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Meta-Analysis
. 2020 Aug 13;8(8):CD005552.
doi: 10.1002/14651858.CD005552.pub3.

Metformin versus the combined oral contraceptive pill for hirsutism, acne, and menstrual pattern in polycystic ovary syndrome

Eloise Fraison  1 , Elena Kostova  2 , Lisa J Moran  3 , Sophia Bilal  4 , Carolyn C Ee  5 , Christos Venetis  6 , Michael F Costello  7
Affiliations
Meta-Analysis

Metformin versus the combined oral contraceptive pill for hirsutism, acne, and menstrual pattern in polycystic ovary syndrome

Eloise Fraison et al. Cochrane Database Syst Rev. .

Abstract

Background: Metformin has been proposed as possibly a safer and more effective long-term treatment than the oral contraceptive pill (OCP) in women with polycystic ovary syndrome (PCOS). It is important to directly compare the efficacy and safety of metformin versus OCP in the long-term treatment of women with PCOS. This is an update of a Cochrane Review comparing insulin sensitising agents with the OCP and only includes studies on metformin.

Objectives: To assess the effectiveness and safety of metformin versus the OCP (alone or in combination) in improving clinical, hormonal, and metabolic features of PCOS.

Search methods: In August 2019 we searched the Cochrane Gynaecology and Fertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and CINAHL, the trial registers, handsearched references of the identified articles, and contacted experts in the field to identify additional studies.

Selection criteria: We included randomised controlled trials (RCTs) of the use of metformin versus the OCP (alone or in combination) for women with PCOS.

Data collection and analysis: We used standard methods recommended by Cochrane. The primary review outcomes were the clinical parameters of hirsutism and adverse events, both severe (requiring stopping of medication), and minor. In the presence of substantial heterogeneity (I2 statistic > 50), which could be explained by pre-specified subgroup analyses on the basis of BMI, we reported the subgroups separately.

Main results: This is a substantive update. We identified 38 additional studies. We included 44 RCTs (2253 women), which comprised 39 RCTs on adult women (2047 women) and five RCTs on adolescent women (206 women). Evidence quality ranged from very low to low. The main limitations were risk of bias, imprecision and inconsistency. Metformin versus the OCP In adult women, we are uncertain of the effect of metformin compared to the OCP on hirsutism in subgroup body mass index (BMI) < 25 kg/m2 (mean difference (MD) 0.38, 95% confidence interval (CI) -0.44 to 1.19, 3 RCTs, n = 134, I2 = 50%, very low-quality evidence) and subgroup BMI > 30 kg/m2 (MD -0.38, 95% CI -1.93 to 1.17; 2 RCTs, n = 85, I2 = 34%, low-quality evidence). Metformin may be less effective in improving hirsutism compared to the OCP in the subgroup BMI 25 kg/m2 to 30 kg/m2 (MD 1.92, 95% CI 1.21 to 2.64, 5 RCTs, n = 254, I2 = 0%, low-quality evidence). Metformin may increase severe gastro-intestinal adverse events rate compared to the OCP (Peto odds ratio (OR) 6.42, 95% CI 2.98 to 13.84, 11 RCTs, n = 602, I2 = 0%, low-quality evidence). Metformin may decrease the incidence of severe other adverse events compared to the OCP (Peto OR 0.20, 95% CI 0.09 to 0.44, 8 RCTs, n = 363, I2 = 0%, low-quality evidence). There were no trials reporting on minor adverse events. In adolescents, we are uncertain whether there is a difference between Metformin and the OCP, on hirsutism and adverse events. Metformin versus metformin combined with the OCP In adult women, metformin may be less effective in improving hirsutism compared to Metformin combined with the OCP (MD 1.36, 95% CI 0.62 to 2.11, 3 RCTs, n = 135, I2= 9%, low-quality evidence). We are uncertain if there was a difference between metformin and metformin combined with the OCP for severe gastro-intestinal adverse events (OR 0.74, 95% CI 0.21 to 2.53, 3 RCTs, n = 171, I2 = 0%, low-quality evidence), or for severe other adverse events (OR 0.56, 95% CI 0.11 to 2.82, 2 RCTs, n = 109, I2 = 44%, low-quality evidence). There were no trials reporting on minor adverse events. In adolescents, there were no trials for this comparison. The OCP versus metformin combined with the OCP In adult women, the OCP may be less effective in improving hirsutism compared to metformin combined with the OCP (MD 0.54, 95% CI 0.20 to 0.89, 6 RCTs, n = 389, I2= 1%, low-quality evidence). The OCP may decrease the incidence of severe gastro-intestinal adverse events compared to metformin combined with the OCP (OR 0.20, 95% CI 0.06 to 0.72, 5 RCTs, n = 228, I2 = 0%, low-quality evidence). We are uncertain if there is a difference between the OCP and metformin combined with the OCP for severe other adverse events (OR 1.61, 95% CI 0.49 to 5.37, 4 RCTs, n = 159, I2 = 12%, low-quality evidence). The OCP may decrease the incidence of minor (gastro-intestinal) adverse events compared to metformin combined with the OCP (OR 0.06, 95% CI 0.01 to 0.44, 2 RCTs, n = 98, I2 = 0%, low-quality evidence). In adolescents, we are uncertain whether there is a difference between the OCP, compared to metformin combined with the OCP, on hirsutism or adverse events.

Authors' conclusions: In adult women with PCOS, metformin may be less effective in improving hirsutism compared to the OCP in the subgroup BMI 25 kg/m2 to 30 kg/m2 but we are uncertain if there was a difference between metformin and the OCP in subgroups BMI < 25 kg/m2 and BMI > 30kg/m2. Compared to the OCP, metformin may increase the incidence of severe gastro-intestinal adverse events and decrease the incidence of severe other adverse events with no trials reporting on minor adverse events. Either metformin alone or the OCP alone may be less effective in improving hirsutism compared to metformin combined with the OCP. We are uncertain whether there is a difference between the OCP alone and metformin alone compared to metformin combined with the OCP for severe or minor adverse events except for the OCP versus metformin combined with the OCP where the OCP may decrease the incidence of severe and minor gastro-intestinal adverse events. In adolescent women with PCOS, we are uncertain whether there is a difference between any of the comparisons for hirsutism and adverse events due to either no evidence or very low-quality evidence. Further large well-designed RCTs that stratify for BMI are needed to evaluate metformin versus the OCP and combinations in women with PCOS, in particular adolescent women.

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Conflict of interest statement

M Costello has declared shares in Virtus Health and past sponsorship from Merck Serono for scientific conference presentations.

E Fraison has no conflicts of interest to declare.

L Moran has received a National Heart Foundation Future Leader Fellowship that has funded her work on this review.

S Bilal has no conflicts of interest to declare.

C Ee declares that as a medical research institute, NICM Health Research Institute receives research grants and donations from foundations, universities, government agencies and industry. Sponsors and donors provide untied and tied funding for work to advance the vision and mission of the institute. She confirms that she personally received no industry funding relating to this review.

E Kostova has no conflicts of interest to declare.

C Venetis reports an early career Fellowship from National Health and Medical Research Council of Australia which supported him for this work, personal fees and non‐financial support from Merck Sharpe & Dohme, Merck, Beisins, research grants and non‐financial support from Ferring, outside the submitted work.

Figures

1
1
Study flow diagram.
2
2
'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies
3
3
'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study .
4
4
Forest plot of comparison: 1 Adult ‐ metformin versus OCP (Clinical parameters), outcome: 1.1 Hirsutism ‐ Clinical F‐G score.
5
5
Funnel plot of comparison: 1 Adult ‐ metformin versus OCP (Clinical parameters), outcome: 1.1 Hirsutism ‐ Clinical F‐G score.
6
6
Forest plot of comparison: 1 Adult ‐ metformin versus OCP (Clinical parameters), outcome: 1.4 Adverse events ‐ severe.
1.1
1.1. Analysis
Comparison 1: Adult ‐ Metformin versus OCP (Clinical parameters), Outcome 1: Hirsutism ‐ Clinical F‐G score
1.2
1.2. Analysis
Comparison 1: Adult ‐ Metformin versus OCP (Clinical parameters), Outcome 2: Hirsutism ‐ Subjective visual analogue scale
1.3
1.3. Analysis
Comparison 1: Adult ‐ Metformin versus OCP (Clinical parameters), Outcome 3: Hirsutism ‐ Subjective improvement
1.4
1.4. Analysis
Comparison 1: Adult ‐ Metformin versus OCP (Clinical parameters), Outcome 4: Adverse events ‐ severe
1.5
1.5. Analysis
Comparison 1: Adult ‐ Metformin versus OCP (Clinical parameters), Outcome 5: Improved menstrual pattern (ie. shortening of intermenstrual days)
1.6
1.6. Analysis
Comparison 1: Adult ‐ Metformin versus OCP (Clinical parameters), Outcome 6: Improved menstrual pattern (ie. an initiation of menses or cycle regularity)
1.7
1.7. Analysis
Comparison 1: Adult ‐ Metformin versus OCP (Clinical parameters), Outcome 7: Acne ‐ Visual analogue scale
1.8
1.8. Analysis
Comparison 1: Adult ‐ Metformin versus OCP (Clinical parameters), Outcome 8: Acne ‐ Subjective improvement
1.9
1.9. Analysis
Comparison 1: Adult ‐ Metformin versus OCP (Clinical parameters), Outcome 9: Diagnosis of Type II diabetes mellitus
1.10
1.10. Analysis
Comparison 1: Adult ‐ Metformin versus OCP (Clinical parameters), Outcome 10: Body weight (kg)
1.11
1.11. Analysis
Comparison 1: Adult ‐ Metformin versus OCP (Clinical parameters), Outcome 11: Body Mass Index (kg/m2)
1.12
1.12. Analysis
Comparison 1: Adult ‐ Metformin versus OCP (Clinical parameters), Outcome 12: Blood pressure ‐ systolic (mm Hg)
1.13
1.13. Analysis
Comparison 1: Adult ‐ Metformin versus OCP (Clinical parameters), Outcome 13: Blood pressure ‐ diastolic (mm Hg)
2.1
2.1. Analysis
Comparison 2: Adult ‐ Metformin versus OCP (Hormonal parameters), Outcome 1: Serum total testosterone (nmol/L)
2.2
2.2. Analysis
Comparison 2: Adult ‐ Metformin versus OCP (Hormonal parameters), Outcome 2: Free androgen index (FAI) (%)
3.1
3.1. Analysis
Comparison 3: Adult ‐ Metformin versus OCP (Metabolic parameters), Outcome 1: Fasting insulin (mIU/L)
3.2
3.2. Analysis
Comparison 3: Adult ‐ Metformin versus OCP (Metabolic parameters), Outcome 2: Fasting glucose (mmol/L)
3.3
3.3. Analysis
Comparison 3: Adult ‐ Metformin versus OCP (Metabolic parameters), Outcome 3: Total Cholesterol (mmol/L)
3.4
3.4. Analysis
Comparison 3: Adult ‐ Metformin versus OCP (Metabolic parameters), Outcome 4: HDL Cholesterol (mmol/L)
3.5
3.5. Analysis
Comparison 3: Adult ‐ Metformin versus OCP (Metabolic parameters), Outcome 5: LDL Cholesterol (mmol/L)
3.6
3.6. Analysis
Comparison 3: Adult ‐ Metformin versus OCP (Metabolic parameters), Outcome 6: Triglycerides (mmol/L)
4.1
4.1. Analysis
Comparison 4: Adult ‐ Metformin versus Metformin combined with OCP (Clinical parameters), Outcome 1: Hirsutism ‐ Clinical F‐G score
4.2
4.2. Analysis
Comparison 4: Adult ‐ Metformin versus Metformin combined with OCP (Clinical parameters), Outcome 2: Adverse events ‐severe
4.3
4.3. Analysis
Comparison 4: Adult ‐ Metformin versus Metformin combined with OCP (Clinical parameters), Outcome 3: Body weight (kg)
4.4
4.4. Analysis
Comparison 4: Adult ‐ Metformin versus Metformin combined with OCP (Clinical parameters), Outcome 4: Body Mass Index (kg/m2)
4.5
4.5. Analysis
Comparison 4: Adult ‐ Metformin versus Metformin combined with OCP (Clinical parameters), Outcome 5: Blood pressure ‐ systolic (mm Hg)
4.6
4.6. Analysis
Comparison 4: Adult ‐ Metformin versus Metformin combined with OCP (Clinical parameters), Outcome 6: Blood pressure ‐ diastolic (mm Hg)
5.1
5.1. Analysis
Comparison 5: Adult ‐ Metformin versus Metformin combined with OCP (Hormonal parameters), Outcome 1: Serum total testosterone (nmol/L)
5.2
5.2. Analysis
Comparison 5: Adult ‐ Metformin versus Metformin combined with OCP (Hormonal parameters), Outcome 2: FAI (%)
6.1
6.1. Analysis
Comparison 6: Adult ‐ Metformin versus Metformin combined with OCP (Metabolic parameters), Outcome 1: Fasting insulin (mIU/L)
6.2
6.2. Analysis
Comparison 6: Adult ‐ Metformin versus Metformin combined with OCP (Metabolic parameters), Outcome 2: Fasting glucose (mmol/L)
6.3
6.3. Analysis
Comparison 6: Adult ‐ Metformin versus Metformin combined with OCP (Metabolic parameters), Outcome 3: Total Cholesterol (mmol/L)
6.4
6.4. Analysis
Comparison 6: Adult ‐ Metformin versus Metformin combined with OCP (Metabolic parameters), Outcome 4: HDL Cholesterol (mmol/L)
6.5
6.5. Analysis
Comparison 6: Adult ‐ Metformin versus Metformin combined with OCP (Metabolic parameters), Outcome 5: LDL Cholesterol (mmol/L)
6.6
6.6. Analysis
Comparison 6: Adult ‐ Metformin versus Metformin combined with OCP (Metabolic parameters), Outcome 6: Triglycerides (mmol/L)
7.1
7.1. Analysis
Comparison 7: Adult ‐ OCP versus Metformin combined with OCP (Clinical parameters), Outcome 1: Hirsutism ‐ Clinical F‐G score
7.2
7.2. Analysis
Comparison 7: Adult ‐ OCP versus Metformin combined with OCP (Clinical parameters), Outcome 2: Adverse events ‐ severe
7.3
7.3. Analysis
Comparison 7: Adult ‐ OCP versus Metformin combined with OCP (Clinical parameters), Outcome 3: Adverse events ‐ minor
7.4
7.4. Analysis
Comparison 7: Adult ‐ OCP versus Metformin combined with OCP (Clinical parameters), Outcome 4: Acne ‐ Clinical acne score
7.5
7.5. Analysis
Comparison 7: Adult ‐ OCP versus Metformin combined with OCP (Clinical parameters), Outcome 5: Acne ‐ Subjective improvement
7.6
7.6. Analysis
Comparison 7: Adult ‐ OCP versus Metformin combined with OCP (Clinical parameters), Outcome 6: Body weight (kg)
7.7
7.7. Analysis
Comparison 7: Adult ‐ OCP versus Metformin combined with OCP (Clinical parameters), Outcome 7: Body Mass Index (kg/m2)
7.8
7.8. Analysis
Comparison 7: Adult ‐ OCP versus Metformin combined with OCP (Clinical parameters), Outcome 8: Blood Pressure ‐ Systolic (mmHg)
7.9
7.9. Analysis
Comparison 7: Adult ‐ OCP versus Metformin combined with OCP (Clinical parameters), Outcome 9: Blood Pressure ‐ Diastolic (mmHg)
8.1
8.1. Analysis
Comparison 8: Adult ‐ OCP versus Metformin combined with OCP (Hormonal parameters), Outcome 1: Serum total testosterone (nmol/L)
8.2
8.2. Analysis
Comparison 8: Adult ‐ OCP versus Metformin combined with OCP (Hormonal parameters), Outcome 2: Free androgen index (FAI) (%)
9.1
9.1. Analysis
Comparison 9: Adult ‐ OCP versus Metformin combined with OCP (Metabolic parameters), Outcome 1: Fasting insulin (mIU/L)
9.2
9.2. Analysis
Comparison 9: Adult ‐ OCP versus Metformin combined with OCP (Metabolic parameters), Outcome 2: Fasting glucose (mmol/L)
9.3
9.3. Analysis
Comparison 9: Adult ‐ OCP versus Metformin combined with OCP (Metabolic parameters), Outcome 3: Total Cholesterol (mmol/L)
9.4
9.4. Analysis
Comparison 9: Adult ‐ OCP versus Metformin combined with OCP (Metabolic parameters), Outcome 4: HDL Cholesterol (mmol/L)
9.5
9.5. Analysis
Comparison 9: Adult ‐ OCP versus Metformin combined with OCP (Metabolic parameters), Outcome 5: LDL Cholesterol (mmol/L)
9.6
9.6. Analysis
Comparison 9: Adult ‐ OCP versus Metformin combined with OCP (Metabolic parameters), Outcome 6: Triglycerides (mmol/L)
10.1
10.1. Analysis
Comparison 10: Adolescent ‐ Metformin versus OCP (Clinical parameters), Outcome 1: Hirsutism ‐ Clinical F‐G score
10.2
10.2. Analysis
Comparison 10: Adolescent ‐ Metformin versus OCP (Clinical parameters), Outcome 2: Hirsutism ‐ Subjective improvement
10.3
10.3. Analysis
Comparison 10: Adolescent ‐ Metformin versus OCP (Clinical parameters), Outcome 3: Adverse event ‐ severe
10.4
10.4. Analysis
Comparison 10: Adolescent ‐ Metformin versus OCP (Clinical parameters), Outcome 4: Adverse event ‐ minor
10.5
10.5. Analysis
Comparison 10: Adolescent ‐ Metformin versus OCP (Clinical parameters), Outcome 5: Improved menstrual pattern (ie. an initiation of menses or cycle regularity)
10.6
10.6. Analysis
Comparison 10: Adolescent ‐ Metformin versus OCP (Clinical parameters), Outcome 6: Body Weight (kg)
10.7
10.7. Analysis
Comparison 10: Adolescent ‐ Metformin versus OCP (Clinical parameters), Outcome 7: Body Mass Index (kg/m2)
10.8
10.8. Analysis
Comparison 10: Adolescent ‐ Metformin versus OCP (Clinical parameters), Outcome 8: Blood pressure ‐ systolic (mm Hg)
10.9
10.9. Analysis
Comparison 10: Adolescent ‐ Metformin versus OCP (Clinical parameters), Outcome 9: Blood pressure ‐ diastolic (mm Hg)
11.1
11.1. Analysis
Comparison 11: Adolescent ‐ Metformin versus OCP (Hormonal parameters), Outcome 1: Serum total testosterone (nmol/L)
11.2
11.2. Analysis
Comparison 11: Adolescent ‐ Metformin versus OCP (Hormonal parameters), Outcome 2: Free androgen index (FAI) (%)
12.1
12.1. Analysis
Comparison 12: Adolescent ‐ Metformin versus OCP (Metabolic parameters), Outcome 1: Fasting insulin (mIU/L)
12.2
12.2. Analysis
Comparison 12: Adolescent ‐ Metformin versus OCP (Metabolic parameters), Outcome 2: Fasting glucose (mmol/L)
12.3
12.3. Analysis
Comparison 12: Adolescent ‐ Metformin versus OCP (Metabolic parameters), Outcome 3: Total Cholesterol (mmol/L)
12.4
12.4. Analysis
Comparison 12: Adolescent ‐ Metformin versus OCP (Metabolic parameters), Outcome 4: HDL Cholesterol (mmol/L)
12.5
12.5. Analysis
Comparison 12: Adolescent ‐ Metformin versus OCP (Metabolic parameters), Outcome 5: LDL Cholesterol (mmol/L)
12.6
12.6. Analysis
Comparison 12: Adolescent ‐ Metformin versus OCP (Metabolic parameters), Outcome 6: Triglycerides (mmol/L)
13.1
13.1. Analysis
Comparison 13: Adolescent ‐ OCP versus Metformin combined with OCP (Clinical parameters), Outcome 1: Hirsutism ‐ Clinical F‐G score
13.2
13.2. Analysis
Comparison 13: Adolescent ‐ OCP versus Metformin combined with OCP (Clinical parameters), Outcome 2: Adverse events ‐ severe
13.3
13.3. Analysis
Comparison 13: Adolescent ‐ OCP versus Metformin combined with OCP (Clinical parameters), Outcome 3: Body Mass Index (kg/m2)
13.4
13.4. Analysis
Comparison 13: Adolescent ‐ OCP versus Metformin combined with OCP (Clinical parameters), Outcome 4: Blood Pressure ‐ Systolic (mmHg)
13.5
13.5. Analysis
Comparison 13: Adolescent ‐ OCP versus Metformin combined with OCP (Clinical parameters), Outcome 5: Blood Pressure ‐ Diastolic (mmHg)
14.1
14.1. Analysis
Comparison 14: Adolescent ‐ OCP versus Metformin combined with OCP (Hormonal parameters), Outcome 1: Serum total testosterone (nmol/L)
14.2
14.2. Analysis
Comparison 14: Adolescent ‐ OCP versus Metformin combined with OCP (Hormonal parameters), Outcome 2: Free androgen index (FAI) (%)
15.1
15.1. Analysis
Comparison 15: Adolescent ‐ OCP versus Metformin combined with OCP (Metabolic parameters), Outcome 1: Fasting glucose (mmol/L)
15.2
15.2. Analysis
Comparison 15: Adolescent ‐ OCP versus Metformin combined with OCP (Metabolic parameters), Outcome 2: Total Cholesterol (mmol/L)
15.3
15.3. Analysis
Comparison 15: Adolescent ‐ OCP versus Metformin combined with OCP (Metabolic parameters), Outcome 3: HDL Cholesterol (mmol/L)
15.4
15.4. Analysis
Comparison 15: Adolescent ‐ OCP versus Metformin combined with OCP (Metabolic parameters), Outcome 4: LDL Cholesterol (mmol/L)
15.5
15.5. Analysis
Comparison 15: Adolescent ‐ OCP versus Metformin combined with OCP (Metabolic parameters), Outcome 5: Triglycerides (mmol/L)
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Update of

References

References to studies included in this review

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Harborne 2003 {published and unpublished data}
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Hoeger 2008a {published data only}
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Jin 2006 {published data only}
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Kaya 2015 {published data only}
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Kebapcilar 2009a {published data only}
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Kebapcilar 2009b {published data only}
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Kilic 2011 {published data only}
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    1. Kumar Y, Kotwal N, Singh Y, Upreti V, Somani S, Hari Kumar KV. A randomized, controlled trial comparing the metformin, oral contraceptive pills and their combination in patients with polycystic ovarian syndrome. Journal of Family Medicine and Primary Care 2018;7:551-6. - PMC - PubMed
Liu 2006 {published data only}
    1. Liu JX, Dang JM, Wu YZ, Zheng N, Wu XK. The effect of combination therapy with Metformin and combined Cyproterone Acetate/Ethynil Estradiol on PCOS patients. Chinese Journal of Postgraduate Medicine 2006;19:530-3.
Luque‐Ramirez 2007a {published data only}
    1. Luque-Ramirez M, Alvarez-Blasco F, Botella-Carretero JI, Martinez-Bermejo E, Lasuncion MA, Escobar-Morreale HF. Comparison of ethinyl-estradiol plus cyproterone acetate versus metformin effects on classic metabolic cardiovascular risk factors in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 04/2007;92:2453-61. - PubMed
Luque‐Ramirez 2007b {published data only}
    1. Luque-Ramirez M, Alvarez-Blasco F, Botella-Carretero J I, Sanchon R, San Millan JL, Escobar-Morreale HF. Increased body iron stores of obese women with polycystic ovary syndrome are a consequence of insulin resistance and hyperinsulinism and are not a result of reduced menstrual losses. Diabetes Care 09/2007;30:2309-13. - PubMed
Luque‐Ramirez 2008a {published data only}
    1. Luque-Ramirez M, Alvarez-Blasco F, Uriol Rivera MG, Escobar-Morreale HF. Serum uric acid concentration as non-classic cardiovascular risk factor in women with polycystic ovary syndrome: effect of treatment with ethinyl-estradiol plus cyproterone acetate versus metformin. Human Reproduction 2008;23:1594-601. - PubMed
Luque‐Ramirez 2009b {published data only}
    1. Luque-Ramirez M, Mendieta-Azcona C, Alvarez-Blasco F, Escobar-Morreale HF. Effects of Metformin versus Ethinyl-estradiol plus cyproterone acetate on ambulatory blood pressure monitoring and carotid intima media thickness in women with the polycystic ovary syndrome. Fertility and Sterility 2008;91:2527-36. - PubMed
Lv 2005 {published data only}
    1. Lv L, Liu Y, Sun Y, Tan K. Effects of Metformin combined with cyproterone acetate on clinical features, endocrine and metabolism of non-obese women with polycystic ovarian syndrome. Journal of Huazhong University of Science and Technology 2005;25:194-7. - PubMed
Meyer 2007 {published data only}
    1. Meyer C, McGrath BP, Teede HJ. Effect of medical therapy on insulin resistance and the cardiovascular system in polycystic ovary syndrome. Diabetes Care 2007;30(3):471-8. - PubMed
Mhao 2015 {published data only}
    1. Mhao NS, Al-Hilli SA, Hadi NR, Jamil DA, Al-Aubaidy HA. A comparative study to illustrate the benefits of using ethinyl estradiol-cyproterone acetate over metformin in patients with polycystic ovarian syndrome. Diabetes and Metabolic Syndrome: Clinical Research and Reviews 2015;10S:S95-S98. - PubMed
Moran 2010 {published data only}
    1. Moran LJ, Meyer C, Hutchison SK, Zoungas S, Teede HJ. Novel inflammatory markers in overweight women with or without polycystic ovary syndrome and following pharmacological intervention. Journal of Endocrinological Investigation 2010;33:258-65. - 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 & Metabolism 2000;85(9):3161-8. - PubMed
Morin‐Papunen 2003 {published data only}
    1. Morin-Papunen L, Vauhkonen I, Koivunen R, Ruokonen A, Martikainen H, Tapanainen JS. Metformin versus ethinyl estradiol-cyproterone acetate in the treatment of nonobese women with polycystic ovary syndrome: a randomized study. The Journal of Clinical Endocrinology & Metabolism 2003;88(1):148-56. - PubMed
Moro 2013 {published data only}
    1. Moro F, Morciano A, Tropea A, Sagnella F, Palla C, Scarinci E, et al. Effects of drospirenone-ethinylestradiol and/or metformin on CD4+ CD28 null T lymphocytes frequency in women with hyperinsulinemia having polycystic ovary syndrome: a randomized clinical trial. Reproductive Science 2013;20(12):1508-17. - PubMed
Ozgurtas 2008 {published data only}
    1. Ozgurtas T, Oktenli C, Dede M, Tapan S, Kenar L, Sanisoglu SY, et al. Metformin and oral contraceptive treatment reduced circulating asymmetric dimethylarginine (ADMA) levels in patients with polycystic ovary syndrome (PCOS). Atherosclerosis 2008;200:336-44. - PubMed
Rautio 2005 {published data only}
    1. Rautio K, Tapanainen JS, Ruokonen A, Morin-Papunen LC. Effects of metformin and ethinyl-estradiol-cyproterone acetate on lipid levels in obese and non-obese women with polycystic ovary syndrome. European Journal of Endocrinology 2005;152:269-75. - PubMed
Ruan 2018 {published data only}
    1. Ruan X, Song J, Gu M, Wang L, Wang H, Mueck AO. Effect of Diane-35, alone or in combination with orlistat or metformin in Chinese polycystic ovary syndrome patients. Archives of Gynecology and Obstetrics 2018;297:1557-63. - PubMed
Sahu 2018 {published data only}
    1. Sahu A, Tripathy P, Mohanty J, Nagy A. Doppler analysis of ovarian stromal blood flow changes after treatment with metformin versus ethinyl estradiol-cyproterone acetate in women with polycystic ovarian syndrome: a randomized controlled trial. Journal of Gynecology Obstetrics and Human Reproduction 2018;48(5):335-9. - PubMed
Song 2017 {published data only}
    1. Song J, Ruan X, Gu M, Wang L, Wang H, Mueck AO. Effect of orlistat or metformin in overweight and obese polycystic ovary syndrome patients with insulin resistance. Gynecological Endocrinology 2018;34:413-7. - PubMed
Teng 2007 {published data only}
    1. Teng YQ, Zheng JH, Han XY. Evaluation of clinical efficacy of Metformin in treating polycystic ovary syndrome. Journal of Harbin Medical University 2007;41:405-6.
Wei 2012 {published data only}
    1. Wei W, Zhao H, Wang A, Sui M, Liang K, Deng H, et al. A clinical study on the short-term effect of berberine in comparison to metformin on the metabolic characteristics of women with polycystic ovary syndrome. European Journal of Endocrinology 2012;166:99-105. - PubMed
Wu 2008 {published data only}
    1. Wu J, Zhu Y, Jiang Y, Cao Y. Effects of metformin and ethinyl estradiol-cyproterone acetate on clinical, endocrine and metabolic factors in women with polycystic ovary syndrome. Gynecological Endocrinology 2008;24:392-8. - PubMed

References to studies excluded from this review

Alpanes 2017 {published data only}
    1. Alpanes M, Alvarez-Blasco F, Fernandez-Duran E, Luque-Ramirez M, Escobar-Morreale HF. Combined oral contraceptives plus spironolactone compared with Metformin in women with polycystic ovary syndrome: a one-year randomized clinical trial. European Journal of Endocrinology 2017;177:399-408. - PubMed
Altinok 2018 {published data only}
    1. Altinok ML, Ravn P, Andersen M, Glintoborg D. Effect of 12-months treatment with metformin and/or oral contraceptives on health-related quality of life in polycystic ovary syndrome. Gynecological Endocrinology 2018;34(10):859-63. - PubMed
Bachani 2016 {published data only}
    1. Bachani S, Ganju Malla V. Identifying risk factors and screening tests for extent of metabolic risk in urban adolescent girls in a developing nation. International journal of child and adolescent health 2016;9(3):347-53.
Bhattacharya 2012 {published data only}
    1. Battacharya SM, Jha A. Comparative study of the therapeutic effects of oral contraceptive pills containing desogestrel, cyproterone acetate, and drospirenone in patients with polycystic ovary syndrome. Fertility and sterility 2012;98(4):1053-9. - PubMed
Bredella 2013 {published data only}
    1. Bredella MA, McManus S, Misra M. Impact of metformin monotherapy versus metformin with oestrogen-progesterone on lipids in adolescent girls with polycystic ovarian syndrome. Clinical Endocrinology 2013;79(2):199-203. - PMC - PubMed
Burchall 2015 {published data only}
    1. Burchall GF, Piva TJ, Linden MD, Gibson-Helm ME, Ranasinha S, Teede HJ. Comprehensive assessment of the hemostatic system in polycystic ovarian syndrome. Seminars in Thrombosis and Hemostasis 2016;42:55-62. - PubMed
Cakiroglu 2013 {published data only}
    1. Cakiroglu Y, Vural B, Isgoren S. The effects of drospirenone-ethinyl estradiol and drospirenone-ethinyl estradiol + metformin on ovarian ultrasonographic markers, body fat mass index, leptin, and ghrelin. Archive of Gynecology and Obstetrics 2013;288:213-20. - PubMed
Diaz 2016 {published data only}
    1. Diaz M, Gallego-Escuredo JM, Zegher F. Effect of ethinylestradiol-cyproterone acetate vs. pioglitazone-flutamide-metformin on plasma FGF21 levels in adolescent girls with androgen excess. Diabetes and Metabolism 2016;42:196-9. - PubMed
Glintborg 2014b {published data only}
    1. Glintborg D, Mumm H, Altinok ML, Richelsen B, Bruun JM, Andersen M. Adiponectin, interleukin-6, monocyte chemoattractant protein-1, and regional fat mass during 12-months randomized treatment with metformin and/or contraceptives in polycystic ovary syndrome. Journal of Endocrinal Investigation 2014;37:757-64. - PubMed
Glintborg 2015 {published data only}
    1. Glintborg D, Sidelmann JJ, Altinok ML, Mumm H, Andersen M. Increased thrombin generation in women with polycystic ovary syndrome. A pilot study on the effect of metformin and oral contraceptives. Metabolism 2015;64:1272-8. - PubMed
Glintborg 2017 {published data only}
    1. Glintborg D, Mumm H, Holst JJ, Andersen M. Effect of oral contraceptives and/or metformin on GLP-1 secretion and reactive hypoglycemia in polycystic ovary syndrome. Endocrine connections 2017;6:267-277. - PMC - PubMed
Hadziomerovic‐Pekic 2010 {published data only}
    1. Hadziomerovic-Pekic D, Wildt L, Weiss JM, Moeller K, Mattle V, Seeber BE. Metformin, naltrexone, or the combination of prednisolone and antiandrogenic oral contraceptives as first-line therapy in hyperinsulinemic women with polycystic ovary syndrome. Fertility and Sterility 2010;94(6):2385-8. - PubMed
Harris‐Glocker 2009 {published data only}
    1. Harris-Glocker M, Davidson K, Kochman L, Guzick D, Hoeger K. Improvement in quality of life questionnaire measures (PCOSQ) in obese adolescent females with PCOS treated with Lifestyle changes and oral contraceptives, with or without Metformin. Fertility and Sterility 2009;93(3):1016-9. - PMC - PubMed
Hu 2010 {published data only}
    1. Hu Z, Wang Y, Qiao J, Li M, Chi H, Chen X. The role of family history in clinical symptoms and therapeutic outcomes of women with polycystic ovary syndrome. International Journal of Gynecology and Obstetrics 2010;108:35-9. - PubMed
Hutchison 2008 {published data only}
    1. Hutchison SK, Harrison C, Stepto N, Meyer C, Teede HJ. Retinol-binding protein 4 and insulin resistance in polycystic ovary syndrome. Cardiovascular and Metabolic Risk 2008;31:1427-32. - PMC - PubMed
Ibanez 2010 {published data only}
    1. Ibanez L, Lopez-Bermejo A, Diaz M, Enriquez G, Rio L, Zegher F. Low-dose pioglitazone, flutamide, metformin plus an oestro-progestagen for non-obese young women with polycystic ovary syndrome: increasing efficacy and persistent safety over 30 months. Gynecological Endocrinology 2010;26(12):869-73. - PubMed
Ibanez 2017 {published data only}
    1. Ibanez L, Rio L, Diaz M, Sebastiani G, Pozo OJ, Lopez-Bermejo A, et al. Normalizing ovulation rate by preferential reduction of hepato-visceral fat in adolescent girls with polycystic ovary syndrome. Journal of Adolescent Health 2017;61:446-53. - PubMed
Kebapcilar 2010 {published data only}
    1. Kebapcilar L, Kebapcilar AG, Bilgir O, Taner CE, Bozkaya G, Yilidiz Y, et al. Metformin plus oral contraceptive may decrease plasma sCD40 ligand in women with PCOS patients. Gynecological Endocrinology 2010;27(2):91-5. - PubMed
Kim 2010 {published data only}
    1. Kim C-H, Jeon G-H, Kim S-R, Kim S-H, Chae H-D, Kang B-M. Effects of pioglitazone on ovarian stromal blood flow, ovarian stimulation, and in vitro fertilization outcome in patients with polycystic ovary syndrome. Fertility and Sterility 2010;94:236-41. - PubMed
Ladson 2011 {published data only}
    1. Ladson G, Dodson WC, Sweet SD, Archibong AE, Kunselman AR, Demers LM, et al. Effects of metformin in adolescents with polycystic ovary syndrome undertaking lifestyle therapy: a pilot randomized double-blind study. Fertility and Sterility 2011;95(8):2595-8. - PMC - PubMed
Lazaro 2011 {published data only}
    1. Lazaro I, Diaz M, Cabre A, Masana L, Ibanez L. Fatty acid-blinding protein-4 plasma levels are associated to metabolic abnormalities and response to therapy in girls and young women with androgen excess. Gynecological Endocrinology 2011;27(11):935-9. - PubMed
Lemay 2006 {published data only}
    1. Lemay A, Dodin S, Turcot L, Déchêne F, Forest J-C. Rosiglitazone and ethinyl estradiol/cyproterone acetate as single and combined treatment of overweight women with polycystic ovary syndrome and insulin resistance. Human Reproduction 2006;21(1):121-8. - PubMed
Luque‐Ramirez 2008c {published data only}
    1. Luque-Ramirez M, Alvarez-Blasco F, Escobar-Morreale HF. Antiandrogenic contraceptives increase serum adiponectin in obese polycystic ovary syndrome patients. Obesity 2008;17(1):3-9. - PubMed
Luque‐Ramirez 2009 {published data only}
    1. Luque-Ramirez M, Mendieta-Azcona C, Rey Sanchez JM, Maties M, Escobar-Morreale HF. Effects of an antiandrogenic oral contraceptive pill compared with metformin on blood coagulation tests and endothelial function in women with the polycystic ovary syndrome: influence of obesity and smoking. European Journal of Endocrinology 2009;160:469-80. - PubMed
Luque‐Ramirez 2010a {published data only}
    1. Luque-Ramirez M, Escobar-Morreale HF. Treatment of polycystic ovary syndrome (PCOS) with metformin ameliorates insulin resistance in parallel with decrease of serum interleukine-6 concentrations. Hormone and Metabolic Research 2010;42:815-20. - PubMed
Luque‐Ramirez 2011 {published data only}
    1. Luque-Ramirez M, Alvarez-Blasco F, Alpanes M, Escobar-Morreale HF. Role of decreased circulating hepcidin concentrations in the iron excess of women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2011;96(3):846-52. - PubMed
Mehrabian 2016 {published data only}
    1. Mehrabian F, Ghasemi-Tehrani H, Mohamadkhani M, Moeinoddini M, Karimzadeh P. Comparison of the effects of metformin, flutamide plus oral contraceptives, and simvastatin on the metabolic consequences of polycystic ovary syndrome. Journal of Research in Medical Sciences 2016;21:7. - PMC - PubMed
Mitkov 2005 {published data only}
    1. Mitkov M, Pehlivanov B, Terzieva D. Combined use of metformin and ethinyl estradiol-cyproterone acetate in polycystic ovary syndrome. European Journal of Obstetrics and Gynecology and Reproductive Biology 2005;118:209-13. - PubMed
Moghtadaei 2009 {published data only}
    1. Moghtadaei P, Sardari F. Metabolic and endocrine effect of metformin and metformin plus cyclic dydrogestrel in women with polycystic ovarian syndrome. Cell Journal 2009;11:67-8.
Moretti 2016 {published data only}
    1. Moretti CG, Guccione L, di Giacinto P, Cannuccia A, Meleca C, Lanzolla G, et al. Efficacy and safety of myo-inositol supplementation in the treatment of obese hirsute PCOS women: comparative evaluation with OCP+bicalutamide therapy. In: Endocrine Society Journal, poster SUN-153. 2016.
NCT02866786 {published data only}
    1. NCT02866786. The effect of OCP and Metformin on Clinical, hormonal, metabolic and ultrasonographic characteristics in PCOS. clinicaltrials.gov/show/NCT02866786 (first received 15 August 2016).
Orbetzova 2011 {published data only}
    1. Orbetzova MM, Pehlivanov BK, Mitko MM, Atanassova IB, Kamenov ZA, Kolarov GB, et al. Effect of short-term standard therapeutic regimens on neuropeptide Y and adipose tissue hormones in overweight insulin-resistant women with polycystic ovary syndrome. Folia Medica 2011;53(3):15-24. - PubMed
Panidis 2011 {published data only}
    1. Panidis D, Georgopoulos NA, Piouka A, Katsikis I, Saltamavros AD, Decavalas G, et al. The impact of oral contraceptives and metformin on anti-Müllerian hormone serum levels in women with polycystic ovary syndrome and biochemical hyperandrogenemia. Gynecological Endocrinology 2011;27(8):587-92. - PubMed
Pedersen 2018 {published data only}
    1. Pedersen AJ, Stage TB, Glintborg D, Andersen M, Christensen MM. The pharmacogenetics of metformin in women with polycystic ovary syndrome: a randomized trial. Basic and Clinical Pharmacology and Toxicology 2018;122:239-44. - PubMed
Romualdi 2010 {published data only}
    1. Romualdi D, Giuliani M, Cristello F, Fulghesu AM, Selvaggi L, Lanzone A, et sl. 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
Suvarna 2016 {published data only}
    1. Suvarna Y, Maity N, Kalra P, Shivamurthy MC. Comparison of efficacy of metformin and oral contraceptive combination of ethinyl estradiol and drospirenone in polycystic ovary syndrome. Journal of the Turkish-German Gynecological Association 2016;17:6-9. - PMC - PubMed
Teede 2010b {published data only}
    1. Teede HJ, Meyer C, Hutchison SK, Zoungas S, McGrath BP, Moran LJ. Endothelial function and insulin resistance in polycystic ovary syndrome: the effects of medical therapy. Fertility and Sterility 2010;93(1):184-91. - PubMed
Wang 2016 {published data only}
    1. Wang Q-Y, Song Y, Huang W, Xiao L, Wang Q-S, Feng G-M. Comparison of drospirenone with cyproterone acetate containing oral contraceptives, combined with metformin and lifestyle modifications in women with polycystic ovary syndrome and metabolic disorders: a prospective randomized control trial. Chinese Medical Journal 2016;129(8):883-90. - PMC - PubMed

References to studies awaiting assessment

Fruzzeti 2009 {published data only}
    1. Fruzzetti F, Perini D, Lazzarini V, Parrini D, Gambacciani M, Genazzani RA. Comparison of effects of 3 mg drospirenone plus 20 µg ethinyl estradiol alone or combined with metformin or cyproterone acetate on classic metabolic cardiovascular risk factors in nonobese women with polycystic ovary syndrome. Fertility and Sterility 2009;94:1793-8. - PubMed
Spremovic‐Radjenovic 2014 {published data only}
    1. Spremovic-Radjenovic S, Sreckovic S, Gudovic A, Djakonovic M, Bila J, Radonjic-Lazovic G. Comparison of the effects of dianogest/ethinyl estradiol and metformin on metabolic parameters in non-obese women with polycystic ovary syndrome. In: Poster, European Society of Contraception and Reproductive Health, S207. 2014.
Vieira 2010 {published data only}
    1. Vieira CS, Fernandes JB, Soares GM, Martins WP, Silva-de-Sà MF, Ferriani RA. Addition of low dose of metformin to the oral contraceptive has no great advantage in terms of cardiovascular risk markers in women with polycystic ovary syndrome regardless insulin resistance. Fertility and Sterility 2010;94(4 Suppl 1):S63-4. [Oral communication O-217]

References to ongoing studies

NCT02744131 {published data only}
    1. OCP vs metformin for Improvement in clinical symptoms and metabolic markers in Indian PCOS women (OCP). Ongoing study. 04/2016. Contact author for more information.
NCT03229057 {published data only}
    1. Comparing the effects of oral contraceptive pills versus metformin (COMET-PCOS). Ongoing study. Juillet 2017. Contact author for more information.
NCT03905941 {published data only}
    1. Relative desirability of metformin vs. birth control pill in treating PCOS in women of later reproductive age. Ongoing study. March 2020. Contact author for more information.

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References to other published versions of this review

Costello 2005
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MeSH terms