The role of glucagon-like peptide-1 receptor agonists in the correction of immune and metabolic disorders in women with reproductive dysfunction

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert prominent metabolic and immunomodulatory properties that make them promising agents for the correction of reproductive disorders in obese women. Weight loss, increased insulin sensitivity, normalization of androgen profiles, and restoration of ovulatory function are primarily relevant in polycystic ovary syndrome (PCOS) and unexplained infertility. At the level of immune regulation, GLP-1RAs contribute to downregulated pro-inflammatory cytokine expression, increased percentage of regulatory T cells (Treg), and recovered Th17 (T helper 17 cells)/Treg balance, thereby improving endometrial receptivity and conditions for successful implantation. A close association has been established between obesity, insulin resistance, and chronic inflammation collectively contributing to reduced fertility and increased risk of recurrent miscarriage. GLP-1RAs target key pathogenic mechanisms underlying these conditions, extending beyond their glucose-lowering effects. Furthermore, their potential in decreasing the incidence of immune-related reproductive losses has been observed. Despite high efficacy before pregnancy, the use of GLP-1RAs during gestation remains limited due to potential embryotoxicity. The lack of large-scale randomized clinical trials in reproductive cohorts restrains the broad integration of these agents into clinical protocols. A promising direction is introduction of GLP-1RAs in preconception preparation regimens for women with obesity, PCOS, and immune imbalance.

1. The World Health Organization. Infertility. Available at: https://www.who.int/ru/news-room/fact-sheets/detail/infertility. [Accessed: 11.04.2025].

2. Guidelines. Habitual miscarriage. 2025. [Privichniy vyikidish. 2025]. Moscow: Ministerstvo zdravoohraneniya Rossijskoj Federacii, 2025. (In Russ.). Available at: https://cr.minzdrav.gov.ru/view-cr/721_2. [Accessed: 25.05.2025].

3. Practice Committee of the American Society for Reproductive Medicine. Electronic address: asrm@asrm.org. Definitions of infertility and recurrent pregnancy loss: a committee opinion. Fertil Steril. 2020;113(3):533–5. https://doi.org/10.1016/j.fertnstert.2019.11.025.

4. Gorbatenko N.V., Bezhenar V.F., Fishman M.B. Obesity and reproductive health of women [Vliyanie ozhireniya na razvitie narusheniya reproduktivnoj funkcii u zhenshshin]. Ozhirenie i metabolism. 2017;14(1):3–8. (In Russ.). https://doi.org/10.14341/omet201713-8.

5. Genovese H.G., McQueen D.B. The prevalence of sporadic and recurrent pregnancy loss. Fertil Steril. 2023;120(5):934–6. https://doi.org/10.1016/j.fertnstert.2023.08.954.

6. Batrak N.V., Malyshkina A.I., Sotnikova N.Yu., Kroshkina N.V. Clinical and immunological features of pregnant women with a history of recurrent miscarriage. [Kliniko-immunologicheskie osobennosti beremennyh s privychnym nevynashivaniem v anamneze]. Rossijskij vestnik akushera-ginekologa. 2015;15(3):35–9. (In Russ.). https://doi.org/10.17116/rosakush201515335-39.

7. Kwak-Kim J., AlSubki L., Luu T. et al. The role of immunologic tests for subfertility in the clinical environment. Fertil Steril. 2022;117(6):1132–43. https://doi.org/10.1016/j.fertnstert.2022.04.009.

8. Cavalcante M.B., Sarno M., Barini R. Immune biomarkers in cases of recurrent pregnancy loss and recurrent implantation failure. Minerva Obstet Gynecol. 2025;77(1):34–44. https://doi.org/10.23736/S2724-606X.24.05549-0.

9. Broughton D.E., Moley K.H. Obesity and female infertility: potential mediators of obesity's impact. Fertil Steril. 2017;107(4):840–7. https://doi.org/10.1016/j.fertnstert.2017.01.017.

10. Tikhonenko E.V., Babenko A.Y., Shlyakhto E.V. Predictors of effectiveness of glucagon-like peptide-1 receptor agonist therapy in patients with type 2 diabetes and obesity [Prediktory effektivnosti terapii agonistami receptorov glyukagonopodobnogo peptida-1 u pacientov s saharnym diabetom 2 tipa i ozhireniem.]. Ozhirenie i metabolism. 2018;15(4):22–30. (In Russ.). https://doi.org/10.14341/omet9584.

11. Alfaris N., Waldrop S., Johnson V. et al. GLP-1 single, dual, and triple receptor agonists for treating type 2 diabetes and obesity: a narrative review. EClinicalMedicine. 2024;75:102782. https://doi.org/10.1016/j.eclinm.2024.102782.

12. Bendotti G., Montefusco L., Lunati M.E. et al. The anti-inflammatory and immunological properties of GLP-1 Receptor Agonists. Pharmacol Res. 2022;182:106320. https://doi.org/10.1016/j.phrs.2022.106320.

13. Ennab F., Atiomo W. Obesity and female infertility. Best Pract Res Clin Obstet Gynaecol. 2023;89:102336. https://doi.org/10.1016/j.bpobgyn.2023.102336.

14. Gonçalves C.C.R.A., Feitosa B.M., Cavalcante B.V. et al. Obesity and recurrent miscarriage: The interconnections between adipose tissue and the immune system. Am J Reprod Immunol. 2023;90(3):e13757. https://doi.org/10.1111/aji.13757.

15. Kalugina A.S., Bobrov K.Yu. Polycyctic ovary syndrome: modern view and it’s role in infertility (a review). [Sindrom polikistoznyh yaichnikov: sovremennye predstavleniya i rol' v probleme besplodiya (obzor literatury)]. Problemy reprodukcii. 2015;21(2):31–5. (In Russ.). https://doi.org/10.17116/repro201521231-35.

16. Luan Y.Y., Zhang L., Peng Y.Q. et al. Immune regulation in polycystic ovary syndrome. Clin Chim Acta. 2022;531:265–72. https://doi.org/10.1016/j.cca.2022.04.234.

17. Saito S., Nakashima A., Shima T., Ito M. Th1/Th2/Th17 and regulatory T-cell paradigm in pregnancy. Am J Reprod Immunol. 2010;63(6):601–10. https://doi.org/10.1111/j.1600-0897.2010.00852.x.

18. Wang W., Sung N., Gilman-Sachs A., Kwak-Kim J. T helper (Th) cell profiles in pregnancy and recurrent pregnancy losses: Th1/Th2/Th9/Th17/Th22/Tfh cells. Front Immunol. 2020;11:2025. https://doi.org/10.3389/fimmu.2020.02025.

19. Yousefzadeh Y., Soltani-Zangbar M.S., Hemmatzadeh M. et al. Fetomaternal immune tolerance: crucial mechanisms of tolerance for successful pregnancy in humans. Immunol Invest. 2022;51(4):1108–125. https://doi.org/10.1080/08820139.2021.1909061.

20. Li D., Zheng L., Zhao D. et al. The role of immune cells in recurrent spontaneous abortion. Reprod Sci. 2021;28(12):3303–15. https://doi.org/10.1007/s43032-021-00599-y.

21. True H., Blanton M., Sureshchandra S., Messaoudi I. Monocytes and macrophages in pregnancy: the good, the bad, and the ugly. Immunol Rev. 2022;308(1):77–92. https://doi.org/10.1111/imr.13080.

22. Zhao Q.Y., Li Q.H., Fu Y.Y. et al. Decidual macrophages in recurrent spontaneous abortion. Front Immunol. 2022;13:994888. https://doi.org/10.3389/fimmu.2022.994888.

23. Galstyan G.R., Karataeva E.A., Yudovich E.A. Evolution of glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes [Evolyuciya agonistov receptorov glyukagonopodobnogo peptida-1 v terapii saharnogo diabeta 2 tipa]. Saharnyj diabet. 2017;20(4):286–98. (In Russ.). https://doi.org/10.14341/DM8804.

24. Ussher J.R., Drucker D.J. Glucagon-like peptide 1 receptor agonists: cardiovascular benefits and mechanisms of action. Nat Rev Cardiol. 2023;20(7):463–74. https://doi.org/10.1038/s41569-023-00849-3.

25. Klen J., Dolžan V. Glucagon-like peptide-1 receptor agonists in the management of type 2 diabetes mellitus and obesity: the impact of pharmacological properties and genetic factors. Int J Mol Sci. 2022;23(7):3451. https://doi.org/10.3390/ijms23073451.

26. Vlasov T.D., Simanenkova A.V., Dora S.V., Shlyakhto E.V. Mechanisms of neuroprotective action of incretin mimetics. [Mekhanizmy nejroprotektivnogo dejstviya inkretinomimetikov]. Saharnyj diabet. 2016;19(1):16–23. (In Russ.). https://doi.org/10.14341/DM7192.

27. Tobaiqy M. A review of serious adverse events linked with GLP-1 agonists in type 2 diabetes mellitus and obesity treatment. Pharmacol Rep. 2024;76(5):981–90. https://doi.org/10.1007/s43440-024-00629-x.

28. Muller D.R.P., Stenvers D.J., Malekzadeh A. et al. Effects of GLP-1 agonists and SGLT2 inhibitors during pregnancy and lactation on offspring outcomes: a systematic review of the evidence. Front Endocrinol (Lausanne). 2023;14:1215356. https://doi.org/10.3389/fendo.2023.1215356.

29. Dao K., Shechtman S., Weber-Schoendorfer C. et al. Use of GLP1 receptor agonists in early pregnancy and reproductive safety: a multicentre, observational, prospective cohort study based on the databases of six Teratology Information Services. BMJ Open. 2024;14(4):e083550. https://doi.org/10.1136/bmjopen-2023-083550.

30. Zhou J., Wei Z., Lai W. et al. The safety profile of usage of glucagon-like peptide-1 receptor agonists in pregnancy: a pharmacovigilance analysis based on the Food and Drug Administration Adverse Event Reporting System. Br J Clin Pharmacol. 2025;91(4):1272–80. https://doi.org/10.1111/bcp.16354.

31. Diab H., Fuquay T., Datta P. et al. Subcutaneous semaglutide during breastfeeding: infant safety regarding drug transfer into human milk. Nutrients. 2024;16(17):2886. https://doi.org/10.3390/nu16172886.

32. Caldwell A.E., Gorczyca A.M., Bradford A.P. et al. Effectiveness of preconception weight loss interventions on fertility in women: a systematic review and meta-analysis. Fertil Steril. 2024;122(2):326–40. https://doi.org/10.1016/j.fertnstert.2024.02.038.

33. Carson S.A., Kallen A.N. Diagnosis and management of infertility: a review. JAMA. 2021;326(1):65–76. https://doi.org/10.1001/jama.2021.4788.

34. Seifer D.B., Feinberg E.C., Hsu A.L. Ovarian aging and fertility. JAMA. 2024;332(20):1750–1. https://doi.org/10.1001/jama.2024.18207.

35. Elmaleh-Sachs A., Schwartz J.L., Bramante C.T. et al. Obesity management in adults: a review. JAMA. 2023;330(20):2000–15. https://doi.org/10.1001/jama.2023.19897.

36. Xie Z., Zheng G., Liang Z. et al. Seven glucagon-like peptide-1 receptor agonists and polyagonists for weight loss in patients with obesity or overweight: an updated systematic review and network meta-analysis of randomized controlled trials. Metabolism. 2024;161:156038. https://doi.org/10.1016/j.metabol.2024.156038.

37. Wadden T.A., Bailey T.S., Billings L.K. et al. Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 Randomized Clinical Trial. JAMA. 2021;325(14):1403–13. https://doi.org/10.1001/jama.2021.1831.

38. Jastreboff A.M., Aronne L.J., Ahmad N.N. et al. SURMOUNT-1 Investigators. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205–16. https://doi.org/10.1056/NEJMoa2206038.

39. Scragg J., Hobson A., Willis L. et al. Effect of weight loss interventions on the symptomatic burden and biomarkers of polycystic ovary syndrome: a systematic review of randomized controlled trials. Ann Intern Med. 2024;177(12):1664–74. https://doi.org/10.7326/M23-3179.

40. Ruiz-González D., Cavero-Redondo I., Hernández-Martínez A. et al. 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 Update. 2024;30(4):472–87. https://doi.org/10.1093/humupd/dmae008.

41. Austregésilo de Athayde De Hollanda Morais B., Martins Prizão V., de Moura de Souza M. et al. The efficacy and safety of GLP-1 agonists in PCOS women living with obesity in promoting weight loss and hormonal regulation: a meta-analysis of randomized controlled trials. J Diabetes Complications. 2024;38(10):108834. https://doi.org/10.1016/j.jdiacomp.2024.108834.

42. Lyu X., Lyu T., Wang X. et al. The antiobesity effect of GLP-1 receptor agonists alone or in combination with metformin in overweight/obese women with polycystic ovary syndrome: a systematic review and meta-analysis. Int J Endocrinol. 2021;2021:6616693. https://doi.org/10.1155/2021/6616693.

43. Hoek A., Wang Z., van Oers A.M. et al. Effects of preconception weight loss after lifestyle intervention on fertility outcomes and pregnancy complications. Fertil Steril. 2022;118(3):456–62. https://doi.org/10.1016/j.fertnstert.2022.07.020.

44. Chen J., Mei A., Wei Y. et al. GLP-1 receptor agonist as a modulator of innate immunity. Front Immunol. 2022;13:997578. https://doi.org/10.3389/fimmu.2022.997578.

45. Yusta B., Baggio L.L., Koehler J. et al. GLP-1R agonists modulate enteric immune responses through the intestinal intraepithelial lymphocyte GLP-1R. Diabetes. 2015;64(7):2537–49. https://doi.org/10.2337/db14-1577.

46. Desai A., Petrov J., Hashash J.G. et al. Use of glucagon-like peptide-1 receptor agonists for type 2 diabetes mellitus and outcomes of inflammatory bowel disease. Aliment Pharmacol Ther. 2024;60(5):620–32. https://doi.org/10.1111/apt.18138.

47. Boshchenko A.A., Maslov L.N., Mukhomedzyanov A.V. et al. Peptides are cardioprotective drugs of the future: the receptor and signaling mechanisms of the cardioprotective effect of glucagon-like peptide-1 receptor agonists. Int J Mol Sci. 2024;25(9):4900. https://doi.org/10.3390/ijms25094900.

48. Kopp K.O., Glotfelty E.J., Li Y., Greig N.H. Glucagon-like peptide-1 (GLP-1) receptor agonists and neuroinflammation: Implications for neurodegenerative disease treatment. Pharmacol Res. 2022;186:106550. https://doi.org/10.1016/j.phrs.2022.106550.

49. Nasonov Е.L., Panevin Т.S., Troshina Е.А. Glucagon-like peptide-1 receptor agonists: Prospects for use in rheumatology. [Agonisty receptorov glyukagonopodobnogo peptida-1: perspektivy primeneniya v revmatologii]. Nauchno-prakticheskaya revmatologiya. 2024;62(2):135–44. (In Russ.). https://doi.org/10.47360/1995-4484-2024-135-144.

50. Aslam B., Bin Zafar M.D., Changez M.I.K. et al. Exploring the potential impact of GLP-1 receptor agonists in cancer therapy. Minerva Endocrinol (Torino). 2023 Dec. https://doi.org/10.23736/S2724-6507.23.04101-5. [Online ahead of print].

51. Alhajahjeh A., Al-Faouri R., Bahmad H.F. et al. From diabetes to oncology: glucagon-like peptide-1 (GLP-1) receptor agonist's dual role in prostate cancer. Cancers (Basel). 2024;16(8):1538. https://doi.org/10.3390/cancers16081538.

52. Wu A.Y., Cahill K.N., Toki S., Peebles R.S. Evaluating the glucagon-like peptide-1 receptor in managing asthma. Curr Opin Allergy Clin Immunol. 2022;22(1):36–41. https://doi.org/10.1097/ACI.0000000000000797.

53. Cai R., Yang Q., Liao Y. et al. Immune treatment strategies in unexplained recurrent pregnancy loss. Am J Reprod Immunol. 2025;93(2):e70060. https://doi.org/10.1111/aji.70060.

54. Garmendia J.V., De Sanctis C.V., Hajdúch M., De Sanctis J.B. Exploring the immunological aspects and treatments of recurrent pregnancy loss and recurrent implantation failure. Int J Mol Sci. 2025;26(3):1295. https://doi.org/10.3390/ijms26031295.

55. Cavalcante M.B., Sarno M., Barini R. Lymphocyte immunotherapy in recurrent miscarriage and recurrent implantation failure. Am J Reprod Immunol. 2021;85(4):e13408. https://doi.org/10.1111/aji.13408.

56. Cavalcante M.B., Alcântara da Silva P.H., Sampaio O.G.M. et al. The use of immunotherapies for recurrent miscarriage: an overview of systematic reviews and meta-analysis. J Reprod Immunol. 2023;158:103986. https://doi.org/10.1016/j.jri.2023.103986.

57. Cavalcante M.B., Tavares A.C.M., Rocha C.A. et al. Calcineurin inhibitors in the management of recurrent miscarriage and recurrent implantation failure: systematic review and meta-analysis. J Reprod Immunol. 2023;160:104157. https://doi.org/10.1016/j.jri.2023.104157.

58. Tong X., Song X., Zhang Y., Zhao Q. Efficacy and safety of glucagon-like peptide-1 receptor agonists in the treatment of polycystic ovary syndrome – a systematic review and meta-analysis. Arch Physiol Biochem. 2024;130(6):1005-1011. https://doi.org/10.1080/13813455.2024.2380422.

59. Salamun V., Jensterle M., Janez A., Vrtacnik Bokal E. Liraglutide increases IVF pregnancy rates in obese PCOS women with poor response to first-line reproductive treatments: a pilot randomized study. Eur J Endocrinol. 2018;179(1):1–11. https://doi.org/10.1530/EJE-18-0175.

60. Drucker D.J. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 2018;27(4):740-756. https://doi.org/10.1016/j.cmet.2018.03.001.