Проведен анализ данных, имеющихся в современной литературе, о применении соматотропного гормона (СТГ) при овариальной стимуляции в программах вспомогательных репродуктивных технологий (ВРТ). Рутинное использование СТГ при овариальной стимуляции у пациенток с нормальным исходным уровнем данного гормона не повышает частоту наступления беременности и рождения ребенка в программах ВРТ. Также никаких преимуществ применения СТГ не выявлено для пациенток с синдромом поликистозных яичников, несмотря на отмеченное в исследовании увеличение уровней инсулина и инсулиноподобного фактора роста 1 в сыворотке крови пациенток. Основное внимание исследователей в данной области направлено на изучение применения СТГ у пациенток с бедным овариальным ответом. Согласно результатам метаанализа, проведенного X.-L. Li и соавт. (2017 г.), применение СТГ при овариальной стимуляции пациенток с бедным овариальным ответом позволяет добиться повышения числа полученных ооцитов, числа зрелых (MII) ооцитов, снижения частоты отмены переноса эмбриона и не влияет на частоту оплодотворения. Частота наступления беременности и частота живорождения значимо выше в группе применения СТГ в 1,65 (95% доверительный интервал 1,23–2,22) и 1,73 раза (95% доверительный интервал 1,25–2,40) соответственно. Таким образом, целесообразно использовать СТГ при овариальной стимуляции у пациенток с бедным овариальным ответом, поскольку это позволяет повысить частоту живорождения в программах ВРТ почти в 2 раза. Тем не менее дальнейшие исследования должны быть направлены на определение оптимальной дозировки препарата и оценку безопасности его применения в программах ВРТ с изучением отдаленных исходов.
The paper analyzes the literature data on the use of the growth hormone (GH) in ovarian stimulation in assisted reproductive technologies (ART). Routine use of GH in ovarian stimulation in patients with a normal GH level does not increase pregnancy and childbirth rates in ART. Also, no benefits of using GH have been identified for patients with polycystic ovary syndrome, despite the increase in insulin and IGF-1 blood levels. The main research focus is to study the use of GH in patients with poor ovarian response. According to the meta-analysis conducted by X.-L. Li et al. (2017), GH in ovarian stimulation of poor ovarian responders increases the number of received oocytes, mature oocytes number, reduces the embryo transfer cancellation rate and does not affect the fertilization rate. The pregnancy and live birth rates are significantly higher in the group of GH use – by 1.65 (95% CI 1.23–2.22) and 1.73 (95% CI 1.25–2.40) times, respectively. Thus, it is advisable to use GH in ovarian stimulation in poor ovarian responders, since it allows to increases live birth rate in ART. However, further studies should determine the optimal GH dose and assesse it`s safety in ART programs.
1. Homburg R, Eshel A, Abdalla HI, Jacobs H.S. Growth hormone facilitates ovulation induction by gonadotrophins. Clin Endocrinol (Oxf) 1988; 29 (1): 113–7.
2. Owen EJ, West C, Mason BA, Jacobs HS. Co-treatment with growth hormone of sub-optimal responders in IVF-ET. Hum Reprod 1991; 6 (4): 524–8.
3. Hart RJ, Rombauts L, Norman RJ. Growth hormone in IVF cycles: any hope? Curr Opin Obstet Gynecol 2017; 29 (3): 119–25.
4. Menezo YJR, Nicollet B, Rollet J, Hazout A. Pregnancy and delivery after in vitro maturation of naked ICSI-GV oocytes with GH and transfer of a frozen thawed blastocyst: case report. J Assist Reprod Genet 2006; 23 (1): 47–9.
5. Bachelot A, Monget P, Imbert-Bolloré P et al. Growth hormone is required for ovarian follicular growth. Endocrinology 2002; 143 (10): 4104–12.
6. Mendoza C, Ruiz-Requena E, Ortega E et al. Follicular fluid markers of oocyte developmental potential. Hum Reprod 2002; 17 (4): 1017–22.
7. Oosterhuis GJ, Vermes I, Lambalk CB et al. Insulin-like growth factor (IGF)-I and IGF binding protein-3 concentrations in fluid from human stimulated follicles. Hum Reprod 1998; 13 (2): 285–9.
8. Mendoza C, Cremades N, Ruiz-Requena E et al. Relationship between fertilization results after intracytoplasmic sperm injection, and intrafollicular steroid, pituitary hormone and cytokine concentrations. Hum Reprod 1999; 14 (3): 628–35.
9. Tarlatzis BC, Pazaitou K, Bili H et al. Growth hormone, oestradiol, progesterone and testosterone concentrations in follicular fluid after ovarian stimulation with various regimes for assisted reproduction. Hum Reprod 1993; 8 (10): 1612–6.
10. Tesarik J, Hazout A, Mendoza C. Improvement of delivery and live birth rates after ICSI in women aged >40 years by ovarian co-stimulation with growth hormone. Hum Reprod 2005; 20 (9): 2536–41.
11. Regan SLP, Knight PG, Yovich JL et al. Growth hormone during in vitro fertilization in older women modulates the density of receptors in granulosa cells, with improved pregnancy outcomes. Fertil Steril 2018; 110 (7): 1298–310.
12. Bassiouny YA, Dakhly DMR, Bayoumi YA, Hashish NM. Does the addition of growth hormone to the in vitro fertilization/intracytoplasmic sperm injection antagonist protocol improve outcomes in poor responders? A randomized, controlled trial. Fertil Steril 2016; 105 (3): 697–702.
13. Bayoumi YA, Dakhly DMR, Bassiouny YA, Hashish NM. Addition of growth hormone to the microflare stimulation protocol among women with poor ovarian response. Int J Gynaecol Obstet 2015; 131 (3): 305–8.
14. Chen Y, Liu F, Nong Y et al. Clinical efficacy and mechanism of growth hormone action in patients experiencing repeat implantation failure. Can J Physiol Pharmacol 2018; 96 (9): 929–32.
15. Younis JS, Simon A, Koren R et al. The effect of growth hormone supplementation on in vitro fertilization outcome: a prospective randomized placebo-controlled double-blind study. Fertil Steril 1992; 58 (3): 575–80.
16. Bergh C, Hillensjö T, Wikland M et al. Adjuvant growth hormone treatment during in vitro fertilization: a randomized, placebo-controlled study. Fertil Steril 1994; 62 (1): 113–20.
17. Homburg R, Levy T, Ben-Rafael Z. Adjuvant growth hormone for induction of ovulation with gonadotrophin-releasing hormone agonist and gonadotrophins in polycystic ovary syndrome: a randomized, double-blind, placebo controlled trial. Hum Reprod 1995; 10 (10): 2550–3.
18. Kolibianakis EM, Venetis CA, Diedrich K et al. Addition of growth hormone to gonadotrophins in ovarian stimulation of poor responders treated by in-vitro fertilization: a systematic review and meta-analysis. Hum Reprod Update 2009; 15 (6): 613–22.
19. Kyrou D, Kolibianakis EM, Venetis CA et al. How to improve the probability of pregnancy in poor responders undergoing in vitro fertilization: a systematic review and meta-analysis. Fertil Steril 2009; 91 (3): 749–66.
20. Li X-L, Wang L, Lv F et al. The influence of different growth hormone addition protocols to poor ovarian responders on clinical outcomes in controlled ovary stimulation cycles: A systematic review and meta-analysis. Medicine (Baltimore) 2017; 96 (12): e6443.
21. Meldrum DR, Quaas AM, Su HI. Why is growth hormone underutilized for our most difficult IVF couples? Fertil Steril 2018; 110 (7): 1261–2.
22. Papathanasiou A, Searle BJ, King NMA, Bhattacharya S. Trends in “poor responder” research: lessons learned from RCTs in assisted conception. Hum Reprod Update 2016; 22 (3): 306–19.
23. Сыркашева А.Г., Ильина Е.О., Долгушина Н.В. Бесплодие у женщин старшего репродуктивного возраста: причины, тактика ведения, перспективы использования преимплантационного генетического скрининга (обзор литературы). Гинекология. 2016; 18 (3): 40–3.
[Syrkasheva A.G., Ilina E.O., Dolgushina N.V. Infertility in women of advanced age: etiology, management, application of preimplantation genetic screening. Gynecology. 2016; 18 (3): 40–3 (in Russian).]
24. Ванян Р.Э., Долгушина Н.В. Клинико-анамнестические факторы риска развития «бедного» овариального ответа в программах вспомогательных репродуктивных технологий. Гинекология. 2014; 16 (5): 73–7.
[Vanyan R.E., Dolgushina N.V. Risk factors of poor ovarian response in IVF practice. Gynecology. 2014; 16 (5): 73–7 (in Russian).]
25. Бейк Е.П., Сыркашева А.Г., Долгушина Н.В. Эффективность программ вспомогательных репродуктивных технологий у пациенток позднего репродуктивного возраста. Гинекология. 2018; 20 (1): 109–12.
[Beik E.P., Syrkasheva A.G., Dolgushina N.V. Effectiveness of programs of auxiliary reproductive technologies in patients of late reproductive age. Gynecology. 2018; 20 (1): 109–12. DOI: 10.26442/2079-5696_20.1.109-112 (in Russian).]
26. Huang ZH, Baxter RC, Hughes SM et al. Supplementary growth hormone treatment of women with poor ovarian response to exogenous gonadotrophins: changes in serum and follicular fluid insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3). Hum Reprod 1993; 8 (6): 850–7.
27. Jeve YB, Bhandari HM. Effective treatment protocol for poor ovarian response: A systematic review and meta-analysis. J Hum Reprod Sci 2016; 9 (2): 70–81.
28. Guan Q, Ma H, Wang Y, Zhang F. Effects of co-administration of growth hormone (GH) and aspirin to women during in vitro fertilization and embryo transfer (IVF-ET) cycles. Zhonghua Nan Ke Xue 2007; 13 (9): 798–800.
29. Kucuk T, Kozinoglu H, Kaba A. Growth hormone co-treatment within a GnRH agonist long protocol in patients with poor ovarian response: a prospective, randomized, clinical trial. J Assist Reprod Genet 2008; 25 (4): 123–7.
30. Eftekhar M, Aflatoonian A, Mohammadian F, Eftekhar T. Adjuvant growth hormone therapy in antagonist protocol in poor responders undergoing assisted reproductive technology. Arch Gynecol Obstet 2013; 287 (5): 1017–21.
31. Møller J, Nielsen S, Hansen TK. Growth hormone and fluid retention. Horm Res 1999; 51 (Suppl. 3): 116–20.
32. Kokshoorn NE, Biermasz NR, Roelfsema F et al. GH replacement therapy in elderly GH-deficient patients: a systematic review. Eur J Endocrinol 2011; 164 (5): 657–65.
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1. Homburg R, Eshel A, Abdalla HI, Jacobs H.S. Growth hormone facilitates ovulation induction by gonadotrophins. Clin Endocrinol (Oxf) 1988; 29 (1): 113–7.
2. Owen EJ, West C, Mason BA, Jacobs HS. Co-treatment with growth hormone of sub-optimal responders in IVF-ET. Hum Reprod 1991; 6 (4): 524–8.
3. Hart RJ, Rombauts L, Norman RJ. Growth hormone in IVF cycles: any hope? Curr Opin Obstet Gynecol 2017; 29 (3): 119–25.
4. Menezo YJR, Nicollet B, Rollet J, Hazout A. Pregnancy and delivery after in vitro maturation of naked ICSI-GV oocytes with GH and transfer of a frozen thawed blastocyst: case report. J Assist Reprod Genet 2006; 23 (1): 47–9.
5. Bachelot A, Monget P, Imbert-Bolloré P et al. Growth hormone is required for ovarian follicular growth. Endocrinology 2002; 143 (10): 4104–12.
6. Mendoza C, Ruiz-Requena E, Ortega E et al. Follicular fluid markers of oocyte developmental potential. Hum Reprod 2002; 17 (4): 1017–22.
7. Oosterhuis GJ, Vermes I, Lambalk CB et al. Insulin-like growth factor (IGF)-I and IGF binding protein-3 concentrations in fluid from human stimulated follicles. Hum Reprod 1998; 13 (2): 285–9.
8. Mendoza C, Cremades N, Ruiz-Requena E et al. Relationship between fertilization results after intracytoplasmic sperm injection, and intrafollicular steroid, pituitary hormone and cytokine concentrations. Hum Reprod 1999; 14 (3): 628–35.
9. Tarlatzis BC, Pazaitou K, Bili H et al. Growth hormone, oestradiol, progesterone and testosterone concentrations in follicular fluid after ovarian stimulation with various regimes for assisted reproduction. Hum Reprod 1993; 8 (10): 1612–6.
10. Tesarik J, Hazout A, Mendoza C. Improvement of delivery and live birth rates after ICSI in women aged >40 years by ovarian co-stimulation with growth hormone. Hum Reprod 2005; 20 (9): 2536–41.
11. Regan SLP, Knight PG, Yovich JL et al. Growth hormone during in vitro fertilization in older women modulates the density of receptors in granulosa cells, with improved pregnancy outcomes. Fertil Steril 2018; 110 (7): 1298–310.
12. Bassiouny YA, Dakhly DMR, Bayoumi YA, Hashish NM. Does the addition of growth hormone to the in vitro fertilization/intracytoplasmic sperm injection antagonist protocol improve outcomes in poor responders? A randomized, controlled trial. Fertil Steril 2016; 105 (3): 697–702.
13. Bayoumi YA, Dakhly DMR, Bassiouny YA, Hashish NM. Addition of growth hormone to the microflare stimulation protocol among women with poor ovarian response. Int J Gynaecol Obstet 2015; 131 (3): 305–8.
14. Chen Y, Liu F, Nong Y et al. Clinical efficacy and mechanism of growth hormone action in patients experiencing repeat implantation failure. Can J Physiol Pharmacol 2018; 96 (9): 929–32.
15. Younis JS, Simon A, Koren R et al. The effect of growth hormone supplementation on in vitro fertilization outcome: a prospective randomized placebo-controlled double-blind study. Fertil Steril 1992; 58 (3): 575–80.
16. Bergh C, Hillensjö T, Wikland M et al. Adjuvant growth hormone treatment during in vitro fertilization: a randomized, placebo-controlled study. Fertil Steril 1994; 62 (1): 113–20.
17. Homburg R, Levy T, Ben-Rafael Z. Adjuvant growth hormone for induction of ovulation with gonadotrophin-releasing hormone agonist and gonadotrophins in polycystic ovary syndrome: a randomized, double-blind, placebo controlled trial. Hum Reprod 1995; 10 (10): 2550–3.
18. Kolibianakis EM, Venetis CA, Diedrich K et al. Addition of growth hormone to gonadotrophins in ovarian stimulation of poor responders treated by in-vitro fertilization: a systematic review and meta-analysis. Hum Reprod Update 2009; 15 (6): 613–22.
19. Kyrou D, Kolibianakis EM, Venetis CA et al. How to improve the probability of pregnancy in poor responders undergoing in vitro fertilization: a systematic review and meta-analysis. Fertil Steril 2009; 91 (3): 749–66.
20. Li X-L, Wang L, Lv F et al. The influence of different growth hormone addition protocols to poor ovarian responders on clinical outcomes in controlled ovary stimulation cycles: A systematic review and meta-analysis. Medicine (Baltimore) 2017; 96 (12): e6443.
21. Meldrum DR, Quaas AM, Su HI. Why is growth hormone underutilized for our most difficult IVF couples? Fertil Steril 2018; 110 (7): 1261–2.
22. Papathanasiou A, Searle BJ, King NMA, Bhattacharya S. Trends in “poor responder” research: lessons learned from RCTs in assisted conception. Hum Reprod Update 2016; 22 (3): 306–19.
23. Syrkasheva A.G., Ilina E.O., Dolgushina N.V. Infertility in women of advanced age: etiology, management, application of preimplantation genetic screening. Gynecology. 2016; 18 (3): 40–3 (in Russian).
24. Vanyan R.E., Dolgushina N.V. Risk factors of poor ovarian response in IVF practice. Gynecology. 2014; 16 (5): 73–7 (in Russian).
25. Beik E.P., Syrkasheva A.G., Dolgushina N.V. Effectiveness of programs of auxiliary reproductive technologies in patients of late reproductive age. Gynecology. 2018; 20 (1): 109–12. DOI: 10.26442/2079-5696_20.1.109-112 (in Russian).
26. Huang ZH, Baxter RC, Hughes SM et al. Supplementary growth hormone treatment of women with poor ovarian response to exogenous gonadotrophins: changes in serum and follicular fluid insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3). Hum Reprod 1993; 8 (6): 850–7.
27. Jeve YB, Bhandari HM. Effective treatment protocol for poor ovarian response: A systematic review and meta-analysis. J Hum Reprod Sci 2016; 9 (2): 70–81.
28. Guan Q, Ma H, Wang Y, Zhang F. Effects of co-administration of growth hormone (GH) and aspirin to women during in vitro fertilization and embryo transfer (IVF-ET) cycles. Zhonghua Nan Ke Xue 2007; 13 (9): 798–800.
29. Kucuk T, Kozinoglu H, Kaba A. Growth hormone co-treatment within a GnRH agonist long protocol in patients with poor ovarian response: a prospective, randomized, clinical trial. J Assist Reprod Genet 2008; 25 (4): 123–7.
30. Eftekhar M, Aflatoonian A, Mohammadian F, Eftekhar T. Adjuvant growth hormone therapy in antagonist protocol in poor responders undergoing assisted reproductive technology. Arch Gynecol Obstet 2013; 287 (5): 1017–21.
31. Møller J, Nielsen S, Hansen TK. Growth hormone and fluid retention. Horm Res 1999; 51 (Suppl. 3): 116–20.
32. Kokshoorn NE, Biermasz NR, Roelfsema F et al. GH replacement therapy in elderly GH-deficient patients: a systematic review. Eur J Endocrinol 2011; 164 (5): 657–65.
ФГБУ «Национальный медицинский исследовательский центр акушерства, гинекологии и перинатологии им. акад. В.И. Кулакова» Минздрава России, Москва, Россия
*romanov1553@yandex.ru
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Andrey Yu. Romanov*, Anastasiya G. Syrkasheva, Nataliya V. Dolgushina, Elena A. Kalinina
Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia
*romanov1553@yandex.ru