Efficacy of different growth hormone addition protocols on the outcomes of infertile patients in IVF cycles: a systematic review_Chinese Journal of Evidence-Based Medicine

Authors：

HOU Haiyan ^1,2 ^# , QIN Yan ¹ ^# ,  YU Qi ^2,3 , ZHEN Jingran ³ , HU Chunxiu ¹ , WANG Rui ¹ , CHEN Juan ¹ , LI Yindan ¹

1. Department of Reproductive Medicine, Characteristic Medical Center of PAP, Tianjin 300162, P.R.China;
2. Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100036, P.R.China;
3. Gynecological Endocrinology and Reproduction Center, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100036, P.R.China;

Corresponding author：

YU Qi, Email: yuqimd@163.com

Keywords：

Growth hormone; In-vitro fertilization; IVF; Live birth rate; Poor ovarian response; Systematic review; Meta-analysis; Randomized controlled trial

DOI：

10.7507/1672-2531.201906018

Video：

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Objectives To systematically review the efficacy of adjuvant growth hormone (GH) in IVF protocols.Methods CBM, WanFang Data, CNKI, VIP, PubMed, EMbase, Web of Science and The Cochrane Library databases were electronically searched to collect randomized controlled trials (RCTs) on the efficacy of adjuvant GH in IVF protocols from inception to October 2019. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies, then, the meta-analysis was performed by using RevMan 5.3 software.Results A total of 10 RCTs involving 691 infertile females were included. Results of meta-analysis demonstrated that adjuvant GH in IVF protocols could increase collected oocytes number (MD=1.58, 95%CI 1.29 to 1.87, P<0.000 01), MⅡ stage oocytes number (MD=2.26, 95%CI 1.77 to 2.74, P<0.000 01), implantation rate (RR=1.20, 95%CI 1.02 to 1.40, P=0.03), clinical pregnancy rate (RR=1.46, 95%CI 1.08 to 1.98, P=0.01) and live birth rate (RR=1.62, 95%CI 1.05 to 2.51, P=0.03). However, there was no difference in fertilization rate (RR=1.06, 95%CI 0.97 to 1.16, P<0.18), miscarriage rate (RR=1.44, 95%CI 0.65 to 3.17, P=0.37) and adverse reactions between two groups.Conclusions Current evidence shows that GH can improve the fertility outcomes of IVF cycles in patients with POR, elderly or previous IVF failures. But due to limited quality and quantity of the included studies, more high-quality studies are required to verify the above conclusion.

Citation： HOU Haiyan, QIN Yan, YU Qi, ZHEN Jingran, HU Chunxiu, WANG Rui, CHEN Juan, LI Yindan. Efficacy of different growth hormone addition protocols on the outcomes of infertile patients in IVF cycles: a systematic review. Chinese Journal of Evidence-Based Medicine, 2020, 20(4): 418-425. doi: 10.7507/1672-2531.201906018 Copy

1.	Surrey ES, Schoolcraft WB. Evaluating strategies for improving ovarian response of the poor responder undergoing assisted reproductive techniques. Fertil Steril, 2000, 73(4): 667-676.
2.	Ferraretti AP, La Marca A, Fauser BC, et al. ESHRE consensus on the definition of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod, 2011, 26(7): 1616-1624.
3.	Bentov Y, Yavorska T, Esfandiari N, et al. The contribution of mitochondrial function to reproductive aging. J Assist Reprod Genet, 2011, 28(9): 773-783.
4.	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): 749-766.
5.	Yovich JL, Stanger JD. Growth hormone supplementation improves implantation and pregnancy productivity rates for poor-prognosis patients undertaking IVF. Reprod Biomed Online, 2010, 21(1): 37-49.
6.	Weall BM, Al-Samerria S, Conceicao J, et al. A direct action for GH in improvement of oocyte quality in poor-responder patients. Reproduction, 2015, 149(2): 147-154.
7.	Du XF, Yang XH, Li J, et al. Growth hormone co-treatment within a GnRH agonist long protocol improves implantation and pregnancy rates in patients undergoing IVF-ET. Arch Gynecol Obstet, 2016, 294(4): 877-883.
8.	Dakhly DM, Bayoumi YA, Gad Allah SH. Which is the best IVF/ICSI protocol to be used in poor responders receiving growth hormone as an adjuvant treatment? A prospective randomized trial. Gynecol Endocrinol, 2016, 32(2): 116-119.
9.	Ho YK, Lee TH, Lee CI, et al. Effects of growth hormone plus gonadotropins on controlled ovarian stimulation in infertile women of advanced age, poor responders, and previous in vitro fertilization failure patients. Taiwan J Obstet Gynecol, 2017, 56(6): 806-810.
10.	Ob'edkova K, Kogan I, Krikheli I, et al. Growth hormone co-treatment in IVF/ICSI cycles in poor responders. Gynecol Endocrinol, 2017, 33(sup1): 15-17.
11.	Bachelot A, Monget P, Imbert-Bollore P, et al. Growth hormone is required for ovarian follicular growth. Endocrinology, 2002, 143(10): 4104-4112.
12.	Kotarba D, Kotarba J, Hughes E. Growth hormone for in vitro fertilization. Cochrane Database Syst Rev, 2000, (2): CD000099.
13.	Harper K, Proctor M, Hughes E. Growth hormone for in vitro fertilization. Cochrane Database Syst Rev, 2003, (3): CD000099.
14.	Ahmad G, Brown J, Duffy JM, et al. Growth hormone for in vitro fertilization. Cochrane Database Syst Rev, 2009, (4): CD000099.
15.	Duffy JM, Ahmad G, Mohiyiddeen L, et al. Growth hormone for in vitro fertilization. Cochrane Database Syst Rev, 2010, (1): CD000099.
16.	Yu X, Ruan J, He LP, et al. Efficacy of growth hormone supplementation with gonadotrophins in vitro fertilization for poor ovarian responders: an updated meta-analysis. Int J Clin Exp Med, 2015, 8(4): 4954-4967.
17.	Li XL, 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.
18.	Owen EJ, Shoham Z, Mason BA, et al. Cotreatment with growth hormone, after pituitary suppression, for ovarian stimulation in in vitro fertilization: a randomized, double-blind, placebo-control trial. Fertil Steril, 1991, 56(6): 1104-1110.
19.	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): 575-580.
20.	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): 113-120.
21.	Dor J, Seidman DS, Amudai E, et al. Adjuvant growth hormone therapy in poor responders to in-vitro fertilization: a prospective randomized placebo-controlled double-blind study. Hum Reprod, 1995, 10(1): 40-43.
22.	Suikkari A, MacLachlan V, Koistinen R, et al. Double-blind placebo controlled study: human biosynthetic growth hormone for assisted reproductive technology. Fertil Steril, 1996, 65(4): 800-805.
23.	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): 123-127.
24.	Eftekhar M, Aflatoonian A, Mohammadian F, et al. Adjuvant growth hormone therapy in antagonist protocol in poor responders undergoing assisted reproductive technology. Arch Gynecol Obstet, 2013, 287(5): 1017-1021.
25.	Bassiouny YA, Dakhly DMR, Bayoumi YA, et al. 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.
26.	Dakhly DMR, Bassiouny YA, Bayoumi YA, et al. The addition of growth hormone adjuvant therapy to the long down regulation protocol in poor responders undergoing in vitro fertilization: Randomized control trial. Eur J Obstet Gynecol Reprod Biol, 2018, 228: 161-165.
27.	Safdarian L, Aghahosseini M, Alyasin A, et al. Growth hormone (GH) improvement of ovarian responses and pregnancy outcome in poor ovarian responders: a randomized study. Asian Pac J Cancer Prev, 2019, 20(7): 2033-2037.
28.	Cahill DJ, Wardle PG. Management of infertility. BMJ, 2002, 325(7354): 28-32.
29.	Marchal R, Caillaud M, Martoriati A, et al. Effect of growth hormone (GH) on in vitro nuclear and cytoplasmic oocyte maturation, cumulus expansion, hyaluronan synthases, and connexins 32 and 43 expression, and GH receptor messenger RNA expression in equine and porcine species. Biol Reprod, 2003, 69(3): 1013-1022.
30.	Gonzalez-Añover P, Encinas T, Garcia-Garcia RM, et al. Ovarian response in sheep superovulated after pretreatment with growth hormone and GnRH antagonists is weakened by failures in oocyte maturation. Zygote, 2004, 12(4): 301-304.
31.	Busnelli A, Papaleo E, Del Prato D, et al. A retrospective evaluation of prognosis and cost-effectiveness of IVF in poor responders according to the Bologna criteria. Hum Reprod, 2015, 30(2): 315-322.
32.	Chu K, Pang W, Sun N, et al. Outcomes of poor responders following growth hormone co-treatment with IVF/ICSI mild stimulation protocol: a retrospective cohort study. Arch Gynecol Obstet, 2018, 297(5): 1317-1321.
33.	Cai MH, Liang XY, Wu YQ, et al. Six-week pretreatment with growth hormone improves clinical outcomes of poor ovarian responders undergoing in vitro fertilization treatment: a self-controlled clinical study. J Obstet Gynaecol Res, 2019, 45(2): 376-381.
34.	Starbuck MJ, Inskeep EK, Dailey RA. Effect of a single growth hormone (rbST) treatment at breeding on conception rates and pregnancy retention in dairy and beef cattle. Anim Reprod Sci, 2006, 93(3-4): 349-359.
35.	Pandian Z, McTavish AR, Aucott L, et al. Interventions for 'poor responders' to controlled ovarian hyper stimulation (COH) in in-vitro fertilisation (IVF). Cochrane Database Syst Rev, 2010, (1): CD004379.

1. Surrey ES, Schoolcraft WB. Evaluating strategies for improving ovarian response of the poor responder undergoing assisted reproductive techniques. Fertil Steril, 2000, 73(4): 667-676.
2. Ferraretti AP, La Marca A, Fauser BC, et al. ESHRE consensus on the definition of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod, 2011, 26(7): 1616-1624.
3. Bentov Y, Yavorska T, Esfandiari N, et al. The contribution of mitochondrial function to reproductive aging. J Assist Reprod Genet, 2011, 28(9): 773-783.
4. 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): 749-766.
5. Yovich JL, Stanger JD. Growth hormone supplementation improves implantation and pregnancy productivity rates for poor-prognosis patients undertaking IVF. Reprod Biomed Online, 2010, 21(1): 37-49.
6. Weall BM, Al-Samerria S, Conceicao J, et al. A direct action for GH in improvement of oocyte quality in poor-responder patients. Reproduction, 2015, 149(2): 147-154.
7. Du XF, Yang XH, Li J, et al. Growth hormone co-treatment within a GnRH agonist long protocol improves implantation and pregnancy rates in patients undergoing IVF-ET. Arch Gynecol Obstet, 2016, 294(4): 877-883.
8. Dakhly DM, Bayoumi YA, Gad Allah SH. Which is the best IVF/ICSI protocol to be used in poor responders receiving growth hormone as an adjuvant treatment? A prospective randomized trial. Gynecol Endocrinol, 2016, 32(2): 116-119.
9. Ho YK, Lee TH, Lee CI, et al. Effects of growth hormone plus gonadotropins on controlled ovarian stimulation in infertile women of advanced age, poor responders, and previous in vitro fertilization failure patients. Taiwan J Obstet Gynecol, 2017, 56(6): 806-810.
10. Ob'edkova K, Kogan I, Krikheli I, et al. Growth hormone co-treatment in IVF/ICSI cycles in poor responders. Gynecol Endocrinol, 2017, 33(sup1): 15-17.
11. Bachelot A, Monget P, Imbert-Bollore P, et al. Growth hormone is required for ovarian follicular growth. Endocrinology, 2002, 143(10): 4104-4112.
12. Kotarba D, Kotarba J, Hughes E. Growth hormone for in vitro fertilization. Cochrane Database Syst Rev, 2000, (2): CD000099.
13. Harper K, Proctor M, Hughes E. Growth hormone for in vitro fertilization. Cochrane Database Syst Rev, 2003, (3): CD000099.
14. Ahmad G, Brown J, Duffy JM, et al. Growth hormone for in vitro fertilization. Cochrane Database Syst Rev, 2009, (4): CD000099.
15. Duffy JM, Ahmad G, Mohiyiddeen L, et al. Growth hormone for in vitro fertilization. Cochrane Database Syst Rev, 2010, (1): CD000099.
16. Yu X, Ruan J, He LP, et al. Efficacy of growth hormone supplementation with gonadotrophins in vitro fertilization for poor ovarian responders: an updated meta-analysis. Int J Clin Exp Med, 2015, 8(4): 4954-4967.
17. Li XL, 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.
18. Owen EJ, Shoham Z, Mason BA, et al. Cotreatment with growth hormone, after pituitary suppression, for ovarian stimulation in in vitro fertilization: a randomized, double-blind, placebo-control trial. Fertil Steril, 1991, 56(6): 1104-1110.
19. 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): 575-580.
20. 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): 113-120.
21. Dor J, Seidman DS, Amudai E, et al. Adjuvant growth hormone therapy in poor responders to in-vitro fertilization: a prospective randomized placebo-controlled double-blind study. Hum Reprod, 1995, 10(1): 40-43.
22. Suikkari A, MacLachlan V, Koistinen R, et al. Double-blind placebo controlled study: human biosynthetic growth hormone for assisted reproductive technology. Fertil Steril, 1996, 65(4): 800-805.
23. 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): 123-127.
24. Eftekhar M, Aflatoonian A, Mohammadian F, et al. Adjuvant growth hormone therapy in antagonist protocol in poor responders undergoing assisted reproductive technology. Arch Gynecol Obstet, 2013, 287(5): 1017-1021.
25. Bassiouny YA, Dakhly DMR, Bayoumi YA, et al. 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.
26. Dakhly DMR, Bassiouny YA, Bayoumi YA, et al. The addition of growth hormone adjuvant therapy to the long down regulation protocol in poor responders undergoing in vitro fertilization: Randomized control trial. Eur J Obstet Gynecol Reprod Biol, 2018, 228: 161-165.
27. Safdarian L, Aghahosseini M, Alyasin A, et al. Growth hormone (GH) improvement of ovarian responses and pregnancy outcome in poor ovarian responders: a randomized study. Asian Pac J Cancer Prev, 2019, 20(7): 2033-2037.
28. Cahill DJ, Wardle PG. Management of infertility. BMJ, 2002, 325(7354): 28-32.
29. Marchal R, Caillaud M, Martoriati A, et al. Effect of growth hormone (GH) on in vitro nuclear and cytoplasmic oocyte maturation, cumulus expansion, hyaluronan synthases, and connexins 32 and 43 expression, and GH receptor messenger RNA expression in equine and porcine species. Biol Reprod, 2003, 69(3): 1013-1022.
30. Gonzalez-Añover P, Encinas T, Garcia-Garcia RM, et al. Ovarian response in sheep superovulated after pretreatment with growth hormone and GnRH antagonists is weakened by failures in oocyte maturation. Zygote, 2004, 12(4): 301-304.
31. Busnelli A, Papaleo E, Del Prato D, et al. A retrospective evaluation of prognosis and cost-effectiveness of IVF in poor responders according to the Bologna criteria. Hum Reprod, 2015, 30(2): 315-322.
32. Chu K, Pang W, Sun N, et al. Outcomes of poor responders following growth hormone co-treatment with IVF/ICSI mild stimulation protocol: a retrospective cohort study. Arch Gynecol Obstet, 2018, 297(5): 1317-1321.
33. Cai MH, Liang XY, Wu YQ, et al. Six-week pretreatment with growth hormone improves clinical outcomes of poor ovarian responders undergoing in vitro fertilization treatment: a self-controlled clinical study. J Obstet Gynaecol Res, 2019, 45(2): 376-381.
34. Starbuck MJ, Inskeep EK, Dailey RA. Effect of a single growth hormone (rbST) treatment at breeding on conception rates and pregnancy retention in dairy and beef cattle. Anim Reprod Sci, 2006, 93(3-4): 349-359.
35. Pandian Z, McTavish AR, Aucott L, et al. Interventions for 'poor responders' to controlled ovarian hyper stimulation (COH) in in-vitro fertilisation (IVF). Cochrane Database Syst Rev, 2010, (1): CD004379.

Chinese Journal of Evidence-Based Medicine

Efficacy of different growth hormone addition protocols on the outcomes of infertile patients in IVF cycles: a systematic review

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