded placebo-controlled trial. Hum Reprod 2001;16: 1625-31.[Abstract/Free Full Text]
18. Pasquali R, Gambineri A, Biscotti D, Vicennati V, Gagliardi L, Colitta D, et al. Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome. J Clin Endocrinol Metab 2000;85: 2767-74.[Abstract/Free Full Text]
19. Sturrock ND, Lannon B, Fay TN. Metformin does not enhance ovulation induction in clomiphene resistant polycystic ovary syndrome in clinical practice. Br J Clin Pharmacol 2002;53: 469-73.[CrossRef][Web of Science][Medline]
20. Vandermolen DT, Ratts VS, Evans WS, Stovall DW, Kauma SW, Nestler JE. Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertil Steril 2001;75: 310-5.[CrossRef][Web of Science][Medline]
21. Yarali H, Yildiz BO, Demirol A, Zeyneloglu HB, Yigit N, Bukulmez O, et al. Co-administration of metformin during rFSH treatment in patients with clomiphene citrate-resistant polycystic ovarian syndrome: a prospective randomized trial. Hum Reprod 2002;17: 289-94.[Abstract/Free Full Text]
22. Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 1996;335: 617-23.[Abstract/Free Full Text]
23. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med 1998;338: 1876-80.[Abstract/Free Full Text]
24. El-Biely MM, Habba M. The use of metformin to augment the induction of ovulation in obese infertile patients with polycystic ovary syndrome. Middle East Fertil Soc J 2001;6: 43-9.
25. Kousta E, White DM, Franks S. Modern use of clomiphene citrate in induction of ovulation. Hum Reprod Update 1997;3: 359-65.[Abstract/Free Full Text]
26. Messinis IE, Milingos SD. Current and future status of ovulation induction in polycystic ovary syndrome. Hum Reprod Update 1997;3: 235-53.[Abstract/Free Full Text]
27. Levene MI, Wild J, Steer P. Higher multiple births and the modern management of infertility in Britain. Br J Obstet Gynaecol 1992;99: 607-13.[Web of Science][Medline]
28. Reaven GM. Insulin resistance: a chicken that has come to roost. Ann N Y Acad Sci 1999;892: 45-57.[CrossRef][Web of Science][Medline]
29. Hague WM, Davoren PM, Oliver J, Rowan J. Contraindications to use of metformin. Metformin may be useful in gestational diabetes. BMJ 2003;326: 762.[Free Full Text]
30. Clark AM, Thornley B, Tomlinson L, Galletley C, Norman RJ. Weight loss in obese infertile women results in improvement in reproductive outcome for all forms of fertility treatment. Hum Reprod 1998;13: 1502-5.[Abstract/Free Full Text]
31. Royal College of Obstetrics and Gynaecology. Evidence-based clinical guideline No. 2: the initial investigation and management of the infertile couple. London: RCOG Press, 1998.
32. Norman RJ, Davies MJ, Lord J, Moran LJ. The role of lifestyle modification in polycystic ovary syndrome. Trends Endocrinol Metab 2002;13: 251-7.[CrossRef][Web of Science][Medline]
33. Nestler JE. Metformin and the polycystic ovary syndrome. J Clin Endocrinol Metab 2001;86: 1430.[Free Full Text]
34. Royal College of Obstetrics and Gynaecology. Evidence-based clinical guidelines No. 3: the management of infertility in secondary care. London: RCOG Press, 1998
35. Royal College of Obstetrics and Gynaecology. Long-term consequences of polycystic ovary syndrome. London, RCOG, 2003. (Clinical Green Top Guideline No 33.)

(Accepted August 7, 2003)

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    StumbleUpon    Technorati    What's this?

Relevant Articles

Drugs for anovulatory infertility in polycystic ovary syndrome

Hesham Al-Inany and Neil Johnson
BMJ 2006 332: 1461-1462. [Extract] [Full Text] [PDF]

Obesity, polycystic ovary syndrome, infertility treatment: Lifestyle modification is paramount

Jonathan M Lord and Robert Norman
BMJ 2006 332: 609. [Extract] [Full Text]

Metformin is effective in treating polycystic ovary syndrome
BMJ 2003 327: 0. [Full Text]

This article has been cited by other articles:

• Teelucksingh, S., Pinto Pereira, L. M (2009). Metformin: an important tool for endocrinology in the West Indies. New tricks for an old drug. British Journal of Diabetes & Vascular Disease 9: 232-236 [Abstract]  
• Cheang, K. I., Huszar, J. M., Best, A. M., Sharma, S., Essah, P. A., Nestler, J. E. (2009). Long-term effect of metformin on metabolic parameters in the polycystic ovary syndrome. Diabetes and Vascular Disease Research 6: 110-119 [Abstract]  
• Metwally, M., Amer, S., Li, T.C., Ledger, W.L. (2009). An RCT of metformin versus orlistat for the management of obese anovulatory women. Hum Reprod 24: 966-975 [Abstract] [Full text]  
• Palomba, S., Falbo, A., Zullo, F., Orio, F. Jr. (2009). Evidence-Based and Potential Benefits of Metformin in the Polycystic Ovary Syndrome: A Comprehensive Review. Endocr. Rev. 30: 1-50 [Abstract] [Full text]  
• Ghiyath Shayeb, A., Bhattacharya, S. (2009). Review: Male obesity and reproductive potential. British Journal of Diabetes & Vascular Disease 9: 7-12 [Abstract]  
• Sathyapalan, T., Kilpatrick, E. S., Coady, A.-M., Atkin, S. L. (2009). The Effect of Atorvastatin in Patients with Polycystic Ovary Syndrome: A Randomized Double-Blind Placebo-Controlled Study. J. Clin. Endocrinol. Metab. 94: 103-108 [Abstract] [Full text]  
• Keely, E (2008). Type 2 diabetes in pregnancy: importance of optimized care before, during and after pregnancy. Obstet Med 1: 72-77 [Abstract] [Full text]  
• Hoeger, K., Davidson, K., Kochman, L., Cherry, T., Kopin, L., Guzick, D. S. (2008). The Impact of Metformin, Oral Contraceptives, and Lifestyle Modification on Polycystic Ovary Syndrome in Obese Adolescent Women in Two Randomized, Placebo-Controlled Clinical Trials. J. Clin. Endocrinol. Metab. 93: 4299-4306 [Abstract] [Full text]  
• Jensterle, M., Sebestjen, M., Janez, A., Prezelj, J., Kocjan, T., Keber, I., Pfeifer, M. (2008). Improvement of endothelial function with metformin and rosiglitazone treatment in women with polycystic ovary syndrome. Eur J Endocrinol 159: 399-406 [Abstract] [Full text]  
• Cataldo, N. A., Barnhart, H. X., Legro, R. S., Myers, E. R., Schlaff, W. D., Carr, B. R., Diamond, M. P., Carson, S. A., Steinkampf, M. P., Coutifaris, C., McGovern, P. G., Gosman, G., Nestler, J. E., Giudice, L. C., for the Reproductive Medicine Network, (2008). Extended-Release Metformin Does Not Reduce the Clomiphene Citrate Dose Required to Induce Ovulation in Polycystic Ovary Syndrome. J. Clin. Endocrinol. Metab. 93: 3124-3127 [Abstract] [Full text]  
• Jensterle, M., Janez, A., Mlinar, B., Marc, J., Prezelj, J., Pfeifer, M. (2008). Impact of metformin and rosiglitazone treatment on glucose transporter 4 mRNA expression in women with polycystic ovary syndrome.. Eur J Endocrinol 158: 793-801 [Abstract] [Full text]  
• Glintborg, D., Andersen, M., Hagen, C., Heickendorff, L., Hermann, A. P. (2008). Association of Pioglitazone Treatment with Decreased Bone Mineral Density in Obese Premenopausal Patients with Polycystic Ovary Syndrome: A Randomized, Placebo-Controlled Trial. J. Clin. Endocrinol. Metab. 93: 1696-1701 [Abstract] [Full text]  
• Nestler, J. E. (2008). Metformin for the Treatment of the Polycystic Ovary Syndrome. NEJM 358: 47-54 [Full text]  
• Moll, E., van der Veen, F., van Wely, M. (2007). The role of metformin in polycystic ovary syndrome: a systematic review. Hum Reprod Update 13: 527-537 [Abstract] [Full text]  
• Trolle, B., Flyvbjerg, A., Kesmodel, U., Lauszus, F.F. (2007). Efficacy of metformin in obese and non-obese women with polycystic ovary syndrome: a randomized, double-blinded, placebo-controlled cross-over trial. Hum Reprod 22: 2967-2973 [Abstract] [Full text]  
• Barbieri, R. L. (2007). Clomiphene Versus Metformin for Ovulation Induction in Polycystic Ovary Syndrome: The Winner Is ..... J. Clin. Endocrinol. Metab. 92: 3399-3401 [Full text]  
• Palomba, S., Orio, F. Jr., Falbo, A., Russo, T., Tolino, A., Zullo, F. (2007). Clomiphene Citrate Versus Metformin as First-Line Approach for the Treatment of Anovulation in Infertile Patients with Polycystic Ovary Syndrome. J. Clin. Endocrinol. Metab. 92: 3498-3503 [Abstract] [Full text]  
• Shojania, K. G., Sampson, M., Ansari, M. T., Ji, J., Doucette, S., Moher, D. (2007). How Quickly Do Systematic Reviews Go Out of Date? A Survival Analysis. ANN INTERN MED 147: 224-233 [Abstract] [Full text]  
• Palomba, S., Falbo, A., Russo, T., Manguso, F., Tolino, A., Zullo, F., De Feo, P., Orio, F. Jr. (2007). Insulin Sensitivity after Metformin Suspension in Normal-Weight Women with Polycystic Ovary Syndrome. J. Clin. Endocrinol. Metab. 92: 3128-3135 [Abstract] [Full text]  
• Rowan, J. A., on behalf of the MiG Investigators, (2007). A Trial in Progress: Gestational Diabetes: Treatment with metformin compared with insulin (the Metformin in Gestational Diabetes [MiG] trial). Diabetes Care 30: S214-S219 [Full text]  
• Panidis, D., Farmakiotis, D., Bell, D. S.H., Geberhiwot, T., Jones, A. F., Legro, R. S., Myers, E. R. (2007). Treatment of Infertility in the Polycystic Ovary Syndrome. NEJM 356: 1999-2001 [Full text]  
• Zisser, H. C. (2007). Polycystic Ovary Syndrome and Pregnancy: Is Metformin the Magic Bullet?. Diabetes Spectr. 20: 85-89 [Abstract] [Full text]  
• Legro, R. S., Barnhart, H. X., Schlaff, W. D., Carr, B. R., Diamond, M. P., Carson, S. A., Steinkampf, M. P., Coutifaris, C., McGovern, P. G., Cataldo, N. A., Gosman, G. G., Nestler, J. E., Giudice, L. C., Leppert, P. C., Myers, E. R., the Cooperative Multicenter Reproductive Medicine, (2007). Clomiphene, Metformin, or Both for Infertility in the Polycystic Ovary Syndrome. NEJM 356: 551-566 [Abstract] [Full text]  
• Guzick, D. S. (2007). Treating the Polycystic Ovary Syndrome the Old-Fashioned Way. NEJM 356: 622-624 [Full text]  
• Legro, R. S. (2007). A 27-Year-Old Woman With a Diagnosis of Polycystic Ovary Syndrome. JAMA 297: 509-519 [Abstract] [Full text]  
• Freemark, M. (2007). Pharmacotherapy of Childhood Obesity: An evidence-based, conceptual approach. Diabetes Care 30: 395-402 [Full text]  
• Gambineri, A., Patton, L., Vaccina, A., Cacciari, M., Morselli-Labate, A. M., Cavazza, C., Pagotto, U., Pasquali, R. (2006). Treatment with Flutamide, Metformin, and Their Combination Added to a Hypocaloric Diet in Overweight-Obese Women with Polycystic Ovary Syndrome: A Randomized, 12-Month, Placebo-Controlled Study. J. Clin. Endocrinol. Metab. 91: 3970-3980 [Abstract] [Full text]  
• Al-Inany, H., Johnson, N. (2006). Drugs for anovulatory infertility in polycystic ovary syndrome.. BMJ 332: 1461-1462 [Full text]  
• Pasquali, R., Gambineri, A. (2006). Insulin-sensitizing agents in polycystic ovary syndrome.. Eur J Endocrinol 154: 763-775 [Abstract] [Full text]  
• Costello, M. F., Chapman, M., Conway, U. (2006). A systematic review and meta-analysis of randomized controlled trials on metformin co-administration during gonadotrophin ovulation induction or IVF in women with polycystic ovary syndrome. Hum Reprod 21: 1387-1399 [Abstract] [Full text]  
• Ibanez, L., de Zegher, F. (2006). Low-dose flutamide-metformin therapy for hyperinsulinemic hyperandrogenism in non-obese adolescents and women. Hum Reprod Update 12: 243-252 [Abstract] [Full text]  
• Lord, J. M, Norman, R. (2006). Obesity, polycystic ovary syndrome, infertility treatment: Lifestyle modification is paramount. BMJ 332: 609-609 [Full text]  
• Eisenhardt, S., Schwarzmann, N., Henschel, V., Germeyer, A., von Wolff, M., Hamann, A., Strowitzki, T. (2006). Early Effects of Metformin in Women with Polycystic Ovary Syndrome: A Prospective Randomized, Double-Blind, Placebo-Controlled Trial. J. Clin. Endocrinol. Metab. 91: 946-952 [Abstract] [Full text]  
• Palomba, S., Russo, T., Orio, F. Jr, Falbo, A., Manguso, F., Cascella, T., Tolino, A., Carmina, E., Colao, A., Zullo, F. (2006). Uterine effects of metformin administration in anovulatory women with polycystic ovary syndrome. Hum Reprod 21: 457-465 [Abstract] [Full text]  
• (2006). Polycystic Ovary Syndrome. JWatch Women's Health 2006: 9-9 [Full text]  
• Cataldo, N. A., Abbasi, F., McLaughlin, T. L., Basina, M., Fechner, P. Y., Giudice, L. C., Reaven, G. M. (2006). Metabolic and ovarian effects of rosiglitazone treatment for 12 weeks in insulin-resistant women with polycystic ovary syndrome. Hum Reprod 21: 109-120 [Abstract] [Full text]  
• Eijkemans, M. J.C., Polinder, S., Mulders, A. G.M.G.J., Laven, J. S.E., Habbema, J.D. F., Fauser, B. C.J.M. (2005). Individualized cost-effective conventional ovulation induction treatment in normogonadotrophic anovulatory infertility (WHO group 2). Hum Reprod 20: 2830-2837 [Abstract] [Full text]  
• Messinis, I. E. (2005). Ovulation induction: a mini review. Hum Reprod 20: 2688-2697 [Abstract] [Full text]  
• Penna, I.A.A., Canella, P.R.B., Reis, R.M., Silva de Sa, M.F., Ferriani, R.A. (2005). Acarbose in obese patients with polycystic ovarian syndrome: a double-blind, randomized, placebo-controlled study. Hum Reprod 20: 2396-2401 [Abstract] [Full text]  
• Harborne, L. R., Sattar, N., Norman, J. E., Fleming, R. (2005). Metformin and Weight Loss in Obese Women with Polycystic Ovary Syndrome: Comparison of Doses. J. Clin. Endocrinol. Metab. 90: 4593-4598 [Abstract] [Full text]  
• Bloomgarden, Z. T. (2005). Second World Congress on the Insulin Resistance Syndrome: Mediators, pediatric insulin resistance, the polycystic ovary syndrome, and malignancy. Diabetes Care 28: 1821-1830 [Full text]  
• Palomba, S., Orio, F. Jr., Falbo, A., Manguso, F., Russo, T., Cascella, T., Tolino, A., Carmina, E., Colao, A., Zullo, F. (2005). Prospective Parallel Randomized, Double-Blind, Double-Dummy Controlled Clinical Trial Comparing Clomiphene Citrate and Metformin as the First-Line Treatment for Ovulation Induction in Nonobese Anovulatory Women with Polycystic Ovary Syndrome. J. Clin. Endocrinol. Metab. 90: 4068-4074 [Abstract] [Full text]  
• Checa, M.A., Requena, A., Salvador, C., Tur, R., Callejo, J., Espinos, J.J., Fabregues, F., Herrero, J., (Reproductive Endocrinology Interest Group of the, (2005). Insulin-sensitizing agents: use in pregnancy and as therapy in polycystic ovary syndrome. Hum Reprod Update 11: 375-390 [Abstract] [Full text]  
• Legro, R. S., Gnatuk, C. L., Kunselman, A. R., Dunaif, A. (2005). Changes in Glucose Tolerance over Time in Women with Polycystic Ovary Syndrome: A Controlled Study. J. Clin. Endocrinol. Metab. 90: 3236-3242 [Abstract] [Full text]  
• van Santbrink, E. J P, Hohmann, F. P, Eijkemans, M. J C, Laven, J. S E, Fauser, B. C J M (2005). Does metformin modify ovarian responsiveness during exogenous FSH ovulation induction in normogonadotrophic anovulation? A placebo-controlled double-blind assessment. Eur J Endocrinol 152: 611-617 [Abstract] [Full text]  
• Kimmel, B., Inzucchi, S. E. (2005). Oral Agents for Type 2 Diabetes: An Update. Clin. Diabetes 23: 64-76 [Abstract] [Full text]  
• Ortega-Gonzalez, C., Luna, S., Hernandez, L., Crespo, G., Aguayo, P., Arteaga-Troncoso, G., Parra, A. (2005). Responses of Serum Androgen and Insulin Resistance to Metformin and Pioglitazone in Obese, Insulin-Resistant Women with Polycystic Ovary Syndrome. J. Clin. Endocrinol. Metab. 90: 1360-1365 [Abstract] [Full text]  
• Jayagopal, V., Kilpatrick, E. S., Holding, S., Jennings, P. E., Atkin, S. L. (2005). Orlistat Is as Beneficial as Metformin in the Treatment of Polycystic Ovarian Syndrome. J. Clin. Endocrinol. Metab. 90: 729-733 [Abstract] [Full text]  
• Cibula, D., Fanta, M., Vrbikova, J., Stanicka, S., Dvorakova, K., Hill, M., Skrha, J., Zivny, J., Skrenkova, J. (2005). The effect of combination therapy with metformin and combined oral contraceptives (COC) versus COC alone on insulin sensitivity, hyperandrogenaemia, SHBG and lipids in PCOS patients. Hum Reprod 20: 180-184 [Abstract] [Full text]  
• Muth, S., Norman, J., Sattar, N., Fleming, R. (2004). Women with polycystic ovary syndrome (PCOS) often undergo protracted treatment with metformin and are disinclined to stop: indications for a change in licensing arrangements?. Hum Reprod 19: 2718-2720 [Abstract] [Full text]  
• Daskalopoulou, S. S., Mikhailidis, D. P., Elisaf, M. (2004). Prevention and Treatment of the Metabolic Syndrome. ANGIOLOGY 55: 589-612 [Abstract]  
• Daskalopoulou, S. S., Mikhailidis, D. P., Elisaf, M. (2004). Prevention and Treatment of the Metabolic Syndrome. ANGIOLOGY 55: 589-612 [Abstract]  
• Kashyap, S., Wells, G. A., Rosenwaks, Z. (2004). Insulin-sensitizing agents as primary therapy for patients with polycystic ovarian syndrome. Hum Reprod 19: 2474-2483 [Abstract] [Full text]  
• Norman, R. J. (2004). Metformin--Comparison with Other Therapies in Ovulation Induction in Polycystic Ovary Syndrome. J. Clin. Endocrinol. Metab. 89: 4797-4800 [Full text]  
• Panidis, D., Kourtis, A., Kukuvitis, A., Farmakiotis, D., Xita, N., Georgiou, I., Tsatsoulis, A. (2004). Association of the T45G polymorphism in exon 2 of the adiponectin gene with polycystic ovary syndrome: role of {Delta}4-androstenedione. Hum Reprod 19: 1728-1733 [Abstract] [Full text]  
• Legro, R. S., Myers, E., for the Reproductive Medicine Network, (2004). Surrogate end-points or primary outcomes in clinical trials in women with polycystic ovary syndrome?. Hum Reprod 19: 1697-1704 [Abstract] [Full text]  
• Collins, J. A., Van Steirteghem, A. (2004). Overall prognosis with current treatment of infertility. Hum Reprod Update 10: 309-316 [Abstract] [Full text]  
• Ganie, M. A., Khurana, M. L., Eunice, M., Gulati, M., Dwivedi, S. N., Ammini, A. C. (2004). Comparison of Efficacy of Spironolactone with Metformin in the Management of Polycystic Ovary Syndrome: An Open-Labeled Study. J. Clin. Endocrinol. Metab. 89: 2756-2762 [Abstract] [Full text]  
• Hoeger, K. M, Guzick, D. S (2004). Review: metformin used alone or combined with clomifene may improve ovulation rates in the polycystic ovary syndrome. Evid. Based Med. 9: 85-85 [Full text]  
• Norman, R. J., Noakes, M., Wu, R., Davies, M. J., Moran, L., Wang, J. X. (2004). Improving reproductive performance in overweight/obese women with effective weight management. Hum Reprod Update 10: 267-280 [Abstract] [Full text]  
• Bloomgarden, Z. T. (2004). Definitions of the Insulin Resistance Syndrome: The 1st World Congress on the Insulin Resistance Syndrome. Diabetes Care 27: 824-830 [Full text]  
• (2003). Metformin Induces Ovulation in Polycystic Ovary Syndrome. JWatch General 2003: 4-4 [Full text]  

Rapid Responses:

Read all Rapid Responses

hirsutism and metformin

mohamed hassanein
bmj.com, 25 Oct 2003 [Full text]

Continuing metformin through pregnancy may enhance beneficial reproductive effect

Alexandros Sotiriadis, et al.
bmj.com, 26 Oct 2003 [Full text]

Hypothesis?

Jaspreet Singh SOMAL
bmj.com, 28 Oct 2003 [Full text]

Hypothesis: Mutation of transepithelial Chloride transport?

Friedrich Flachsbart
bmj.com, 29 Oct 2003 [Full text]

Effect of metformin on weight in polycystic ovary syndrome (PCO): evidence that age is important.

Gul Bano, et al.
bmj.com, 1 Nov 2003 [Full text]

Metformin in polycystic ovary syndrome: Metformin and contrast media

Ferdinand Frauscher, et al.
bmj.com, 4 Nov 2003 [Full text]

Metformin; are we vigilant enough?

Justin C Lee, et al.
bmj.com, 25 Nov 2003 [Full text]

Author's Response

Jonathan M Lord
bmj.com, 24 Nov 2003 [Full text]

Thrombosis to survive infections is the common focus of polycystic diseases!

Friedrich Flachsbart
bmj.com, 8 Feb 2004 [Full text]

Theres nothing like weight reduction for PCOS

Dr Jayaraman Nambiar
bmj.com, 22 Dec 2004 [Full text]

Online poll

Find out more >>