Фармако­генетический подход к ведению женщин с непрогнозируемым «бедным» ответом на овариальную стимуляцию в программе экстракорпорального оплодотворения

1. Sun H., Gong T.T., Jiang Y.T., Zhang S., Zhao Y.H., Wu Q.J. Global, regional, and national prevalence and disability-adjusted life-years for infertility in 195 countries and territories 1990-2017: results from a global burden of disease study 2017. Aging (Albany NY). 2019; 11(23): 10952-91. https://dx.doi.org/10.18632/aging.102497.
2. Alviggi C., Andersen C.Y., Buehler K., Conforti A., De Placido G., Esteves S.C. et al.; Poseidon Group (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number). A new more detailed stratification of low responders to ovarian stimulation: from a poor ovarian response to a low prognosis concept. Fertil. Steril. 2016; 105(6): 1452-3. https://dx.doi.org/10.1016/j.fertnstert.2016.02.005.
3. Alviggi C., Conforti A., Santi D., Esteves S.C., Andersen C.Y., Humaidan P. et al. Clinical relevance of genetic variants of gonadotrophins and their receptors in controlled ovarian stimulation: a systematic review and meta-analysis. Hum. Reprod. Update. 2018; 24(5): 599-614. https://dx.doi.org/10.1093/humupd/dmy019.
4. Klinkert E.R., Broekmans F.J., Looman C.W., Habbema J.D., te Velde E.R. Expected poor responders on the basis of an antral follicle count do not benefit from a higher starting dose of gonadotrophins in IVF treatment: a randomized controlled trial. Hum. Reprod. 2005; 20(3): 611-5. https://dx.doi.org/10.1093/humrep/ deh663.
5. Polyzos N.P., Drakopoulos P. Management strategies for POSEIDON’s Group 1. Front. Endocrinol. Lausanne). 2019; 10: 679. https://dx.doi.org/10.3389/fendo.2019.00679.
6. Conforti A., Tüttelmann F., Alviggi C., Behre H.M., Fischer R., Hu L. et al. Effect of genetic variants of gonadotropins and their receptors on ovarian stimulation outcomes: A Delphi consensus. Front. Endocrinol. (Lausanne). 2022; 12: 797365. https://dx.doi.org/10.3389/fendo.2021.797365.
7. Li Y., Li X., Yang X., Cai S., Lu G., Lin G. et al. Cumulative live birth rates in low prognosis patients according to the POSEIDON criteria: an analysis of 26,697 cycles of in vitro fertilization/intracytoplasmic sperm injection. Front. Endocrinol. (Lausanne). 2019; 10: 642. https://dx.doi.org/10.3389/fendo.2019.00642.
8. Paffoni A., Cesana S., Corti L., Ballabio E., Salemi C., Kunderfranco A.,Bianchi M.C. Pregnancy rate in IVF patients with unexpected poor response to ovarian stimulation. Gynecol. Endocrinol. 2022; 38(9): 736-41.https://dx.doi.org/10.1080/09513590.2022.2100339.
9. La Marca A., Sunkara S.K. Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice. Hum. Reprod. Update. 2014; 20(1):124-40. https://dx.doi.org/10.1093/humupd/dmt037.
10. Назаренко Т.А., Краснопольская К.В. “Бедный ответ”. Тактика ведения пациенток со сниженной реакцией на стимуляцию гонадотропинами в программах ЭКО. 2-е изд. М.: МЕДпресс-информ; 2013. 80c. 
11. La Marca A., Sighinolfi G., Argento C., Grisendi V., Casarini L., Volpe A. et al. Polymorphisms in gonadotropin and gonadotropin receptor genes as markers of ovarian reserve and response in in vitro fertilization. Fertil. Steril. 2013; 99(4): 970-8.e1. https://dx.doi.org/10.1016/j.fertnstert.2013.01.086.
12. Kalinderi K., Asimakopoulos B., Nikolettos N., Manolopoulos V.G. Pharmacogenomics in IVF: a new era in the concept of personalized medicine. Reprod. Sci. 2019; 26(10): 1313-25. https://dx.doi.org/10.1177/1933719118765970.
13. Squassina A., Manchia M., Manolopoulos V.G., Artac M., Lappa-Manakou C., Karkabouna S. et al. Realities and expectations of pharmacogenomics and personalized medicine: impact of translating genetic knowledge into clinical practice. Pharmacogenomics. 2010; 11(8): 1149-67. https://dx.doi.org/10.2217/pgs.10.97.
14. Seng K.C., Seng C.K. The success of the genome-wide association approach: a brief story of a long struggle. Eur. J. Hum. Genet. 2008; 16(5): 554-64.https://dx.doi.org/10.1038/ejhg.2008.12.
15. Perez Mayorga M., Gromoll J., Behre H.M., Gassner C., Nieschlag E., Simoni M. Ovarian response to follicle-stimulating hormone (FSH) stimulation depends on the FSH receptor genotype. J. Clin. Endocrinol. Metab. 2000; 85(9): 3365-9. https://dx.doi.org/ 10.1210/jcem.85.9.6789.
16. Владимирова И.В., Донников А.Е., Баранова Е.Е., Калинина Е.А. Анализ полиморфизма гена рецептора фолликулостимулирующего гормона для прогноза исхода программы экстракорпорального оплодотворения. Клиническая лабораторная диагностика. 2014; 59(9): 135.
17. Bayraktar B., Güleç E.Ş., Kutbay Y.B., Köse C., Gür E.B., Demir A. Does follicle-stimulating hormone receptor polymorphism status affect in vitro fertilization-intracytoplasmic sperm injection results and live birth rate? A retrospective study. J. Hum. Reprod. Sci. 2022; 15(1): 58-63. https://dx.doi.org/10.4103/jhrs.jhrs_165_21.
18. Pabalan N., Trevisan C.M., Peluso C., Jarjanazi H., Christofolini D.M., Barbosa C.P., Bianco B. Evaluating influence of the genotypes in the follicle stimulating hormone receptor (FSHR) Ser680Asn (rs6166) polymorphism on poor and hyper-responders to ovarian stimulation: a meta-analysis. J. Ovarian Res. 2014; 7: 285. https://dx.doi.org/10.1186/s13048-014-0122-2.
19. Alviggi C., Conforti A., Caprio F., Gizzo S., Noventa M., Strina I. et al. In estimated good prognosis patients could unexpected “Hyporespnse” to controlled ovarian stimulation be related to genetic polymorphisms of FSH receptor? Reprod. Sci. 2016; 23(8): 1103-8. https://dx.doi.org/10.1177/1933719116630419.
20. Tang H., Yan Y., Wang T., Zhang T., Shi W., Fan R. et al. Effect of follicle-stimulating hormone receptor Asn680Ser polymorphism on the outcomes of controlled ovarian hyperstimulation: an updated meta-analysis of 16 cohort studies. J. Assist. Reprod. Genet. 2015; 32(12): 1801-10.https://dx.doi.org/10.1007/s10815-015-0600-5.
21. Huang X., Li L., Hong L., Zhou W., Shi H., Zhang H. et al. The Ser680Asn olymorphism in the follicle-stimulating hormone receptor gene is associated with the ovarian response in controlled ovarian hyperstimulation. Clin. Endocrinol. (Oxford). 2015; 82(4): 577-83. https://dx.doi.org/10.1111/cen.12573.
22. Yan Y., Gong Z., Zhang L., Li Y., Li X. et al. Association of follicle-stimulating gormone receptor polymorphisms with ovarian response in Chinese women: a prospective clinical study. PLoS One. 2013; 8(10): e78138.https://dx.doi.org/10.1371/journal.pone.0078138.
23. Achrekar S.K., Modi D.N., Desai S.K., Mangoli V.S., Mangoli R.V., Mahale S.D. Follicle-stimulating hormone receptor polymorphism (Thr307Ala) is associated with variable ovarian response and ovarian hyperstimulation syndrome in indian women. Fertil. Steril. 2009; 91(2): 432-9. https://dx.doi.org/10.1016/j.fertnstert.2007.11.093.
24. Čuš M., Vlaisavljević V., Repnik K., Potočnik U., Kovačič B. Could polymorphisms of some hormonal receptor genes, involved in folliculogenesis help in predicting patient response to controlled ovarian stimulation? J. Assist. Reprod. Genet. 2019; 36(1): 47-55. https://dx.doi.org/10.1007/s10815-018-1357-4.
25. Desai S.S., Achrekar S.K., Pathak B.R., Desai S.K., Mangoli V.S., Mangoli R.V., Mahale S.D. Follicle-stimulating hormone receptor polymorphism (G-29A) is associated with altered level of receptor expression in granulosa cells. J. Clin. Endocrinol. Metab. 2011; 96(9): 2805-12. https://dx.doi.org/10.1210/jc.2011-1064.
26. Polyzos N.P., Neves A.R., Drakopoulos P., Spits C., Alvaro Mercadal B., Garcia S. et al. The effect of polymorphisms in FSHR and FSHB genes on ovarian response: a prospective multicenter multinational study in Europe and Asia. Hum. Reprod. 2021; 36(6): 1711-21. https://dx.doi.org/10.1093/humrep/deab068.
27. Rull K., Grigorova M., Ehrenberg A., Vaas P., Sekavin A., Nõmmemees D. et al. FSHB -211 G>T is a major genetic modulator of reproductive physiology and health in childbearing age women. Hum. Reprod. 2018; 33(5): 954-66.https://dx.doi.org/10.1093/humrep/dey057.
28. Trevisan C.M., de Oliveira R., Christofolini D.M., Barbosa C.P., Bianco B. Effects of a polymorphism in the promoter region of the follicle-stimulating hormone subunit Beta (FSHB) gene on female reproductive outcomes. Genet. Test. Mol. Biomarkers. 2019; 23(1): 39-44. https://dx.doi.org/10.1089/gtmb.2018.0182.
29. Schüring A.N., Busch A.S., Bogdanova N., Gromoll J., Tüttelmann F. Effects of the FSH-β-subunit promoter polymorphism -211G->T on the hypothalamic-pituitary-ovarian axis in normally cycling women indicate a gender-specific regulation of gonadotropin secretion. J. Clin. Endocrinol. Metab. 2013; 98(1): E82-6. https://dx.doi.org/10.1210/jc.2012-2780.
30. Alviggi C., Clarizia R., Pettersson K., Mollo A., Humaidan P., Strina I. et al. Suboptimal response to GnRHa long protocol is associated with a common LH polymorphism. Reprod. Biomed. Online. 2011; 22(Suppl. 1): S67-72.https://dx.doi.org/10.1016/S1472-6483(11)60011-4.
31. Loutradis D., Theofanakis C., Anagnostou E., Mavrogianni D., Partsinevelos G.A. Genetic profile of SNP(s) and ovulation induction. Curr. Pharm. Biotechnol. 2012; 13(3): 417-25. https://dx.doi.org/10.2174/138920112799361954.
32. Ga R., Cheemakurthi R., Kalagara M., Prathigudupu K., Balabomma K.L., Mahapatro P. et al. Effect of LHCGR gene polymorphism (rs2293275) on LH supplementation protocol outcomes in second IVF cycles: a retrospective study. Front. Endocrinol. (Lausanne). 2021; 12: 628169. https://dx.doi.org/10.3389/fendo.2021.628169.
33. Alviggi C., Pettersson K., Longobardi S., Andersen C.Y., Conforti A., De Rosa P. et al. A common polymorphic allele of the LH beta-subunit gene is associated with higher exogenous FSH consumption during controlled ovarian stimulation for assisted reproductive technology. Reprod. Biol. Endocrinol. 2013; 11: 51. https://dx.doi.org/10.1186/1477-7827-11-51.
34. Altmäe S., Hovatta O., Stavreus-Evers A., Salumets A. Genetic predictors of controlled ovarian hyperstimulation: where do we stand today? Hum. Reprod. Update. 2011; 17(6): 813-28. https://dx.doi.org/10.1093/humupd/dmr034.
35. Papaleo E., Vanni V.S., Vigano P., La Marca A., Pagliardini L., Vitrano R. et al. Recombinant LH administration in subsequent cycle after “unexpected” poor response to recombinant FSH monotherapy. Gynecol. Endocrinol. 2014; 30(11): 813-6. https://dx.doi.org/10.3109/09513590.2014.9 32342.
36. de Mattos C.S., Trevisan C.M., Peluso C., Adami F., Cordts E.B., Christofolini D.M. et al. ESR1 and ESR2 gene polymorphisms are associated with human reproduction outcomes in Brazilian women. J. Ovarian Res. 2014; 7: 114. https://dx.doi.org/10.1186/s13048-014-0114-2.
37. Boudjenah R., Molina-Gomes D., Torre A., Bergere M., Bailly M., Boitrelle F. et al. Genetic polymorphisms influence the ovarian response to rFSH stimulation in patients undergoing in vitro fertilization programs with ICSI. PLoS One. 2012; 7(6): e38700. https://dx.doi.org/10.1371/journal.pone.0038700.
38. Motawi T.M.K., Rizk S.M., Maurice N.W., Maged A.M., Raslan A.N.,Sawaf A.H. The role of gene polymorphisms and AMH level in prediction of poor ovarian response in Egyptian women undergoing IVF procedure. J. Assist. Reprod. Genet. 2017; 34(12): 1659-66. https://dx.doi.org/10.1007/s10815-017-1013-4.
39. Sindiani A.M., Batiha O., Al-Zoubi E., Khadrawi S., Alsoukhni G., Alkofahi A. et al. Association of single-nucleotide polymorphisms in the ESR2 and FSHR genes with poor ovarian response in infertile Jordanian women. Clin. Exp. Reprod. Med. 2021; 48(1): 69-79. https://dx.doi.org/10.5653/cerm.2020.03706.
40. Altmäe S., Haller K., Peters M., Hovatta O., Stavreus-Evers A., Karro H. et al. Allelic estrogen receptor 1 (ESR1) gene variants predict the outcome of ovarian stimulation in in vitro fertilization. Mol. Hum. Reprod. 2007; 13(8): 521-6. https://dx.doi.org/10.1093/molehr/gam035.
41. Rzeszowska M., Leszcz A., Putowski L., Hałabiś M., Tkaczuk-Włach J., Kotarski J., Polak G. Anti-Müllerian hormone: structure, properties and appliance. Ginekol. Polska. 2016; 87(9): 669-74. https://dx.doi.org/10.5603/gp.2016.0064.
42. Imbeaud S., Faure E., Lamarre I., Mattéi M.G., di Clemente N., Tizard R. et al. Insensitivity to anti-Müllerian hormone due to a mutation in the human anti-Müllerian hormone receptor. Nat. Genet. 1995; 11(4): 382-8.https://dx.doi.org/10.1038/ng1295-382.
43. Yoshida Y., Yamashita Y., Saito N., Ono Y., Yamamoto H., Nakamura Y. et al. Analyzing the possible involvement of anti-Müllerian hormone and anti-Müllerian hormone receptor II single nucleotide polymorphism in infertility. J. Assist. Reprod. Genet. 2014; 31(2): 163-8. https://dx.doi.org/10.1007/s10815-013-0134-7.
44. Meireles A.J.C., Bilibio J.P., Lorenzzoni P.L., Conto E., Nascimento F.C.D., Cunha-Filho J.S.D. Association of FSHR, LH, LHR, BMP15, GDF9, AMH, and AMHR polymorphisms with poor ovarian response in patients undergoing in vitro fertilization. JBRA Assist. Reprod. 2021; 25(3): 439-46.https://dx.doi.org/10.5935/1518-0557.20210004.
45. Simpson E.R., Mahendroo M.S., Means G.D., Kilgore M.W., Hinshelwood M.M., Graham-Lorence S. et al. Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocr. Rev. 1994; 15: 342-55.
46. Лапштаева А.В., Еремкина Т.Я., Сычев И.В. Актуальность разработки персонализированного подхода к стимуляции суперовуляции в программах экстракорпорального оплодотворения. Фармакогенетика и фармакогеномика. 2019; 1: 17-24. https://dx.doi.org/10.24411/2588-0527-2019-10037. 
47. Altmäe S., Haller K., Peters M., Saare M., Hovatta O., Stavreus-Evers A. et al. Aromatase gene (CYP19A1) variants, female infertility and ovarian stimulation outcome: a preliminary report. Reprod. Biomed. Online. 2009; 18(5): 651-7. https://dx.doi.org/10.1016/s1472-6483(10)60009-0.
48. Lazaros L.A., Hatzi E.G., Pamporaki C.E., Sakaloglou P.I., Xita N.V.,Markoula S.I. et al. The ovarian response to standard gonadotrophin stimulation depends on FSHR, SHBG and CYP19 gene synergism. J. Assist. Reprod. Genet. 2012; 29(11): 1185-91. https://dx.doi.org/10.1007/s10815-012-9849-0.
49. Juengel J.L., McNatty K.P. The role of proteins of the transforming growth factor-beta superfamily in the intraovarian regulation of follicular development. Hum. Reprod. Update. 2005; 11(2): 143-60. https://dx.doi.org/10.1093/humupd/dmh061.
50. Elvin J.A., Yan C., Wang P., Nishimori K., Matzuk M.M. Molecular characterization of the follicle defects in the growth differentiation factor 9-deficient ovary. Mol. Endocrinol. 1999; 13(6): 1018-34. https://dx.doi.org/10.1210/mend.13.6.0309.
51. Dragovic R.A., Ritter L.J., Schulz S.J., Amato F., Armstrong D.T., Gilchrist R.B. Role of oocyte-secreted growth differentiation factor 9 in the regulation of mouse cumulus expansion. Endocrinology. 2005; 146(6): 2798-806.https://dx.doi.org/10.1210/en.2005-0098.
52. Dong J., Albertini D.F., Nishimori K., Kumar T.R., Lu N., Matzuk M.M. Growth differentiation factor-9 is required during early ovarian folliculogenesis. Nature. 1996; 383(6600): 531-5. https://dx.doi.org/10.1038/383531a0.
53. SerdyńskaSzuster M., Jędrzejczak P., Ożegowska K.E., Hołysz H., Pawelczyk L., Jagodziński P.P. Effect of growth differentiation factor9 C447T and G546A polymorphisms on the outcomes of in vitro fertilization. Mol. Med. Rep. 2016; 13(5): 4437-42. https://dx.doi.org/10.3892/mmr.2016.5060.
54. Bilibio J.P., Meireles A.J.C., Conto E., Lorenzzoni P.L., Nascimento F.C.D., Cunha-Filho J.S.D. GDF9 polymorphisms: influence on ovarian response in women undergoing controlled ovarian hyperstimulation. JBRA Assist. Reprod. 2020; 24(4): 447-53. https://dx.doi.org/10.5935/1518-0557.20200027.
55. Meireles A.J.C., Bilibio J.P., Lorenzzoni P.L., Conto E., Nascimento F.C.D., Cunha-Filho J.S.D. Association of FSHR, LH, LHR, BMP15, GDF9, AMH, and AMHR polymorphisms with poor ovarian response in patients undergoing in vitro fertilization. JBRA Assist. Reprod. 2021; 25(3): 439-46.https://dx.doi.org/10.5935/1518-0557.20210004.

Поступила 31.10.2022

Принята в печать 28.11.2022