The effect of a low-carbohydrate versus mediterranean diet on growth factors in women with polycystic ovary syndrome: Data from a randomized trial

Aim. To present a pre-specified secondary analysis of the randomized trial and compare the effects of a low-carbohydrate versus a Mediterranean diet on growth factor levels, as well as on lipid profile and ovulatory function in women with PCOS. Materials and methods. Eighty-seven patients with PCOS were randomized to either a low-carbohydrate diet (n = 44) or a Mediterranean diet (n = 43). The research protocol is registered on clinicaltrials.gov (NCT05272657). Fasting serum samples were collected at baseline and after 3 months of the dietary intervention. In this study, we conducted a secondary analysis of changes in anthropometric measures, lipid profile, ovulatory function, and circulating growth factors (EGF, FGF2, FLT3L, PDGF-AA, PDGF-AB/BB, VEGF-α).

Results. Weight loss was comparable between the groups. The Mediterranean diet led to significantly greater reductions in total cholesterol and LDL cholesterol and restored ovulation more frequently. In the analyzed subgroup, the Mediterranean diet reduced FLT3L, FGF2, PDGF-AA, and PDGF-AB/BB levels, whereas the low-carbohydrate diet increased them. Several of these differences remained significant after correction for multiple comparisons.

Conclusion. Despite similar weight loss, the Mediterranean diet was superior to the low-carbohydrate diet regarding lipid profile improvement, restoration of ovulatory function, and modulation of key angiogenesis/fibrosis factors in women with PCOS. These findings point to potential pathogenetic benefits of the Mediterranean diet, which warrant confirmation in larger and longer-term studies.

1. Suturina L, Lizneva D, Lazareva L, Danusevich I, Nadeliaeva I, Belenkaya L et al. Ethnicity and the prevalence of polycystic ovary syndrome: the Eastern Siberia PCOS Epidemiology and Phenotype Study. J Clin Endocrinol Metab. 2024;110(1):e32–e43. https://doi.org/10.1210/clinem/dgae424.

2. Gao X, Zhao S, Du Y, Yang Z, Tian Y, Zhao J et al. Data-driven subtypes of polycystic ovary syndrome and their association with clinical outcomes. Nat Med. 2025;31(12):4214–4224. https://doi.org/10.1038/s41591-025-03984-1.

3. Chen X, Wan Y, Xie L. Insulin resistance in polycystic ovary syndrome: pathophysiological mechanisms of menstrual dysfunction and evidencebased treatment strategies. Biol Reprod. 2025;113(6):1340–1354. https://doi.org/10.1093/biolre/ioaf197.

4. Houston EJ, Templeman NM. Reappraising the relationship between hyperinsulinemia and insulin resistance in PCOS. J Endocrinol. 2025;265(2):e240269. https://doi.org/10.1530/JOE-24-0269.

5. Nestler JE, Jakubowicz DJ, de Vargas FA, Brik C, Quintero A, Medina F. Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. J Clin Endocrinol Metab. 1998;83(6):2001–2005. https://doi.org/10.1210/jcem.83.6.4886.

6. Saxena P, Prakash A, Nigam A, Mishra A. Polycystic ovary syndrome: is obesity a sine qua non? A clinical, hormonal, and metabolic assessment in relation to body mass index. Indian J Endocrinol Metab. 2012;16(6):996–999. https://doi.org/10.4103/2230-8210.103011.

7. Ibanez L, Oberfield SE, Witchel S, Auchus RJ, Chang RJ, Codner E et al. An international consortium update: pathophysiology, diagnosis, and treatment of polycystic ovarian syndrome in adolescence. Horm Res Paediatr. 2017;88(6):371–395. https://doi.org/10.1159/000479371.

8. Patil K, Joseph S, Shah J, Mukherjee S. An integrated in silico analysis highlighted angiogenesis regulating miRNA-mRNA network in PCOS pathophysiology. J Assist Reprod Genet. 2022;39(2):427–440. https://doi.org/10.1007/s10815-022-02396-1.

9. Ambekar AS, Kelkar DS, Pinto SM, Sharma R, Hinduja I, Zaveri K et al. Proteomics of follicular fluid from women with polycystic ovary syndrome suggests molecular defects in follicular development. J Clin Endocrinol Metab. 2015;100(2):744–753. https://doi.org/10.1210/jc.2014-2086.

10. Tal R, Seifer DB, Arici A. The emerging role of angiogenic factor dysregulation in the pathogenesis of polycystic ovarian syndrome. Semin Reprod Med. 2015;33(3):195–207. https://doi.org/10.1055/s-0035-1552582.

11. Vimalraj S. A concise review of VEGF, PDGF, FGF, Notch, angiopoietin, and HGF signalling in tumor angiogenesis with a focus on alternative approaches and future directions. Int J Biol Macromol. 2022;221:1428–1438. https://doi.org/10.1016/j.ijbiomac.2022.09.129.

12. Ziemak H, Kulus M, Krajnik K, Kulus J, Chwarzyński M, Ciorga M et al. Angiogenesis in the ovary – proangiogenic factors and their clinical applications. Biomed Pharmacother. 2025;191:118416. https://doi.org/10.1016/j.biopha.2025.118416.

13. Di Pietro M, Pascuali N, Parborell F, Abramovich D. Ovarian angiogenesis in polycystic ovary syndrome. Reproduction. 2018;155(5):R199–R209. https://doi.org/10.1530/REP-17-0597.

14. Moayeri A, Rostamzadeh A, Raoofi A, Rezaie MJ, Abasian Z, Ahmadi R. Retinoic acid and fibroblast growth factor-2 play a key role on modulation of sex hormones and apoptosis in a mouse model of polycystic ovary syndrome induced by estradiol valerate. Taiwan J Obstet Gynecol. 2020;59(6):882–890. https://doi.org/10.1016/j.tjog.2020.08.004.

15. Jankowska-Ziemak H, Kulus M, Partynska A, Kulus J, Data KP, Domagala D et al. The role of growth factors and signaling pathways in ovarian angiogenesis. Cells. 2025;14(19):1555. https://doi.org/10.3390/cells14191555.

16. Adamyan LV, Andreeva EN, Absatarova YuS, Grigoryan OR, Dedov II, Melnichenko GA et al. Russian national clinical recommendations "Polycystic ovary syndrome". Version of 2025 year. Bulletin of Reproductive Health. 2025;4(3):28–39. (In Russ.) https://doi.org/10.14341/brh12773.

17. Tosatti JAG, Magalhães FM, Gomes KB. Effects of the very low-carbohydrate ketogenic diet in women with polycystic ovary syndrome: a systematic review with meta-analysis of clinical trials. Br J Nutr. 2026;135(2):178–193. https://doi.org/10.1017/S0007114525105692.

18. Yang J, Liang J, Xu J, Lin T, Ye Q, Lin Q et al. The impact of dietary interventions on polycystic ovary syndrome patients with a BMI ≥ 25 kg/m²: a systematic review and meta-analysis of randomized controlled trials. Reprod Med Biol. 2024;23(1):e12607. https://doi.org/10.1002/rmb2.12607.

19. Gautam R, Maan P, Jyoti A, Kumar A, Malhotra N, Arora T. The role of lifestyle interventions in PCOS management: a systematic review. Nutrients. 2025;17(2):310. https://doi.org/10.3390/nu17020310.

20. Patel E. Dietary interventions for modulating the gut microbiome in PCOS management. Front Endocrinol. 2026;17:1713408. https://doi.org/10.3389/ fendo.2026.1713408.

21. Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19(1):41–47. https://doi.org/10.1093/humrep/deh098.

22. Muniyappa R, Madan R, Varghese RT, Feingold KR, Adler RA, Ahmed SF et al. Assessing insulin sensitivity and resistance in humans. Endotext. 2000. Available at: https://pubmed.ncbi.nlm.nih.gov/25905189/.

23. Frankenfield D, Roth-Yousey L, Compher C. Comparison of predictive equations for resting metabolic rate in healthy nonobese and obese adults: a systematic review. J Am Diet Assoc. 2005;105(5):775–789. https://doi.org/10.1016/j.jada.2005.02.005.

24. Dedov II, Mokrysheva NG, Melnichenko GA, Troshina EA, Mazurina NV, Ershova EV et al. Clinical recommendations «Gestational diabetes mellitus» of the Russian Ministry of Health. Version of the year 2024. Bulletin of Reproductive Health. 2025;4(2):14–30. (In Russ.) https://doi.org/10.14341/brh12763.

25. Feinman RD, Pogozelski WK, Astrup A, Bernstein RK, Fine EJ, Westman EC et al. Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base. Nutrition. 2015;31(1):1–13. https://doi.org/10.1016/j.nut.2014.06.011.

26. Tosti V, Bertozzi B, Fontana L. Health benefits of the Mediterranean diet: metabolic and molecular mechanisms. J Gerontol A Biol Sci Med Sci. 2018;73(3):318–326. https://doi.org/10.1093/gerona/glx227.

27. Pustozerov E, Popova P. Mobile-based decision support system for gestational diabetes mellitus. In: Proceedings – 2018 Ural Symposium on Biomedical Engineering, Radioelectronics and Information Technology, Usbereit 2018. Yekaterinburg, 7–8 May 2018. IEEE; 2018, pp. 45–48. https://doi.org/10.1109/USBEREIT.2018.8384546.

28. Geva E, Jaffe RB. Role of vascular endothelial growth factor in ovarian physiology and pathology. Fertil Steril. 2000;74(3):429–438. https://doi.org/10.1016/s0015-0282(00)00670-1.

29. Ferrara N. Vascular endothelial growth factor. Trends Cardiovasc Med. 1993;3(6):244–250. https://doi.org/10.1016/1050-1738(93)90046-9.

30. Agrawal R, Sladkevicius P, Engmann L, Conway GS, Payne NN, Bekis J et al. Serum vascular endothelial growth factor concentrations and ovarian stromal blood flow are increased in women with polycystic ovaries. Hum Reprod. 1998;13(3):651–655. https://doi.org/10.1093/humrep/13.3.651.

31. Resende AV, Mendes MC, de Moura MD, Mendonca HC, Gomes Premoli AC, Reis RM et al. Doppler study of the uterine arteries and ovarian stroma in patients with polycystic ovary syndrome. Gynecol Obstet Invest. 2001;52(3):153–157. https://doi.org/10.1159/000052964.

32. Abd El Aal DEM, Mohamed SA, Amine AF, Meki AR. Vascular endothelial growth factor and insulin-like growth factor-1 in polycystic ovary syndrome and their relation to ovarian blood flow. Eur J Obstet Gynecol Reprod Biol. 2005;118(2):219–224. https://doi.org/10.1016/j.ejogrb.2004.07.024.

33. Artini PG, Monti M, Matteucci C, Valentino V, Cristello F, Genazzani AR. Vascular endothelial growth factor and basic fibroblast growth factor in polycystic ovary syndrome during controlled ovarian hyperstimulation. Gynecol Endocrinol. 2006;22(8):465–470. https://doi.org/10.1080/09513590600906607.

34. Artini PG, Ruggiero M, Parisen Toldin MR, Monteleone P, Monti M, Cela V, Genazzani AR. Vascular endothelial growth factor and its soluble receptor in patients with polycystic ovary syndrome undergoing IVF. Hum Fertil. 2009;12(1):40–44. https://doi.org/10.1080/14647270802621358.

35. Scotti L, Parborell F, Irusta G, De Zuñiga I, Bisioli C, Pettorossi H et al.. Platelet-derived growth factor BB and DD and angiopoietin1 are altered in follicular fluid from polycystic ovary syndrome patients. Mol Reprod Dev. 2014;81(8):748–756. https://doi.org/10.1002/mrd.22343.

36. Di Pietro M, Scotti L, Irusta G, Tesone M, Parborell F, Abramovich D. Local administration of platelet-derived growth factor B (PDGFB) improves follicular development and ovarian angiogenesis in a rat model of polycystic ovary syndrome. Mol Cell Endocrinol. 2016;433:47–55. https://doi.org/10.1016/j.mce.2016.05.022.

37. Siregar AB, Shalihat HK, Sihite H. Impact of Mediterranean dietary patterns on metabolic, hormonal, and reproductive outcomes in women with polycystic ovary syndrome: a systematic review. Intisari Sains Medis. 2025;16(3):1406–1414. https://doi.org/10.15562/ism.v16i3.2558.

38. Barrea L, Arnone A, Annunziata G, Muscogiuri G, Laudisio D, Salzano C et al. Adherence to the Mediterranean diet, dietary patterns and body composition in women with polycystic ovary syndrome (PCOS). Nutrients. 2019;11(10):2278. https://doi.org/10.3390/nu11102278.

39. Schwingshackl L, Krause M, Schmucker C, Hoffmann G, Rücker G, Meerpohl JJ. Impact of different types of olive oil on cardiovascular risk factors: a systematic review and network meta-analysis. Nutr Metab Cardiovasc Dis. 2019;29(10):1030–1039. https://doi.org/10.1016/j.numecd.2019.07.001.

40. Anderson JW, Baird P, Davis RH Jr, Ferreri S, Knudtson M, Koraym A et al. Health benefits of dietary fiber. Nutr Rev. 2009;67(4):188–205. https://doi.org/10.1111/j.1753-4887.2009.00189.x.

41. Diha AM, Uddin MSS, Anha KM, Bekele FD, Naima J, Al-Khulaifi AAS et al. Effects of ketogenic diet (KD) on metabolic, endocrine, and reproductive outcomes in overweight/obese women with polycystic ovary syndrome (PCOS): a systematic review. Cureus. 2026;18(2):e103615. https://doi.org/10.7759/cureus.103615.