Основные направления и перспективы в терапии синдрома поликистоза яичников

Статья посвящена актуальной гинекологической проблеме женщин репродуктивного возраста – синдрому поликистоза яичников (СПКЯ) и возможностям его фармакотерапии. Сложность в выборе фармакотерапии заболевания заключается в том, что необходимо учитывать все его клинические проявления, не ограничиваясь нарушениями менструального цикла и бесплодием. СПКЯ сопровождается, как правило, гирсутизмом, ожирением, снижением толерантности к глюкозе и другими проявлениями в различных системах органов, связанных с метаболическими нарушениями. Эти проявления существенно снижают качество жизни пациенток и также требуют фармакологической коррекции. В настоящее время первой линией препаратов в лечении СПКЯ остаются комбинированные оральные контрацептивы (КОК), которые используются женщинами уже на протяжении десятков лет, но обладают множественными нежелательными реакциями. Последнее служит поводом для поиска других методов фармакотерапии, обладающих высокой эффективностью и безопасностью. Одним из таких препаратов является пероральный сахароснижающий препарат метформин, доказавший свою эффективность в лечении СПКЯ. На стадии исследования находятся агонисты рецепторов глюкагоноподобного пептида-1, продолжается разработка тактики лечения СПКЯ с использованием сахароснижающих препаратов, обладающих антагонизмом к глюкагону. Расширение возможности выбора фармакотерапии, благодаря поиску новых более эффективных и безопасных лекарственных средств, и сочетание ее с другими методами лечения делают возможным контроль над СПКЯ с учетом индивидуальных особенностей пациенток.

1. Andrade V.H., Mata A.M., Borges R.S., Costa-Silva D.R., Martins L.M., Ferreira P.M., CunhaNunes L.C., Silva B.B. Current aspects of polycystic ovary syndrome: A literature review. Rev. Assoc. Med. Bras (1992). 2016;62(9):867–871. doi: 10.1590/1806-9282.62.09.867

2. Asuncion M., Calvo R.M., San Millan J.L., Sancho J., Avila S., Escobar-Morreale H.F. A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J. Clin. Endocrinol. Metab. 2000;85(7):2434–2438. doi: 10.1210/jcem.85.7.6682

3. Yildiz B.O., Bozdag G., Yapici Z., Esinler I., Yarali H. Prevalence, phenotype and cardiometabolic risk of polycystic ovary syndrome under different diagnostic criteria. Hum. Reprod. Open. 2012;27(10): 3067–3073. doi: 10.1093/humrep/des232

4. Rosenfield R.L., Ehrmann D.A. The pathogenesis of polycystic ovary syndrome (PCOS): The hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocr. Rev. 2016;37(5):467–520. doi: 10.1210/er.2015-1104

5. Norman R.J., Dewailly D., Legro R.S., Hickey T.E. Polycystic ovary syndrome. Lancet. 2007;370(9588):685–697 doi: 10.1016/S0140-6736(07)61345-2

6. Legro R.S., Arslanian S.A., Ehrmann D.A., Hoeger K.M., Murad M.H., Pasquali R., Welt C.K. Endocrine Society. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 2013;98(12):4565–4592. doi: 10.1210/jc.2013-2350

7. Bednarska S., Siejka A. The pathogenesis and treatment of polycystic ovary syndrome: What’s new? Adv. Clin. Exp. Med. 2017;26(2):359–367. doi: 10.17219/acem/59380

8. Demissie M., Lazic M., Foecking E.M., Aird F., Dunaif A., Levine J.E. Transient prenatal androgen exposure produces metabolic syndrome in adult female rats. Am. J. Physiol Endocrinol. Metab. 2008;95(2):262–268. doi: 10.1152/ajpendo.90208.2008

9. Dumesic D.A., Oberfield S.E., Stener-Victorin E., Marshall J.C., Laven J.S., Legro R.S. Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome. Endocr. Rev. 2015;36(5):487–525. doi: /10.1210/er.2015-1018

10. Azziz R., Woods K.S., Reyna R., Key T.J., Knochenhauer E.S., Yildiz B.O. The prevalence and features of the polycystic ovary syndrome in an unselected population. J. Clin. Endocrinol. Metab. 2004;89(6):2745– 2749. doi: 10.1210/jc.2003-032046

11. Moran C., Tena G., Moran S., Ruiz P., Reyna R., Duque X. Prevalence of polycystic ovary syndrome and related disorders in mexican women. Gynecol. Obstet. Invest. 2010;69(4):274–280. doi: 10.1159/000277640

12. Diamanti-Kandarakis E., Kouli C.R., Bergiele A.T., Filandra F.A., Tsianateli T.C., Spina G.G., Zapanti E.D., Bartzis M.I. A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic profile. J. Clin. Endocrinol. Metab. 1999;84(11):4006–4011. doi: 10.1210/jcem.84.11.6148

13. Diamanti-Kandarakis E., Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr. Rev. 2012;33(6):981–1030. doi: 10.1210/er.2011-1034

14. Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endoc. Rev. 1997;18(6):774–800. doi: 10.1210/edrv.18.6.0318

15. da Silva B.B., Lopes-Costa P.V., Rosal M.A., Pires C.G., dos Santos L.G., Gontijo J.A., Alencar A.P., de Jesus Simões M. Morphological and morphometric analysis of the adrenal cortex of androgenized female rats. Gynecol. Obstet. Invest. 2007;64(1):44–48. doi: 10.1159/000098956

16. Peters H., Byskov A.G., Himelstein-Braw R., Faber M. Follicular growth: the basic event in the mouse and human ovary. J. Reprod. Fertil. 1975;45(3):559– 566. doi: 10.1530/jrf.0.0450559

17. Fortune J.E., Cushman R.A., Wahl C.M., Kito S. The primordial to primary follicle transition. Mol. Cell Endocrinol. 2000;163(1-2):53–60. doi: 10.1016/s0303-7207(99)00240-3

18. John G.B., Gallardo T.D., Shirley L.J., Castrillon D.H. Foxo3 is a PI3K-dependent molecular switch controlling the initiation of oocyte growth. Dev. Biol. 2008;321(1):197–204. doi: 10.1016/j.ydbio.2008.06.017

19. Reddy P., Liu L., Adhikari D., Jagarlamudi K., Rajareddy S., Shen Y., Du C., Tang W., Hämäläinen T., Peng S.L., Lan Z.J., Cooney A.J., Huhtaniemi I., Liu K. Oocyte-specific deletion of Pten causes premature activation of the primordial follicle pool. Science. 2008;319(5863):611–613. doi: 10.1126/science.1152257

20. Dumesic D.A., Richards J.S. Ontogeny of the ovary in polycystic ovary syndrome. Fertil Steril. 2013;100(1):23–38. doi: 10.1016/j.fertnstert.2013.02.01

21. Khashchenko E., Uvarova E., Vysokikh M., Ivanets T., Krechetova L., Tarasova N., Sukhanova I., Mamedova F., Borovikov P., Balashov I., Sukhikh G. The relevant hormonal levels and diagnostic features of polycystic ovary syndrome in adolescents. J. Clin. Med. 2020;9(6):1831. doi: 10.3390/jcm9061831

22. Balen A.H., Rutherford A.J. Managing anovulatory infertility and polycystic ovary syndrome. BMJ. 2007;335(7621):663–666. doi: 10.1136/bmj.39335.462303.80

23. Moutos D., Smith S., Zacur H. The effect of monophasic combinations of ethinyl estradiol and norethindrone on gonadotropins, androgens and sex hormone binding globulin: a randomized trial. Contraception. 1995;52(2):105–109. doi: 10.1016/s0010-7824(95)00137-9

24. Willis D.S., Watson H., Mason H.D., Galea R., Brincat M., Franks S. Premature response to luteinizing hormone of granulosa cells from anovulatory women with polycystic ovary syndrome: relevance to mechanism of anovulation. J. Clin. Endocrinol. Metab. 1998;83(11):3984–3991. doi: 10.1210/jcem.83.11.5232

25. Magoffin D.A. Ovarian theca cell. Int. J. Biochem. Cell Biol. 2005;37(7):1344–1349. doi: 10.1016/j.biocel.2005.01.016

26. Edson M.A., Nagaraja A.K., Matzuk M.M. The mammalian ovary from genesis to revelation. Endocr. Rev. 2009;30(6):624–712. doi: 10.1210/er.2009-0012

27. Barbieri R.L., Makris A., Randall R.W., Daniels G., Kistner R.W., Ryan K.J. Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism. J. Clin. Endocrinol. Metab. 1986;62(5):904–910. doi: /10.1210/jcem-62-5-904

28. Conway G.S., Jacobs H.S., Holly J.M., Wass J.A. Effects of luteinizing hormone, insulin, insulin-like growth factor-I and insulin-like growth factor small binding protein 1 in the polycystic ovary syndrome. Clin. Endocrinol. (Oxf). 1990;33(5):593–603. doi: 10.1111/j.1365-2265.1990.tb03897

29. Park Y.W., Zhu S., Palaniappan L., Heshka S., Carnethon M.R., Heymsfield S.B. The metabolic syndrome: prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988–1994. Arch. Intern. Med. 2003;163(4):427–436. doi: 10.1001/archinte.163.4.427

30. Legro R.S., Kunselman A.R., Dodson W.C., Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J. Clin. Endocrinol. Metab. 1999;84(1):165–169. doi: 10.1210/jcem.84.1.5393

31. Mani H., Levy M.J., Davies M.J., Morris D.H., Gray L.J., Bankart J., Blackledge H., Khunti K., Howlett T.A. Diabetes and cardiovascular events in women with polycystic ovary syndrome: a 20-year retrospective cohort study. Clin. Endocrinol. (Oxf). 2013;373(22):2117–2128. doi: 10.1111/cen.12068

32. de Groot P.C., Dekkers O.M., Romijn J.A., Dieben S.W., Helmerhorst F.M. PCOS, coronary heart disease, stroke and the influence of obesity: a systematic review and meta-analysis. Hum. Reprod. Update. 2011;17(4):495–500. doi: 10.1093/humupd/dmr001

33. Синдром поликистоза яичников. Клинические рекомендации. 2016. Режим доступа: https://rae-org.ru/system/files/documents/pdf/kr258_sindrom_polikistoza_yaichnikov.pdf Polycystic ovary syndrome. Clinical guidelines. 2016. Available at: https://rae-org.ru/system/files/documents/pdf/kr258_sindrom_polikistoza_yaichnikov.pdf [In Russian].

34. Tay C.T., Joham A.E., Hiam D.S., Gadalla M.A., Pundir J., Thangaratinam S., Teede H.J., Moran L.J. Pharmacological and surgical treatment of nonreproductive outcomes in polycystic ovary syndrome: An overview of systematic reviews. Clin. Endocrinol. (Oxf). 2018;89(5):35–553. doi: 10.1111/cen.1375

35. Menshawy A., Ismail A., Abdel-Maboud M., El-Din A.A., Elgebaly A., Gadelkarim M., Bahbah E.I., Abdelghany M.F., Samy A., Abbas A.M. Effect of chlormadinone acetate versus drospirenone-containing oral contraceptives on the endocrinal features of women with polycystic ovary syndrome: Systematic review and meta-analysis of randomized clinical trials. J. Gynecol. Obstet. Hum. Reprod. 2019;48(9):763–770. doi: 10.1016/j.jogoh.2019.03.025

36. Schlesselman J.J. Risk of endometrial cancer in relation to use of combined oral contraceptives. A practitioner’s guide to meta-analysis. Hum. Reprod. 1997;12(9):1851–1863. doi: 10.1093/humrep/12.9.1851

37. Manson J.E., Rimm E.B., Colditz G.A., Willett W.C., Nathan D.M., Arky R.A., Rosner B., Hennekens C.H., Speizer F.E., Stampfer M.J. A prospective study of postmenopausal estrogen therapy and subsequent incidence of non-insulin-dependent diabetes mellitus. Ann. Epidemiol. 1992;2(5):665–673 doi: 10.1016/1047-2797(92)90011-e

38. Rabe T., Luxembourg B., Ludwig M., Dinger J., Bauersachs R., Rott H., Mueck A.O., Albring C. Contraception and thrombophilia – a statement from the German Society for Gynecological Endocrinology and Reproductive Medicine and the Professional Association of German Gynaecologists. J. Reproduktions Med. Endokrinol. 2011;8(1):126–167. doi: 10.18370/2309-4117.2019.45.52-56

39. Hickson S.S., Miles K.L., McDonnell B.J., Cockcroft J.R., Wilkinson I.B., McEniery C.M., ENIGMA Study Investigators. Use of the oral contraceptive pill is associated with increased large artery stiffness in young women: the ENIGMA study. J. Hypertens. 2011;29(6):1155–1159. doi: 10.1097/HJH.0b013e328346a5af

40. Amiri M., Ramezani-Tehrani F., Nahidi F., Kabir A., Azizi F. Comparing the effects of combined oral contraceptives containing progestins with low androgenic and antiandrogenic activities on the hypothalamic-pituitary-gonadal axis in patients with polycystic ovary syndrome: systematic review and meta-analysis. JMIR Res. Protoc. 2018;7(4):e113. doi: 10.2196/resprot.9024

41. Azziz R. The evaluation and management of hirsutism. Obstet. Gynecol. 2003;101(5 Pt 1):995–1007. doi: 10.1016/s0029-7844(02)02725-4

42. Talbott E., Guzick D., Clerici A., Berga S., Detre K., Weimer K., Kuller L. Coronary heart disease risk factors in women with polycystic ovary syndrome. Arterioscler. Thromb. Vasc. Biol. 1995;15(7):821–826. doi: 10.1161/01.atv.15.7.821

43. Watanabe R.M., Azen C.G., Roy S., Perlman J.A., Bergman R.N. Defects in carbohydrate metabolism in oral contraceptive users without apparent metabolic risk factors. J. Clin. Endocrinol. Metab. 1994;79(5):1277– 1283. doi: 10.1210/jcem.79.5.7962320

44. Plewig G., Cunliffe W.J., Binder N., Höschen K. Efficacy of an oral contraceptive containing EE 0.03 mg and CMA 2 mg (Belara) in moderate acne resolution: a randomized, double-blind, placebo-controlled Phase III trial. Contraception. 2009;80(1):25–33. doi: 10.1016/j.contraception.2009.02.016

45. Guyatt G.H., Oxman A.D., Vist G.E., Kunz R., Falck-Ytter Y., Alonso-Coello P., Schünemann H.J., GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008; 336 (7650): 924–926. doi: 10.1136/bmj.39489.470347

46. Jung-Hoffmann C., Kuhl H. Divergent effects of two low-dose oral contraceptives on sex hormone-binding globulin and free testosterone. Am. J. Obstet. Gynecol. 1987;156(53):199–203. doi: 10.1016/0002-9378(87)90238-9

47. Winkler U.H., Sudik R. The effects of two monophasic oral contraceptives containing 30 mcg of ethinyl estradiol and either 2 mg of chlormadinone acetate or 0.15 mg of desogestrel on lipid, hormone and metabolic parameters. Contraception. 2009;79(1):15– 23. doi: 10.1016/j.contraception.2008.08.011

48. Cibula D., Fanta M., Vrbikova J., Stanicka S., Dvorakova K., Hill M., Skrha J., Zivny J., Skrenkova J. The effect of combination therapy with metformin and combined oral contraceptives (COC) versus COC alone on insulin sensitivity, hyperandrogenaemia, SHBG and lipids in PCOS patients. Hum. Reprod. 2005;20(1):180–184. doi: 10.1093/humrep/deh588

49. Franks S. When should an insulin sensitizing agent be used in the treatment of polycystic ovary syndrome? Clin. Endocrinol. (Oxf). 2011;74(2):148–151. doi: 10.1111/j.1365-2265.2010.03934.x

50. Velazquez E.M., Mendoza S., Hamer T., Sosa F., Glueck C.J. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism. 1994;43(5):647–654. doi: 10.1016/0026-0495(94)90209-7

51. Zakikhani M., Dowling R., Fantus I.G., Sonenberg N., Pollak M. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res. 2006;66(21):10269–10273. doi: 10.1158/0008-5472.CAN-06-1500

52. Unlühizarci K., Keleştimur F., Bayram F., Sahin Y., Tutus A. The effects of metformin on insulin resistance and ovarian steroidogenesis in women with polycystic ovary syndrome. Clin. Endocrinol. (Oxf). 1999;51(2):231–236. doi: 10.1046/ j.1365-2265.1999.00786

53. Crave J.C., Fimbel S., Lejeune H., Cugnardey N., Déchaud H., Pugeat M. Effects of diet and metformin administration on sex hormone-binding globulin, androgens, and insulin in hirsute and obese women. J. Clin. Endocrinol. Metab. 1995;80(7):2057–2062. doi: 10.1210/jcem.80.7.7608255

54. Crosignani P.G., Colombo M., Vegetti W., Somigliana E., Gessati A., Ragni G. Overweight and obese anovulatory patients with polycystic ovaries: parallel improvements in anthropometric indices, ovarian physiology and fertility rate induced by diet. Hum. Reprod. 2003;18(9):1928–1932. doi: 10.1093/humrep/deg367

55. Clark A.M., Ledger W., Galletly C., Tomlinson L., Blaney F., Wang X., Norman R.J. Weight loss results in significant improvement in pregnancy and ovulation rates in anovulatory obese women. Hum. Reprod. 1995;10(10):2705–2712. doi: 10.1093/oxfordjournals.humrep.a135772

56. Wang A., Mo T., Li Q., Shen C., Liu M. The effectiveness of metformin, oral contraceptives, and lifestyle modification in improving the metabolism of overweight women with polycystic ovary syndrome: a network meta-analysis. Endocrine. 2019;64(2):220– 232. doi: 10.1007/s12020-019-01860-w

57. Kujawska-Luczak M., Szulinska M., Skrypnik D., Musialik K., Swora-Cwynar E., Kregielska-Narozna M., Markuszewski L., Grzymislawska M., Bogdanski P. The influence of orlistat, metformin and diet on serum levels of insulin-like growth factor-1 in obeses women with and without insulin resistance. J. Physiol. Pharmacol. 2018;69(5):738–745. doi: 10.26402/jpp.2018.5.08

58. McDuffie J.R., Calis K.A., Booth S.L., Uwaifo G.I., Yanovski J.A. Effects of orlistat on fat-soluble vitamins in obese adolescents. Pharmacotherapy. 2002;22(7):814–822. doi: 10.1592/phco.22.11.814.33627

59. Escobar-Morreale H.F., Botella-Carretero J.I., Alvarez-Blasco F., Sancho J., San Millán J.L. The polycystic ovary syndrome associated with morbid obesity may resolve after weight loss induced by bariatric surgery. J. Clin. Endocrinol. Metab. 2005;90(12):6364–6369. doi: 10.1210/jc.2005-1490

60. Cena H., Chiovato L., Nappi R.E. Obesity, polycystic ovary syndrome, and infertility: a new avenue for GLP-1 receptor agonists. J. Clin. Endocrinol. Metab. 2020;105(8):2695–2709. doi: 10.1210/clinem/dgaa285

61. Coskun T., Sloop K.W., Loghin C., Alsina-Fernandez J., Urva S., Bokvist K.B., Cui X., Briere D.A., Cabrera O., Roell W.C., Kuchibhotla U., Moyers J.S., Benson C.T., Gimeno R.E., D’Alessio D.A., Haupt A. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept. Mol. Metab. 2018;(18):3–14. doi: 10.1016/j.molmet.2018.09.009

62. Frias J.P., Bastyr E.J., Vignati L., Tschöp M.H., Schmitt C., Owen K., Christensen R.H., DiMarchi R.D. The sustained effects of a dual GIP/GLP-1 receptor agonist, NNC0090-2746, in patients with type 2 diabetes. Cell. Metab. 2017;26(2):343–352. doi: 10.1016/j.cmet.2017.07.011

63. Henderson S.J., Konkar A., Hornigold D.C., Trevaskis J.L., Jackson R., Fritsch Fredin M., Jansson-Löfmark R., Naylor J., Rossi A., Bednarek M.A., Bhagroo N., Salari H., Will S., Oldham S., Hansen G., Feigh M., Klein T., Grimsby J., Maguire S., Jermutus L., Rondinone C.M., Coghlan M.P. Robust anti-obesity and metabolic effects of a dual GLP-1/glucagon receptor peptide agonist in rodents and non-human primates. Diabetes Obes. Metab. 2016;18(12):1176–1190. doi: 10.1111/dom.12735

64. Zhou J., Cai X., Huang X., Dai Y., Sun L., Zhang B., Yang B., Lin H., Huang W., Qian H. A novel glucagon-like peptide-1/glucagon receptor dual agonist exhibits weight-lowering and diabetes-protective effects. Eur. J. Med. Chem. 2017;138:1158–1169. doi: 10.1016/j.ejmech.2017.07.046

65. Müller T.D., Finan B., Clemmensen C., DiMarchi R.D., Tschöp M.H. The new biology and pharmacology of glucagon. Physiol. Rev. 2017;97(2):721–766. doi: 10.1152/physrev.00025.2016

66. Garthe I., Raastad T., Refsnes P.E., Koivisto A., Sundgot-Borgen J. Effect of two different weight-loss rates on body composition and strength and powerrelated performance in elite athletes. Int. J. Sport Nutr. Exerc. Metab. 2011;21(2):97–104. doi: 10.1123/ijsnem.21.2.97

67. Vuylsteke V., Chastain L.M., Maggu G.A., Brown C. Imeglimin: a potential new multi-target drug for type 2 diabetes. Drugs RD. 2015;15(3):227–232. doi: 10.1007/s40268-015-0099-3

68. Yaribeygi H., Maleki M., Sathyapalan T., Jamialahmadi T., Sahebkar A. Molecular mechanisms by which imeglimin improves glucose homeostasis. J. Diabetes Res. 2020;(2):1–5. doi: 10.1155/2020/8768954

69. Paoli A., Mancin L., Giacona M.C., Bianco A., Caprio M. Effects of a ketogenic diet in overweight women with polycystic ovary syndrome. J. Transl. Med. 2020;18(1):104. doi: 10.1186/s12967-020-02277-0

70. Jensterle M., Kravos N.A., Ferjan S., Goricar K., Dolzan V., Janez A. Long-term efficacy of metformin in overweight-obese PCOS: longitudinal follow-up of retrospective cohort. Endocr. Connect. 2020;9(1):44–54. doi: 10.1530/EC-19-0449

71. Hallakou-Bozec S., Vial G., Kergoat M., Fouqueray P., Bolze S., Borel A.L., Fontaine E., Moller D.E. Mechanism of action of Imeglimin: A novel therapeutic agent for type 2 diabetes. Diabetes Obes. Metab. 2021;23(3):664–673. doi: 10.1111/dom.14277

72. Papaetis G.S., Filippou P.K., Constantinidou K.G., Stylianou C.S. Liraglutide: New perspectives for the treatment of polycystic ovary syndrome. Clin. Drug Investig. 2020;40(8):695–713. doi: 10.1007/s40261-020-00942-2

73. Abdalla M.A., Deshmukh H., Atkin S., Sathyapalan T. A review of therapeutic options for managing the metabolic aspects of polycystic ovary syndrome. Ther. Adv. Endocrinol. Metab. 2020; 2042018820938305. doi: 10.1177/2042018820938305