Semaglutide and metformin improve menstrual cyclicity in overweight/obese women with polycystic ovary syndrome: a randomized trial

Abstract

Aim: This study investigated the effects of semaglutide combined with metformin on body weight, glucose and lipid metabolism, sex hormone levels, menstrual cyclicity, and psychological parameters of women living with polycystic ovary syndrome (PCOS)-related infertility and overweight/obesity.

Methods: Sixty-four patients living with infertility and PCOS [body mass index (BMI) ≥ 24 kg/m²] were randomly assigned to standard (n = 32) or semaglutide-intensified treatment groups (n = 32). Both groups underwent lifestyle modification interventions. The standard group received metformin monotherapy [500 mg three times daily (TID)] for 12 weeks, whereas the semaglutide-intensified treatment group received metformin and semaglutide for 12 weeks. An 8-week washout period followed treatment.

Results: The semaglutide-intensified treatment group showed a higher percentage of patients with restored menstrual cycles (86.87% vs. 60.00%, P = 0.038). Significant reductions in luteinizing hormone (LH), androgen levels, and the LH/follicle-stimulating hormone ratio were observed. Greater reductions were also noted in BMI, waist and hip circumference, absolute weight loss, body fat percentage, fasting plasma glucose, fasting insulin, and Homeostatic Model Assessment of Insulin Resistance (P < 0.05). No significant differences were observed in total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels. Psychological distress was not exacerbated in the semaglutide-intensified treatment group.

Conclusion: In women living with PCOS-related infertility and overweight/obesity, semaglutide combined with metformin provided superior improvements in weight reduction, glucose metabolism, insulin sensitivity, and menstrual cyclicity compared with metformin monotherapy, without exacerbating psychological distress. These findings suggest that semaglutide represents a promising therapeutic option for the clinical management of this population.

Keywords

Semaglutide / metformin / polycystic ovary syndrome / obesity / menstrual cyclicity / glucose metabolism

References

[1] Datta J,Tanton C.Prevalence of infertility and help seeking among 15 000 women and men.Hum Reprod2016;31:2108-18 PMCID:PMC4991655

[2] Zhou Z,Wu H.Epidemiology of infertility in China: a population-based study.BJOG2018;125:432-41

[3] Zhang X,Zhao Z.Geographic variation in prevalence of adult obesity in china: results from the 2013-2014 national chronic disease and risk factor surveillance.Ann Intern Med2020;172:291-3

[4] Barbouni K,Metallinou D.When weight matters: how obesity impacts reproductive health and pregnancy - a systematic review.Curr Obes Rep2025;14:37 PMCID:PMC12003489

[5] Johnson AP,Simon J.Special considerations in assisted reproductive technology for patients with obesity.Fertil Steril2025;124:212-8

[6] Lash MM.Impact of obesity on women’s health.Fertil Steril2009;91:1712-6

[7] Wu M,Zhu Q.Adipose tissue and ovarian aging: potential mechanism and protective strategies.Ageing Res Rev2022;80:101683

[8] Rafael F,Bellver J.The combined effect of BMI and age on ART outcomes.Hum Reprod2023;38:886-94

[9] Wang RQ,Chen GT,Xia LB.Obesity and recurrent spontaneous abortion: the crucial role of weight management in pregnancy.Reprod Biol Endocrinol2025;23:10 PMCID:PMC11752768

[10] Cozzolino M,Meseguer M,Bellver J.Female obesity increases the risk of miscarriage of euploid embryos.Fertil Steril2021;115:1495-502

[11] Palomba S,Giudice LC.Endometrial function in women with polycystic ovary syndrome: a comprehensive review.Hum Reprod Update2021;27:584-618

[12] Balen AH,Misso M.The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance.Hum Reprod Update2016;22:687-708

[13] Tay CT,Bahri Khomami M,Harrison CL.High prevalence of medical conditions and unhealthy lifestyle behaviours in women with PCOS during preconception: findings from the Australian Longitudinal Study on Women’s Health.Hum Reprod2023;38:2267-76 PMCID:PMC10628491

[14] Zhang Y,Zhao H.Polycystic ovary syndrome: a metabolic disorder with therapeutic opportunities.Cell Metab2025;37:1932-49

[15] Experts Consensus Group on the Body Quality Management Approach and Process for Overweight/Obese Infertility Patients. Expert consensus on the weight management of overweight/obese infertility patients in China.Chin J Reprod Contracept2020;40:965-71. (in Chinese)

[16] Ruiz-González D,Hernández-Martínez A.Comparative efficacy of exercise, diet and/or pharmacological interventions on BMI, ovulation, and hormonal profile in reproductive-aged women with overweight or obesity: a systematic review and network meta-analysis.Hum Reprod Update2024;30:472-87 PMCID:PMC11215161

[17] Saadati S,Godini R,Teede H.Metformin use in women with polycystic ovary syndrome (PCOS): opportunities, benefits, and clinical challenges.Diabetes Obes Metab2025;27 Suppl 3:31-47 PMCID:PMC12094230

[18] Sharpe A,Tang T,Balen AH.Metformin for ovulation induction (excluding gonadotrophins) in women with polycystic ovary syndrome.Cochrane Database Syst Rev2019;12:CD013505 PMCID:PMC6915832

[19] Abu-Hamdah R,Meneilly GS,Andersen DK.Clinical review: the extrapancreatic effects of glucagon-like peptide-1 and related peptides.J Clin Endocrinol Metab2009;94:1843-52 PMCID:PMC2690432

[20] Drucker DJ.Efficacy and safety of GLP-1 medicines for type 2 diabetes and obesity.Diabetes Care2024;47:1873-88

[21] Papamargaritis D,Holst JJ.New therapies for obesity.Cardiovasc Res2024;119:2825-42 PMCID:PMC10874276

[22] Wilding JPH,Kushner RF.Once-weekly semaglutide in adults with overweight or obesity. Reply.N Engl J Med2021;385:e4

[23] Garvey WT,Bhatta M.STEP 5 Study GroupTwo-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial.Nat Med2022;28:2083-91 PMCID:PMC9556320

[24] Tzang CC,Luo CA.Metabolic rebound after GLP-1 receptor agonist discontinuation: a systematic review and meta-analysis.EClinicalMedicine2025;90:103680 PMCID:PMC12702299

[25] Jensen SBK,Sandsdal RM.Healthy weight loss maintenance with exercise, GLP-1 receptor agonist, or both combined followed by one year without treatment: a post-treatment analysis of a randomised placebo-controlled trial.EClinicalMedicine2024;69:102475 PMCID:PMC10965408

[26] Jensterle M,Fliers E,Vrtacnik-Bokal E.The role of glucagon-like peptide-1 in reproduction: from physiology to therapeutic perspective.Hum Reprod Update2019;25:504-17

[27] Salamun V,Janez A.Liraglutide increases IVF pregnancy rates in obese PCOS women with poor response to first-line reproductive treatments: a pilot randomized study.Eur J Endocrinol2018;179:1-11

[28] Liu X,Zheng SY.Efficacy of exenatide on weight loss, metabolic parameters and pregnancy in overweight/obese polycystic ovary syndrome.Clin Endocrinol2017;87:767-74

[29] Nylander M,Clausen HV,Faber J.Effects of liraglutide on ovarian dysfunction in polycystic ovary syndrome: a randomized clinical trial.Reprod Biomed Online2017;35:121-7

[30] Siamashvili M.Update on the effects of GLP-1 receptor agonists for the treatment of polycystic ovary syndrome.Expert Rev Clin Pharmacol2021;14:1081-9

[31] Darıcı E,Leemans L.From body mass index to body composition in female infertility.Reprod Biomed Online2025;51:104941

[32] Ling J,Huang W.Combined liraglutide and metformin therapy in overweight or obese women with polycystic ovary syndrome: a systematic review and meta-analysis.Diabetes Obes Metab2025;27:6139-53 PMCID:PMC12515772

[33] Wen Q,Liang Y.Short-term effect of beinaglutide combined with metformin versus metformin alone on weight loss and metabolic profiles in obese patients with polycystic ovary syndrome: a pilot randomized trial.Front Endocrinol2023;14:1156521 PMCID:PMC10280986

[34] Huang R.The safety and efficacy of liraglutide combined with metformin in clinical treatment of polycystic ovary syndrome patients: a meta-analysis.BMC Womens Health2025;25:282 PMCID:PMC12143058

[35] Xing C,Zhang J.Effect of metformin versus metformin plus liraglutide on gonadal and metabolic profiles in overweight patients with polycystic ovary syndrome.Front Endocrinol2022;13:945609 PMCID:PMC9428699

[36] Carmina E.Semaglutide treatment of excessive body weight in obese PCOS patients unresponsive to lifestyle programs.J Clin Med2023;12:5921 PMCID:PMC10531549

[37] Younis JS,Fauser BCJM.Does an association exist between menstrual cycle length within the normal range and ovarian reserve biomarkers during the reproductive years?.Hum Reprod Update2020;26:904-28

[38] Zeng X,Liu YT,Mo ZC.Polycystic ovarian syndrome: correlation between hyperandrogenism, insulin resistance and obesity.Clin Chim Acta2020;502:214-21

[39] Lazaridou S,Tziomalos K.Prevalence, pathogenesis and management of prediabetes and type 2 diabetes mellitus in patients with polycystic ovary syndrome.Hormones2017;16:373-80

[40] Roberts R,Kasaven L.Obesity and female reproductive health; is there a role for glucagon-like peptide-1 receptor agonists?.Obes Rev2026;27:e70015

[41] Bednarz K,Cwynar M.The role of Glp-1 receptor agonists in insulin resistance with concomitant obesity treatment in polycystic ovary syndrome.Int J Mol Sci2022;23 PMCID:PMC9029608

[42] Guo S,Liu M.Semaglutide alleviates ovarian oxidative stress and autophagy via the PI3K/AKT/mTOR pathway in mice with polycystic ovary syndrome.Drug Des Devel Ther2025;19:4297-310 PMCID:PMC12109608

[43] Jensterle M,Goričar K.Short-term effectiveness of low dose liraglutide in combination with metformin versus high dose liraglutide alone in treatment of obese PCOS: randomized trial.BMC Endocr Disord2017;17:5 PMCID:PMC5286837

[44] Wang Y,Li K.The prevalence of anxiety and depression of different severity in women with polycystic ovary syndrome: a meta-analysis.Gynecol Endocrinol2021;37:1072-8

[45] Greenwood EA,Cedars MI,Eisenberg E.Eunice Kennedy Shriver National Institute of Child Health and Human Development Reproductive Medicine NetworkInsulin resistance is associated with depression risk in polycystic ovary syndrome.Fertil Steril2018;110:27-34 PMCID:PMC6392023

[46] Chen X,Wang W,Pan Q.The antidepressant effects of GLP-1 receptor agonists: a systematic review and meta-analysis.Am J Geriatr Psychiatry2024;32:117-27