Polycystic Ovary Syndrome, Insulin Resistance and Weight: Sequencing Treatment When Goals Conflict
DOI:
https://doi.org/10.5281/zenodo.22261277Keywords:
Polycystic ovary syndrome, Metformin, Combined oral contraceptive, Insulin resistance, Treatment sequencingAbstract
Polycystic ovary syndrome affects more than one woman in ten and presents with reproductive, dermatological and metabolic
features that do not respond to the same treatment. A meta-analysis of 36 randomised trials, conducted to inform the 2023
international guideline, found the combined oral contraceptive superior for cycle regularity and metformin superior for metabolic
outcomes, with metformin lowering insulin by 27.12 pmol/L and triglycerides by 0.15 mmol/L relative to the pill. For hirsutism
there was no difference between them. Combining the two improved biochemical hyperandrogenism, insulin and insulin resistance
beyond the pill alone, yet produced no difference in clinical outcomes. Body mass index modified the comparison, with metformin
favoured metabolically above 25 kg/m2 and the pill favoured for hirsutism below it. Underlying all of this is an awkward fact:
insulin resistance is described as a key feature of the syndrome while routine clinical measurement of it is not recommended,
because available measures are inaccurate.
References
Teede HJ, Tay CT, Laven JJE, Dokras A, Moran LJ, Piltonen TT, et al. "Recommendations from the 2023 international evidence-based guideline for the assessment and management of polycystic ovary syndrome". J Clin Endocrinol Metab 108(2023):2447-2469.
Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, et al. "The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report". Fertil Steril 91(2009):456-488.
Wekker V, van Dammen L, Koning A, Heida KY, Painter RC, Limpens J, et al. "Long-term cardiometabolic disease risk in women with PCOS: a systematic review and meta-analysis". Hum Reprod Update 26(2020):942-960.
Legro RS, Arslanian SA, Ehrmann DA, Hoeger KM, Murad MH, Pasquali R, et al. "Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline". J Clin Endocrinol Metab 98(2013):4565-4592.
Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, et al. "Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome". Hum Reprod 33(2018):1602-1618.
Monash University Centre for Research Excellence in Women s Health in Reproductive Life. "International evidence-based guideline for the assessment and management of polycystic ovary syndrome 2023: summary". Monash University, Melbourne (2023).
Melin J, Forslund M, Alesi S, Piltonen T, Romualdi D, Spritzer PM, et al. "Metformin and combined oral contraceptive pills in the management of polycystic ovary syndrome: a systematic review and meta-analysis". J Clin Endocrinol Metab 109(2024):e817-e836.
Martin KA, Anderson RR, Chang RJ, Ehrmann DA, Lobo RA, Murad MH, et al. "Evaluation and treatment of hirsutism in premenopausal women: an Endocrine Society clinical practice guideline". J Clin Endocrinol Metab 103(2018):1233-1257.
Cassar S, Misso ML, Hopkins WG, Shaw CS, Teede HJ, Stepto NK. "Insulin resistance in polycystic ovary syndrome: a systematic review and meta-analysis of euglycaemic-hyperinsulinaemic clamp studies". Hum Reprod 31(2016):2619-2631.
Adolescent review authors. "Comparative efficacy of metformin and combined oral contraceptives in the management of adolescent polycystic ovary syndrome: a systematic review of randomized controlled trials". Cureus 17(2025):e83521.
Zhu T, Cui J, Goodarzi MO. "Polycystic ovary syndrome and risk of type 2 diabetes, coronary heart disease, and stroke". Diabetes 70(2021):627-637.
Pirotta S, Joham AJ, Moran LJ, Skouteris H, Lim SS. "Human papillomavirus and weight stigma in women with polycystic ovary syndrome: a qualitative exploration". Health Expect 24(2021):1-10.
Naderpoor N, Shorakae S, de Courten B, Misso ML, Moran LJ, Teede HJ. "Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis". Hum Reprod Update 21(2015):560-574.
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". N Engl J Med 356(2007):551-566.
Legro RS, Brzyski RG, Diamond MP, Coutifaris C, Schlaff WD, Casson P, et al. "Letrozole versus clomiphene for infertility in the polycystic ovary syndrome". N Engl J Med 371(2014):119-129.
Costello MF, Misso ML, Balen A, Boyle J, Devoto L, Garad RM, et al. "Evidence summaries and recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome: assessment and treatment of infertility". Hum Reprod Open 2019(2019):hoy021.
Ibanez L, de Zegher F. "Adolescent PCOS: a postpubertal central obesity syndrome". Trends Mol Med 29(2023):354-363.
Ibanez L, Del 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". J Adolesc Health 61(2017):446-453.
Forslund M, Melin J, Alesi S, Piltonen T, Romualdi D, Tay CT, et al. "Different kinds of oral contraceptive pills in polycystic ovary syndrome: a systematic review and meta-analysis". Eur J Endocrinol 189(2023):S1-S16.
Alesi S, Forslund M, Melin J, Romualdi D, Peña A, Tay CT, et al. "Efficacy and safety of anti-obesity medications in women with polycystic ovary syndrome: a systematic review and meta-analysis". Obes Rev 24(2023):e13606.
Moran LJ, Hutchison SK, Norman RJ, Teede HJ. "Lifestyle changes in women with polycystic ovary syndrome". Cochrane Database Syst Rev (2011):CD007506.
Dokras A, Stener-Victorin E, Yildiz BO, Li R, Ottey S, Shah D, et al. "Androgen Excess and Polycystic Ovary Syndrome Society: position statement on depression, anxiety, quality of life, and eating disorders in polycystic ovary syndrome". Fertil Steril 109(2018):888-899.
Cooney LG, Lee I, Sammel MD, Dokras A. "High prevalence of moderate and severe depressive and anxiety symptoms in polycystic ovary syndrome: a systematic review and meta-analysis". Hum Reprod 32(2017):1075-1091.
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". Hum Reprod 28(2013):777-784.
Diamanti-Kandarakis E, Dunaif A. "Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications". Endocr Rev 33(2012):981-1030.
Lim SS, Hutchison SK, Van Ryswyk E, Norman RJ, Teede HJ, Moran LJ. "Lifestyle changes in women with polycystic ovary syndrome". Cochrane Database Syst Rev (2019):CD007506.
Joham AE, Norman RJ, Stener-Victorin E, Legro RS, Franks S, Moran LJ, et al. "Polycystic ovary syndrome". Lancet Diabetes Endocrinol 10(2022):668-680.
Palomba S, Falbo A, Zullo F, Orio F. "Evidence-based and potential benefits of metformin in the polycystic ovary syndrome: a comprehensive review". Endocr Rev 30(2009):1-50.
Amiri M, Ramezani Tehrani F, Nahidi F, Kabir A, Azizi F, Carmina E. "Effects of oral contraceptives on metabolic profile in women with polycystic ovary syndrome: a meta-analysis comparing products containing cyproterone acetate with third generation progestins". Metabolism 73(2017):22-35.
Luque-Ramirez M, Nattero-Chavez L, Ortiz Flores AE, Escobar-Morreale HF. "Combined oral contraceptives and/or antiandrogens versus insulin sensitizers for polycystic ovary syndrome: a systematic review and meta-analysis". Hum Reprod Update 24(2018):225-241.
Glintborg D, Andersen M. "Management of endocrine disease: morbidity in polycystic ovary syndrome". Eur J Endocrinol 176(2017):R53-R65.
Bahri Khomami M, Joham AE, Boyle JA, Piltonen T, Silagy M, Arora C, et al. "Increased maternal pregnancy complications in polycystic ovary syndrome appear to be independent of obesity: a systematic review and meta-analysis". Obes Rev 20(2019):659-674.
