Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2017 Nov 29;11(11):CD003053.
doi: 10.1002/14651858.CD003053.pub6.

Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility

Lara C Morley  1 , Thomas Tang, Ephia Yasmin, Robert J Norman, Adam H Balen
Affiliations
Meta-Analysis

Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility

Lara C Morley et al. Cochrane Database Syst Rev. .

Abstract

Background: Polycystic ovary syndrome (PCOS) is characterised by infrequent or absent ovulation, and high levels of androgens and insulin (hyperinsulinaemia). Hyperinsulinaemia occurs secondary to insulin resistance and is associated with increased risk of cardiovascular disease and diabetes mellitus. Insulin-sensitising agents such as metformin may be effective in treating PCOS-related anovulation.

Objectives: To evaluate the effectiveness and safety of insulin-sensitising drugs in improving reproductive and metabolic outcomes for women with PCOS undergoing ovulation induction.

Search methods: We searched the following databases from inception to January 2017: Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL. We searched registers of ongoing trials and reference lists from relevant studies.

Selection criteria: We included randomised controlled trials of insulin-sensitising drugs compared with placebo, no treatment, or an ovulation-induction agent for women with oligo and anovulatory PCOS.

Data collection and analysis: Two review authors independently assessed studies for eligibility and bias. Primary outcomes were live birth rate and gastrointestinal adverse effects. Secondary outcomes included other pregnancy outcomes, menstrual frequency and metabolic effects. We combined data to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I2 statistic and reported quality of the evidence for primary outcomes using GRADE methodology.

Main results: We assessed the interventions metformin, clomiphene citrate, metformin plus clomiphene citrate, D-chiro-inositol, rosiglitazone and pioglitazone. We compared these with each other, placebo or no treatment. We included 48 studies (4451 women), 42 of which investigated metformin (4024 women). Evidence quality ranged from very low to moderate. Limitations were risk of bias (poor reporting of methodology and incomplete outcome data), imprecision and inconsistency. Metformin versus placebo or no treatmentThe evidence suggests that metformin may improve live birth rates compared with placebo (OR 1.59, 95% CI 1.00 to 2.51, 4 studies, 435 women, I2 = 0%, low-quality evidence). The metformin group experienced more gastrointestinal side effects (OR 4.76, 95% CI 3.06 to 7.41, 7 studies, 670 women, I2 = 61%, moderate-quality evidence) but had higher rates of clinical pregnancy (OR 1.93, 95% CI 1.42 to 2.64, 9 studies, 1027 women, I2 = 43%, moderate-quality evidence), ovulation (OR 2.55, 95% CI 1.81 to 3.59, 14 studies, 701 women, I2 = 58%, moderate-quality evidence) and menstrual frequency (OR 1.72, 95% CI 1.14 to 2.61, 7 studies, 427 women, I2 = 54%, low-quality evidence). There was no clear evidence of a difference in miscarriage rates (OR 1.08, 95% CI 0.50 to 2.35, 4 studies, 748 women, I2 = 0%, low-quality evidence). Metformin plus clomiphene citrate versus clomiphene citrate alone There was no conclusive evidence of a difference between the groups in live birth rates (OR 1.21, 95% CI 0.92 to 1.59, 9 studies, 1079 women, I2 = 20%, low-quality evidence), but gastrointestinal side effects were more common with combined therapy (OR 3.97, 95% CI 2.59 to 6.08, 3 studies, 591 women, I2 = 47%, moderate-quality evidence). However, the combined therapy group had higher rates of clinical pregnancy (OR 1.59, 95% CI 1.27 to 1.99, 16 studies, 1529 women, I2 = 33%, moderate-quality evidence) and ovulation (OR 1.57, 95% CI 1.28 to 1.92, 21 studies, 1624 women, I2 = 64%, moderate-quality evidence). There was a statistically significant difference in miscarriage rate per woman, with higher rates in the combined therapy group (OR 1.59, 95% CI 1.03 to 2.46, 9 studies, 1096 women, I2 = 0%, low-quality evidence) but this is of uncertain clinical significance due to low-quality evidence, and no clear difference between groups when we analysed miscarriage per pregnancy (OR 1.30, 95% CI 0.80 to 2.12, 8 studies; 400 pregnancies, I2 = 0%, low-quality evidence). Metformin versus clomiphene citrateWhen all studies were combined, findings for live birth were inconclusive and inconsistent (OR 0.71, 95% CI 0.49 to 1.01, 5 studies, 741 women, I2 = 86%, very low-quality evidence). In subgroup analysis by obesity status, obese women had a lower birth rate in the metformin group (OR 0.30, 95% CI 0.17 to 0.52, 2 studies, 500 women, I2 = 0%, very low-quality evidence), while data from the non-obese group showed a possible benefit from metformin, with high heterogeneity (OR 1.71, 95% CI 1.00 to 2.94, 3 studies, 241 women, I2 = 78%, very low-quality evidence). Similarly, among obese women taking metformin there were lower rates of clinical pregnancy (OR 0.34, 95% CI 0.21 to 0.55, 2 studies, 500 women, I2 = 0%, very low-quality evidence) and ovulation (OR 0.29, 95% CI 0.20 to 0.43 2 studies, 500 women, I2 = 0%, low-quality evidence) while among non-obese women, the metformin group had more pregnancies (OR 1.56, 95% CI 1.05 to 2.33, 5 studies, 490 women, I2 = 41%, very low-quality evidence) and no clear difference in ovulation rates (OR 0.81, 95% CI 0.51 to 1.28, 4 studies, 312 women, low-quality evidence, I2=0%). There was no clear evidence of a difference in miscarriage rates (overall: OR 0.92, 95% CI 0.50 to 1.67, 5 studies, 741 women, I2 = 52%, very low-quality evidence). D-chiro-inositol (2 studies), rosiglitazone (1 study) or pioglitazone (1 study) versus placebo or no treatmentWe were unable to draw conclusions regarding other insulin-sensitising drugs as no studies reported primary outcomes.

Authors' conclusions: Our updated review suggests that metformin alone may be beneficial over placebo for live birth, although the evidence quality was low. When metformin was compared with clomiphene citrate, data for live birth were inconclusive, and our findings were limited by lack of evidence. Results differed by body mass index (BMI), emphasising the importance of stratifying results by BMI. An improvement in clinical pregnancy and ovulation suggests that clomiphene citrate remains preferable to metformin for ovulation induction in obese women with PCOS.An improved clinical pregnancy and ovulation rate with metformin and clomiphene citrate versus clomiphene citrate alone suggests that combined therapy may be useful although we do not know whether this translates into increased live births. Women taking metformin alone or with combined therapy should be advised that there is no evidence of increased miscarriages, but gastrointestinal side effects are more likely.

PubMed Disclaimer

Conflict of interest statement

LCM: none known TT: received consultancy fee from Finox Biotech for advisory board meeting in 2016; Finox do not manufacture insulin sensitisers. EY: received travel costs and meeting expenses to attend Ferring advisory board in 2017; Ferring do not manufacture insulin sensitisers. RN: received consultancy fee from Ferring for advisory board meeting; Ferring do not manufacture insulin sensitisers. AB: NHS Consultant in Reproductive Medicine and clinical lead for the Leeds Centre for Reproductive Medicine, which performs all fertility treatments funded by the NHS; partner in Genesis LLP, the private arm on the Leeds Centre for Reproductive Medicine, which performs all self‐funded fertility treatments using identical protocols to the NHS; Chair, Clinical Board, IVI, UK; Chair, British Fertility Society; Chair, NHS England IVF Pricing Development Expert Advisory Group; Chair, World Health Organization Expert Working Group on Global Infertility Guidelines, Management of PCOS; consultant for ad hoc advisory boards for Ferring Pharmaceuticals, Astra Zeneca, Merck Serono, IBSA, Clear Blue, Gideon Richter, Uteron Pharma & former member of ethics committee for OvaScience. Merck manufacture some products containing metformin.

Figures

1
1
Study flow diagram since publication
2
2
Study flow diagram 2017 update
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
4
4
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
5
5
Forest plot of comparison: 1 Metformin versus placebo or no treatment, outcome: 1.1 Live birth rate
6
6
Forest plot of comparison: 2 Metformin combined with clomiphene citrate versus clomiphene citrate alone, outcome: 2.1 Live birth rate
7
7
Forest plot of comparison: 3 Metformin versus clomiphene citrate, outcome: 3.1 Live birth.
1.1
1.1. Analysis
Comparison 1 Metformin versus placebo or no treatment, Outcome 1 Live birth rate.
1.2
1.2. Analysis
Comparison 1 Metformin versus placebo or no treatment, Outcome 2 Adverse events (gastrointestinal side effects).
1.3
1.3. Analysis
Comparison 1 Metformin versus placebo or no treatment, Outcome 3 Clinical pregnancy rate.
1.4
1.4. Analysis
Comparison 1 Metformin versus placebo or no treatment, Outcome 4 Ovulation rate.
1.5
1.5. Analysis
Comparison 1 Metformin versus placebo or no treatment, Outcome 5 Menstrual frequency.
1.6
1.6. Analysis
Comparison 1 Metformin versus placebo or no treatment, Outcome 6 Miscarriage rate per woman.
1.7
1.7. Analysis
Comparison 1 Metformin versus placebo or no treatment, Outcome 7 Sensitivity analysis: miscarriage rate per pregnancy.
1.8
1.8. Analysis
Comparison 1 Metformin versus placebo or no treatment, Outcome 8 Body mass index (kg/m2).
1.9
1.9. Analysis
Comparison 1 Metformin versus placebo or no treatment, Outcome 9 Waist‐hip ratio.
1.10
1.10. Analysis
Comparison 1 Metformin versus placebo or no treatment, Outcome 10 Blood pressure ‐ systolic (mm Hg).
1.11
1.11. Analysis
Comparison 1 Metformin versus placebo or no treatment, Outcome 11 Blood pressure ‐ diastolic (mm Hg).
1.12
1.12. Analysis
Comparison 1 Metformin versus placebo or no treatment, Outcome 12 Serum testosterone (nmol/L).
1.13
1.13. Analysis
Comparison 1 Metformin versus placebo or no treatment, Outcome 13 Serum sex hormone‐binding globulin (nmol/L).
1.14
1.14. Analysis
Comparison 1 Metformin versus placebo or no treatment, Outcome 14 Fasting glucose (mmol/L).
1.15
1.15. Analysis
Comparison 1 Metformin versus placebo or no treatment, Outcome 15 Fasting insulin (mIU/L).
1.16
1.16. Analysis
Comparison 1 Metformin versus placebo or no treatment, Outcome 16 Total cholesterol (mmol/L).
1.17
1.17. Analysis
Comparison 1 Metformin versus placebo or no treatment, Outcome 17 Triglyceride levels (mmol/L).
2.1
2.1. Analysis
Comparison 2 Metformin combined with clomiphene citrate versus clomiphene citrate alone, Outcome 1 Live birth rate.
2.2
2.2. Analysis
Comparison 2 Metformin combined with clomiphene citrate versus clomiphene citrate alone, Outcome 2 Adverse events.
2.3
2.3. Analysis
Comparison 2 Metformin combined with clomiphene citrate versus clomiphene citrate alone, Outcome 3 Clinical pregnancy rate.
2.4
2.4. Analysis
Comparison 2 Metformin combined with clomiphene citrate versus clomiphene citrate alone, Outcome 4 Ovulation rate.
2.5
2.5. Analysis
Comparison 2 Metformin combined with clomiphene citrate versus clomiphene citrate alone, Outcome 5 Ovulation rate: subgroup analysis by sensitivity to clomiphene citrate.
2.6
2.6. Analysis
Comparison 2 Metformin combined with clomiphene citrate versus clomiphene citrate alone, Outcome 6 Miscarriage rate per woman.
2.7
2.7. Analysis
Comparison 2 Metformin combined with clomiphene citrate versus clomiphene citrate alone, Outcome 7 Sensitivity analysis: miscarriage rate per pregnancy.
2.8
2.8. Analysis
Comparison 2 Metformin combined with clomiphene citrate versus clomiphene citrate alone, Outcome 8 Multiple pregnancy rate per woman.
2.9
2.9. Analysis
Comparison 2 Metformin combined with clomiphene citrate versus clomiphene citrate alone, Outcome 9 Senstivity analysis: multiple pregnancy rate per pregnancy.
3.1
3.1. Analysis
Comparison 3 Metformin versus clomiphene citrate, Outcome 1 Live birth.
3.2
3.2. Analysis
Comparison 3 Metformin versus clomiphene citrate, Outcome 2 Clinical pregnancy rate.
3.3
3.3. Analysis
Comparison 3 Metformin versus clomiphene citrate, Outcome 3 Ovulation rate.
3.4
3.4. Analysis
Comparison 3 Metformin versus clomiphene citrate, Outcome 4 Miscarriage rate per woman.
3.5
3.5. Analysis
Comparison 3 Metformin versus clomiphene citrate, Outcome 5 Sensitivity analysis: miscarriage rate per pregnancy.
3.6
3.6. Analysis
Comparison 3 Metformin versus clomiphene citrate, Outcome 6 Multiple pregnancy rate per woman.
3.7
3.7. Analysis
Comparison 3 Metformin versus clomiphene citrate, Outcome 7 Sensitivity analysis: multiple pregnancy rate per pregnancy.
4.1
4.1. Analysis
Comparison 4 D‐chiro‐inositol versus placebo or no treatment, Outcome 1 Ovulation.
4.2
4.2. Analysis
Comparison 4 D‐chiro‐inositol versus placebo or no treatment, Outcome 2 Body mass index (kg/m2).
4.3
4.3. Analysis
Comparison 4 D‐chiro‐inositol versus placebo or no treatment, Outcome 3 Waist‐hip ratio.
4.4
4.4. Analysis
Comparison 4 D‐chiro‐inositol versus placebo or no treatment, Outcome 4 Blood pressure ‐ systolic (mm Hg).
4.5
4.5. Analysis
Comparison 4 D‐chiro‐inositol versus placebo or no treatment, Outcome 5 Blood pressure ‐ diastolic (mm Hg).
4.6
4.6. Analysis
Comparison 4 D‐chiro‐inositol versus placebo or no treatment, Outcome 6 Serum testosterone (nmol/L).
4.7
4.7. Analysis
Comparison 4 D‐chiro‐inositol versus placebo or no treatment, Outcome 7 Serum sex hormone‐binding globulin (nmol/L).
4.8
4.8. Analysis
Comparison 4 D‐chiro‐inositol versus placebo or no treatment, Outcome 8 Fasting glucose (mmol/L).
4.9
4.9. Analysis
Comparison 4 D‐chiro‐inositol versus placebo or no treatment, Outcome 9 Fasting insulin (mIU/L).
4.10
4.10. Analysis
Comparison 4 D‐chiro‐inositol versus placebo or no treatment, Outcome 10 Total cholesterol (mmol/L).
4.11
4.11. Analysis
Comparison 4 D‐chiro‐inositol versus placebo or no treatment, Outcome 11 Triglyceride levels (mmol/L).
5.1
5.1. Analysis
Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 1 Ovulation rate.
5.2
5.2. Analysis
Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 2 Menstrual frequency.
5.3
5.3. Analysis
Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 3 Body mass index (kg/m2).
5.4
5.4. Analysis
Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 4 Waist‐hip ratio.
5.5
5.5. Analysis
Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 5 Blood pressure ‐ systolic (mm Hg).
5.6
5.6. Analysis
Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 6 Blood pressure ‐ diastolic (mm Hg).
5.7
5.7. Analysis
Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 7 Serum testosterone (nmol/L).
5.8
5.8. Analysis
Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 8 Serum sex hormone‐binding globulin (nmol/L).
5.9
5.9. Analysis
Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 9 Fasting glucose (mmol/L).
5.10
5.10. Analysis
Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 10 Fasting insulin (mIU/L).
5.11
5.11. Analysis
Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 11 Total cholesterol (mmol/L).
5.12
5.12. Analysis
Comparison 5 Rosiglitazone versus placebo or no treatment, Outcome 12 Triglyceride levels (mmol/L).
6.1
6.1. Analysis
Comparison 6 Pioglitazone versus placebo or no treatment, Outcome 1 Menstrual frequency.
6.2
6.2. Analysis
Comparison 6 Pioglitazone versus placebo or no treatment, Outcome 2 Body mass index (kg/m2).
6.3
6.3. Analysis
Comparison 6 Pioglitazone versus placebo or no treatment, Outcome 3 Waist‐hip ratio.
6.4
6.4. Analysis
Comparison 6 Pioglitazone versus placebo or no treatment, Outcome 4 Serum testosterone (nmol/L).
6.5
6.5. Analysis
Comparison 6 Pioglitazone versus placebo or no treatment, Outcome 5 Serum sex hormone‐binding globulin (nmol/L).
6.6
6.6. Analysis
Comparison 6 Pioglitazone versus placebo or no treatment, Outcome 6 Fasting insulin (mIU/L).
See this image and copyright information in PMC

Update of

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

References to studies included in this review

Ayaz 2013 {published data only}
    1. Ayaz A, Alwan Y, Farooq MU. Efficacy of combined metformin‐clomiphene citrate in comparison with clomiphene citrate alone in infertile women with polycystic ovarian syndrome (PCOS). Journal of Medicine and Life 2013;6:199‐201. - PMC - PubMed
    1. Ayaz A, Alwan Y, Farooq MU. Metformin‐clomiphene citrate vs. clomiphene citrate alone: polycystic ovarian syndrome. Journal of Human Reproductive Sciences 2013;6:15‐8. - PMC - PubMed
Baillargeon 2004 {published data only}
    1. Baillargeon JP, Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Nestler JE. Effects of metformin and rosiglitazone, alone and in combination, in nonobese women with polycystic ovary syndrome and normal indices of insulin sensitivity. Fertility and Sterility 2004;82:893‐902. - PubMed
Begum 2014 {published data only}
    1. Begum H, Chowdhury TA, Begum F, Begum SN, Kabir N, Haque MDA. Effect of metformin and clomiphene citrate in improving fertility in subfertility women with polycystic ovary syndrome: a randomised controlled trial. Bangladesh Journal of Obstetrics and Gynaecology 2014;29:15‐20.
Ben Ayed 2009 {published data only}
    1. Ben Ayed B, Dammak Dit Mlik S, Ben Arab H, Trabelssi H, Chahtour H, Mathlouthi N. Metformin effects on clomifene‐induced ovulation in the polycystic ovary syndrome. Tunisie Medicale 2009;87(1):43‐8. - PubMed
Boudhraa 2010 {published data only}
    1. Boudhrâa K, Jellouli MA, Amri M, Farhat M, Torkhani F, Gara MF. Indication of metformin in the management of hormonal dysfunction secondary to polycystic ovarian syndrome: prospective comparative study of 63 cases. [La metformine dans la prise en charge de l'infertilite du SOPK hors FIV etude prospective comparative a propos de 63 cas]. Tunisie Medicale 2010;88(5):335‐40. - PubMed
Brettenthaler 2004 {published data only}
    1. Aigner E, Bachofner N, Klein K, Geyter C, Hohla F, Patsch W, et al. Retinol‐binding protein 4 in polycystic ovary syndrome‐‐association with steroid hormones and response to pioglitazone treatment. Journal of Clinical Endocrinology and Metabolism 2009;94(4):1229‐35. - PubMed
    1. Brettenthaler N, Geyter C, Huber PR, Keller U. Effect of the insulin sensitizer pioglitazone on insulin resistance, hyperandrogenism, and ovulatory dysfunction in women with polycystic ovary syndrome. Journal of Clinical Epidemiology 2004;89:3835‐40. - PubMed
Carmina 2004 {published data only}
    1. Carmina E, Lobo RA. Does metformin induce ovulation in normoandrogenic anovulatory women?. American Journal of Obstetrics and Gynecology 2004;191:1580‐4. - PubMed
Chou 2003 {published data only}
    1. Chou KH, Eye Corleta H, Capp E, Spritzer PM. Clinical, metabolic and endocrine parameters in response to metformin in obese women with polycystic ovary syndrome: a randomized, double‐blind and placebo‐controlled trial. Hormone and Metabolic Research 2003;35:86‐91. - PubMed
Eisenhardt 2006 {published data only}
    1. Eisenhardt S, Schwarzmann N, Henschel V, Germeyer A, Wolff M, Hamann A, et al. Early effects of metformin in women with polycystic ovary syndrome: a prospective randomized, double‐blind, placebo‐controlled trial. Journal of Clinical Endocrinology and Metabolism 2006;91:946‐52. - PubMed
El‐Biely 2001 {published data only}
    1. 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 Fertility Society Journal 2001;6(1):43‐9.
Fleming 2002 {published data only}
    1. 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. Journal of Clinical Endocrinology and Metabolism 2002;87(2):569‐74. - PubMed
    1. Fleming R, Hopkinson ZE, Wallace E, Greer IA, Sattar N. Metformin treatment improves ovulation frequency in women with oligomenorrhoea: a randomized, double blind placebo trial. Human Fertility 2000; Vol. 3, issue 4:389‐90.
Gerli 2003 {published data only}
    1. Gerli S, Mignosa M, Renzo GC. Effects of inositol on ovarian function and metabolic factors in women with PCOS: a randomized double blind placebo‐controlled trial. European Review for Medical and Pharmacological Sciences 2003;7:151‐9. [Original article] - PubMed
    1. Gerli S, Papaleo E, Ferrari A, Renzo GC. Randomized, double blind placebo‐controlled trial: effects of myo‐inositol on ovarian function and metabolic factors in women with PCOS. European Review for Medical and Pharmacological Sciences 2007;11(5):347‐54. - PubMed
Glintborg 2005 {published data only}
    1. Glintborg D, Frystyk J, Hojlund K, Andersen KK, Henriksen JE, Hermann A, et al. Total and high molecular weight (HMW) adiponectin levels and measures of glucose and lipid metabolism following pioglitazone treatment in a randomized placebo‐controlled study in polycystic ovary syndrome. Clinical Endocrinology (Oxford) 2008;68(2):165‐74. - PubMed
    1. Glintborg D, Hermann AP, Andersen M, Hagen C, Beck‐Nielsen H, Veldhuis JD, et al. Effect of pioglitazone on glucose metabolism and luteinizing hormone secretion in women with polycystic ovary syndrome. Fertility and Sterility 2006;86:385‐97. - PubMed
    1. Glintborg D, Hojlund K, Andersen M, Henriksen JE, Beck‐Nielsen H, Handberg A. Soluble CD36 and risk markers of insulin resistance and atherosclerosis are elevated in polycystic ovary syndrome and significantly reduced during pioglitazone treatment. Diabetes Care 2008;31:328‐34. - PubMed
    1. Glintborg D, Stoving RK, Hagen C, Hermann AP, Frystyk J, Veldhuis JD, et al. Pioglitazone treatment increases spontaneous growth hormone (GH) secretion and stimulated GH levels in polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2005;90:5605‐12. [original article] - PubMed
Hoeger 2004 {published data only}
    1. Hoeger KM, Kochman L, Wixom N, Craig K, Miller RK, Guzick DS. A randomized, 48‐week, placebo‐controlled trial of intensive lifestyle modification and/or metformin therapy in overweight women with polycystic ovary syndrome: a pilot study. Fertility and Sterility 2004;82:421‐9. - PubMed
Hwu 2005 {published data only}
    1. Hwu YM, Lin SY, Huang WY, Lin MH, Lee RK. Ultra‐short metformin pretreatment for clomiphene citrate‐resistant polycystic ovary syndrome. International Journal of Gynaecology and Obstetrics 2005;90:39‐43. - PubMed
Jakubowicz 2001 {published data only}
    1. 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. Journal of Clinical Endocrinology and Metabolism 2001;86(3):1126‐33. - PubMed
Kar 2015 {published data only}
    1. Kar S. Metabolic risks of the lean PCOS woman. Fertility and Sterility ASRM abstracts 2013;100(S359):P‐730.
    1. Kar S, Sanchita S. Clomiphene citrate, metformin or a combination of both as the first line ovulation induction drug for Asian Indian women with polycystic ovarian syndrome: a randomized controlled trial. Journal of Human Reproductive Science 2015;8:197‐201. - PMC - PubMed
Karimzadeh 2007 {published data only}
    1. Karimzadeh M, Tayebi N, Eftekhar M, Sakhavat L, Taheripanah R, Zare F. The effect of administration of metformin on lipid profile changes and insulin resistance in patients with polycystic ovary syndrome. Middle East Fertility Society Journal 2007;12(3):174‐8.
Karimzadeh 2010 {published data only}
    1. Karimzadeh MA, Javedani M. An assessment of lifestyle modification versus medical treatment with clomiphene citrate, metformin, and clomiphene citrate‐metformin in patients with polycystic ovary syndrome. Fertility and Sterility 2010;94(1):216‐20. - PubMed
Khorram 2006 {published data only}
    1. Khorram O, Helliwell JP, Katz S, Bonpane CM, Jaramillo L Khorram O, et al. Two weeks of metformin improves clomiphene citrate‐induced ovulation and metabolic profiles in women with polycystic ovary syndrome. Fertility and Sterility 2006;85:1448‐51. - PubMed
Lam 2011 {published data only}
    1. Lam PM, Tam WH, Ma RC, Cheung LP, Tsui MH, Tong PC, et al. The reproductive and metabolic effect of rosiglitazone on Chinese women with polycystic ovarian syndrome ‐ a double‐blind randomized placebo‐controlled study. Fertility and Sterility 2011;96(2):445‐51. - PubMed
Legro 2007 {published data only}
    1. Cataldo N, Barnhart H, Legro R, Myers E, Schlaff W, Carr B, et al. Extended‐release metformin does not reduce the clomiphene citrate dose required to induce ovulation in polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2008;93(8):3147‐7. - PMC - PubMed
    1. Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. New England Journal of Medicine 2007;356:551‐66. [original article] - PubMed
Lord 2006 {published data only}
    1. Lord J, Thomas R, Fox B, Acharya U, Wilkin T. The effect of metformin on fat distribution and the metabolic syndrome in women with polycystic ovary syndrome‐‐a randomised, double‐blind, placebo‐controlled trial. British Journal of Obstetrics and Gynaecology 2006;113:817‐24. - PubMed
Machado 2012 {published data only}
    1. Machado RC, Machado NA, Geber S. Evaluation of the use of metformin for ovulation in patients with PCOS resistant to isolated use of clomiphene citrate. Brazilian Journal Assisted Reproduction 2012;16(1):27‐31.
Maciel 2004 {published data only}
    1. Maciel GA, Soares Jr JM, Alves da Motta EL, Abi Haidar M, Lima GR, Baracat EC, et al. Nonobese women with polycystic ovary syndrome respond better than obese women to treatment with metformin. Fertility and Sterility 2004;81:355‐60. - PubMed
Malkawi 2002 {published data only}
    1. 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 Medical Journal 2002;23(6):663‐6. [MEDLINE: ] - PubMed
Moghetti 2000 {published data only}
    1. 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. Journal of Clinical Endocrinology and Metabolism 2000;85(1):139‐46. - PubMed
Moll 2006 {published data only}
    1. Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, 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;332:1485. [original article] - PMC - PubMed
    1. Moll E, Korevaar JC, Bossuyt PM, Veen F. Does adding metformin to clomifene citrate lead to higher pregnancy rates in a subset of women with polycystic ovary syndrome?. Human Reproduction 2008;23(8):1830‐4. - PMC - PubMed
    1. Moll E, Wely M, Lambalk CB, Bossuyt PM, Veen F. Health‐related quality of life in women with newly diagnosed polycystic ovary syndrome randomized between clomifene citrate plus metformin or clomifene citrate plus placebo. Human Reproduction 2012;27:3273‐8. - PubMed
Morin‐Papunen 2012 {published data only}
    1. Morin‐Papunen L, Rantala AS, Unkila‐Kallio L, Tiitinen A, Hippeläinen M, Perheentupa A, et al. Metformin improves pregnancy and live‐birth rates in women with polycystic ovary syndrome (PCOS): a multicenter, double‐blind, placebo‐controlled randomized trial. Journal of Clinical Endocrinology and Metabolism 2012;97:1492‐1500. - PubMed
Nestler 1998 {published data only}
    1. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on spontaneous and clomiphene‐induced ovulation in the polycystic ovary syndrome. New England Journal of Medicine 1998;338(26):1876‐80. - PubMed
Nestler 1999 {published data only}
    1. Nestler JE, Jakubowicz DJ, Reamer P, Gunn RD, Allan G. Ovulatory and metabolic effects of D‐chiro‐inositol in the polycystic ovary syndrome. New England Journal of Medicine 1999;340(17):1314‐20. - PubMed
Ng 2001 {published data only}
    1. 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. Human Reproduction 2001;16(8):1625‐31. - PubMed
Onalan 2005 {published data only}
    1. Onalan G, Goktolga U, Ceyhan T, Bagis T, Onalan R, Pabuccu R. Predictive value of glucose‐insulin ratio in PCOS and profile of women who will benefit from metformin therapy: obese, lean, hyper or normoinsulinemic?. European Journal of Obstetrics, Gynecology, and Reproductive Biology 2005;123:204‐11. - PubMed
Otta 2010 {published data only}
    1. Otta CF, Wior M, Iraci GS, Kaplan R, Torres D, Gaido MI, et al. Clinical, metabolic, and endocrine parameters in response to metformin and lifestyle intervention in women with polycystic ovary syndrome: a randomized, double‐blind, and placebo control trial. Gynecological Endocrinology 2010;26(3):173‐8. - PubMed
Palomba 2005 {published data only}
    1. Palomba S, Orio F Jr, Falbo A, Manguso F, Russo T, Cascella T, et al. 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. Journal of Clinical Endocrinology and Metabolism 2005;90(7):4068‐74. [original article] - PubMed
    1. Palomba S, Orio F Jr, Falbo A, Russo T, Tolino A, Zullo F. Effects of metformin and clomiphene citrate on ovarian vascularity in patients with polycystic ovary syndrome. Fertility and Sterility 2006;86:1694‐701. - PubMed
Pasquali 2000 {published data only}
    1. Casimirri F, Biscotti M, Gambineri A, Calzoni F, Eliana B, Pasquali R. Metformin improves insulin, body fat distribution, and androgens in obese women with and without the polycystic ovary syndrome. International Journal of Obesity 1997;21 Suppl 2:61.
    1. 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. Journal of Clinical Endocrinology and Metabolism 2000;85(8):2767‐74. - PubMed
PCOSMIC 2010 {published data only}
    1. Johnson NP, Bontekoe S, Stewart AW. Analysis of factors predicting success of metformin and clomiphene treatment for women with infertility owing to PCOS‐related ovulation dysfunction in a randomised controlled trial. Australian & New Zealand Journal of Obstetrics & Gynaecology 2011;51:252‐6. - PubMed
    1. Johnson NP, Stewart AW, Falkiner J, Farquhar CM, Milsom S, Singh V‐P, et al. on behalf of REACT‐NZ (REproduction And Collaborative Trials in New Zealand), a multi‐centre fertility trials group. PCOSMIC: a multi‐centre randomized trial in women with Polycystic Ovary Syndrome evaluating Metformin for Infertility with Clomiphene. Human Reproduction 2010;25(7):1675‐83. [MEDLINE: 10.1093/humrep/deq100] - DOI - PubMed
Rautio 2006 {published data only}
    1. Rautio K, Tapanainen JS, Ruokonen A, Morin‐Papunen LC. Endocrine and metabolic effects of rosiglitazone in overweight women with PCOS: a randomized placebo‐controlled study. Human Reproduction 2006;21:1400‐7. - PubMed
    1. Rautio K, Tapanainen JS, Ruokonen A, Morin‐Papunen LC. Rosiglitazone treatment alleviates inflammation and improves liver function in overweight women with polycystic ovary syndrome: a randomized placebo‐controlled study. Fertility and Sterility 2007;87(1):202‐6. - PubMed
Romualdi 2010 {published data only}
    1. Romualdi D, Giuliani M, Cristello F, Fulghesu AM, Selvaggi L, Lanzone A, et al. Metformin effects on ovarian ultrasound appearance and steroidogenic function in normal‐weight normoinsulinemic women with polycystic ovary syndrome: a randomized double‐blind placebo‐controlled clinical trial. Fertility and Sterility 2010;93(7):2303‐10. - PubMed
Sahin 2004 {published data only}
    1. Sahin Y, Yirmibes U, Kelestimur F, Aygen E. The effects of metformin on insulin resistance, clomiphene‐induced ovulation and pregnancy rates in women with polycystic ovary syndrome. European Journal of Obstetrics, Gynecology, and Reproductive Biology 2004;113:214‐20. - PubMed
Siebert 2009 {published data only}
    1. Siebert T, Kruger T, Lombard C. Evaluating the equivalence of clomiphene citrate with and without metformin in ovulation induction in PCOS patients. Journal of Assisted Reproduction and Genetics 2009;26(4):165‐71. - PMC - PubMed
Sturrock 2002 {published data only}
    1. Sturrock NDC, Lannon B, Fay TN. Metformin does not enhance ovulation induction in clomiphene resistant polycystic ovary syndrome in clinical practice. British Journal of Clinical Pharmacology 2002;53(5):469‐73. [MEDLINE: ] - PMC - PubMed
Tang 2006 {published data only}
    1. Tang T, Glanville J, Hayden CJ, White D, Barth JH, Balen AH. Combined lifestyle modification and metformin in obese patients with polycystic ovary syndrome. A randomized, placebo‐controlled, double‐blind multicentre study. Human Reproduction 2006;21:80‐9. - PubMed
Trolle 2007 {published data only}
    1. Trolle B, Flyvbjerg A, Kesmodel U, Lauszus FF. Efficacy of metformin in obese and non‐obese women with polycystic ovary syndrome: a randomized, double‐blinded, placebo‐controlled cross‐over trial. Human Reproduction 2007;22(11):2967‐73. [original article] - PubMed
    1. Trolle B, Flyvbjerg A, Kesmodel U, Lauszus FF. Efficacy of metformin in obese and non‐obese women with polycystic ovary syndrome: a randomized, double‐blinded, placebo‐controlled cross‐over trial. Obstetrics and Gynecological Survey 2008;63(2):96‐8. - PubMed
Vandermolen 2001 {published data only}
    1. 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. Fertility and Sterility 2001;75:310‐5. - PubMed
Williams 2009 {published data only}
    1. Williams SC, Pastore LM, Shelly WB, Bailey AP, Baras DC, Bateman BG. A randomized, placebo‐controlled study of the influence of instant‐release metformin on response to clomiphene citrate and time to conception in polycystic ovary syndrome. Fertility and Sterility 2009;92 Suppl(3):105.
Yarali 2002 {published data only}
    1. 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. Human Reproduction 2002;17(2):289‐94. - PubMed
    1. Yarali H, Yyldyz B, Demirol A, Zeyneloglu H, Yigit N, Bukulmez O. Co‐administration of metformin during recombinant follicle stimulating hormone (recombinant FSH) treatment using the low‐dose step protocol in patients with clomiphene citrate resistant polycystic ovary syndrome (PCOS): a prospective randomized trial. Fertility and Sterility 2001;76 Suppl(3):36.
Zain 2009 {published data only}
    1. Zain MM, Jamaluddin R, Ibrahim A, Norman RJ. Comparison of clomiphene citrate, metformin, or the combination of both for first‐line ovulation induction, achievement of pregnancy, and live birth in Asian women with polycystic ovary syndrome: a randomized controlled trial. Fertility and Sterility 2009;91(2):514‐21. - PubMed

References to studies excluded from this review

Abuelghar 2013 {published data only}
    1. Abuelghar WM, Elkady OS, Khamees AA. Clomiphene citrate alone, in combination with metformin or in combination with pioglitazone as first line therapy in induction of ovulation in infertile women with polycystic ovary syndrome, a randomised controlled trial. Middle East Fertility Society Journal 2013;18:135‐41.
Aroda 2009 {published data only}
    1. Aroda V, Ciaraldi T, Burke P, Mudaliar S, Clopton P, Phillips S, et al. Metabolic and hormonal changes induced by pioglitazone in polycystic ovary syndrome: a randomized, placebo‐controlled clinical trial. Journal of Clinical Endocrinology and Metabolism 2009;94(2):469‐76. - PMC - PubMed
Azziz 2001 {published data only}
    1. Azziz R, Ehrmann D, Legro RS, Whitcomb RW, Hanley R, Fereshetian AG, et al. Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo‐controlled trial. Journal of Clinical Endocrinology and Metabolism 2001;86(4):1626‐32. [original article] - PubMed
    1. Guyatt G, Weaver B, Cronin L, Dooley JA, Azziz R. Health‐related quality of life in women with polycystic ovary syndrome, a self‐administered questionnaire, was validated. Journal of Clinical Epidemiology 2004;57:1279‐87. - PubMed
    1. Legro RS, Azziz R, Ehrmann D, Fereshetian AG, O'Keefe M, Ghazzi MN. Minimal response of circulating lipids in women with polycystic ovary syndrome to improvement in insulin sensitivity with troglitazone. Journal of Clinical Endocrinology and Metabolism 2003;88:5137‐44. - PubMed
Azziz 2003 {published data only}
    1. Azziz R, Ehrmann DA, Legro RS, Fereshetian AG, O'Keefe M, Ghazzi MN. Troglitazone decreases adrenal androgen levels in women with polycystic ovary syndrome. Fertility and Sterility 2003;79:932‐7. - PubMed
Chaudhry 2016 {published data only}
    1. Chaudhry I, Nisa SU, Nia SU. Comparison between pioglitazone and metformin in terms of efficacy in patients with polycystic ovarian syndrome. Pakistan Journal of Medical and Health Sciences 2016;10:574‐7.
Chaudhury 2008 {published data only}
    1. Chaudhury K, Chaudhury S, Chowdhury S. Does metformin augment the ovulation inducing effects of clomiphene in non‐obese women with polycystic ovary syndrome?. Journal of the Indian Medical Association 2008;106(10):643‐8. - PubMed
Constantino 2009 {published data only}
    1. Costantino D, Minozzi G, Minozzi F, Guaraldi C. Metabolic and hormonal effects of myo‐inositol in women with polycystic ovary syndrome: a double‐blind trial. European Review for Medical and Pharmacological Sciences 2009;13(2):105‐10. - PubMed
Crave 1995 {published data only}
    1. Crave JC, Fimbel S, Lejeune H, Cugnardey N, Dechaud H, Pugeat M. Effects of diet and metformin administration on sex hormone‐binding globulin, androgens, and insulin in hirsute and obese women. Journal of Clinical Endocrinology and Metabolism 1995;80(7):2057‐62. - PubMed
Curi 2012 {published data only}
    1. Curi DD, Fonseca AM, Marcondes JA, Almeida JA, Bagnoli VR, Soares JM Jr, et al. Metformin versus lifestyle changes in treating women with polycystic ovary syndrome. Gynecological Endocrinology 2010;28:182‐5. - PubMed
De Leo 1999 {published data only}
    1. Leo V, Marca A, Ditto A, Morgante G, Cianci A. Effects of metformin on gonadotropin‐induced ovulation in women with polycystic ovary syndrome. Fertility and Sterility 1999;72(2):282‐5. - PubMed
Dunaif 1996 {published data only}
    1. Dunaif A, Scott D, Finegood D, Quintana B, Whitcomb R. The insulin‐sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 1996;81(9):3299‐306. - PubMed
Elter 2002 {published data only}
    1. Elter K, Imir G, Durmusoglu F. Clinical, endocrine and metabolic effects of metformin added to ethinyl estradiol‐cyproterone acetate in non‐obese women with polycystic ovarian syndrome: a randomized controlled study. Human Reproduction 2002;17(7):1729‐37. [MEDLINE: ] - PubMed
Farzadi 2006 {published data only}
    1. Farzadi L, Salman S. Metformin‐therapy effects in 50 clomiphene citrate resistant PCOS patients. Journal of Medical Science 2006;6:765‐71.
Heathcote 2013 {published data only}
    1. Heathcote G, Forbes K, Lee A, Gregor M, Luscombe G, Boothroyd C. Live birth rate after metformin and clomiphene vs clomiphene alone in polycystic ovary syndrome (PCOS): a randomized, double‐blind, placebo‐controlled trial. Draft paper supplied by authors.
Hou 2000 {published data only}
    1. Hou J, Yu J, Wei M. Study on treatment of hyperandrogenism and hyperinsulinism in polycystic ovary syndrome with Chinese herbal formula "tiangui fang". Zhongguo Zhong Xi Yi Jie He Za Zhi 2000;20(8):589‐92. - PubMed
Ibanez 2002 {published data only}
    1. Ibanez L, Valls C, Ferrer A, Ong K, Dunger D, De‐Zegher F. Additive effects of insulin‐sensitizing and anti‐androgen treatment in young, nonobese women with hyperinsulinism, hyperandrogenism, dyslipidemia, and anovulation. Journal of Clinical Endocrinology and Metabolism 2002;87(6):2870‐4. [MEDLINE: ] - PubMed
Kazerooni 2009 {published data only}
    1. Kazerooni T, Ghaffarpasand F, Kazerooni Y, Kazerooni M, Setoodeh S. Short‐term metformin treatment for clomiphene citrate‐resistant women with polycystic ovary syndrome. International Journal of Gynaecology and Obstetrics 2009;107(1):50‐3. - PubMed
Kelly 2002 {published data only}
    1. Kelly CJ, Gordon D. The effect of metformin on hirsutism in polycystic ovary syndrome. European Journal of Endocrinology 2002;147(2):217‐21. [MEDLINE: ] - PubMed
Kocak 2002 {published data only}
    1. 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. Fertility and Sterility 2002;77(1):101‐6. - PubMed
Ladson 2011 {published data only}
    1. Ladson G, Dodson WC, Sweet SD, Archibong AE, Kunselman AR, Demers LM, et al. The effects of metformin with lifestyle therapy in polycystic ovary syndrome: a randomized double‐blind study. Fertility and Sterility 2011;95(3):1059‐66. - PMC - PubMed
Leanza 2014 {published data only}
    1. Leanza V, Coco L, Grasso F, Leanza G, Zarbo G, Palumbo M. Ovulation induction with clomiphene citrate and metformin in women with polycystic ovary syndrome. Minerva Ginecologica 2014;66(3):299‐301. - PubMed
Mantzoros 1997 {published data only}
    1. Mantzoros CS, Dunaif A, Flier JS. Leptin concentrations in the polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 1997;82(6):1687‐91. - PubMed
Morin‐Papunen 2000 {published data only}
    1. Morin‐Papunen LC, Vauhkonen I, Koivunen RM, Ruokonen A, Martikainen HK, Tapanainen JS. Endocrine and metabolic effects of metformin versus ethinyl estradiol‐cyproterone acetate in obese women with polycystic ovary syndrome: a randomized study. Journal of Clinical Endocrinology and Metabolism 2000;85(9):3161‐8. [DOI: 10.1210/jcem.85.9.6792] - PubMed
Morin‐Papunen 2010 {published data only}
    1. Morin‐Papunen L, Rantala A, Unkila‐Kallio L, Tiitinen A, Hippelainen M, Tinkanen H, et al. Metformin improves pregnancy and live birth rates in women with polycystic ovary syndrome ‐ a multicentre placebo‐controlled randomised trial. 26th Annual Meeting of the European Society of Human Reproduction and Embryology, ESHRE Rome Italy 2010;25:i67‐8.
Nestler 1996 {published data only}
    1. Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. New England Journal of Medicine 1996;335(9):617‐23. - PubMed
Nestler 1997 {published data only}
    1. Nestler JE, Jakubowicz DJ. Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17 alpha activity and serum androgens. Journal of Clinical Endocrinology and Metabolism 1997;82(12):4075‐9. - PubMed
Palomba 2011 {published data only}
    1. Palomba S, Falbo A, Cello A, Cappiello F, Tolino A, Zullo F. Does metformin affect the ovarian response to gonadotropins for in vitro fertilization treatment in patients with polycystic ovary syndrome and reduced ovarian reserve? A randomized controlled trial. Fertility and Sterility 2011;96:1128‐33. - PubMed
Papaleo 2009 {published data only}
    1. Papaleo E, Unfer V, Baillargeon JP, Fusi F, Occhi F, Santis L. Myo‐inositol may improve oocyte quality in intracytoplasmic sperm injection cycles. A prospective, controlled, randomized trial. Fertility and Sterility 2009;91:1750‐4. - PubMed
Ramzy 2003 {published data only}
    1. Ramzy A, El‐Kateb S, Al‐Inany H, Aboulmaaty Z, Badie M. The use of metformin in overweight and lean infertile patients with polycystic ovarian syndrome: a randomised controlled trial. Middle East Fertility Society Journal 2003;8:143‐9.
Refaie 2005 {published data only}
    1. Refaie A, Ibrahim G, Oash S. Characteristics of polycystic ovary syndrome with and without insulin resistance and the role of insulin sensitizing drug (metformin) in its management. Middle East Fertility Society Jounal 2005;10:142‐9.
Rouzi 2006 {published data only}
    1. Rouzi AA, Ardawi MS. A randomized controlled trial of the efficacy of rosiglitazone and clomiphene citrate versus metformin and clomiphene citrate in women with clomiphene citrate‐resistant polycystic ovary syndrome. Fertility and Sterility 2006;85:428‐35. - PubMed
Salman 2014 {published data only}
    1. Salman SA, Farghaly TA, Attallah DA, Abdel‐Hafeez HA, Shaaban OM. Insulin sensitizing agent (metformin) improves clinical pregnancy rate in clomiphene citrate resistant polycystic ovarian syndrome patients with acanthosis nigricans. Fertility and Sterility 2014;102(Supplement 3):e139.
Santonocito 2009 {published data only}
    1. Santonocito V, Rapisarda V, Abruzzo SRM, Pollicino R, Coco L, Zarbo G. Comparison between clomiphene citrate and metformin for induction of ovulatory cycles in infertile nonobese women with polycystic ovary syndrome. Giornale Italiano di Ostetricia e Ginecologia 2009;31(11‐12):455‐60.
Shobokshi 2003 {published data only}
    1. Shobokshi A, Shaarawy M. Correction of insulin resistance and hyperandrogenism in polycystic ovary syndrome by combined rosiglitazone and clomiphene citrate therapy. Journal of the Society for Gynecologic Investigation 2003;10:99‐104. - PubMed
Unfer 2011 {published data only}
    1. Unfer V, Carlomagno G, Rizzo P, Raffone E, Roseff S. Myo‐inositol rather than D‐chiro‐inositol is able to improve oocyte quality in intracytoplasmic sperm injection cycles. A prospective, controlled, randomized trial. European Review for Medical and Pharmacological Sciences 2011;15:452‐7. - PubMed

Additional references

Abu Hashim 2016
    1. Abu Hashim H. Twenty years of ovulation induction with metformin for PCOS; what is the best available evidence?. Reproductive BioMedicine Online 2016;32:44‐53. - PubMed
Alebic 2014
    1. Alebić MS, Bulum T, Stojanović N, Duvnjak L. Definition of insulin resistance using the homeostasis model assessment (HOMA‐IR) in IVF patients diagnosed with polycystic ovary syndrome (PCOS) according to the Rotterdam criteria. Endocrine 2014;47:625‐30. - PubMed
Alvarez‐Blasco 2006
    1. Alvarez‐Blasco F, Botella‐Carretero JI, San Millán JL, Escobar‐Morreale HF. Prevalence and characteristics of the polycystic ovary syndrome in overweight and obese women. Archives of Internal Medicine 2006;166:2081‐6. - PubMed
Apridonidze 2005
    1. Apridonidze T, Essah PA, Iuorno MJ, Nestler JE. Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2005;90:1929‐35. - PubMed
Azziz 2005
    1. Azziz R, Marin C, Hoq L, Badamgarav E, Song P. Health care‐related economic burden of the polycystic ovary syndrome during the reproductive life span. Journal of Clinical Endocrinology and Metabolism 2005;90:4650‐8. - PubMed
Balen 2014
    1. Balen AH. Infertility in Practice. 4th Edition. Boca Raton: CRC Press, 2014. [13:978‐1‐84184‐5]
Balen 2016
    1. Balen AH, Morley LC, Misso M, Franks S, Legro RS, Wijeyaratne CN, et al. The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance. Human Reproduction Update 2016;22:687‐708. [DOI: 10.1093/humupd/dmw025] - DOI - PubMed
Bordewijk 2017
    1. Bordewijk EM, Nahuis M, Costello MF, Veen F, Tso LO, Mol BWJ, et al. Metformin during ovulation induction with gonadotrophins followed by timed intercourse or intrauterine insemination for subfertility associated with polycystic ovary syndrome. Cochrane Database of Systematic Reviews 2017, Issue 1. [DOI: 10.1002/14651858.CD009090.pub2] - DOI - PMC - PubMed
Cassina 2014
    1. Cassina M, Donà M, Gianantonio E, Litta P, Clementi M. First‐trimester exposure to metformin and risk of birth defects: a systematic review and meta‐analysis. Human Reproduction Update 2014;20:656‐69. - PubMed
Cedergren 2004
    1. Cedergren MI. Maternal morbid obesity and the risk of adverse pregnancy outcome. Obstetrics and Gynecology 2004;103:219‐24. - PubMed
Celik 2014
    1. Celik C, Tasdemir N, Abali R, Bastu E, Yilmaz M. Progression to impaired glucose tolerance or type 2 diabetes mellitus in polycystic ovary syndrome: a controlled follow‐up study. Fertility and Sterility 2014;101:1123‐8. - PubMed
Colca 2013
    1. Colca JR, McDonald WG, Cavey GS, Cole SL, Holewa DD, Brightwell‐Conrad AS, et al. Identification of a mitochondrial target of thiazolidinedione insulin sensitizers (mTOT)‐‐relationship to newly identified mitochondrial pyruvate carrier proteins. PLoS One 2013;8:Epub ahead of print. - PMC - PubMed
Costello 2003
    1. Costello MF, Eden JA. A systematic review of the reproductive system effects of metformin in patients with polycystic ovary syndrome. Fertility and Sterility 2003;79:1‐13. - PubMed
Costello 2007
    1. Costello M, Shrestha B, Eden J, Sjoblom P, Johnson N. Insulin‐sensitising drugs versus the combined oral contraceptive pill for hirsutism, acne and risk of diabetes, cardiovascular disease, and endometrial cancer in polycystic ovary syndrome. Cochrane Database of Systematic Reviews 2007, Issue 1. [DOI: 10.1002/14651858.CD005552.pub2; PUBMED: 17253562] - DOI - PubMed
De Frene 2014
    1. Frène V, Vansteelandt S, T'Sjoen G, Gerris J, Somers S, Vercruysse L, et al. A retrospective study of the pregnancy, delivery and neonatal outcome in overweight versus normal weight women with polycystic ovary syndrome. Human Reproduction 2014;29:2333‐8. - PubMed
Deeks 2011
    1. Deeks JJ, Higgins JPT, Altman DG (editors). Chapter 9: Analysing data and undertaking meta‐analyses. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Diamanti‐Kandarakis 2010
    1. Diamanti‐Kandarakis E, Christakou CD, Kandarakis E, Economou F. Metformin: an old medication of new fashion: evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome. European Journal of Endocrinology 2010;162:193‐212. - PubMed
Ehrmann 2006
    1. Ehrmann DA, Liljenquist DR, Kasza K, Azziz R, Legro RS, Ghazzi MN. Prevalence and predictors of the metabolic syndrome in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2006;91:48‐53. - PubMed
EMA 2011
    1. European Medicines Agency. European Medicines Agency clarifies opinion on pioglitazone and the risk of bladder cancer. www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2011/10/... Accessed 2011.
ESHRE/ASRM 2004
    1. The 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). Human Reproduction 2004;19(1):41. - PubMed
ESHRE/ASRM 2008
    1. The Thessaloniki ESHRE/ASRM‐sponsored PCOS consensus workshop group. Consensus on infertility treatment related to polycystic ovary syndrome. Human Reproduction 2008;23:462‐77. - PubMed
Fauser 2012
    1. Fauser BC, Tarlatzis BC, Rebar RW, Legro RS, Balen AH, Lobo R, et al. Consensus on women's health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM‐sponsored 3rd PCOS Consensus Workshop Group. Fertility and Sterility 2012;97:28‐38. [PUBMED: 22153789] - PubMed
FDA 2002
    1. FDA (Federal Drug Administration). www.fda.gov Accessed 14 January 2003.
Ford 2004
    1. Ford ES. The metabolic syndrome and mortality from cardiovascular disease and all‐causes: findings from the National Health and Nutrition Examination Survey II Mortality Study. Atherosclerosis 2004;173:309‐14. - PubMed
Franik 2014
    1. Franik S, Kremer JAN, Nelen W, Farquhar C. Aromatase inhibitors for subfertile women with polycystic ovary syndrome. Cochrane Database of Systematic Reviews 2014, Issue 2. [DOI: 10.1002/14651858.CD010287.pub2] - DOI - PubMed
Gillies 2007
    1. Gillies CL, Abrams KR, Lambert PC, Cooper NJ, Sutton AJ, Hsu RT, et al. Pharmacological and lifestyle interventions to prevent or delay type 2 diabetes in people with impaired glucose tolerance: systematic review and meta‐analysis. BMJ 2007;334:299. - PMC - PubMed
GRADEpro GDT 2015 [Computer program]
    1. McMaster University (developed by Evidence Prime). GRADEpro GDT. Hamilton (ON): McMaster University (developed by Evidence Prime), Accessed 2015‐2017.
Graham 2003
    1. Graham DJ, Green L, Senior JR, Nourjah P. Troglitazone‐induced liver failure: a case study. The American Journal of Medicine 2003;114:299‐306. - PubMed
Hahn 2007
    1. Hahn S, Tan S, Sack S, Kimmig R, Quadbeck B, Mann K, et al. Prevalence of the metabolic syndrome in German women with polycystic ovary syndrome. Experimental and Clinical Endocrinology & Diabetes 2007;115:130‐5. - PubMed
Higgins 2003
    1. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta‐analyses. BMJ 2003;327:557‐60. - PMC - PubMed
Higgins 2011
    1. Higgins JPT, Altman DG, Sterne JAC (editors). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Huber‐Buchholz 1999
    1. Huber‐Buchholz MM, Carey DG, Norman RJ. Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone. Journal of Clinical Endocrinology and Metabolism 1999;84:1470‐4. - PubMed
Jensterle 2014
    1. Jensterle M, Kocjan T, Pfeifer M, Janez A. Short‐term intervention with liraglutide improved eating behaviour in obese women with polycystic ovary syndrome. Endocrine Research 2014;40:133‐8. - PubMed
Kiddy 1992
    1. Kiddy DS, Hamilton‐Fairley D, Bush A, Short F, Anyaoku V, Reed MJ, et al. Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clinical Endocrinology (Oxford) 1992;36:105‐11. - PubMed
Knowler 2002
    1. Knowler WC, Barrett‐Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. New England Journal of Medicine 2002;346:393‐403. - PMC - PubMed
Lago 2007
    1. Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta‐analysis of randomised clinical trials. Lancet 2007;370(9593):1129‐36. - PubMed
Lefebvre 2011
    1. Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Legro 2006a
    1. Legro RS. Type 2 diabetes and polycystic ovary syndrome. Fertility and Sterility 2006;86 Suppl 1:16‐7. - PubMed
Legro 2006b
    1. Legro RS, Myers ER, Barnhart HX, Carson SA, Diamond MP, Carr BR, et al. and Reproductive Medicine Network. The Pregnancy in Polycystic Ovary Syndrome Study: baseline characteristics of the randomized cohort including racial effects. Fertility and Sterility 2006;86(4):914‐33. - PubMed
Lord 2002
    1. Lord J, Wilkin T. Polycystic ovary syndrome and fat distribution: the central issue?. Hum Fertil (Camb) 2002;5:67‐71. - PubMed
March 2010
    1. March WA, Moore VM, Willson KJ, Phillips DI, Norman RJ, Davies MJ. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Human Reproduction 2010;25:544‐51. - PubMed
Misso 2013
    1. Misso ML, Costello MF, Garrubba M, Wong J, Hart R, Rombauts L, et al. Metformin versus clomiphene citrate for infertility in non‐obese women with polycystic ovary syndrome: a systematic review and meta‐analysis. Human Reproduction Update 2013;19:2‐11. - PubMed
Moran 2011
    1. Moran LJ, Hutchison SK, Norman RJ, Teede HJ. Lifestyle changes in women with polycystic ovary syndrome. Cochrane Database of Systematic Reviews 2011, Issue 7. [DOI: 10.1002/14651858.CD007506.pub3] - DOI - PubMed
Moran 2012
    1. Moran LJ, Deeks AA, Gibson‐Helm ME, Teede HJ. Psychological parameters in the reproductive phenotypes of polycystic ovary syndrome. Human Reproduction 2012;27:2082‐8. - PubMed
Palomba 2009
    1. Palomba S, Pasquali R, Orio Jr F, Nestler JE. Clomiphene citrate, metformin or both as first‐step approach in treating anovulatory infertility in patients with polycystic ovary syndrome (PCOS): a systematic review of head‐to‐head randomized controlled studies and meta‐analysis. Clinical Endocrinology 2009;70:311‐21. - PubMed
Pasquali 2003
    1. Pasquali R, Pelusi C, Genghini S, Cacciari M, Gambineri A. Obesity and reproductive disorders in women. Human Reproduction Update 2003;9:359‐72. - PubMed
Pernicova 2014
    1. Pernicova I, Korbonits M. Metformin‐‐mode of action and clinical implications for diabetes and cancer. Nature Reviews. Endocrinology 2014;10:143‐56. [DOI: 10.1038/nrendo.2013.256] - DOI - PubMed
Rautio 2006a
    1. Rautio K, Tapanainen JS, Ruokonen A, Morin‐Papunen LC. Endocrine and metabolic effects of rosiglitazone in overweight women with PCOS: a randomized placebo‐controlled study. Human Reproduction 2006;21:1400‐7. - PubMed
Rautio 2006b
    1. Rautio K, Tapanainen JS, Ruokonen A, Morin‐Papunen LC. Rosiglitazone treatment alleviates inflammation and improves liver function in overweight women with polycystic ovary syndrome: a randomized placebo‐controlled study. Fertility and Sterility 2007;87(1):202‐6. - PubMed
RevMan 2014 [Computer program]
    1. Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager 5 (RevMan 5). Version 5.3. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
Robinson 1993
    1. Robinson S, Kiddy D, Gelding SV, Willis D, Niththyananthan R, Bush A, et al. The relationship of insulin insensitivity to menstrual pattern in women with hyperandrogenism and polycystic ovaries. Clinical Endocrinology (Oxford) 1993;39:351‐5. - PubMed
Schünemann 2011
    1. Schünemann HJ, Oxman AD, Higgins JPT, Vist GE, Glasziou P, Guyatt GH. Chapter 11: Presenting results and ‘Summary of findings' tables. In: Higgins JPT, Green S (editors), Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Schünemann 2013
    1. Schünemann H, Brożek J, Guyatt G, Oxman A, editors. GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013. The GRADE Working Group, 2013. Available from guidelinedevelopment.org/handbook.
Siebert 2012
    1. Siebert, TI, Viola MI, Steyn DW, Kruger TF. Is metformin indicated as primary ovulation induction agent in women with PCOS? A systematic review and meta‐analysis. Gynecologic and Obstetric Investigation 2012;73:304‐13. - PubMed
Soares 2007
    1. Soares EM, Azevedo GD, Gadelha RG, Lemos TM, Maranhao TM. Prevalence of the metabolic syndrome and its components in Brazilian women with polycystic ovary syndrome. Fertility and Sterility 2007;88(5):1389‐95. - PubMed
Stein 1935
    1. Stein. Amenorrhea associated with bilateral polycystic ovaries. American Journal of Obstetrics and Gynecology 1935;29:181‐91.
Stepto 2013
    1. Stepto NK, Cassar S, Joham AE, Hutchison SK, Harrison CL, Goldstein RF, et al. Women with polycystic ovary syndrome have intrinsic insulin resistance on euglycaemic‐hyperinsulaemic clamp. Human Reproduction 2013;28:544‐51. - PubMed
Sterne 2011
    1. Sterne JAC, Egger M, Moher D (editors). Chapter 10: Addressing reporting biases. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Intervention. Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Tso 2014
    1. Tso L, Costello MF, Albuquerque LE, Andriolo RB, Macedo CR. Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. Cochrane Database of Systematic Reviews 2014, Issue 11. [DOI: 10.1002/14651858.CD006105.pub3] - DOI - PMC - PubMed
Uusitupa 2000
    1. Uusitupa M, Louheranta A, Lindstrom J, Valle T, Sundvall J, Eriksson J, et al. The Finnish Diabetes Prevention Study. British Journal of Nutrition 2000;83 Suppl 1:137‐42. - PubMed
Velazquez 1997
    1. Velazquez E, Acosta A, Mendoza SG. Menstrual cyclicity after metformin therapy in polycystic ovary syndrome. Obstetrics and Gynecology 1997;90:392‐5. - PubMed
Weerakiet 2007
    1. Weerakiet S, Bunnag P, Phakdeekitcharoen B, Wansumrith S, Chanprasertyothin S, Jultanmas R, et al. Prevalence of the metabolic syndrome in Asian women with polycystic ovary syndrome: using the International Diabetes Federation criteria. Gynecological Endocrinology 2007;23:153‐60. - PubMed
Wijeyaratne 2002
    1. Wijeyaratne CN, Balen AH, Barth JH, Belchetz PE. Clinical manifestations and insulin resistance (IR) in polycystic ovary syndrome (PCOS) among South Asians and Caucasians: is there a difference?. Clinical Endocrinology (Oxford) 2002;57:343‐50. - PubMed
Wijeyaratne 2004
    1. Wijeyaratne CN, Nirantharakumar K, Balen AH, Barth JH, Sheriff R, Belchetz PE. Plasma homocysteine in polycystic ovary syndrome: does it correlate with insulin resistance and ethnicity?. Clinical Endocrinology (Oxford) 2004;60:560‐7. - PubMed
Yki‐Jarvinen 2004
    1. Yki‐Jarvinen H. Thiazolidinediones. New England Journal of Medicine 2004;351:1106‐18. - PubMed
Zhang 2012
    1. Zhang Y, Ye J. Mitochondrial inhibitor as a new class of insulin sensitizer. Acta Pharmacologica Sinica 2012;2:341‐9. - PMC - PubMed

References to other published versions of this review

Lord 2003
    1. Lord JM, Flight IH, Norman RJ. Insulin‐sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D‐chiro‐inositol) for polycystic ovary syndrome. Cochrane Database of Systematic Reviews 2003, Issue 3. [DOI: 10.1002/14651858.CD003053] - DOI - PubMed
Tang 2009
    1. Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. Insulin‐sensitising drugs (metformin, rosiglitazone, pioglitazone, D‐chiro‐inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database of Systematic Reviews 2009, Issue 3. [DOI: 10.1002/14651858.CD003053.pub4; PUBMED: 20091537] - DOI - PubMed
Tang 2012
    1. Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. Insulin‐sensitising drugs (metformin, rosiglitazone, pioglitazone, D‐chiro‐inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database of Systematic Reviews 2012, Issue 5. [DOI: 10.1002/14651858.CD003053.pub5] - DOI - PubMed

Publication types

MeSH terms