The Complex Landscape of Polycystic Ovarian Syndrome: From Causes to Cutting-Edge Treatments
Abstract
Polycystic ovarian syndrome (PCOS), or hyperandrogenic anovulation (HA), is a common endocrine condition in 4-10% of women of reproductive age globally. PCOS is diagnosed when these symptoms substantially compromise the quality of life. The etiology of the condition is multifactorial and includes genetic and environmental causes such as hormonal dysregulation, chronic low-grade inflammation, insulin resistance, and hyperandrogenism. These disrupt folliculogenesis and heighten the potential for comorbidities such as type II diabetes and endometrial cancer.
New research points to dysbiosis of gut microbiota in the pathophysiology of PCOS, with disturbed microbial patterns playing a role in metabolic and hormonal dysfunction. Microbiota-directed therapy, including fecal microbiota transplantation (FMT), probiotics, synbiotics, and prebiotics, have been found to have promise in enhancing hormonal homeostasis and decreasing inflammation.
This review summarizes the risk factors affecting PCOS development, prevalence, and modulation and discusses novel therapeutic approaches such as IL-22 and miRNA therapy. It highlights the importance of gut dysbiosis and examines microbiota-based treatments that may assist in the management of the heterogeneous phenotypes of PCOS, providing new directions for enhancing patient outcomes
Downloads
References
El Hayek S, Bitar L, Hamdar LH, Mirza FG, Daoud G. Polycystic ovarian syndrome: an updated overview. Frontiers in physiology. 2016 Apr 5; 7:124.
Motlagh Asghari K, Nejadghaderi SA, Alizadeh M, Sanaie S, Sullman MJ, Kolahi AA, Avery J, Safiri S. Burden of polycystic ovary syndrome in the Middle East and North Africa region, 1990–2019. Scientific Reports. 2022 Apr 29;12(1):7039.
Balen AH, Tan SL, MacDougall J, Jacobs HS. Miscarriage rates following in-vitro fertilization are increased in women with polycystic ovaries and reduced by pituitary desensitization with buserelin. Human Reproduction. 1993 Jun 1;8(6):959-64.
Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO. The prevalence and features of polycystic ovary syndrome in an unselected population. The Journal of Clinical Endocrinology & Metabolism. 2004 Jun 1;89(6):2745-9.
Bharathi RV, Swetha S, Neerajaa J, Madhavica JV, Janani DM, Rekha SN, Ramya S, Usha B. An epidemiological survey: Effect of predisposing factors for PCOS in Indian urban and rural population. Middle East Fertility Society Journal. 2017 Dec 1;22(4):313-6.
Bremer AA. Polycystic ovary syndrome in the pediatric population. Metabolic syndrome and related disorders. 2010 Oct 1;8(5):375-94.
Azziz R, Marin C, Hoq L, Badamgarav E, Song P. Health care-related economic burden of the polycystic ovary syndrome during the reproductive life span. The Journal of Clinical Endocrinology & Metabolism. 2005 Aug 1;90(8):4650-8.
Liu J, Wu Q, Hao Y, Jiao M, Wang X, Jiang S, Han L. Measuring the global disease burden of polycystic ovary syndrome in 194 countries: Global Burden of Disease Study 2017. Human Reproduction. 2021 Apr 1;36(4):1108-19.
Hashemipour M, Amini M, Iranpour R, Sadri GH, Javaheri N, Haghighi S, Hovsepian S, Javadi AA, Nematbakhsh M, Sattari G. Prevalence of congenital hypothyroidism in Isfahan, Iran: results of a survey on 20,000 neonates. Hormone research. 2004 Sep 1;62(2):79-83.
Lujan ME, Chizen DR, Pierson RA. Diagnostic criteria for polycystic ovary syndrome: pitfalls and controversies. Journal of obstetrics and gynecology Canada. 2008 Aug 1;30(8):671-9.
Batra M, Bhatnager R, Kumar A, Suneja P, Dang AS. The interplay between PCOS and microbiome: The road less traveled. American Journal of Reproductive Immunology. 2022 Aug;88(2): e13580.
Merkin SS, Phy JL, Sites CK, Yang D. Environmental determinants of polycystic ovary syndrome. Fertility and sterility. 2016 Jul 1;106(1):16-24.
Ibáñez L, Oberfield SE, Witchel S, Auchus RJ, Chang RJ, Codner E, Dabadghao P, Darendeliler F, Elbarbary NS, Gambineri A, Garcia Rudaz C. An international consortium update: pathophysiology, diagnosis, and treatment of polycystic ovarian syndrome in adolescence. Hormone research in pediatrics. 2017 Jun 1;88(6):371-95.
Mumusoglu S, Yildiz BO. Polycystic ovary syndrome phenotypes and prevalence: differential impact of diagnostic criteria and clinical versus unselected population. Current Opinion in Endocrine and Metabolic Research. 2020 Jun 1; 12:66-71.
Witchel SF, Oberfield SE, Peña AS. Polycystic ovary syndrome: pathophysiology, presentation, and treatment with emphasis on adolescent girls. Journal of the Endocrine Society. 2019 Aug;3(8):1545-73.
Singh S, Pal N, Shubham S, Sarma DK, Verma V, Marotta F, Kumar M. Polycystic ovary syndrome: etiology, current management, and future therapeutics. Journal of Clinical Medicine. 2023 Feb 11;12(4):1454.
Bulsara J, Patel P, Soni A, Acharya S. A review: brief insight into polycystic ovarian syndrome. Endocrine and Metabolic Science. 2021 Jun 30; 3:100085.
Walters KA, Gilchrist RB, Ledger WL, Teede HJ, Handelsman DJ, Campbell RE. New perspectives on the pathogenesis of PCOS: neuroendocrine origins. Trends in Endocrinology & Metabolism. 2018 Dec 1;29(12):841-52.
Kanbour SA, Dobs AS. Hyperandrogenism in women with polycystic ovarian syndrome: Pathophysiology and controversies. Androgens: Clinical Research and Therapeutics. 2022 Mar 1;3(1):22-30.
Barrea L, Marzullo P, Muscogiuri G, Di Somma C, Scacchi M, Orio F, Amaretti G, Colao A, Savastano S. Source and amount of carbohydrate in the diet and inflammation in women with polycystic ovary syndrome. Nutrition research reviews. 2018 Dec;31(2):291-301.
Ding H, Zhang J, Zhang F, Zhang S, Chen X, Liang W, Xie Q. Resistance to the insulin and elevated level of androgen: A major cause of polycystic ovary syndrome. Frontiers in endocrinology. 2021 Oct 20; 12:741764. Kandaraki E, Chatzigeorgiou A, Livadas S, Palioura E, Economou F, Koutsilieris M, Palimeri S, Panidis D, Diamanti-Kandarakis E. Endocrine disruptors and polycystic ovary syndrome (PCOS): elevated serum levels of bisphenol A in women with PCOS. The Journal of Clinical Endocrinology & Metabolism. 2011 Mar 1;96(3): E480-4.
Konieczna A, Rachoń D, Owczarek K, Kubica P, Kowalewska A, Kudłak B, Wasik A, Namieśnik J. Serum bisphenol A concentrations correlate with serum testosterone levels in women with polycystic ovary syndrome. Reproductive Toxicology. 2018 Dec 1; 82:32-7.
Vagi SJ, Azziz-Baumgartner E, Sjödin A, Calafat AM, Dumesic D, Gonzalez L, Kato K, Silva MJ, Ye X, Azziz R. Exploring the potential association between brominated diphenyl ethers, polychlorinated biphenyls, organochlorine pesticides, perfluorinated compounds, phthalates, and bisphenol a in polycystic ovary syndrome: A case–control study. BMC endocrine disorders. 2014 Dec; 14:1-2.
Priya K, Setty M, Babu UV, Pai KS. Implications of environmental toxicants on ovarian follicles: how they can adversely affect female fertility? Environmental Science and Pollution Research. 2021 Dec;28(48):67925-39.
Anantha Subramanian P, Ananth S, Kumaraguru S, Barathi S, Santosh W, Vasantharekha R. Associated effects of endocrine disrupting chemicals (EDCs) on neuroendocrine axes and neurotransmitter profile in polycystic ovarian syndrome condition. In Proceedings of the Zoological Society 2021 Dec (pp. 1-9). Springer India.
Palioura E, Diamanti-Kandarakis E. Polycystic ovary syndrome (PCOS) and endocrine disrupting chemicals (EDCs). Reviews in Endocrine and Metabolic Disorders. 2015 Dec;16(4):365-71.
Zhang B, Zhou W, Shi Y, Zhang J, Cui L, Chen ZJ. Lifestyle and environmental contributions to ovulatory dysfunction in women of polycystic ovary syndrome. BMC endocrine disorders. 2020 Dec; 20:1-7.
Victor VM, Rocha M, Banuls C, Alvarez A, de Pablo C, Sanchez-Serrano M, Gomez M, Hernandez-Mijares A. Induction of oxidative stress and human leukocyte/endothelial cell interactions in polycystic ovary syndrome patients with insulin resistance. The Journal of Clinical Endocrinology & Metabolism. 2011 Oct 1;96(10):3115-22.
Yang Q, Zhao Y, Qiu X, Zhang C, Li R, Qiao J. Association of serum levels of typical organic pollutants with polycystic ovary syndrome (PCOS): a case–control study. Human Reproduction. 2015 Aug 1;30(8):1964-73.
Lin SY, Yang YC, Chang CY, Lin CC, Hsu WH, Ju SW, Hsu CY, Kao CH. Risk of polycystic ovary syndrome in women exposed to fine air pollutants and acidic gases: a nationwide cohort analysis. International Journal of Environmental Research and Public Health. 2019 Dec;16(23):4816.
Nilsson E, Klukovich R, Sadler-Riggleman I, Beck D, Xie Y, Yan W, Skinner MK. Environmental toxicant induced epigenetic transgenerational inheritance of ovarian pathology and granulosa cell epigenome and transcriptome alterations: ancestral origins of polycystic ovarian syndrome and primary ovarian insufficiency. Epigenetics. 2018 Aug 3;13(8):875-95.
Kazemi M, Hadi A, Pierson RA, Lujan ME, Zello GA, Chilibeck PD. Effects of dietary glycemic index and glycemic load on cardiometabolic and reproductive profiles in women with polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials. Advances in Nutrition. 2021 Jan 1;12(1):161-78.
González F, Considine RV, Abdelhadi OA, Acton AJ. Saturated fat ingestion promotes lipopolysaccharide-mediated inflammation and insulin resistance in polycystic ovary syndrome. The Journal of Clinical Endocrinology & Metabolism. 2019 Mar;104(3):934-46.
Wang T, Sha L, Li Y, Zhu L, Wang Z, Li K, Lu H, Bao T, Guo L, Zhang X, Wang H. Dietary α-Linolenic acid-rich flaxseed oil exerts beneficial effects on polycystic ovary syndrome through sex steroid hormones—microbiota—inflammation axis in rats. Frontiers in endocrinology. 2020 May 27; 11:284.
Barber TM, Hanson P, Weickert MO, Franks S. Obesity and polycystic ovary syndrome: implications for pathogenesis and novel management strategies. Clinical Medicine Insights: Reproductive Health. 2019 Sep; 13:1179558119874042.
Glueck CJ, Goldenberg N. Characteristics of obesity in polycystic ovary syndrome: Etiology, treatment, and genetics. Metabolism. 2019 Mar 1;92:108-20.
Barber TM, Kabisch S, Pfeiffer AF, Weickert MO. The health benefits of dietary fibre. Nutrients. 2020 Oct 21;12(10):3209.
Hoover SE, Gower BA, Cedillo YE, Chandler-Laney PC, Deemer SE, Goss AM. Changes in ghrelin and glucagon following a low glycemic load diet in women with PCOS. The Journal of Clinical Endocrinology & Metabolism. 2021 May 1;106(5):e2151-61.
Akintayo CO, Johnson AD, Badejogbin OC, Olaniyi KS, Oniyide AA, Ajadi IO, Ojewale AO, Adeyomoye OI, Kayode AB. High fructose-enriched diet synergistically exacerbates endocrine but not metabolic changes in letrozole-induced polycystic ovarian syndrome in Wistar rats. Heliyon. 2021 Jan 1;7(1).
Porchia LM, Hernandez-Garcia SC, Gonzalez-Mejia ME, López-Bayghen E. Diets with lower carbohydrate concentrations improve insulin sensitivity in women with polycystic ovary syndrome: a meta-analysis. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2020 May 1; 248:110-7.
Shishehgar F, Mirmiran P, Rahmati M, Tohidi M, Ramezani Tehrani F. Does a restricted energy low glycemic index diet have a different effect on overweight women with or without polycystic ovary syndrome. BMC endocrine disorders. 2019 Dec; 19:1-1.
Paoli A, Mancin L, Giacona MC, Bianco A, Caprio M. Effects of a ketogenic diet in overweight women with polycystic ovary syndrome. Journal of translational medicine. 2020 Dec; 18:1-1.
Kshetrimayum C, Sharma A, Mishra VV, Kumar S. Polycystic ovarian syndrome: Environmental/occupational, lifestyle factors; an overview. Journal of the Turkish German Gynecological Association. 2019 Nov 28;20(4):255.
Szczuko M, Kikut J, Szczuko U, Szydłowska I, Nawrocka-Rutkowska J, Ziętek M, Verbanac D, Saso L. Nutrition strategy and life style in polycystic ovary syndrome—narrative review. Nutrients. 2021 Jul 18;13(7):2452.
Patten RK, Boyle RA, Moholdt T, Kiel I, Hopkins WG, Harrison CL, Stepto NK. Exercise interventions in polycystic ovary syndrome: a systematic review and meta-analysis. Frontiers in physiology. 2020 Jul 7; 11:606.
Kumar R, Minerva S, Shah R, Bhat A, Verma S, Chander G, Bhat GR, Thapa N, Bhat A, Wakhloo A, Ganie MA. Role of genetic, environmental, and hormonal factors in the progression of PCOS: A review. J. Reprod. Healthc. Med. 2022;3(3):3.
Khan MJ, Ullah A, Basit S. Genetic basis of polycystic ovary syndrome (PCOS): current perspectives. The application of clinical genetics. 2019 Dec 24:249-60.
Ajmal N, Khan SZ, Shaikh R. Polycystic ovary syndrome (PCOS) and genetic predisposition: A review article. European journal of obstetrics & gynecology and reproductive biology: X. 2019 Jul 1; 3:100060.
Singh S, Sharma P, Pal N, Kumawat M, Shubham S, Sarma DK, Tiwari RR, Kumar M, Nagpal R. Impact of environmental pollutants on gut microbiome and mental health via the gut–brain axis. Microorganisms. 2022 Jul 19;10(7):1457.
Yurtdaş G, Akdevelioğlu Y. A new approach to polycystic ovary syndrome: the gut microbiota. Journal of the American College of Nutrition. 2020 May 18;39(4):371-82.
Rizk MG, Thackray VG. Intersection of polycystic ovary syndrome and the gut microbiome. Journal of the Endocrine Society. 2021 Feb;5(2): bvaa177.
Tremellen K, Pearce K. Dysbiosis of gut microbiota (DOGMA)–a novel theory for the development of polycystic ovarian syndrome. Medical hypotheses. 2012 Jul 1;79(1):104-12.
Martin, K.A.; Chang, R.J.; Ehrmann, D.A.; Ibanez, L.; Lobo, R.A.; Rosenfield, R.L.; Shapiro, J.; Montori, V.M.; Swiglo, B.A. Evaluation and treatment of hirsutism in premenopausal women: An endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 2008, 93, 1105–1120.
ESHRE TR, ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertility and sterility. 2004 Jan 1;81(1):19-25.
Rashid R, Mir SA, Kareem O, Ali T, Ara R, Malik A, Amin F, Bader GN. Polycystic ovarian syndrome-current pharmacotherapy and clinical implications. Taiwanese Journal of Obstetrics and Gynecology. 2022 Jan 1;61(1):40-50.
Zimmerman Y, Eijkemans MJ, Coelingh Bennink HJ, Blankenstein MA, Fauser BC. The effect of combined oral contraception on testosterone levels in healthy women: a systematic review and meta-analysis. Human reproduction update. 2014 Jan 1;20(1):76-105.
Rodriguez Paris V, Bertoldo MJ. The mechanism of androgen actions in PCOS etiology. Medical sciences. 2019 Aug 28;7(9):89.
Calaf J, Lopez E, Millet A, Alcañiz J, Fortuny A, Vidal O, Callejo J, Escobar-Jimenez F, Torres E, Espinos JJ. Long-term efficacy and tolerability of flutamide combined with oral contraception in moderate to severe hirsutism: a 12-month, double-blind, parallel clinical trial. The Journal of Clinical Endocrinology & Metabolism. 2007 Sep 1;92(9):3446-52.
Paradisi R, Fabbri R, Battaglia C, Venturoli S. Ovulatory effects of flutamide in the polycystic ovary syndrome. Gynecological Endocrinology. 2013 Apr 1;29(4):391-5.
Diamanti-Kandarakis E, Mitrakou A, Raptis S, Tolis G, Duleba AJ. The effect of a pure antiandrogen receptor blocker, flutamide, on the lipid profile in the polycystic ovary syndrome. The Journal of Clinical Endocrinology & Metabolism. 1998 Aug 1;83(8):2699-705.
Badawy A, Elnashar A. Treatment options for polycystic ovary syndrome. International journal of women's health. 2011 Feb 8:25-35.
Zulian E, Sartorato P, Benedini S, Baro G, Armanini D, Mantero F, Scaroni C. Spironolactone in the treatment of polycystic ovary syndrome: effects on clinical features, insulin sensitivity and lipid profile. Journal of endocrinological investigation. 2005 Mar; 28:49-53.
Tartagni MV, Alrasheed H, Damiani GR, Montagnani M, Maria A, De Pergola G, Tartagni M, Loverro G. Intermittent low-dose finasteride administration is effective for treatment of hirsutism in adolescent girls: a pilot study. Journal of pediatric and adolescent gynecology. 2014 Jun 1;27(3):161-5.
Lakryc EM, Motta EL, Soares JM, Haidar MA, Rodrigues de Lima G, Baracat EC. The benefits of finasteride for hirsute women with polycystic ovary syndrome or idiopathic hirsutism. Gynecological endocrinology. 2003 Jan 1;17(1):57-63.
Abdalla MA, Deshmukh H, Atkin S, Sathyapalan T. A review of therapeutic options for managing the metabolic aspects of polycystic ovary syndrome. Therapeutic advances in endocrinology and metabolism. 2020 Jul; 11:2042018820938305.
Grundy SM. Obesity, metabolic syndrome, and coronary atherosclerosis. Circulation. 2002 Jun 11;105(23):2696-8.
Curi DD, Fonseca AM, Marcondes JA, Almeida JA, Bagnoli VR, Soares Jr JM, Baracat EC. Metformin versus lifestyle changes in treating women with polycystic ovary syndrome. Gynecological Endocrinology. 2012 Mar 1;28(3):182-5.
Fleming R, Hopkinson ZE, Wallace AM, Greer IA, Sattar N. Ovarian function and metabolic factors in women with oligomenorrhea treated with metformin in a randomized double-blind placebo-controlled trial. The Journal of Clinical Endocrinology & Metabolism. 2002 Feb 1;87(2):569-74.
Ng EH, Wat NM, Ho PC. Effects of metformin on ovulation rate, hormonal and metabolic profiles in women with clomiphene-resistant polycystic ovaries: a randomized, double-blinded placebo-controlled trial. Human Reproduction. 2001 Aug 1;16(8):1625-31.
Madnani N, Khan K, Chauhan P, Parmar G. Polycystic ovarian syndrome. Indian journal of dermatology, venereology and leprology. 2013 May 1; 79:310.
Xu Y, Wu Y, Huang Q. Comparison of the effect between pioglitazone and metformin in treating patients with PCOS: a meta-analysis. Archives of gynecology and obstetrics. 2017 Oct; 296:661-77.
Zhao H, Xing C, Zhang J, He B. Comparative efficacy of oral insulin sensitizers metformin, thiazolidinediones, inositol, and berberine in improving endocrine and metabolic profiles in women with PCOS: a network meta-analysis. Reproductive health. 2021 Dec;18:1-2.
Christin-Maitre, S.; Hugues, J.N. A comparative randomized multicentric study comparing the step-up versus step-down protocol in polycystic ovary syndrome. Hum. Reprod. 2003, 18, 1626–1631.
Gysler, M.; March, C.M.; Mishell, D.R., Jr.; Bailey, E.J. A decade’s experience with an individualized clomiphene treatment regimen including its effect on the postcoital test. Fertil. Steril. 1982, 37, 161–167.
Casper, R.F.; Mitwally, M.F. Use of the aromatase inhibitor letrozole for ovulation induction in women with polycystic ovarian syndrome. Clin. Obstet. Gynecol. 2011, 54, 685–695.
Carroll, N.; Palmer, J.R. A comparison of intrauterine versus intracervical insemination in fertile single women. Fertil. Steril. 2001, 75, 656–660.
Lin, M.W.; Wu, M.H. The role of vitamin D in polycystic ovary syndrome. Indian J. Med. Res. 2015, 142, 238–240.
dehghani Firouzabadi, R.; Aflatoonian, A.; Modarresi, S.; Sekhavat, L.; MohammadTaheri, S. Therapeutic effects of calcium & vitamin D supplementation in women with PCOS. Complement. Ther. Clin. Pract. 2012, 18, 85–88.
Rashidi, B.; Haghollahi, F.; Shariat, M.; Zayerii, F.J. The effects of calcium-vitamin D and metformin on polycystic ovary syndrome: A pilot study. Eur. J. Obstet. Gynecol. Reprod. Biol. 2009, 48, 142–147.
Irani, M.; Minkoff, H.; Seifer, D.B.; Merhi, Z. Vitamin D increases serum levels of the soluble receptor for advanced glycation end products in women with PCOS. J. Clin. Endocrinol. Metab. 2014, 99, E886–E890.
Shojaeian, Z.; Sadeghi, R.; Latifnejad Roudsari, R. Calcium and vitamin D supplementation effects on metabolic factors, menstrual cycles and follicular responses in women with polycystic ovary syndrome: A systematic review and meta-analysis. Casp. J. Intern. Med. 2019, 10, 359–369.
Bordewijk EM, Ng KY, Rakic L, Mol BW, Brown J, Crawford TJ, van Wely M. Laparoscopic ovarian drilling for ovulation induction in women with anovulatory polycystic ovary syndrome. Cochrane Database of Systematic Reviews. 2020(2).
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2025 Gokila Devi S, Dinesh Kumar S, Shalini M, Vivekanandan C, Mohamed Yousuf K S, Evelyn Sharon S

This work is licensed under a Creative Commons Attribution 4.0 International License.
You are free to:
- Share — copy and redistribute the material in any medium or format
- Adapt — remix, transform, and build upon the material for any purpose, even commercially.
Terms:
- Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.
- No additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.

