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Published in: Reproductive Biology and Endocrinology 1/2020

Open Access 01-12-2020 | Research

Growth hormone alleviates oxidative stress and improves the IVF outcomes of poor ovarian responders: a randomized controlled trial

Authors: Yan Gong, Kun Zhang, Dongsheng Xiong, Jiajing Wei, Hao Tan, Shengfang Qin

Published in: Reproductive Biology and Endocrinology | Issue 1/2020

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Abstract

Background

Oxidative stress (OS), defined as an imbalance between excessive reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) production and antioxidant insufficiency, has been suggested to be involved in the pathogenesis of poor ovarian response (POR). Growth hormone (GH) can reduce OS in some cell types. This study investigated whether GH can improve OS and the in vitro fertilization and embryo transfer (IVF-ET) outcomes of poor ovarian responders.

Methods

This study enrolled 105 patients with POR and 58 patients without POR (controls) who were diagnosed according to the Bologna criteria and underwent conventional IVF-ET. Poor ovarian responders were randomly assigned to two groups: the POR-GH group, which received pretreatment with GH 4 IU/d on day 2 of the previous menstrual cycle before IVF until the trigger day, and the POR-C group, which received no pretreatment. OS markers in follicular fluid (FF), ROS levels in granulosa cells (GCs), and the IVF outcomes of the groups were compared.

Results

Endometrial thickness on trigger day, the number of cleaved embryos, the number of higher-quality embryos, and the rates of embryo formation, higher-quality embryo formation, implantation and clinical pregnancy were significantly increased in the POR-GH group compared with the POR-C group (P < 0.05). Moreover, compared to those in the non-POR group, FF malondialdehyde (MDA), total oxidant status (TOS), oxidative stress index (OSI) and ROS levels in GCs were significantly higher, whereas superoxide dismutase (SOD) and the total antioxidant capacity (TAC) were significantly lower in the POR-C group (P < 0.05). Furthermore, compared with those in the POR-C group, the FF TAC was significantly increased in the POR-GH group, and TOS, OSI and intracellular ROS levels were significantly reduced (P < 0.05).

Conclusions

Pretreatment with GH alleviates OS and improves oocyte quality and IVF outcomes of poor ovarian responders.

Trial registration

Literature
1.
go back to reference Ferraretti AP, La Marca a, Fauser BC, Tarlatzis B, Nargund G, Gianaroli L. Definition EwgoPOR. ESHRE consensus on the definition of ‘poor response’ to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod. 2011;26:1616–24.CrossRef Ferraretti AP, La Marca a, Fauser BC, Tarlatzis B, Nargund G, Gianaroli L. Definition EwgoPOR. ESHRE consensus on the definition of ‘poor response’ to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod. 2011;26:1616–24.CrossRef
2.
go back to reference Kolibianakis EM, Venetis CA, Diedrich K, Tarlatzis BC, Griesinger G. 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;15:613–22.CrossRef Kolibianakis EM, Venetis CA, Diedrich K, Tarlatzis BC, Griesinger G. 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;15:613–22.CrossRef
3.
go back to reference Jeve YB, Bhandari HM. Effective treatment protocol for poor ovarian response: a systematic review and meta-analysis. J Hum Reprod Sci. 2016;9:70–81.CrossRef Jeve YB, Bhandari HM. Effective treatment protocol for poor ovarian response: a systematic review and meta-analysis. J Hum Reprod Sci. 2016;9:70–81.CrossRef
4.
go back to reference Kyrou D, Kolibianakis EM, Venetis CA, Papanikolaou EG, Bontis J, Tarlatzis BC. How to improve the probability of pregnancy in poor responders undergoing in vitro fertilization: a systematic review and meta-analysis. Fertil Steril. 2009;91:749–66.CrossRef Kyrou D, Kolibianakis EM, Venetis CA, Papanikolaou EG, Bontis J, Tarlatzis BC. How to improve the probability of pregnancy in poor responders undergoing in vitro fertilization: a systematic review and meta-analysis. Fertil Steril. 2009;91:749–66.CrossRef
5.
go back to reference Eichenlaub-Ritter U. Oocyte ageing and its cellular basis. Int J Dev Biol. 2012;56:841–52.CrossRef Eichenlaub-Ritter U. Oocyte ageing and its cellular basis. Int J Dev Biol. 2012;56:841–52.CrossRef
6.
go back to reference Tatone C, Amicarelli F, Carbone MC, Monteleone P, Caserta D, Marci R, et al. Cellular and molecular aspects of ovarian follicle ageing. Hum Reprod Update. 2008;14:131–42.CrossRef Tatone C, Amicarelli F, Carbone MC, Monteleone P, Caserta D, Marci R, et al. Cellular and molecular aspects of ovarian follicle ageing. Hum Reprod Update. 2008;14:131–42.CrossRef
7.
go back to reference Luddi A, Capaldo A, Focarelli R, Gori M, Morgante G, Piomboni P, et al. Antioxidants reduce oxidative stress in follicular fluid of aged women undergoing IVF. Reprod Biol Endocrinol. 2016;14:57.CrossRef Luddi A, Capaldo A, Focarelli R, Gori M, Morgante G, Piomboni P, et al. Antioxidants reduce oxidative stress in follicular fluid of aged women undergoing IVF. Reprod Biol Endocrinol. 2016;14:57.CrossRef
8.
go back to reference Murri M, Luque-Ramirez M, Insenser M, Ojeda-Ojeda M, Escobar-Morreale HF. Circulating markers of oxidative stress and polycystic ovary syndrome (PCOS): a systematic review and meta-analysis. Hum Reprod Update. 2013;19:268–88.CrossRef Murri M, Luque-Ramirez M, Insenser M, Ojeda-Ojeda M, Escobar-Morreale HF. Circulating markers of oxidative stress and polycystic ovary syndrome (PCOS): a systematic review and meta-analysis. Hum Reprod Update. 2013;19:268–88.CrossRef
9.
go back to reference Aruoma OI, Grootveld M, Bahorun T. Free radicals in biology and medicine: from inflammation to biotechnology. Biofactors. 2006;27:1–3.CrossRef Aruoma OI, Grootveld M, Bahorun T. Free radicals in biology and medicine: from inflammation to biotechnology. Biofactors. 2006;27:1–3.CrossRef
10.
go back to reference Kregel KC, Zhang HJ. An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations. Am J Physiol Regul Integr Comp Physiol. 2007;292:R18–36.CrossRef Kregel KC, Zhang HJ. An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations. Am J Physiol Regul Integr Comp Physiol. 2007;292:R18–36.CrossRef
11.
go back to reference Hull KL, Harvey S. Growth hormone and reproduction: a review of endocrine and autocrine/paracrine interactions. Int J Endocrinol 2014, 2014:234014. Hull KL, Harvey S. Growth hormone and reproduction: a review of endocrine and autocrine/paracrine interactions. Int J Endocrinol 2014, 2014:234014.
12.
go back to reference Alviggi C, Humaidan P, Howles CM, Tredway D, Hillier SG. Biological versus chronological ovarian age: implications for assisted reproductive technology. Reprod Biol Endocrinol. 2009;7:101.CrossRef Alviggi C, Humaidan P, Howles CM, Tredway D, Hillier SG. Biological versus chronological ovarian age: implications for assisted reproductive technology. Reprod Biol Endocrinol. 2009;7:101.CrossRef
13.
go back to reference Weall BM, Al-Samerria S, Conceicao J, Yovich JL, Almahbobi G. A direct action for GH in improvement of oocyte quality in poor-responder patients. Reproduction. 2015;149:147–54.CrossRef Weall BM, Al-Samerria S, Conceicao J, Yovich JL, Almahbobi G. A direct action for GH in improvement of oocyte quality in poor-responder patients. Reproduction. 2015;149:147–54.CrossRef
14.
go back to reference Suzuki K, Yanagi K, Shimizu M, Wakamatsu S, Niitani T, Hosonuma S, et al. Effect of growth hormone replacement therapy on plasma diacron-reactive oxygen metabolites and endothelial function in Japanese patients: the GREAT clinical study. Endocr J. 2018;65:101–11.CrossRef Suzuki K, Yanagi K, Shimizu M, Wakamatsu S, Niitani T, Hosonuma S, et al. Effect of growth hormone replacement therapy on plasma diacron-reactive oxygen metabolites and endothelial function in Japanese patients: the GREAT clinical study. Endocr J. 2018;65:101–11.CrossRef
15.
go back to reference Brioche T, Kireev RA, Cuesta S, Gratas-Delamarche A, Tresguerres JA, Gomez-Cabrera MC, et al. Growth hormone replacement therapy prevents sarcopenia by a dual mechanism: improvement of protein balance and of antioxidant defenses. J Gerontol A Biol Sci Med Sci. 2014;69:1186–98.CrossRef Brioche T, Kireev RA, Cuesta S, Gratas-Delamarche A, Tresguerres JA, Gomez-Cabrera MC, et al. Growth hormone replacement therapy prevents sarcopenia by a dual mechanism: improvement of protein balance and of antioxidant defenses. J Gerontol A Biol Sci Med Sci. 2014;69:1186–98.CrossRef
16.
go back to reference Kato Y, Iwase M, Ichihara S, Kanazawa H, Hashimoto K, Noda A, et al. Beneficial effects of growth hormone-releasing peptide on myocardial oxidative stress and left ventricular dysfunction in dilated cardiomyopathic hamsters. Circ J. 2010;74:163–70.CrossRef Kato Y, Iwase M, Ichihara S, Kanazawa H, Hashimoto K, Noda A, et al. Beneficial effects of growth hormone-releasing peptide on myocardial oxidative stress and left ventricular dysfunction in dilated cardiomyopathic hamsters. Circ J. 2010;74:163–70.CrossRef
17.
go back to reference Li R, Albertini DF. The road to maturation: somatic cell interaction and self-organization of the mammalian oocyte. Nat Rev Mol Cell Biol. 2013;14:141–52.CrossRef Li R, Albertini DF. The road to maturation: somatic cell interaction and self-organization of the mammalian oocyte. Nat Rev Mol Cell Biol. 2013;14:141–52.CrossRef
18.
go back to reference Barroso G, Barrionuevo M, Rao P, Graham L, Danforth D, Huey S, et al. Vascular endothelial growth factor, nitric oxide, and leptin follicular fluid levels correlate negatively with embryo quality in IVF patients. Fertil Steril. 1999;72:1024–6.CrossRef Barroso G, Barrionuevo M, Rao P, Graham L, Danforth D, Huey S, et al. Vascular endothelial growth factor, nitric oxide, and leptin follicular fluid levels correlate negatively with embryo quality in IVF patients. Fertil Steril. 1999;72:1024–6.CrossRef
19.
go back to reference Alpha Scientists in Reproductive M, Embryology ESIGo. The Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting. Hum Reprod. 2011;26:1270–83.CrossRef Alpha Scientists in Reproductive M, Embryology ESIGo. The Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting. Hum Reprod. 2011;26:1270–83.CrossRef
20.
go back to reference Navot D, Bergh PA, Laufer N. Reprint of: ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment. Fertil Steril. 2019;112:e209–21.CrossRef Navot D, Bergh PA, Laufer N. Reprint of: ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment. Fertil Steril. 2019;112:e209–21.CrossRef
21.
go back to reference Yang S, Wang Q, Huang W, Song Y, Feng G, Zhou L, et al. Are serum chemerin levels different between obese and non-obese polycystic ovary syndrome women? Gynecol Endocrinol. 2016;32:38–41.CrossRef Yang S, Wang Q, Huang W, Song Y, Feng G, Zhou L, et al. Are serum chemerin levels different between obese and non-obese polycystic ovary syndrome women? Gynecol Endocrinol. 2016;32:38–41.CrossRef
22.
go back to reference Zhang R, Liu H, Bai H, Zhang Y, Liu Q, Guan L, et al. Oxidative stress status in Chinese women with different clinical phenotypes of polycystic ovary syndrome. Clin Endocrinol. 2017;86:88–96.CrossRef Zhang R, Liu H, Bai H, Zhang Y, Liu Q, Guan L, et al. Oxidative stress status in Chinese women with different clinical phenotypes of polycystic ovary syndrome. Clin Endocrinol. 2017;86:88–96.CrossRef
23.
go back to reference Zhou M, Liu XH, Liu QQ, Chen M, Bai H, Guan LB, et al. Lactonase activity, status, and genetic variations of Paraoxonase 1 in women with gestational diabetes mellitus. J Diabetes Res 2020, 2020:3483427. Zhou M, Liu XH, Liu QQ, Chen M, Bai H, Guan LB, et al. Lactonase activity, status, and genetic variations of Paraoxonase 1 in women with gestational diabetes mellitus. J Diabetes Res 2020, 2020:3483427.
24.
go back to reference Fujimoto VY, Bloom MS, Huddleston HG, Shelley WB, Ocque AJ, Browne RW. Correlations of follicular fluid oxidative stress biomarkers and enzyme activities with embryo morphology parameters during in vitro fertilization. Fertil Steril. 2011;96:1357–61.CrossRef Fujimoto VY, Bloom MS, Huddleston HG, Shelley WB, Ocque AJ, Browne RW. Correlations of follicular fluid oxidative stress biomarkers and enzyme activities with embryo morphology parameters during in vitro fertilization. Fertil Steril. 2011;96:1357–61.CrossRef
25.
go back to reference Siristatidis C, Vogiatzi P, Varounis C, Askoxylaki M, Chrelias C, Papantoniou N. The effect of reactive oxygen species on embryo quality in IVF. Vivo. 2016;30:149–53.CrossRef Siristatidis C, Vogiatzi P, Varounis C, Askoxylaki M, Chrelias C, Papantoniou N. The effect of reactive oxygen species on embryo quality in IVF. Vivo. 2016;30:149–53.CrossRef
26.
go back to reference Oyawoye OA, Abdel-Gadir A, Garner A, Leonard AJ, Perrett C, Hardiman P. The interaction between follicular fluid total antioxidant capacity, infertility and early reproductive outcomes during in vitro fertilization. Redox Rep. 2009;14:205–13.CrossRef Oyawoye OA, Abdel-Gadir A, Garner A, Leonard AJ, Perrett C, Hardiman P. The interaction between follicular fluid total antioxidant capacity, infertility and early reproductive outcomes during in vitro fertilization. Redox Rep. 2009;14:205–13.CrossRef
27.
go back to reference Scalici E, Traver S, Molinari N, Mullet T, Monforte M, Vintejoux E, et al. Cell-free DNA in human follicular fluid as a biomarker of embryo quality. Hum Reprod. 2014;29:2661–9.CrossRef Scalici E, Traver S, Molinari N, Mullet T, Monforte M, Vintejoux E, et al. Cell-free DNA in human follicular fluid as a biomarker of embryo quality. Hum Reprod. 2014;29:2661–9.CrossRef
28.
go back to reference Uyar A, Torrealday S, Seli E. Cumulus and granulosa cell markers of oocyte and embryo quality. Fertil Steril. 2013;99:979–97.CrossRef Uyar A, Torrealday S, Seli E. Cumulus and granulosa cell markers of oocyte and embryo quality. Fertil Steril. 2013;99:979–97.CrossRef
29.
30.
go back to reference Carbone MC, Tatone C, Delle Monache S, Marci R, Caserta D, Colonna R, et al. Antioxidant enzymatic defences in human follicular fluid: characterization and age-dependent changes. Mol Hum Reprod. 2003;9:639–43.CrossRef Carbone MC, Tatone C, Delle Monache S, Marci R, Caserta D, Colonna R, et al. Antioxidant enzymatic defences in human follicular fluid: characterization and age-dependent changes. Mol Hum Reprod. 2003;9:639–43.CrossRef
31.
go back to reference Aurrekoetxea I, Ruiz-Sanz JI, del Agua AR, Navarro R, Hernandez ML, Matorras R, et al. Serum oxidizability and antioxidant status in patients undergoing in vitro fertilization. Fertil Steril. 2010;94:1279–86.CrossRef Aurrekoetxea I, Ruiz-Sanz JI, del Agua AR, Navarro R, Hernandez ML, Matorras R, et al. Serum oxidizability and antioxidant status in patients undergoing in vitro fertilization. Fertil Steril. 2010;94:1279–86.CrossRef
32.
go back to reference Agarwal A, Aponte-Mellado A, Premkumar BJ, Shaman A, Gupta S. The effects of oxidative stress on female reproduction: a review. Reprod Biol Endocrinol. 2012;10:49.CrossRef Agarwal A, Aponte-Mellado A, Premkumar BJ, Shaman A, Gupta S. The effects of oxidative stress on female reproduction: a review. Reprod Biol Endocrinol. 2012;10:49.CrossRef
33.
go back to reference 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;20:2536–41.CrossRef 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;20:2536–41.CrossRef
34.
go back to reference Sharara FI, Nieman LK. Growth hormone receptor messenger ribonucleic acid expression in leiomyoma and surrounding myometrium. Am J Obstet Gynecol. 1995;173:814–9.CrossRef Sharara FI, Nieman LK. Growth hormone receptor messenger ribonucleic acid expression in leiomyoma and surrounding myometrium. Am J Obstet Gynecol. 1995;173:814–9.CrossRef
35.
go back to reference Xue-Mei W, Hong J, Wen-Xiang Z, Yang L. The effects of growth hormone on clinical outcomes after frozen-thawed embryo transfer. Int J Gynaecol Obstet. 2016;133:347–50.CrossRef Xue-Mei W, Hong J, Wen-Xiang Z, Yang L. The effects of growth hormone on clinical outcomes after frozen-thawed embryo transfer. Int J Gynaecol Obstet. 2016;133:347–50.CrossRef
36.
go back to reference Cui N, Li AM, Luo ZY, Zhao ZM, Xu YM, Zhang J, et al. Effects of growth hormone on pregnancy rates of patients with thin endometrium. J Endocrinol Investig. 2019;42:27–35.CrossRef Cui N, Li AM, Luo ZY, Zhao ZM, Xu YM, Zhang J, et al. Effects of growth hormone on pregnancy rates of patients with thin endometrium. J Endocrinol Investig. 2019;42:27–35.CrossRef
37.
go back to reference 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;287:1017–21.CrossRef 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;287:1017–21.CrossRef
38.
go back to reference Norman RJ, Alvino H, Hull LM, Mol BW, Hart RJ, Kelly TL, et al. Human growth hormone for poor responders: a randomized placebo-controlled trial provides no evidence for improved live birth rate. Reprod BioMed Online. 2019;38:908–15.CrossRef Norman RJ, Alvino H, Hull LM, Mol BW, Hart RJ, Kelly TL, et al. Human growth hormone for poor responders: a randomized placebo-controlled trial provides no evidence for improved live birth rate. Reprod BioMed Online. 2019;38:908–15.CrossRef
Metadata
Title
Growth hormone alleviates oxidative stress and improves the IVF outcomes of poor ovarian responders: a randomized controlled trial
Authors
Yan Gong
Kun Zhang
Dongsheng Xiong
Jiajing Wei
Hao Tan
Shengfang Qin
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Reproductive Biology and Endocrinology / Issue 1/2020
Electronic ISSN: 1477-7827
DOI
https://doi.org/10.1186/s12958-020-00648-2

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