Combined Oral Contraceptives for Polycystic Ovary Syndrome: Pro and Contra (Review)

INTRODUCTION. Polycystic ovary syndrome (PCOS) is the main cause of female infertility. Clinical practice guidelines on PCOS recommend combined oral contraceptives (COCs) as first-line therapy. Given the association of PCOS with a number of clinical conditions, including obesity, type 2 diabetes mellitus, metabolic syndrome, anxiety and depressive disorders, an increased risk of endometrial cancer, and cardiovascular diseases, it is important to describe and systematise data on the benefits and risks associated with COCs.

AIM. This study aimed to review current data on the use of COCs in PCOS, focusing on the rationality of prescribing, the main risks of using COCs, and the measures to minimise these risks.

DISCUSSION. Hirsutism is the most prominent clinical manifestation of hyperandrogenism; in PCOS, its prevalence is 65–75%. COCs containing progestins with anti-androgenic properties are effective in treating hirsutism and superior to anti-androgens alone. Women with PCOS are at increased risk of endometrial cancer due to prolongation of the oestrogen-dependent proliferative phase. This risk can be mitigated by the normalising effect of COCs on the menstrual cycle and the effect of the progestin component of COCs. This review highlights the controversial nature of data on the association of COCs with emerging or exacerbating mental disorders, impaired glucose tolerance, and arterial hypertension/other cardiovascular risks in PCOS. Since the main safety issue with COCs is their thrombogenicity, clinicians should take special care when prescribing medicinal products from this group to PCOS patients. Data on the effect of COCs on fertility in women with PCOS are limited, but there is published evidence of an adverse effect of long-term use of COCs on the results of assisted reproductive technologies.

CONCLUSIONS. The key benefit of the non-contraceptive use of COCs in PCOS is in treating hyperandrogenism, mainly hirsutism. To achieve effect, the patient should take COCs containing progestins with anti-androgenic properties for at least 6 months. PCOS patients can also use COCs for contraception. Clinicians prescribing COCs to women with PCOS should consider the individual patient context, the aim of treatment, and any potential risks associated with COCs.

1. Adamyan LV, Andreeva EN, Absatarova YuS, Grigoryan OR, Dedov II, Melnichenko GA, et al. Clinical guidelines “Polycystic ovary syndrome”. Problems of Endocrinology. 2022;68(2):112–27 (In Russ.). https://doi.org/10.14341/probl12874

2. Teede HJ, Tay CT, Laven JJE, Dokras A, Moran LJ, Piltonen TT, et al. Recommendations from the 2023 international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Eur J Endocrinol. 2023;189(2):G43–G64. https://doi.org/10.1093/ejendo/lvad096

3. Goodman NF, Cobin RH, Futterweit W, Glueck JS, Legro RS, Carmina E, et al. American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and PCOS Society Disease State clinical review: guide to the best practices in the evaluation and treatment of polycystic ovary syndrome — Part 1. Endocr Pract. 2015;21(11):1291–300. https://doi.org/10.4158/EP15748.DSC

4. Goodman NF, Cobin RH, Futterweit W, Glueck JS, Legro RS, Carmina E, et al. American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and PCOS Society Disease State clinical review: guide to the best practices in the evaluation and treatment of polycystic ovary syndrome — Part 2. Endocr Pract. 2015;21(12):1415–26. https://doi.org/10.4158/EP15748.DSCPT2

5. 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):41–7. https://doi.org/10.1093/humrep/deh098

6. Mumusoglu S, Yildiz BO. Polycystic ovary syndrome phenotypes and prevalence: differential impact of diagnostic criteria and clinical versus unselected population. Curr Opin Endocr Metab Res. 2020;12:66–71. https://doi.org/10.1016/j.coemr.2020.03.004

7. Bozdag G, Mumusoglu S, Zengin D, Karabulut E, Yildiz BO. The prevalence and phenotypic features of polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod. 2016;31(12):2841–55. https://doi.org/10.1093/humrep/dew218

8. Emanuel RHK, Roberts J, Docherty PD, Lunt H, Campbell RE, Möller K. A review of the hormones involved in the endocrine dysfunctions of polycystic ovary syndrome and their interactions. Front Endocrinol (Lausanne). 2022;13:1017468. https://doi.org/10.3389/fendo.2022.1017468

9. Moghetti P, Tosi F, Bonin C, Di Sarra D, Fiers T, Kaufman JM, et al. Divergences in insulin resistance between the different phenotypes of the polycystic ovary syndrome. J Clin Endocrinol Metab. 2013;98(4):E628–37. https://doi.org/10.1210/jc.2012-3908

10. Bremer AA, Miller WL. The serine phosphorylation hypothesis of polycystic ovary syndrome: a unifying mechanism for hyperandrogenemia and insulin resistance. Fertil Steril. 2008;89(5):1039–48. https://doi.org/10.1016/j.fertnstert.2008.02.091

11. Qiao J, Feng HL. Extra- and intra-ovarian factors in polycystic ovary syndrome: impact on oocyte maturation and embryo developmental competence. Hum Reprod Update. 2011;17(1):17–33. https://doi.org/10.1093/humupd/dmq032

12. Melo AS, Ferriani RA, Navarro PA. Treatment of infertility in women with polycystic ovary syndrome: approach to clinical practice. Clinics (São Paulo). 2015;70(11):765–9. https://doi.org/10.6061/clinics/2015(11)09

13. Krentowska A, Kowalska I. Metabolic syndrome and its components in different phenotypes of polycystic ovary syndrome. Diabetes Metab Res Rev. 2022;38(1):e3464. https://doi.org/10.1002/dmrr.3464

14. Jacewicz-Święcka M, Kowalska I. Changes in metabolic profile in the women with a history of PCOS-A long-term follow-up study. J Clin Med. 2020;9(10):3367. https://doi.org/10.3390/jcm9103367

15. Wang Y, Ni Z, Li K. The prevalence of anxiety and depression of different severity in women with polycystic ovary syndrome: a meta-analysis. Gynecol Endocrinol. 2021;37(12):1072–8. https://doi.org/10.1080/09513590.2021.1942452

16. Brutocao C, Zaiem F, Alsawas M, Morrow AS, Murad MH, Javed A. Psychiatric disorders in women with polycystic ovary syndrome: a systematic review and meta-analysis. Endocrine. 2018;62(2):318–25. https://doi.org/10.1007/s12020-018-1692-3

17. Bellver J, Rodríguez-Tabernero L, Robles A, Muñoz E, Martínez F, Landeras J, et al. Polycystic ovary syndrome throughout a woman’s life. J Assist Reprod Genet. 2018;35(1):25–39. https://doi.org/10.1007/s10815-017-1047-7

18. Meczekalski B, Pérez-Roncero GR, López-Baena MT, Chedraui P, Pérez-López FR. The polycystic ovary syndrome and gynecological cancer risk. Gynecol Endocrinol. 2020;36(4):289–93. https://doi.org/10.1080/09513590.2020.1730794

19. Yin W, Falconer H, Yin L, Xu L, Ye W. Association between polycystic ovary syndrome and cancer risk. JAMA Oncol. 2019;5(1):106–7. https://doi.org/10.1001/jamaoncol.2018.5188

20. Sukhikh GT, Prilepskaya VN, eds. National medical criteria for the acceptability of contraceptive methods. Moscow; 2023. EDN: EFKVBW

21. Morimont L, Haguet H, Dogné JM, Gaspard U, Douxfils J. Combined oral contraceptives and venous thromboembolism: review and perspective to mitigate the risk. Front Endocrinol (Lausanne). 2021;12:769187. https://doi.org/10.3389/fendo.2021.769187

22. Sitruk-Ware R, Nath A. Characteristics and metabolic effects of estrogen and progestins contained in oral contraceptive pills. Best Pract Res Clin Endocrinol Metab. 2013;27(1):13–24. https://doi.org/10.1016/j.beem.2012.09.004

23. Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, Thijssen JH. Classification and pharmacology of progestins. Maturitas. 2003;46 Suppl 1:S7–S16. https://doi.org/10.1016/j.maturitas.2003.09.014

24. Seidman L, Kroll R, Howard B, Ricciotti N, Hsieh J, Weiss H. Ovulatory effects of three oral contraceptive regimens: a randomized, open-label, descriptive trial. Contraception. 2015;91(6):495–502. https://doi.org/10.1016/j.contraception.2015.03.001

25. Rivera R, Yacobson I, Grimes D. The mechanism of action of hormonal contraceptives and intrauterine contraceptive devices. Am J Obstet Gynecol. 1999;181(5 Pt 1):1263–9. https://doi.org/10.1016/s0002-9378(99)70120-1

26. Fraser IS, Römer T, Parke S, Zeun S, Mellinger U, Machlitt A, Jensen JT. Effective treatment of heavy and/ or prolonged menstrual bleeding with an oral contraceptive containing estradiol valerate and dienogest: a randomized, double-blind Phase III trial. Hum Reprod. 2011;26(10):2698–708. https://doi.org/10.1093/humrep/der224

27. Klipping C, Duijkers I, Trummer D, Marr J. Suppression of ovarian activity with a drospirenone-containing oral contraceptive in a 24/4 regimen. Contraception. 2008;78(1):16–25. https://doi.org/10.1016/j.contraception.2008.02.019

28. Ferriman D, Gallwey Jd. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab. 1961;21:1440–7. https://doi.org/10.1210/jcem-21-11-1440

29. Bienenfeld A, Azarchi S, Lo Sicco K, Marchbein S, Shapiro J, Nagler AR. Androgens in women: androgen-mediated skin disease and patient evaluation. J Am Acad Dermatol. 2019;80(6):1497–506. https://doi.org/10.1016/j.jaad.2018.08.062

30. Azziz R, Carmina E, Chen Z, Dunaif A, Laven JS, Legro RS, et al. Polycystic ovary syndrome. Nat Rev Dis Primers. 2016;2:16057. https://doi.org/10.1038/nrdp.2016.57

31. Pasquali R, Gambineri A. Therapy in endocrine disease: treatment of hirsutism in the polycystic ovary syndrome. Eur J Endocrinol. 2014;170(2):R75–90. https://doi.org/10.1530/EJE-13-0585

32. Ceruti JM, Leirós GJ, Balañá ME. Androgens and androgen receptor action in skin and hair follicles. Mol Cell Endocrinol. 2018;465:122–33. https://doi.org/10.1016/j.mce.2017.09.009

33. Spritzer PM, Marchesan LB, Santos BR, Fighera TM. Hirsutism, Normal androgens and diagnosis of PCOS. Diagnostics (Basel). 2022;12(8):1922. https://doi.org/10.3390/diagnostics12081922

34. Lowenstein EJ. Diagnosis and management of the dermatologic manifestations of the polycystic ovary syndrome. Dermatol Ther. 2006;19(4):210–23. https://doi.org/10.1111/j.1529-8019.2006.00077.x

35. Legro RS, Arslanian SA, Ehrmann DA, Hoeger KM, Murad MH, Pasquali R, et al. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2013;98(12):4565–92. https://doi.org/10.1210/jc.2013-2350

36. Borzyszkowska D, Niedzielska M, Kozłowski M, Brodowska A, Przepiera A, Malczyk-Matysiak K, et al. Evaluation of hormonal factors in acne vulgaris and the course of acne vulgaris treatment with contraceptive-based therapies in young adult women. Cells. 2022;11(24):4078. https://doi.org/10.3390/cells11244078

37. Ozdemir S, Ozdemir M, Görkemli H, Kiyici A, Bodur S. Specific dermatologic features of the polycystic ovary syndrome and its association with biochemical markers of the metabolic syndrome and hyperandrogenism. Acta Obstet Gynecol Scand. 2010;89(2):199–204. https://doi.org/10.3109/00016340903353284

38. Feng JG, Guo Y, Ma LA, Xing J, Sun RF, Zhu W. Prevalence of dermatologic manifestations and metabolic biomarkers in women with polycystic ovary syndrome in north China. J Cosmet Dermatol. 2018;17(3):511–7. https://doi.org/10.1111/jocd.12387

39. Schmidt TH, Khanijow K, Cedars MI, Huddleston H, Pasch L, Wang ET, et al. Cutaneous findings and systemic associations in women with polycystic ovary syndrome. JAMA Dermatol. 2016;152(4):391–8. https://doi.org/10.1001/jamadermatol.2015.4498

40. Hoeger KM, Dokras A, Piltonen T. Update on PCOS: consequences, challenges, and guiding treatment. J Clin Endocrinol Metab. 2021;106(3):e1071–83. https://doi.org/10.1210/clinem/dgaa839

41. Amiri M, Kabir A, Nahidi F, Shekofteh M, Ramezani Tehrani F. Effects of combined oral contraceptives on the clinical and biochemical parameters of hyperandrogenism in patients with polycystic ovary syndrome: a systematic review and meta-analysis. Eur J Contracept Reprod Health Care. 2018;23(1):64–77. https://doi.org/10.1080/13625187.2018.1435779

42. Morgante G, Cappelli V, Troìa L, De Leo V. Evaluation of different antiandrogenic progestins on clinical and biochemical variables in polycystic ovary syndrome. Eur J Contracept Reprod Health Care. 2020;25(3):176–81. https://doi.org/10.1080/13625187.2020.1736546

43. De Leo V, Morgante G, Piomboni P, Musacchio MC, Petraglia F, Cianci A. Evaluation of effects of an oral contraceptive containing ethinylestradiol combined with drospirenone on adrenal steroidogenesis in hyperandrogenic women with polycystic ovary syndrome. Fertil Steril. 2007;88(1):113–7. https://doi.org/10.1016/j.fertnstert.2006.11.137

44. Barrionuevo P, Nabhan M, Altayar O, Wang Z, Erwin PJ, Asi N, et al. Treatment options for hirsutism: a systematic review and network meta-analysis. J Clin Endocrinol Metab. 2018;103(4):1258–64. https://doi.org/10.1210/jc.2017-02052

45. Bhattacharya SM, Jha A. Comparative study of the therapeutic effects of oral contraceptive pills containing desogestrel, cyproterone acetate, and drospirenone in patients with polycystic ovary syndrome. Fertil Steril. 2012;98(4):1053–9. https://doi.org/10.1016/j.fertnstert.2012.06.035

46. Tang Z, Guan J, Mao JH, Han L, Zhang JJ, Chen R, Jiao Z. Quantitative risk-benefit profiles of oral contraceptives, insulin sensitizers and antiandrogens for women with polycystic ovary syndrome: a model-based meta-analysis. Eur J Pharm Sci. 2023;190:106577. https://doi.org/10.1016/j.ejps.2023.106577

47. Dorgham N, Sharobim A, Haggag H, El-Kalioby M, Dorgham D. Adding combined oral contraceptives or metformin to laser treatment in polycystic ovarian syndrome hirsute patients. J Drugs Dermatol. 2021;20(3):302–6. https://doi.org/10.36849/JDD.5652

48. Shobeiri F, Jenabi E. The association between polycystic ovary syndrome and breast cancer: a meta-analysis. Obstet Gynecol Sci. 2016;59(5):367–72. https://doi.org/10.5468/ogs.2016.59.5.367

49. Harris HR, Terry KL. Polycystic ovary syndrome and risk of endometrial, ovarian, and breast cancer: a systematic review. Fertil Res Pract. 2016;2:14. https://doi.org/10.1186/s40738-016-0029-2

50. Ding DC, Chen W, Wang JH, Lin SZ. Association between polycystic ovarian syndrome and endometrial, ovarian, and breast cancer: a population-based cohort study in Taiwan. Medicine (Baltimore). 2018;97(39):e12608. https://doi.org/10.1097/MD.0000000000012608

51. Li Z, Wang YH, Wang LL, Hu DT, Teng Y, Zhang TY, et al. Polycystic ovary syndrome and the risk of endometrial, ovarian and breast cancer: an updated meta-analysis. Scott Med J. 2022;67(3):109–20. https://doi.org/10.1177/00369330221107099

52. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53297 women with breast cancer and 100239 women without breast cancer from 54 epidemiological studies. Lancet. 1996;347(9017):1713–27. https://doi.org/10.1016/s0140-6736(96)90806-5

53. Mørch LS, Hannaford PC, Lidegaard Ø. Contemporary hormonal contraception and the risk of breast cancer. N Engl J Med. 2018;378(13):1265–6. https://doi.org/10.1056/NEJMc1800054

54. Fitzpatrick D, Pirie K, Reeves G, Green J, Beral V. Combined and progestagen-only hormonal contraceptives and breast cancer risk: a UK nested case–control study and meta-analysis. PLOS Medicine. 2023;20(3):e1004188. https://doi.org/10.1371/journal.pmed.1004188

55. Iversen L, Sivasubramaniam S, Lee AJ, Fielding S, Hannaford PC. Lifetime cancer risk and combined oral contraceptives: the Royal College of General Practitioners’ oral contraception study. Am J Obstet Gynecol. 2017;216(6):580.e1–580.e9. https://doi.org/10.1016/j.ajog.2017.02.002

56. Gottschau M, Kjaer SK, Jensen A, Munk C, Mellemkjaer L. Risk of cancer among women with polycystic ovary syndrome: a Danish cohort study. Gynecol Oncol. 2015;136(1):99–103. https://doi.org/10.1016/j.ygyno.2014.11.012

57. Dumesic DA, Lobo RA. Cancer risk and PCOS. Steroids. 2013;78(8):782–5. https://doi.org/10.1016/j.steroids.2013.04.004

58. Yin W, Falconer H, Yin L, Xu L, Ye W. Association between polycystic ovary syndrome and cancer risk. JAMA Oncol. 2019;5(1):106–7. https://doi.org/10.1001/jamaoncol.2018.5188

59. Indhavivadhana S, Rattanachaiyanont M, Wongwananuruk T, Techatraisak K, Rayasawath N, Dangrat C. Endometrial neoplasia in reproductive-aged Thai women with polycystic ovary syndrome. Int J Gynaecol Obstet. 2018;142(2):170–5. https://doi.org/10.1002/ijgo.12522

60. Fearnley EJ, Marquart L, Spurdle AB, Weinstein P, Webb PM; Australian Ovarian Cancer Study Group and Australian National Endometrial Cancer Study Group. Polycystic ovary syndrome increases the risk of endometrial cancer in women aged less than 50 years: an Australian case-control study. Cancer Causes Control. 2010;21(12):2303–8. https://doi.org/10.1007/s10552-010-9658-7

61. Cooney LG, Dokras A. Beyond fertility: polycystic ovary syndrome and long-term health. Fertil Steril. 2018;110(5):794–809. https://doi.org/10.1016/j.fertnstert.2018.08.021

62. Savaris RF, Groll JM, Young SL, DeMayo FJ, Jeong JW, Hamilton AE, et al. Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles. J Clin Endocrinol Metab. 2011;96(6):1737–46. https://doi.org/10.1210/jc.2010-2600

63. Li X, Feng Y, Lin JF, Billig H, Shao R. Endometrial progesterone resistance and PCOS. J Biomed Sci. 2014;21(1):2. https://doi.org/10.1186/1423-0127-21-2

64. Onstad MA, Schmandt RE, Lu KH. Addressing the role of obesity in endometrial cancer risk, prevention, and treatment. J Clin Oncol. 2016;34(35):4225–30. https://doi.org/10.1200/JCO.2016.69.4638

65. Pérez-Martín AR, Castro-Eguiluz D, Cetina-Pérez L, Velasco-Torres Y, Bahena-González A, Montes-Servín E, et al. Impact of metabolic syndrome on the risk of endometrial cancer and the role of lifestyle in prevention. Bosn J Basic Med Sci. 2022;22(4):499–510. https://doi.org/10.17305/bjbms.2021.6963

66. Michels KA, Pfeiffer RM, Brinton LA, Trabert B. Modification of the associations between duration of oral contraceptive use and ovarian, endometrial, breast, and colorectal cancers. JAMA Oncol. 2018;4(4):516–21. https://doi.org/10.1001/jamaoncol.2017.4942

67. Burchardt NA, Shafrir AL, Kaaks R, Tworoger SS, Fortner RT. Oral contraceptive use by formulation and endometrial cancer risk among women born in 1947– 1964: The Nurses’ Health Study II, a prospective cohort study. Eur J Epidemiol. 2021;36(8):827–39. https://doi.org/10.1007/s10654-020-00705-5

68. Cooney LG, Lee I, Sammel MD, Dokras A. High prevalence of moderate and severe depressive and anxiety symptoms in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod. 2017;32(5):1075–91. https://doi.org/10.1093/humrep/dex044

69. Dovzhenko TV, Ilyina NA, Grodnitskaya EE. Mental disorders in persons with polycystic ovary syndrome. Social and Clinical Psychiatry. 2015;25(2):94– 100 (In Russ.). EDN: UZQCVP

70. Edwards AC, Lönn SL, Crump C, Mościcki EK, Sundquist J, Kendler KS, Sundquist K. Oral contraceptive use and risk of suicidal behavior among young women. Psychol Med. 2022;52(9):1710–7. https://doi.org/10.1017/S0033291720003475

71. Jung SJ, Cho SMJ, Kim HC. Association of oral contraceptive use with suicidal behavior among representative Korean population: results from Korea National Health and Nutrition Examination Survey (2007–2016). J Affect Disord. 2019;243:8–15. https://doi.org/10.1016/j.jad.2018.09.004

72. Yang Q, Lagerberg T, Sjölander A, Bertone-Johnson ER, Fang F, Ye W, et al. Use of hormonal contraceptives and antidepressants and risks of suicidal behavior and accidents among women with premenstrual disorders: a nationwide cohort study. BMC Med. 2022;20(1):482. https://doi.org/10.1186/s12916-022-02671-z

73. Dokras A, Sarwer DB, Allison KC, Milman L, Kris-Etherton PM, Kunselman AR, et al. Weight loss and lowering androgens predict improvements in health-related quality of life in women with PCOS. J Clin Endocrinol Metab. 2016;101(8):2966–74. https://doi.org/10.1210/jc.2016-1896

74. Cinar N, Harmanci A, Demir B, Yildiz BO. Effect of an oral contraceptive on emotional distress, anxiety and depression of women with polycystic ovary syndrome: a prospective study. Hum Reprod. 2012;27(6):1840–5. https://doi.org/10.1093/humrep/des113

75. Amisi CA. Markers of insulin resistance in polycystic ovary syndrome women: an update. World J Diabetes. 2022;13(3):129–49. https://doi.org/10.4239/wjd.v13.i3.129

76. Barber TM. Why are women with polycystic ovary syndrome obese? British Medical Bulletin. 2022;143(1):4–15. https://doi.org/10.1093/bmb/ldac007

77. Guo F, Gong Z, Fernando T, Zhang L, Zhu X, Shi Y. The lipid profiles in different characteristics of women with PCOS and the interaction between dyslipidemia and metabolic disorder states: a retrospective study in Chinese population. Front Endocrinol (Lausanne). 2022;13:892125. https://doi.org/10.3389/fendo.2022.892125

78. Kazemi M, Pierson RA, Lujan ME, Chilibeck PD, McBreairty LE, Gordon JJ, et al. Comprehensive evaluation of type 2 diabetes and cardiovascular disease risk profiles in reproductive-age women with polycystic ovary syndrome: a large Canadian cohort. J Obstet Gynaecol Can. 2019;41(10):1453–60. https://doi.org/10.1016/j.jogc.2018.11.026

79. Bolotova EV, Dudnikova AV, Krutova VA, Prosolupova NS. The frequency and structure of metabolic disorders in obese women in combination with polycystic ovary syndrome. Obesity and Metabolism. 2021;18(3):254–62 (In Russ.). https://doi.org/10.14341/omet12374

80. Kakoly NS, Khomami MB, Joham AE, Cooray SD, Misso ML, Norman RJ, et al. Ethnicity, obesity and the prevalence of impaired glucose tolerance and type 2 diabetes in PCOS: a systematic review and meta-regression. Hum Reprod Update. 2018;24(4):455–67. https://doi.org/10.1093/humupd/dmy007

81. Sanchez-Garrido MA, Tena-Sempere M. Metabolic dysfunction in polycystic ovary syndrome: pathogenic role of androgen excess and potential therapeutic strategies. Mol Metab. 2020;35:100937. https://doi.org/10.1016/j.molmet.2020.01.001

82. Li L, Feng Q, Ye M, He Y, Yao A, Shi K. Metabolic effect of obesity on polycystic ovary syndrome in adolescents: a meta-analysis. J Obstet Gynaecol. 2017;37(8):1036–47. https://doi.org/10.1080/01443615.2017.1318840

83. Behboudi-Gandevani S, Ramezani Tehrani F, Rostami Dovom M, Farahmand M, Bahri Khomami M, Noroozzadeh M, et al. Insulin resistance in obesity and polycystic ovary syndrome: systematic review and meta-analysis of observational studies. Gynecol Endocrinol. 2016;32(5):343–53. https://doi.org/10.3109/09513590.2015.1117069

84. Ollila MM, West S, Keinänen-Kiukaanniemi S, Jokelainen J, Auvinen J, Puukka K, et al. Overweight and obese but not normal weight women with PCOS are at increased risk of type 2 diabetes mellitus—a prospective, population-based cohort study. Hum Reprod. 2017;32(2):423–31. https://doi.org/10.1093/humrep/dew329

85. Forslund M, Landin-Wilhelmsen K, Trimpou P, Schmidt J, Brännström M, Dahlgren E. Type 2 diabetes mellitus in women with polycystic ovary syndrome during a 24-year period: importance of obesity and abdominal fat distribution. Hum Reprod Open. 2020;(1):hoz042. https://doi.org/10.1093/hropen/hoz042

86. Kumarendran B, O’Reilly MW, Subramanian A, Šumilo D, Toulis K, Gokhale KM, et al. Polycystic ovary syndrome, combined oral contraceptives, and the risk of dysglycemia: a population-based cohort study with a nested pharmacoepidemiological case-control study. Diabetes Care. 2021;44(12):2758–66. https://doi.org/10.2337/dc21-0437

87. Wu L, Liu Y, Huang X, Lin K, Liu Y, Li Z, et al. Oral contraceptives (OCs) in combination with metformin versus OCs alone on metabolism in nonobese polycystic ovary syndrome: a meta-analysis and systematic review of randomized controlled trials. Clin Endocrinol (Oxf). 2023;99(1):3–16. https://doi.org/10.1111/cen.14895

88. Gallo MF, Lopez LM, Grimes DA, Carayon F, Schulz KF, Helmerhorst FM. Combination contraceptives: effects on weight. Cochrane Database Syst Rev. 2014;2014(1):CD003987. https://doi.org/10.1002/14651858.CD003987.pub5

89. Hirschberg AL, Byström B, Carlström K, von Schoultz B. Reduced serum cholecystokinin and increase in body fat during oral contraception. Contraception. 1996;53(2):109–13. https://doi.org/10.1016/0010-7824(95)00265-0

90. Arusoglu G, Koksal G, Cinar N, Tapan S, Aksoy DY, Yildiz BO. Basal and meal-stimulated ghrelin, PYY, CCK levels and satiety in lean women with polycystic ovary syndrome: effect of low-dose oral contraceptive. J Clin Endocrinol Metab. 2013;98(11):4475–82. https://doi.org/10.1210/jc.2013-1526

91. Naessén S, Carlström K, Byström B, Pierre Y, Hirschberg AL. Effects of an antiandrogenic oral contraceptive on appetite and eating behavior in bulimic women. Psychoneuroendocrinology. 2007;32(5):548–54. https://doi.org/10.1016/j.psyneuen.2007.03.008

92. Lindh I, Ellström AA, Milsom I. The long-term influence of combined oral contraceptives on body weight. Hum Reprod. 2011;26(7):1917–24. https://doi.org/10.1093/humrep/der094

93. Aydin K, Cinar N, Aksoy DY, Bozdag G, Yildiz BO. Body composition in lean women with polycystic ovary syndrome: effect of ethinyl estradiol and drospirenone combination. Contraception. 2013;87(3):358–62. https://doi.org/10.1016/j.contraception.2012.07.005

94. Berenson AB, Rahman M. Changes in weight, total fat, percent body fat, and central-to-peripheral fat ratio associated with injectable and oral contraceptive use. Am J Obstet Gynecol. 2009;200(3):329.e1–8. https://doi.org/10.1016/j.ajog.2008.12.052

95. Pasquali R, Gambineri A, Anconetani B, Vicennati V, Colitta D, Caramelli E, et al. The natural history of the metabolic syndrome in young women with the polycystic ovary syndrome and the effect of long-term oestrogen-progestagen treatment. Clin Endocrinol (Oxf). 1999;50(4):517–27. https://doi.org/10.1046/j.1365-2265.1999.00701.x

96. Cooney LG, Dokras A. Cardiometabolic risk in polycystic ovary syndrome: current guidelines. Endocrinol Metab Clin North Am. 2021;50(1):83–95. https://doi.org/10.1016/j.ecl.2020.11.001

97. Beglova AYu, Elgina SI. Metabolic and cardiovascular risks in women of reproductive age with polycystic ovary syndrome. Mother and Baby in Kuzbass. 2018;(4):44–9 (In Russ.). EDN: YRNDGH

98. Amiri M, Ramezani Tehrani F, Behboudi-Gandevani S, Bidhendi-Yarandi R, Carmina E. Risk of hypertension in women with polycystic ovary syndrome: a systematic review, meta-analysis and meta-regression. Reprod Biol Endocrinol. 2020;18(1):23. https://doi.org/10.1186/s12958-020-00576-1

99. Daan NM, Louwers YV, Koster MP, Eijkemans MJ, de Rijke YB, Lentjes EW, et al. Cardiovascular and metabolic profiles amongst different polycystic ovary syndrome phenotypes: who is really at risk? Fertil Steril. 2014;102(5):1444–51.e3. https://doi.org/10.1016/j.fertnstert.2014.08.001

100. de Medeiros SF. Risks, benefits size and clinical implications of combined oral contraceptive use in women with polycystic ovary syndrome. Reprod Biol Endocrinol. 2017;15(1):93. https://doi.org/10.1186/s12958-017-0313-y

101. Yildizhan R, Gokce AI, Yildizhan B, Cim N. Comparison of the effects of chlormadinone acetate versus drospirenone containing oral contraceptives on metabolic and hormonal parameters in women with PCOS for a period of two-year follow-up. Gynecol Endocrinol. 2015;31(5):396–400. https://doi.org/10.3109/09513590.2015.1006187

102. Vieira CS, Martins WP, Fernandes JB, Soares GM, dos Reis RM, de Sá MF, Ferriani RA. The effects of 2 mg chormadinone acetate/30 mcg ethinylestradiol, alone or combined with spironolactone, on cardiovascular risk markers in women with polycystic ovary syndrome. Contraception. 2012;86:268–75. https://doi.org/10.1016/j.contraception.2011.12.011

103. Wild RA, Rizzo M, Clifton S, Carmina E. Lipid levels in polycystic ovary syndrome: systematic review and meta-analysis. Fertil Steril. 2011;95:1073–9.e1-11. https://doi.org/10.1016/j.fertnstert.2010.12.027

104. Pinola P, Puukka K, Piltonen TT, Puurunen J, Vanky E, Sundstrom-Poromaa I, et al. Normo- and hyperandrogenic women with polycystic ovary syndrome exhibit an adverse metabolic profile through life. Fertil Steril. 2017;107:788–95.e2. https://doi.org/10.1016/j.fertnstert.2016.12.017

105. Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation. 2007;115(4):459–67. https://doi.org/10.1161/circulationaha.106.628875

106. Meyer ML, Malek AM, Wild RA, Korytkowski MT, Talbott EO. Carotid artery intima-media thickness in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2012;18(2):112–26. https://doi.org/10.1093/humupd/dmr046

107. Meun C, Franco OH, Dhana K, Jaspers L, Muka T, Louwers Y, et al. High androgens in postmenopausal women and the risk for atherosclerosis and cardiovascular disease: the Rotterdam Study. J Clin Endocrinol Metab. 2018;103:1622–30. https://doi.org/10.1210/jc.2017-02421

108. Guan C, Zahid S, Minhas AS, Ouyang P, Vaught A, Baker VL, Michos ED. Polycystic ovary syndrome: a “risk-enhancing” factor for cardiovascular disease. Fertil Steril. 2022;117(5):924–35. https://doi.org/10.1016/j.fertnstert.2022.03.009

109. Carmina E, Campagna AM, Lobo RA. A 20-year follow-up of young women with polycystic ovary syndrome. Obstet Gynecol. 2012;119(2 Pt 1):263–9. https://doi.org/10.1097/AOG.0b013e31823f7135

110. Ramezani Tehrani F, Amiri M, Behboudi-Gandevani S, Bidhendi-Yarandi R, Carmina E. Cardiovascular events among reproductive and menopausal age women with polycystic ovary syndrome: a systematic review and meta-analysis. Gynecol Endocrinol. 2020;36(1):12–23. https://doi.org/10.1080/09513590.2019.1650337

111. Schmidt J, Landin-Wilhelmsen K, Brännström M, Dahlgren E. Cardiovascular disease and risk factors in PCOS women of postmenopausal age: a 21-year controlled follow-up study. J Clin Endocrinol Metab. 2011;96(12):3794–803. https://doi.org/10.1210/jc.2011-1677

112. Bajuk Studen K, Pfeifer M. Cardiometabolic risk in polycystic ovary syndrome. Endocr Connect. 2018;7(7):R238–R251. https://doi.org/10.1530/EC-18-0129

113. Dragoman M, Curtis KM, Gaffield ME. Combined hormonal contraceptive use among women with known dyslipidemias: a systematic review of critical safety outcomes. Contraception. 2016;94(3):280–7. https://doi.org/10.1016/j.contraception.2015.08.002

114. Gariani K, Hugon-Rodin J, Philippe J, Righini M, Blondon M. Association between polycystic ovary syndrome and venous thromboembolism: a systematic review and meta-analysis. Thromb Res. 2020;185:102–8. https://doi.org/10.1016/j.thromres.2019.11.019

115. Lidegaard Ø, Nielsen LH, Skovlund CW, Skjeldestad FE, Løkkegaard E. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. BMJ. 2011;343:d6423. https://doi.org/10.1136/bmj.d6423

116. Kareva EN. Thrombosis and gestagens. Doctor.Ru. 2019;(7):57–64 (In Russ.). https://doi.org/10.31550/1727-2378-2019-162-7-57-64

117. Stocco B, Fumagalli HF, Franceschini SA, Martinez EZ, Marzocchi-Machado CM, de Sá MFS, Toloi MRT. Comparative study of the effects of combined oral contraceptives in hemostatic variables: an observational preliminary study. Medicine (Baltimore). 2015;94(4):e385. https://doi.org/10.1097/MD.0000000000000385

118. Bird ST, Hartzema AG, Brophy JM, Etminan M, Delaney JA. Risk of venous thromboembolism in women with polycystic ovary syndrome: a population-based matched cohort analysis. CMAJ. 2013;185(2):E115–20. https://doi.org/10.1503/cmaj.120677

119. Okoroh EM, Hooper WC, Atrash HK, Yusuf HR, Boulet SL. Is polycystic ovary syndrome another risk factor for venous thromboembolism? United States, 2003– 2008. Am J Obstet Gynecol. 2012;207(5):377.e1–8. https://doi.org/10.1016/j.ajog.2012.08.007

120. Girum T, Wasie A. Return of fertility after discontinuation of contraception: a systematic review and meta-analysis. Contracept Reprod Med. 2018;3:9. https://doi.org/10.1186/s40834-018-0064-y

121. Landersoe SK, Petersen KB, Vassard D, Larsen EC, Nielsen HS, Pinborg A, et al. Concerns on future fertility among users and past-users of combined oral contraceptives: a questionnaire survey. Eur J Contracept Reprod Health Care. 2019;24(5):347–55. https://doi.org/10.1080/13625187.2019.1639659

122. Yland JJ, Bresnick KA, Hatch EE, Wesselink AK, Mikkelsen EM, Rothman KJ, et al. Pregravid contraceptive use and fecundability: prospective cohort study. BMJ. 2020;371:m3966. https://doi.org/10.1136/bmj.m3966

123. Siegel DR, Fresia J, Fought A, Sheeder J, Hampanda K, Appiah L. The effect of hormonal contraception use on ovarian reserve markers and the uptake of assisted reproductive technology in individuals seeking an infertility evaluation. Cureus. 2023;15(6):e40927. https://doi.org/10.7759/cureus.40927

124. Song SY, Yang JB, Song MS, Oh HY, Lee GW, Lee M, et al. Effect of pretreatment with combined oral contraceptives on outcomes of assisted reproductive technology for women with polycystic ovary syndrome: a meta-analysis. Arch Gynecol Obstet. 2019;300(3):737–50. https://doi.org/10.1007/s00404-019-05210-z