Возможности использования агониста ГнРГ для поддержки лютеиновой фазы в программе экстракорпорального оплодотворения
Цель исследования. Оценить влияние комбинированного режима поддержки лютеиновой фазы (ЛФ) с добавлением агониста гонадотропин-рилизинг гормона (аГнРГ) к микронизированному прогестерону и стандартного режима поддержки ЛФ микронизированным прогестероном на эффективность программы экстракорпорального оплодотворения (ЭКО). Материал и методы. Исследование проведено у 207 пациенток в возрасте до 38 лет с трубно-перитонеальным, мужским или сочетанными факторами бесплодия. В день трансвагинальной пункции (ТВП) пациентки были рандомизированы в зависимости от режима поддержки ЛФ: пациентки 1-й группы (n=92) получали натуральный микронизированный прогестерон – 600 мг/день вагинально с 1-х суток после ТВП и однократную дозу трипторелина – 0,1 мг подкожно на 6-е сутки после ТВП; пациентки 2-й группы (n=115) – микронизированный прогестерон 600 мг/день вагинально с 1-х суток после ТВП. Результаты. Анализ эффективности программы ЭКО показал, что у пациенток с комбинированным режимом поддержки ЛФ по сравнению с пациентками со стандартным режимом выявлена более высокая частота имплантации (30,6 и 16,6%, р<0,05), клинической беременности (40,2 и 26,9%, р=0,04), прогрессирующей беременности (36,9 и 21,7%, р=0,01) и родов живым плодом (31,5 и 19,1%, р=0,04). Заключение. Комбинированный режим поддержки ЛФ с использованием аГнРГ оказывает позитивный эффект на исходы программ ЭКО в протоколах с антагонистом ГнРГ.Перминова С.Г., Митюрина Е.В., Савельева Е.М.
Ключевые слова
экстракорпоральное оплодотворение
аГнРГ
поддержка лютеиновой фазы
микронизированный прогестерон
Список литературы
1. Beckers N.G., Macklon N.S., Eijkemans M.J., Ludwig M., Felberbaum R.E., Diedrich K. et al. Nonsupplemented luteal phase characteristics after the administration of recombinant human chorionic gonadotropin, recombinant luteinizing hormone, or gonadotropin-releasing hormone (GnRH) agonist to induce final oocyte maturation in in vitro fertilization patients after ovarian stimulation with recombinant follicle-stimulating hormone and GnRH antagonist cotreatment. J. Clin. Endocrinol. Metab. 2003; 88(9): 4186-92.
2. Fatemi H.M. The luteal phase after 3 decades of IVF: what do we know? Reprod. Biomed. Online. 2009; 19(Suppl. 4): 4331.
3. Tesarik J., Hazout A., Mendoza-Tesarik R., Mendoza N., Mendoza C. Beneficial effect of luteal-phase GnRH agonist administration on embryo implantation after ICSI in both GnRH agonist- and antagonist-treated ovarian stimulation cycles. Hum. Reprod. 2006; 21(10): 2572-9.
4. Oliveira J.B., Baruffi R., Petersen C.G., Mauri A.L., Cavagna M., Franco J.G. Jr. Administration of single-dose GnRH agonist in the luteal phase in ICSI cycles: a meta-analysis. Reprod. Biol. Endocrinol. 2010; 8: 107.
5. Kyrou D., Kolibianakis E.M., Fatemi H.M., Tarlatzi T.B., Devroey P., Tarlatzis B.C. Increased live birth rates with GnRH agonist addition for luteal support in ICSI/IVF cycles: a systematic review and meta-analysis. Hum. Reprod. Update. 2011; 17(6 ): 734-40.
6. Van der Linden M., Buckingham K., Farquhar C., Kremer J.A., Metwally M. Luteal phase support for assisted reproduction cycles. Cochrane Database Syst. Rev. 2011; (10): CD009154.
7. Van der Linden M., Buckingham K., Farquhar C., Kremer J.A., Metwally M. Luteal phase support for assisted reproduction cycles. Cochrane Database Syst. Rev. 2015; (7): CD009154.
8. Fujii S., Sato S., Fukui A., Kimura H., Kasai G., Saito Y. Continuous administration of gonadotrophin-releasing hormone agonist during the luteal phase in IVF. Hum. Reprod. 2001; 16(8): 1671-5.
9. Qublan H., Amarin Z., Al-Quda M., Diab F., Nawasreh M., Malkawi S., Balawneh M. Luteal phase support with GnRH-a improves implantation and pregnancy rates in IVF cycles with endometrium of <or=7 mm on day of egg retrieval. Hum. Fertil. (Camb.). 2008; 11(1): 43-7.
10. Inamdar D.B., Majumdar A. Evaluation of the impact of gonadotropin-releasing hormone agonist as an adjuvant in luteal-phase support on IVF outcome. J. Hum. Reprod. Sci. 2012; 5(3): 279-84.
11. Isik A.Z., Caglar G.S., Sozen E., Akarsu C., Tuncay G., Ozbicer T., Vicdan K. Single-dose GnRH agonist administration in the luteal phase of GnRH antagonist cycles: a prospective randomized study. Reprod. Biomed. Online. 2009; 19(4): 472-7.
12. Martins W.P., Ferriani R.A., Navarro P.A., Nastri C.O. GnRH agonist during luteal phase in women undergoing assisted reproductive techniques: systematic review and meta-analysis of randomized controlled trials. Ultrasound Obstet. Gynecol. 2016; 47(2): 144-51.
13. Pirard C., Donnez J., Loumaye E. GnRH agonist as novel luteal support: results of a randomized, parallel group, feasibility study using intranasal administration of buserelin. Hum. Reprod. 2005; 20(7): 1798-804.
14. Klemmt P.A., Liu F., Carver J.G., Jones C., Brosi D., Adamson J. et al. Effects of gonadotrophin releasing hormone analogues on human endometrial stromal cells and embryo invasion in vitro. Hum. Reprod. 2009; 24(9): 2187-92.
15. Casañ E.M.,Raga F.,Polan M.L. GnRH mRNA and protein expression in human preimplantation embryos. Mol. Hum. Reprod. 1999; 5(3): 234-9.
16. Nam D.H., Lee S.H., Kim H.S., Lee G.S., Jeong Y.W., Kim S. et al. The role of gonadotropin-releasing hormone (GnRH) and its receptor in development of porcine preimplantation embryos derived from in vitro fertilization. Theriogenology. 2005; 63(1): 190-201.
17. Raga F., Casan E.M., Wen Y., Huang H.Y., Bonilla-Musoles F., Polan M. Independent regulation of matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and TIMP-3 in human endometrial stromal cells by gonadotropin-releasing hormone: implications in early human implantation. J. Clin. Endocrinol. Metab. 1999; 84(2): 636-42.
18. Lin L., Roberts V.J., Yen S. Expression of human gonadotropin-releasing hormone receptor gene in the placenta and its functional relationship to human chorionic gonadotropin secretion. J. Clin. Endocrinol. Metab. 1995;80(2): 580-5.
19. Raga F., Casan E.M., Kruessel J.S., Wen Y., Huang H.Y., Nezhat C. et al. Quantitative gonadotropin-releasing hormone gene expression and immunohistochemical localization in human endometrium throughout the menstrual cycle. Biol. Reprod. 1998; 59(3): 661-9.
20. Zhang X., Bocca S., Franchi A., Anderson S., Kaur M., Bajic V.B., Oehninger S. Do GnRH analogues directly affect human endometrial epithelial cell gene expression? Mol. Hum. Reprod. 2010; 16(5): 347-60.
21. Ata B., Yakin K., Balaban B., Urman B. GnRH agonist protocol administration in the luteal phase in ICSI-ET cycles stimulated with the long GnRH agonist protocol: a randomized, controlled double blind study. Hum. Reprod. 2008; 23(3): 668-73.
22. Ata B., Urman B. Single dose GnRH agonist administration in the luteal phase of assisted reproduction cycles: is the effect dependent on the type of GnRH analogue used for pituitary suppression? Reprod. Biomed. Online. 2010; 20(1): 165-6.
23. Zafardoust S., Jeddi-Tehrani M., Akhondi M., Sadeghi M., Kamali K., Mokhtar S. et al. Effect of administration of single dose GnRH agonist in luteal phase on outcome of ICSI-ET cycles in women with previous history of IVF/ICSI failure: a randomized controlled trial. J. Reprod. Infertil. 2015;16(2): 96-101.
24. Isikoglu M., Ozgur K., Oehninger S. Extension of GnRH agonist through the luteal phase to improve the outcome of intracytoplasmic sperm injection. J. Reprod. Med. 2007; 52(7): 639-44.
25. Razieh D.F., Maryam A.R., Nasim T. Beneficial effect of luteal-phase gonadotropin-releasing hormone agonist administration on implantation rate after intracytoplasmic sperm injection. Taiwan. J. Obstet. Gynecol. 2009; 48(3): 245-8.
26. Bar-Hava I., Mizrachi Y., Karfunkel-Doron D., Omer Y., Sheena L., Carmon N., Ben-David G. Intranasal gonadotropin-releasing hormone agonist (GnRHa) for luteal-phase support following GnRHa triggering, a novel approach to avoid ovarian hyperstimulation syndrome in high responders. Fertil. Steril. 2016; 106(2): 330-3.
27. Bar Hava I.,Blueshtein M.,Ganer Herman H.,Omer Y.,Ben David G. Gonadotropin-releasing hormone analogue as sole luteal support in antagonist-based assisted reproductive technology cycles. Fertil. Steril. 2017;107(1): 130-5.
28. Kung H.F.,Chen M.J.,Guua H.F.,Chen Y.F.,Yi Y.C.,Yen-Ping Ho J., Chou M.M. Luteal phase support with decapeptyl improves pregnancy outcomes in intracytoplasmic sperm injection with higher basal follicle-stimulating hormone or lower mature oocytes. J. Chin. Med. Assoc.2014; 77(10): 524-30.
29. Marcus S.F., Ledger W.L. Efficacy and safety of long-acting GnRH agonists in in vitro fertilization and embryo transfer. Hum. Fertil. (Camb.). 2001; 4: 85-93.
30. Cachill D. Risks of GnRH agonist administration in early pregnancy. In: Filicory M., Flamigni C., eds. Ovulation induction: update ’98. London: Parthenon Publishing Group; 1998: 97-105.
31. Wilcox A.J., Weinberg C.R., O’Connor J.F., Baird D.D., Schlatterer J.P., Canfield R.E. et al. Incidence of early loss of pregnancy. N. Engl. J. Med. 1988; 319(4): 189-94.
32. Dolk H., Loane M., Garne E. The prevalence of congenital anomalies in Europe. Adv. Exp. Med. Biol. 2010; 686: 349-64.
33. Orvieto R., Kerner R., Krissi H., Ashkenazi J., Ben Rafael Z., Bar-Hava I. Comparison of leuprolide acetate and triptorelin in assisted reproductive technology cycles: a prospective, randomized study. Fertil. Steril. 2002; 78(6): 1268-71.
34. Ferring. Decapeptyl 0.1 mg. Available at: https://www.old.health.gov. il/units/pharmacy/trufot/alonim/DECAPEPTYL-dr_1382514091053.pdf Accessed September 29, 2016.
Поступила 26.02.2018
Принята в печать 02.03.2018
Об авторах / Для корреспонденции
1. Beckers N.G., Macklon N.S., Eijkemans M.J., Ludwig M., Felberbaum R.E., Diedrich K. et al. Nonsupplemented luteal phase characteristics after the administration of recombinant human chorionic gonadotropin, recombinant luteinizing hormone, or gonadotropin-releasing hormone (GnRH) agonist to induce final oocyte maturation in in vitro fertilization patients after ovarian stimulation with recombinant follicle-stimulating hormone and GnRH antagonist cotreatment. J. Clin. Endocrinol. Metab. 2003; 88(9): 4186-92.
2. Fatemi H.M. The luteal phase after 3 decades of IVF: what do we know? Reprod. Biomed. Online. 2009; 19(Suppl. 4): 4331.
3. Tesarik J., Hazout A., Mendoza-Tesarik R., Mendoza N., Mendoza C. Beneficial effect of luteal-phase GnRH agonist administration on embryo implantation after ICSI in both GnRH agonist- and antagonist-treated ovarian stimulation cycles. Hum. Reprod. 2006; 21(10): 2572-9.
4. Oliveira J.B., Baruffi R., Petersen C.G., Mauri A.L., Cavagna M., Franco J.G. Jr. Administration of single-dose GnRH agonist in the luteal phase in ICSI cycles: a meta-analysis. Reprod. Biol. Endocrinol. 2010; 8: 107.
5. Kyrou D., Kolibianakis E.M., Fatemi H.M., Tarlatzi T.B., Devroey P., Tarlatzis B.C. Increased live birth rates with GnRH agonist addition for luteal support in ICSI/IVF cycles: a systematic review and meta-analysis. Hum. Reprod. Update. 2011; 17(6 ): 734-40.
6. Van der Linden M., Buckingham K., Farquhar C., Kremer J.A., Metwally M. Luteal phase support for assisted reproduction cycles. Cochrane Database Syst. Rev. 2011; (10): CD009154.
7. Van der Linden M., Buckingham K., Farquhar C., Kremer J.A., Metwally M. Luteal phase support for assisted reproduction cycles. Cochrane Database Syst. Rev. 2015; (7): CD009154.
8. Fujii S., Sato S., Fukui A., Kimura H., Kasai G., Saito Y. Continuous administration of gonadotrophin-releasing hormone agonist during the luteal phase in IVF. Hum. Reprod. 2001; 16(8): 1671-5.
9. Qublan H., Amarin Z., Al-Quda M., Diab F., Nawasreh M., Malkawi S., Balawneh M. Luteal phase support with GnRH-a improves implantation and pregnancy rates in IVF cycles with endometrium of <or=7 mm on day of egg retrieval. Hum. Fertil. (Camb.). 2008; 11(1): 43-7.
10. Inamdar D.B., Majumdar A. Evaluation of the impact of gonadotropin-releasing hormone agonist as an adjuvant in luteal-phase support on IVF outcome. J. Hum. Reprod. Sci. 2012; 5(3): 279-84.
11. Isik A.Z., Caglar G.S., Sozen E., Akarsu C., Tuncay G., Ozbicer T., Vicdan K. Single-dose GnRH agonist administration in the luteal phase of GnRH antagonist cycles: a prospective randomized study. Reprod. Biomed. Online. 2009; 19(4): 472-7.
12. Martins W.P., Ferriani R.A., Navarro P.A., Nastri C.O. GnRH agonist during luteal phase in women undergoing assisted reproductive techniques: systematic review and meta-analysis of randomized controlled trials. Ultrasound Obstet. Gynecol. 2016; 47(2): 144-51.
13. Pirard C., Donnez J., Loumaye E. GnRH agonist as novel luteal support: results of a randomized, parallel group, feasibility study using intranasal administration of buserelin. Hum. Reprod. 2005; 20(7): 1798-804.
14. Klemmt P.A., Liu F., Carver J.G., Jones C., Brosi D., Adamson J. et al. Effects of gonadotrophin releasing hormone analogues on human endometrial stromal cells and embryo invasion in vitro. Hum. Reprod. 2009; 24(9): 2187-92.
15. Casañ E.M., Raga F., Polan M.L. GnRH mRNA and protein expression in human preimplantation embryos. Mol. Hum. Reprod. 1999; 5(3): 234-9.
16. Nam D.H., Lee S.H., Kim H.S., Lee G.S., Jeong Y.W., Kim S. et al. The role of gonadotropin-releasing hormone (GnRH) and its receptor in development of porcine preimplantation embryos derived from in vitro fertilization. Theriogenology. 2005; 63(1): 190-201.
17. Raga F., Casan E.M., Wen Y., Huang H.Y., Bonilla-Musoles F., Polan M. Independent regulation of matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and TIMP-3 in human endometrial stromal cells by gonadotropin-releasing hormone: implications in early human implantation. J. Clin. Endocrinol. Metab. 1999; 84(2): 636-42.
18. Lin L., Roberts V.J., Yen S. Expression of human gonadotropin-releasing hormone receptor gene in the placenta and its functional relationship to human chorionic gonadotropin secretion. J. Clin. Endocrinol. Metab. 1995;80(2): 580-5.
19. Raga F., Casan E.M., Kruessel J.S., Wen Y., Huang H.Y., Nezhat C. et al. Quantitative gonadotropin-releasing hormone gene expression and immunohistochemical localization in human endometrium throughout the menstrual cycle. Biol. Reprod. 1998; 59(3): 661-9.
20. Zhang X., Bocca S., Franchi A., Anderson S., Kaur M., Bajic V.B., Oehninger S. Do GnRH analogues directly affect human endometrial epithelial cell gene expression? Mol. Hum. Reprod. 2010; 16(5): 347-60.
21. Ata B., Yakin K., Balaban B., Urman B. GnRH agonist protocol administration in the luteal phase in ICSI-ET cycles stimulated with the long GnRH agonist protocol: a randomized, controlled double blind study. Hum. Reprod. 2008; 23(3): 668-73.
22. Ata B., Urman B. Single dose GnRH agonist administration in the luteal phase of assisted reproduction cycles: is the effect dependent on the type of GnRH analogue used for pituitary suppression? Reprod. Biomed. Online. 2010; 20(1): 165-6.
23. Zafardoust S., Jeddi-Tehrani M., Akhondi M., Sadeghi M., Kamali K., Mokhtar S. et al. Effect of administration of single dose GnRH agonist in luteal phase on outcome of ICSI-ET cycles in women with previous history of IVF/ICSI failure: a randomized controlled trial. J. Reprod. Infertil. 2015;16(2): 96-101.
24. Isikoglu M., Ozgur K., Oehninger S. Extension of GnRH agonist through the luteal phase to improve the outcome of intracytoplasmic sperm injection. J. Reprod. Med. 2007; 52(7): 639-44.
25. Razieh D.F., Maryam A.R., Nasim T. Beneficial effect of luteal-phase gonadotropin-releasing hormone agonist administration on implantation rate after intracytoplasmic sperm injection. Taiwan. J. Obstet. Gynecol. 2009; 48(3): 245-8.
26. Bar-Hava I., Mizrachi Y., Karfunkel-Doron D., Omer Y., Sheena L., Carmon N., Ben-David G. Intranasal gonadotropin-releasing hormone agonist (GnRHa) for luteal-phase support following GnRHa triggering, a novel approach to avoid ovarian hyperstimulation syndrome in high responders. Fertil. Steril. 2016; 106(2): 330-3.
27. Bar Hava I., Blueshtein M., Ganer Herman H., Omer Y., Ben David G. Gonadotropin-releasing hormone analogue as sole luteal support in antagonist-based assisted reproductive technology cycles. Fertil. Steril. 2017;107(1): 130-5.
28. Kung H.F., Chen M.J., Guua H.F., Chen Y.F., Yi Y.C., Yen-Ping Ho J., Chou M.M. Luteal phase support with decapeptyl improves pregnancy outcomes in intracytoplasmic sperm injection with higher basal follicle-stimulating hormone or lower mature oocytes. J. Chin. Med. Assoc. 2014; 77(10): 524-30.
29. Marcus S.F., Ledger W.L. Efficacy and safety of long-acting GnRH agonists in in vitro fertilization and embryo transfer. Hum. Fertil. (Camb.). 2001; 4: 85-93.
30. Cachill D. Risks of GnRH agonist administration in early pregnancy. In: Filicory M., Flamigni C., eds. Ovulation induction: update ’98. London: Parthenon Publishing Group; 1998: 97-105.
31. Wilcox A.J., Weinberg C.R., O’Connor J.F., Baird D.D., Schlatterer J.P., Canfield R.E. et al. Incidence of early loss of pregnancy. N. Engl. J. Med. 1988; 319(4): 189-94.
32. Dolk H., Loane M., Garne E. The prevalence of congenital anomalies in Europe. Adv. Exp. Med. Biol. 2010; 686: 349-64.
33. Orvieto R., Kerner R., Krissi H., Ashkenazi J., Ben Rafael Z., Bar-Hava I. Comparison of leuprolide acetate and triptorelin in assisted reproductive technology cycles: a prospective, randomized study. Fertil. Steril. 2002; 78(6): 1268-71.
34. Ferring. Decapeptyl 0.1 mg. Available at: https://www.old.health.gov. il/units/pharmacy/trufot/alonim/DECAPEPTYL-dr_1382514091053.pdf Accessed September 29, 2016.
Поступила 26.02.2018
Принята в печать 02.03.2018
Received 26.02.2018
Accepted 02.03.2018
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