Metformin and Combined Oral Contraceptive Pills in the Management of Polycystic Ovary Syndrome: A Systematic Review and Meta-analysis

Abstract

Context Polycystic ovary syndrome (PCOS) is affecting more than every tenth woman. Objective As part of the 2023 International PCOS Guidelines update, comparisons between combined oral contraceptive pills (COCP), metformin and combination treatment were evaluated. Data Sources Ovid Medline, Embase, PsycINFO, All EBM and CINAHL were searched. Study Selection Women with PCOS included in randomized controlled trials (RCT). Data Extraction We calculated mean differences (MD) and 95% confidence intervals (CI) regarding anthropometrics, metabolic and hyperandrogenic outcomes. Meta-analyses and quality assessment using GRADE was performed. Data Synthesis The search identified 1660 publications, 36 RCTs were included. For hirsutism no differences were seen when comparing metformin versus COCP, nor when comparing COCP versus combination treatment with metformin and COCP. Metformin was inferior on free androgen index (FAI) (7.08, 95% CI 4.81; 9.36), sex hormone binding globulin (SHBG) (-118.61 nmol/l, 95% CI -174.46; -62.75) and testosterone (0.48 nmol/l,95% CI 0.32; 0.64) compared with COCP. COCP was inferior for FAI (0.58, 95% CI 0.36; 0.80) and SHBG (-16.61 nmol/L, 95% CI -28.51; -4.71) compared with combination treatment, whereas testosterone did not differ. Metformin lowered insulin (-27.12 pmol/l, 95%CI -40.65; -13.59) and triglycerides (-0.15 mmol/l, 95%CI -0.29; -0.01) compared with COCP. COCP was inferior for insulin (17.03 pmol/l, 95%CI 7.79; 26.26) and insulin resistance (0.44, 95%CI 0.17; 0.70) compared with combination treatment. Conclusions The choice of metformin or COCP treatment should be based on symptoms, noting that there are some biochemical benefits from combination treatment, targeting both major endocrine disturbances seen in PCOS; hyperinsulinemia and hyperandrogenism.

View on Metformin: Antidiabetic and Pleiotropic Effects, Pharmacokinetics, Side Effects, and Sex-Related Differences

“…A very recent meta-analysis of 46 RCTs has been performed as a 2023 update of the “International Evidence-based Guidelines for the Assessment and Management of PCOS”, highlighting that metformin is superior to hormonal treatment in controlling the blood sugar, overweight, and lipid profile of PCSO subjects [ 207 , 208 ]. Therefore, metformin is considered a second-line treatment in PCOS that offers benefits for the management of menstrual and ovulatory disorders, hirsutism, and metabolic and cardiovascular disorders [ 209 , 210 ].…”

Metformin beyond type 2 diabetes: Emerging and potential new indications

“…One review focusing on obesity concluded that evidence for the use of anti‐obesity agents (including metformin) for this indication was ‘very limited,’ identifying only 11 relevant trials (including a total of 996 participants with PCOS) with only four included in the meta‐analysis 15 . Another review focusing on the treatment of hirsutism based on 36 relevant trials concluded that the combined oral contraceptive pill was superior to metformin for women with a BMI <25 kg/m 2 , but that the evidence for this outcome in other BMI groups was of very low quality 16 . Another review focusing on lowering weight and testosterone levels with insulin sensitizers (metformin vs. PPARγ agonists) based on 13 randomized controlled trials (RCTs) involving 787 women concluded that metformin was superior to rosiglitazone and non‐inferior to pioglitazone 17 .…”

International evidence‐based guideline on assessment and management of PCOS—A Nordic perspective

“…Combination treatment with COCP and metformin may be beneficial in high metabolic risk groups, including women with BMI ≥30 kg/m 2 , and those with risk factors for type 2 diabetes (T2D). 13 Inositol is not recommended but can be considered based on individual preferences. Potential improvement in metabolic measures is noted, but with limited clinical benefits including in ovulation, hirsutism and weight.…”

“…Combination treatment with COCP and metformin may be beneficial in high metabolic risk groups, including women with BMI ≥30 kg/m 2 , and those with risk factors for type 2 diabetes (T2D) 13 …”