Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting women of reproductive age, characterized by a spectrum of reproductive, endocrine, and metabolic disturbances. The etiology of PCOS encompasses a complex interplay of genetic, metabolic, inflammatory, and oxidative factors, though the precise pathological mechanisms remain inadequately understood. Despite considerable variability in the clinical characteristics and biochemical profiles among individuals with PCOS, abnormalities in follicular development are a hallmark of the condition. Granulosa cells, integral to follicular development, play a pivotal role in follicle maturation. Recent studies have established a strong correlation between granulosa cell programmed cell death and follicular atresia in PCOS. This review provides a comprehensive analysis of the current understanding of granulosa cell programmed cell death and its contribution to follicular atresia within the pathophysiology of PCOS, providing a foundation for future research endeavors. Key words Follicular atresia, Hyperandrogenism, Insulin resistance, Polycystic ovary syndrome, Programmed cell death of granulosa cells.

Department of Gynecology Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine Shanghai China and

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Ajmal N, Khan SZ, Shaikh R. Polycystic ovary syndrome (PCOS) and genetic predisposition: A review article. Eur J Obstet Gynecol Reprod Biol X. 2019;3:100060. doi: 10.1016/j.eurox.2019.100060. PubMed DOI PMC

Zeng X, Xie YJ, Liu YT, Long S-L, Mo Z-C. Polycystic ovarian syndrome: Correlation between hyperandrogenism, insulin resistance and obesity. Clin Chim Acta. 2020;502:214–221. doi: 10.1016/j.cca.2019.11.003. PubMed DOI

Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, Piltonen T, et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril. 2018;110:364–379. doi: 10.1016/j.fertnstert.2018.05.004. PubMed DOI PMC

Siddiqui S, Mateen S, Ahmad R, Moin S. A brief insight into the etiology, genetics, and immunology of polycystic ovarian syndrome (PCOS) J Assist Reprod Gene. 2022;39:2439–2473. doi: 10.1007/s10815-022-02625-7. PubMed DOI PMC

Liang A, Huang L, Liu H, He W, Lei X, Li M, Li S, et al. Resveratrol Improves Follicular Development of PCOS Rats by Regulating the Glycolytic Pathway. Mol Nutr Food Res. 2021;65:e2100457. doi: 10.1002/mnfr.202100457. PubMed DOI

Chang HM, Qiao J, Leung PC. Oocyte-somatic cell interactions in the human ovary-novel role of bone morphogenetic proteins and growth differentiation factors. Hum Reprod Update. 2016;23:1–18. doi: 10.1093/humupd/dmw039. PubMed DOI PMC

Jahromi BN, Mosallanezhad Z, Matloob N, Davari M, Ghobadifar MA. The potential role of granulosa cells in the maturation rate of immature human oocytes and embryo development: A co-culture study. Clin Exp Reprod Med. 2015;42:111–117. doi: 10.5653/cerm.2015.42.3.111. PubMed DOI PMC

Wang X, Yang J, Li H, Mu H, Zeng L, Cai S, Su P, et al. miR-484 mediates oxidative stress-induced ovarian dysfunction and promotes granulosa cell apoptosis via SESN2 downregulation. Redox Biol. 2023;62:102684. doi: 10.1016/j.redox.2023.102684. PubMed DOI PMC

Kulus M, Kranc W, Sujka-Kordowska P, Mozdziak P, Jankowski M, Konverska A, Kulus J, et al. The processes of cellular growth, aging, and programmed cell death are involved in lifespan of ovarian granulosa cells during short-term IVC - Study based on animal model. Theriogenology. 2020;148:76–88. doi: 10.1016/j.theriogenology.2020.02.044. PubMed DOI

Zhang H, Risal S, Gorre N, Busayavalasa K, Li X, Shen Y, Bosbach B, et al. Somatic cells initiate primordial follicle activation and govern the development of dormant oocytes in mice. Curr Biol. 2014;24:2501–2508. doi: 10.1016/j.cub.2014.09.023. PubMed DOI

Stringer JM, Alesi LR, Winship AL, Hutt KJ. Beyond apoptosis: evidence of other regulated cell death pathways in the ovary throughout development and life. Hum Reprod Update. 2023;29:434–456. doi: 10.1093/humupd/dmad005. PubMed DOI PMC

Ketelut-Carneiro N, Fitzgerald KA. Apoptosis, Pyroptosis, and Necroptosis-Oh My! The Many Ways a Cell Can Die. J Mol Biol. 2022;434:167378. doi: 10.1016/j.jmb.2021.167378. PubMed DOI

Liu HL, Meng FX. Effect of oxidative stress on antral follicular atresia in animals and its mechanism. J Nanjing Agricult Univ. 2019;42:6–13.

Wang JP, Zhang KY. Effects of Oxidative Stress on Follicular Atresia in Poultry and Its Mechanism. Chin J Animal Nutr. 2021;33:3001–3009.

Zheng K, Yang MG, Yan CJ, et al. Mitochondrial Dynamics and Apoptosis. Chin J Cell Biol. 2019;41:1467–1476.

Rudnicka E, Kunicki M, Calik-Ksepka A, Suchta K, Duszewska A, Smolarczyk K, Smolarczyk R. Anti-Müllerian Hormone in Pathogenesis, Diagnostic and Treatment of PCOS. Int J Mol Sci. 2021;22:12507. doi: 10.3390/ijms222212507. PubMed DOI PMC

Salehi R, Mazier HL, Nivet A-L, Reunov AA, Lima P, Wang Q, Fiocco A, et al. Ovarian mitochondrial dynamics and cell fate regulation in an androgen-induced rat model of polycystic ovarian syndrome. Sci Rep. 2020;10:1021. doi: 10.1038/s41598-020-57672-w. PubMed DOI PMC

Yang YQ, Wu GX, Yang J. Research progress on the role of heat shock proteins in polycystic ovary syndrome. Prog Obst Gynecol. 2021;30:637–640.

Ni XR, Sun ZJ, Hu GH, Wang R-H. High concentration of insulin promotes apoptosis of primary cultured rat ovarian granulosa cells via its increase in extracellular HMGB1. Reprod Sci. 2015;22:271–277. doi: 10.1177/1933719114549852. PubMed DOI

Liu XS, Qiao YY. Research on the progress about the pathogenesis of spontaneous abortion in patients with polycystic ovary syndrome. Chin J Birth Health Hered. 2021;29:1034–1039.

Zhang Q, Ren J, Wang F, Pan M, Cui L, Li M, Qu F. Mitochondrial and glucose metabolic dysfunctions in granulosa cells induce impaired oocytes of polycystic ovary syndrome through Sirtuin 3. Free Radic Biol Med. 2022;187:1–16. doi: 10.1016/j.freeradbiomed.2022.05.010. PubMed DOI

Ma Y, Zheng L, Wang Y, Gao Y, Xu Y. Arachidonic Acid in Follicular Fluid of PCOS Induces Oxidative Stress in a Human Ovarian Granulosa Tumor Cell Line (KGN) and Upregulates GDF15 Expression as a Response. Front Endocrinol (Lausanne) 2022;13:865748. doi: 10.3389/fendo.2022.865748. PubMed DOI PMC

Sun BY, Han SY. Research progress on the relationship between chronic low-grade inflammation and polycystic ovary syndrome. Chin J Birth Health Hered. 2022;30:161–164.

Wang D, Weng Y, Zhang Y, Wang R, Wang T, Zhou J, Shen S, et al. Exposure to hyperandrogen drives ovarian dysfunction and fibrosis by activating the NLRP3 inflammasome in mice. Sci Total Environ. 2020;745:141049. doi: 10.1016/j.scitotenv.2020.141049. PubMed DOI

Zhang XL, Li Y, Liu L, Wang Z, Xu F. Effect of Inflammatory Markers on the Expression of P53, Bax, Caspase-3, Bcl-2 and Survivin in Human Granulosa Cells. J Pract Obst Gynecol. 2016;32:519–522.

La Merrill MA, Vandenberg LN, Smith MT, Goodson W, Browne P, Patisaul HB, Guyton KZ, et al. Consensus on the key characteristics of endocrine-disrupting chemicals as a basis for hazard identification. Nat Rev Endocrinol. 2020;16:45–57. doi: 10.1038/s41574-019-0273-8. PubMed DOI PMC

Akgül S, Sur Ü, Düzçeker Y, Balcı A, Kızılkan MP, Kanbur N, Bozdağ G, et al. Bisphenol A and phthalate levels in adolescents with polycystic ovary syndrome. Gynecol Endocrinol. 2019;35:1084–1087. doi: 10.1080/09513590.2019.1630608. PubMed DOI

Luo Y, Nie Y, Tang L, Xu CC, Xu L. The correlation between UDP-glucuronosyltransferase polymorphisms and environmental endocrine disruptors levels in polycystic ovary syndrome patients. Medicine (Baltimore) 2020;99:e19444. doi: 10.1097/MD.0000000000019444. PubMed DOI PMC

Wang Y, Zhu Q, Dang X, He Y, Li X, Sun Y. Local effect of bisphenol A on the estradiol synthesis of ovarian granulosa cells from PCOS. Gynecol Endocrinol. 2017;33:21–25. doi: 10.1080/09513590.2016.1184641. PubMed DOI

Zhan W, Tang W, Shen X, Xu H, Zhang J. Exposure to bisphenol A and its analogs and polycystic ovarian syndrome in women of childbearing age: A multicenter case-control study. Chemosphere. 2023;313:137463. doi: 10.1016/j.chemosphere.2022.137463. PubMed DOI

Al-Saleh I. The relationship between urinary phthalate metabolites and polycystic ovary syndrome in women undergoing in vitro fertilization: Nested case-control study. Chemosphere. 2022;286:131495. doi: 10.1016/j.chemosphere.2021.131495. PubMed DOI

Milankov A, Milanović M, Milošević N, Sudji J, Pejaković S, Milić N, Bjelica A, Stojanoska MM. The effects of phthalate exposure on metabolic parameters in polycystic ovary syndrome. Clin Chim Acta. 2023;540:117225. doi: 10.1016/j.cca.2023.117225. PubMed DOI

Zhan W, Qiu W, Ao Y, Zhou W, Sun Y, Zhao H, Zhang J. Environmental Exposure to Emerging Alternatives of Per- and Polyfluoroalkyl Substances and Polycystic Ovarian Syndrome in Women Diagnosed with Infertility: A Mixture Analysis. Environ Health Perspect. 2023;131:57001. doi: 10.1289/EHP11814. PubMed DOI PMC

Gu J, Yuan T, Ni N, Ma Y, Shen Z, Yu X, Shi R, et al. Urinary concentration of personal care products and polycystic ovary syndrome: A case-control study. Environ Res. 2019;168:48–53. doi: 10.1016/j.envres.2018.09.014. PubMed DOI

Guo Z, Qiu H, Wang L, Wang L, Wang C, Chen M, Zuo Z. Association of serum organochlorine pesticides concentrations with reproductive hormone levels and polycystic ovary syndrome in a Chinese population. Chemosphere. 2017;171:595–600. doi: 10.1016/j.chemosphere.2016.12.127. PubMed DOI

Prabhu NB, Adiga D, Kabekkodu SP, Bhat SK, Satyamoorthy K, Rai PS. Bisphenol A exposure modulates reproductive and endocrine system, mitochondrial function and cellular senescence in female adult rats: A hallmarks of polycystic ovarian syndrome phenotype. Environ Toxicol Pharmacol. 2022;96:104010. doi: 10.1016/j.etap.2022.104010. PubMed DOI

Yan W, Li M, Guo Q, Li X, Zhou S, Dai J, Zhang J, et al. Chronic exposure to propylparaben at the humanly relevant dose triggers ovarian aging in adult mice. Ecotoxicol Environ Saf. 2022;235:113432. doi: 10.1016/j.ecoenv.2022.113432. PubMed DOI

Liu J, Wang W, Zhu J, Li Y, Luo L, Huang Y, Zhang W. Di(2-ethylhexyl) phthalate (DEHP) influences follicular development in mice between the weaning period and maturity by interfering with ovarian development factors and microRNAs. Environ Toxicol. 2018;33:535–544. doi: 10.1002/tox.22540. PubMed DOI

Sun J, Gan L, Lv S, Wang T, Dai C, Sun J. Exposure to Di-(2-Ethylhexyl) phthalate drives ovarian dysfunction by inducing granulosa cell pyroptosis via the SLC39A5/NF-κB/NLRP3 axis. Ecotoxicol Environ Saf. 2023;252:114625. doi: 10.1016/j.ecoenv.2023.114625. PubMed DOI

Lin M, Hua R, Ma J, Zhou Y, Li P, Xu X, Yu Z, Quan S. Bisphenol A promotes autophagy in ovarian granulosa cells by inducing AMPK/mTOR/ULK1 signalling pathway. Environ Int. 2021;147:106298. doi: 10.1016/j.envint.2020.106298. PubMed DOI

Du J, Ruan X, Jin F, Li Y, Cheng J, Gu M, Mueck AO. Abnormalities of early folliculogenesis and serum anti-Müllerian hormone in Chinese patients with polycystic ovary syndrome. J Ovarian Res. 2021;14:36. doi: 10.1186/s13048-021-00786-0. PubMed DOI PMC

Cozzolino M, Herraiz S, Titus S, Roberts L, Romeu M, Peinado I, Scott RT, et al. Transcriptomic landscape of granulosa cells and peripheral blood mononuclear cells in women with PCOS compared to young poor responders and women with normal response. Hum Reprod. 2022;37:1274–1286. doi: 10.1093/humrep/deac069. PubMed DOI PMC

Cheng M, Song Z, Guo Y, Luo X, Li X, Wu X, Gong Y. 1α,25-Dihydroxyvitamin D(3) Improves Follicular Development and Steroid Hormone Biosynthesis by Regulating Vitamin D Receptor in the Layers Model. Curr Issues Mol Biol. 2023;45:4017–4034. doi: 10.3390/cimb45050256. PubMed DOI PMC

Wan T, Sun H, Mao Z, Zhang L, Chen X, Shi Y, Shang Y. Vitamin D deficiency inhibits microRNA-196b-5p which regulates ovarian granulosa cell hormone synthesis, proliferation, and apoptosis by targeting RDX and LRRC17. Ann Transl Med. 2021;9:1775. doi: 10.21037/atm-21-6081. PubMed DOI PMC

Lejman-Larysz K, Golara A, Baranowska M, Kozłowski M, Guzik P, Szydłowska I, Nawrocka-Rutkowska J, et al. Influence of Vitamin D on the Incidence of Metabolic Syndrome and Hormonal Balance in Patients with Polycystic Ovary Syndrome. Nutrients. 2023;15:2952. doi: 10.3390/nu15132952. PubMed DOI PMC

Wu R-X, Dong Y-Y, Yang P-W, Wang L, Deng Y-H, Zhang H-W, Huang X-Y. CD36- and obesity-associated granulosa cells dysfunction. Reprod Fertil Dev. 2019;31:993–1001. doi: 10.1071/RD18292. PubMed DOI

Chen X, Liu Y, Shan Y, Jin X, Shi Q, Jia C. Oxidized low-density lipoprotein suppresses mouse granulosa cell differentiation through disruption of the hypoxia-inducible factor 1 pathway. Mol Reprod Dev. 2017;84:1306–1313. doi: 10.1002/mrd.22933. PubMed DOI

Lin X-H, Wang H, Wu D-D, Ullah K, Yu T-T, Rahman TU, Huang H-F. High Leptin Level Attenuates Embryo Development in Overweight/Obese Infertile Women by Inhibiting Proliferation and Promotes Apoptosis in Granule Cell. Horm Metab Res. 2017;49:534–541. doi: 10.1055/s-0043-107617. PubMed DOI

Lou Y, Yu W, Han L, Yang S, Wang Y, Ren T, Yu J, Zhao A. ROS activates autophagy in follicular granulosa cells via mTOR pathway to regulate broodiness in goose. Anim Reprod Sci. 2017;185:97–103. doi: 10.1016/j.anireprosci.2017.08.008. PubMed DOI

Debnath J, Gammoh N, Ryan KM. Autophagy and autophagy-related pathways in cancer. Nat Rev Mol Cell Biol. 2023;24:560–575. doi: 10.1038/s41580-023-00585-z. PubMed DOI PMC

Zhou J, Peng X, Mei S. Autophagy in Ovarian Follicular Development and Atresia. Int J Biol Sci. 2019;15:726–737. doi: 10.7150/ijbs.30369. PubMed DOI PMC

Xu D, Jiang X, He H, Liu D, Yang L, Chen H, Wu L, et al. SIRT2 functions in aging, autophagy, and apoptosis in post-maturation bovine oocytes. Life Sci. 2019;232:116639. doi: 10.1016/j.lfs.2019.116639. PubMed DOI

Escobar ML, Echeverria OM, Palacios-Martínez S, Juárez-Chavero S, Sánchez-Sánchez L, Vázquez-Nin GH. Beclin 1 Interacts With Active Caspase-3 and Bax in Oocytes From Atretic Follicles in the Rat Ovary. J Histochem Cytochem. 2019;67:873–889. doi: 10.1369/0022155419881127. PubMed DOI PMC

Li X, Qi J, Zhu Q, He Y, Wang Y, Lu Y, Wu H, Sun Y. The role of androgen in autophagy of granulosa cells from PCOS. Gynecol Endocrinol. 2019;35:669–672. doi: 10.1080/09513590.2018.1540567. PubMed DOI

Xing J, Qiao G, Luo X, Liu S, Chen S, Ye G, Zhang C, Yi J. Ferredoxin 1 regulates granulosa cell apoptosis and autophagy in polycystic ovary syndrome. Clin Sci (Lond) 2023;137:453–468. doi: 10.1042/CS20220408. PubMed DOI

Stockwell BR. Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell. 2022;185:2401–2421. doi: 10.1016/j.cell.2022.06.003. PubMed DOI PMC

Martínez-García MA, Luque-Ramírez M, San-Millán JL, Escobar-Morreale HF. Body iron stores and glucose intolerance in premenopausal women: role of hyperandrogenism, insulin resistance, and genomic variants related to inflammation, oxidative stress, and iron metabolism. Diabetes Care. 2009;32:1525–1530. doi: 10.2337/dc09-0420. PubMed DOI PMC

Escobar-Morreale HF, Luque-Ramírez M, Alvarez-Blasco F, Botella-Carretero, Sancho J, San Millán JL. Body iron stores are increased in overweight and obese women with polycystic ovary syndrome. Diabetes Care. 2005;28:2042–2044. doi: 10.2337/diacare.28.8.2042. PubMed DOI

Escobar-Morreale HF, Luque-Ramírez M.Role of androgen-mediated enhancement of erythropoiesis in the increased body iron stores of patients with polycystic ovary syndrome Fertil Steril 2011951730–1735.e1.10.1016/j.fertnstert.2011.01.038 PubMed DOI

Escobar-Morreale HF, San Millán JL. Abdominal adiposity and the polycystic ovary syndrome. Trends Endocrinol Metab. 2007;18:266–272. doi: 10.1016/j.tem.2007.07.003. PubMed DOI

Zhang L, Wang F, Li D, Yan Y, Wang H. Transferrin receptor-mediated reactive oxygen species promotes ferroptosis of KGN cells via regulating NADPH oxidase 1/PTEN induced kinase 1/acyl-CoA synthetase long chain family member 4 signaling. Bioengineered. 2021;12:4983–4994. doi: 10.1080/21655979.2021.1956403. PubMed DOI PMC

Huang X, Geng H, Liang C, Xiong X, Du X, Zhuan Q, Liu Z, et al. Leonurine restrains granulosa cell ferroptosis through SLC7A11/GPX4 axis to promote the treatment of polycystic ovary syndrome. Free Radic Biol Med. 2025;226:330–347. doi: 10.1016/j.freeradbiomed.2024.11.021. PubMed DOI

Zhang Y, Hu M, Jia W, Liu G, Zhang J, Wang B, Li J, et al. Hyperandrogenism and insulin resistance modulate gravid uterine and placental ferroptosis in PCOS-like rats. J Endocrinol. 2020;246:247–263. doi: 10.1530/JOE-20-0155. PubMed DOI

Zhang D, Yi S, Cai B, Wang Z, Chen M, Zheng Z, Zhou C. Involvement of ferroptosis in the granulosa cells proliferation of PCOS through the circRHBG/miR-515/SLC7A11 axis. Ann Transl Med. 2021;9:1348. doi: 10.21037/atm-21-4174. PubMed DOI PMC

Snyder AG, Oberst A. The Antisocial Network: Cross Talk Between Cell Death Programs in Host Defense. Annu Rev Immunol. 2021;39:77–101. doi: 10.1146/annurev-immunol-112019-072301. PubMed DOI PMC

Ying Y, Padanilam BJ. Regulation of necrotic cell death: p53, PARP1 and cyclophilin D-overlapping pathways of regulated necrosis? Cell Mol Life Sci. 2016;73:2309–2324. doi: 10.1007/s00018-016-2202-5. PubMed DOI PMC

Wakizoe E, Ashizawa K, Sakamoto SH, Hemmi K, Kobayashi I, Tsuzuki Y. The effects of extracellular ATP and its receptor antagonists on pig oocytes during in vitro maturation. Zygote. 2015;23:885–892. doi: 10.1017/S0967199414000598. PubMed DOI

Blohberger J, Kunz L, Einwang D, Berg U, Berg D, Ojeda SR, Dissen GA, et al. Readthrough acetylcholinesterase (AChE-R) and regulated necrosis: pharmacological targets for the regulation of ovarian functions? Cell Death Dis. 2015;6:e1685. doi: 10.1038/cddis.2015.51. PubMed DOI PMC

Ding J, Wang K, Liu W, She Y, Sun Q, Shi J, Sun H, et al. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature. 2016;535:111–116. doi: 10.1038/nature18590. PubMed DOI

Xiang Y, Ding HM, Chen T, Xu TY, Ge HS. Hyperandrogenism affects ovarian granulosa cell proliferation by inducing pyroptosis. J Repr Med. 2023;32:1399–1406.

Xu R, Zhao H, Qi J, Yao G, He Y, Lu Y, Zhu Q, et al. Local glucose elevation activates pyroptosis via NLRP3 inflammasome in ovarian granulosa cells of overweight patients. FASEB J. 2023;37:e22807. doi: 10.1096/fj.202201796RR. PubMed DOI