早发性卵巢功能不全患者辅助生殖药物预处理新进展

doi:10.12280/gjszjk.20200315

摘要/Abstract

摘要：

早发性卵巢功能不全（POI）是一种严重影响生育期女性身心健康的异质性疾病,发病机制不明。对于POI患者,目前尚缺乏有效手段来预防和（或）恢复其正常卵巢储备功能。对有生育需求的POI患者,适时或及时接受辅助生殖治疗可提高其妊娠率和活产率。行辅助生殖治疗前,对POI患者进行个体化生育力评估,采用多种预处理方案,能有效改善卵巢低反应（POR）,提高辅助生殖的成功率并改善妊娠结局。对POI患者可采用的有关辅助生殖药物预处理的最新进展进行综述,包括激素类药物、抗氧化应激制剂、免疫调节剂、抗凝剂和代谢调节剂,旨在为个体化精准辅助生殖预处理的选择提供参考和借鉴。事实上,POI患者辅助生殖药物预处理对改善妊娠结局非常必要。

关键词: 原发性卵巢功能不全, 生殖技术, 辅助, 移植预处理, 抗氧化剂, 免疫调节

Abstract:

Premature ovarian insufficiency (POI) is a heterogeneous disease that seriously affects the physical and mental health of women during childbearing period. However, the pathogenesis of POI is still unknown. For patients with POI, there is no effective means to prevent and/or restore their normal ovarian reserve. For those POI patients with fertility needs, the timely assisted reproductive treatment can improve their pregnancy rate and live birth rate. Individual fertility assessment of POI patients before assisted reproductive therapy, using a variety of pretreatment regimens, can effectively improve the poor ovarian response (POR), increase the success rate of assisted reproduction and improve pregnancy outcome. This article reviewed the progress in the pretreatment with assisted reproductive drugs in POI patients, including hormonal drugs, antioxidant stress agents, immunomodulators, anticoagulants and metabolic regulators, in order to provide reference for the selection of individual treatment protocols. It is true that the pretreatment with assisted reproductive drugs in patients with POI is very important for improving the pregnancy outcome.

Key words: Primary ovarian insufficiency, Reproductive techniques, assisted, Transplantation conditioning, Antioxidants, Immunomodulation

帅领, 刁瑞英, 吴莎, 钟梅, 汪丽萍. 早发性卵巢功能不全患者辅助生殖药物预处理新进展[J]. 国际生殖健康/计划生育, 2021, 40(1): 53-59.

SHUAI Ling, DIAO Rui-ying, WU Sha, ZHONG Mei, WANG Li-ping. New Progress in Drug Pretreatment in Patients with Premature Ovarian Insufficiency[J]. Journal of International Reproductive Health/Family Planning, 2021, 40(1): 53-59.

图/表 3

参考文献 35

[1]	European Society for Human Reproduction and Embryology (ESHRE) Guideline Group on POI, Webber L, Davies M, et al. ESHRE Guideline: management of women with premature ovarian insufficiency[J]. Hum Reprod, 2016,31(5):926-937. doi: 10.1093/humrep/dew027.
[2]	Chen X, Chen SL, Ye DS, et al. Retrospective analysis of reproductive outcomes in women with primary ovarian insufficiency showing intermittent follicular development[J]. Reprod Biomed Online, 2016,32(4):427-433. doi: 10.1016/j.rbmo.2015.12.011.
[3]	Kotb MM, Hassan AM, AwadAllah AM. Does dehydroepiandrosterone improve pregnancy rate in women undergoing IVF/ICSI with expected poor ovarian response according to the Bologna criteria? A randomized controlled trial[J]. Eur J Obstet Gynecol Reprod Biol, 2016,200:11-15. doi: 10.1016/j.ejogrb.2016.02.009.
[4]	Chern CU, Tsui KH, Vitale SG, et al. Dehydroepiandrosterone (DHEA) supplementation improves in vitro fertilization outcomes of poor ovarian responders, especially in women with low serum concentration of DHEA-S: a retrospective cohort study[J]. Reprod Biol Endocrinol, 2018,16(1):90. doi: 10.1186/s12958-018-0409-z.
[5]	Fouany MR, Sharara FI. Is there a role for DHEA supplementation in women with diminished ovarian reserve?[J]. J Assist Reprod Genet, 2013,30(9):1239-1244. doi: 10.1007/s10815-013-0018-x.
[6]	Lin LT, Wang PH, Wen ZH, et al. The Application of Dehydroepiandrosterone on Improving Mitochondrial Function and Reducing Apoptosis of Cumulus Cells in Poor Ovarian Responders[J]. Int J Med Sci, 2017,14(6):585-594. doi: 10.7150/ijms.18706.
[7]	刘凤霞, 李慕军, 黄千贻. 口服避孕药在辅助生殖技术中的应用[J]. 生殖与避孕, 2015,35(4):277-281. doi: 10.7669/j.issn.0253-357X.2015.04.0277.
[8]	Ortmann O, Weiss JM, Diedrich K. Gonadotrophin-releasing hormone (GnRH) and GnRH agonists: mechanisms of action[J]. Reprod Biomed Online, 2002,5(Suppl 1):1-7. doi: 10.1016/s1472-6483(11)60210-1.
[9]	Chen H, Xiao L, Li J, et al. Adjuvant gonadotropin-releasing hormone analogues for the prevention of chemotherapy-induced premature ovarian failure in premenopausal women[J]. Cochrane Database Syst Rev, 2019,3:CD008018. doi: 10.1002/14651858.CD008018.pub3.
[10]	Lambalk CB, Banga FR, Huirne JA, et al. GnRH antagonist versus long agonist protocols in IVF: a systematic review and meta-analysis accounting for patient type[J]. Hum Reprod Update, 2017,23(5):560-579. doi: 10.1093/humupd/dmx017.
[11]	Al-Inany HG, Youssef MA, Ayeleke RO, et al. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology[J]. Cochrane Database Syst Rev, 2016,4:CD001750. doi: 10.1002/14651858.CD001750.pub4.
[12]	Haas J, Zilberberg E, Nahum R, et al. Does double trigger (GnRH-agonist+hCG) improve outcome in poor responders undergoing IVF-ET cycle? A pilot study[J]. Gynecol Endocrinol, 2019,35(7):628-630. doi: 10.1080/09513590.2019.1576621.
[13]	Hull KL, Harvey S. Growth hormone and reproduction: a review of endocrine and autocrine/paracrine interactions[J]. Int J Endocrinol, 2014,2014:234014. doi: 10.1155/2014/234014.
[14]	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[J]. Arch Gynecol Obstet, 2018,297(5):1317-1321. doi: 10.1007/s00404-018-4725-5.
[15]	Albu D, Albu A. Is growth hormone administration essential for in vitro fertilization treatment of female patients with growth hormone deficiency?[J]. Syst Biol Reprod Med, 2019,65(1):71-74. doi: 10.1080/19396368.2018.1492044.
[16]	谭秀群, 李汝斐, 农柳莹, 等. 体外受精-胚胎移植促排卵早期添加重组人黄体生成素在低黄体生成素患者中的应用效果[J]. 广西医学, 2018,40(11):1174-1177. doi: 10.11675/j.issn.0253-4304.2018.11.06.
[17]	Ferraretti AP, Gianaroli L, Motrenko T, et al. LH pretreatment as a novel strategy for poor responders[J]. Biomed Res Int, 2014,2014:926172. doi: 10.1155/2014/926172.
[18]	Song D, Shi Y, Zhong Y, et al. Efficiency of mild ovarian stimulation with clomiphene on poor ovarian responders during IVF\ICSI procedures: a meta-analysis[J]. Eur J Obstet Gynecol Reprod Biol, 2016,204:36-43. doi: 10.1016/j.ejogrb.2016.07.498.
[19]	潘烨, 王泽, 冯海英, 等. 来曲唑促排卵研究进展[J]. 中国实用妇科与产科杂志, 2018,34(3):340-343. doi: 10.19538/j.fk2018030126.
[20]	Bastu E, Buyru F, Ozsurmeli M, et al. A randomized,single-blind,prospective trial comparing three different gonadotropin doses with or without addition of letrozole during ovulation stimulation in patients with poor ovarian response[J]. Eur J Obstet Gynecol Reprod Biol, 2016,203:30-34. doi: 10.1016/j.ejogrb.2016.05.027.
[21]	Miles MV, Horn PS, Tang PH, et al. Age-related changes in plasma coenzyme Q10 concentrations and redox state in apparently healthy children and adults[J]. Clin Chim Acta, 2004,347(1/2):139-144. doi: 10.1016/j.cccn.2004.04.003.
[22]	Xu Y, Nisenblat V, Lu C, et al. Pretreatment with coenzyme Q10 improves ovarian response and embryo quality in low-prognosis young women with decreased ovarian reserve: a randomized controlled trial[J]. Reprod Biol Endocrinol, 2018,16(1):29. doi: 10.1186/s12958-018-0343-0.
[23]	Li N, Liu L. Mechanism of resveratrol in improving ovarian function in a rat model of premature ovarian insufficiency[J]. J Obstet Gynaecol Res, 2018,44(8):1431-1438. doi: 10.1111/jog.13680.
[24]	Liu M, Yin Y, Ye X, et al. Resveratrol protects against age-associated infertility in mice[J]. Hum Reprod, 2013,28(3):707-717. doi: 10.1093/humrep/des437.
[25]	Tamura H, Takasaki A, Taketani T, et al. Melatonin as a free radical scavenger in the ovarian follicle[J]. Endocr J, 2013,60(1):1-13. doi: 10.1507/endocrj.ej12-0263.
[26]	Yang M, Tao J, Chai M, et al. Melatonin Improves the Quality of Inferior Bovine Oocytes and Promoted Their Subsequent IVF Embryo Development: Mechanisms and Results[J]. Molecules, 2017,22(12):2059. doi: 10.3390/molecules22122059.
[27]	Hoyos-Marulanda V, Alves BS, Rosa P, et al. Effects of polyunsaturated fatty acids on the development of pig oocytes in vitro following parthenogenetic activation and on the lipid content of oocytes and embryos[J]. Anim Reprod Sci, 2019,205:150-155. doi: 10.1016/j.anireprosci.2019.05.003.
[28]	Hohos NM, Elliott EM, Cho KJ, et al. High-fat diet-induced dysregulation of ovarian gene expression is restored with chronic omega-3 fatty acid supplementation[J]. Mol Cell Endocrinol, 2020,499:110615. doi: 10.1016/j.mce.2019.110615.
[29]	Liu X, Lin X, Mi Y, et al. Grape Seed Proanthocyanidin Extract Prevents Ovarian Aging by Inhibiting Oxidative Stress in the Hens[J]. Oxid Med Cell Longev, 2018,2018:9390810. doi: 10.1155/2018/9390810.
[30]	Petríková J, Lazúrová I. Ovarian failure and polycystic ovary syndrome[J]. Autoimmun Rev, 2012,11(6/7):A471-478. doi: 10.1016/j.autrev.2011.11.010.
[31]	Achilli C, Duran-Retamal M, Saab W, et al. The role of immunotherapy in in vitro fertilization and recurrent pregnancy loss: a systematic review and meta-analysis[J]. Fertil Steril, 2018,110(6):1089-1100. doi: 10.1016/j.fertnstert.2018.07.004.
[32]	Kwak-Kim J, Agcaoili MS, Aleta L, et al. Management of women with recurrent pregnancy losses and antiphospholipid antibody syndrome[J]. Am J Reprod Immunol, 2013,69(6):596-607. doi: 10.1111/aji.12114.
[33]	Podfigurna A, Stellmach A, Szeliga A, et al. Metabolic Profile of Patients with Premature Ovarian Insufficiency[J]. J Clin Med, 2018,7(10):374. doi: 10.3390/jcm7100374.
[34]	Kunicki M, Rudnicka E, Skórska J, et al. Insulin resistance indexes in women with premature ovarian insufficiency - a pilot study[J]. Ginekol Pol, 2018,89(7):364-369. doi: 10.5603/GP.a2018.0062.
[35]	Qin X, Du D, Chen Q, et al. Metformin prevents murine ovarian aging[J]. Aging(Albany NY), 2019,11(11):3785-3794. doi: 10.18632/aging.102016.

促排卵药	分泌或合成	半衰期	作用	伴随效应	对垂体反应	不良反应
GnRH	下丘脑分泌	正常	与GnRHR结合,促进LH和FSH释放	正常	正常	正常
GnRHa	人工合成	延长	短期与GnRHR结合,促进LH和FSH释放;持续应用抑制LH和FSH释放	有点火效应	起效慢（2~3周）; 恢复慢（2~3周）	OHSS多
GnRH_A	人工合成	延长	完全阻断内源性GnRH作用,迅速降低血清FSH、LH	无点火效应	起效快（1 h后）; 恢复快（48 h后）	OHSS少; 快速抑制LH峰

促排卵药	分泌或合成	半衰期	作用	伴随效应	对垂体反应	不良反应
GnRH	下丘脑分泌	正常	与GnRHR结合,促进LH和FSH释放	正常	正常	正常
GnRHa	人工合成	延长	短期与GnRHR结合,促进LH和FSH释放;持续应用抑制LH和FSH释放	有点火效应	起效慢（2~3周）; 恢复慢（2~3周）	OHSS多
GnRH_A	人工合成	延长	完全阻断内源性GnRH作用,迅速降低血清FSH、LH	无点火效应	起效快（1 h后）; 恢复快（48 h后）	OHSS少; 快速抑制LH峰

预处理方案	适用亚群	优点	缺点
DHEA	低DHEA患者	有效性确切,不良反应相对较小,成本低	雄激素相关不良反应
COCP	获卵数少的患者	不良反应小,成本低	有效性有待证实
GnRH类似物	短期有生育需求的患者	技术成熟,疗效确切	OHSS等
GH	GHD患者	有效性较确切	费用昂贵
r-LH	低LH或降调过深者	不良反应较小	有效性有待证实
CC和LTZ	降调过深者	成本低	药物安全性及有效性有待证实
抗氧化剂	高龄等	无明显不良反应	有效性有待证实
免疫调节剂	免疫性POI或合并自身免疫性疾病、具有RSA或反复种植失败病史的患者	潜在性,预防胚胎丢失	免疫抑制剂相关不良反应
抗凝剂	合并APS等血栓性疾病、具有RSA或反复种植失败病史的患者	潜在性,预防血栓和胚胎丢失	出血风险
代谢调节剂	代谢紊乱者	潜在性	有效性有待证实

预处理方案	适用亚群	优点	缺点
DHEA	低DHEA患者	有效性确切,不良反应相对较小,成本低	雄激素相关不良反应
COCP	获卵数少的患者	不良反应小,成本低	有效性有待证实
GnRH类似物	短期有生育需求的患者	技术成熟,疗效确切	OHSS等
GH	GHD患者	有效性较确切	费用昂贵
r-LH	低LH或降调过深者	不良反应较小	有效性有待证实
CC和LTZ	降调过深者	成本低	药物安全性及有效性有待证实
抗氧化剂	高龄等	无明显不良反应	有效性有待证实
免疫调节剂	免疫性POI或合并自身免疫性疾病、具有RSA或反复种植失败病史的患者	潜在性,预防胚胎丢失	免疫抑制剂相关不良反应
抗凝剂	合并APS等血栓性疾病、具有RSA或反复种植失败病史的患者	潜在性,预防血栓和胚胎丢失	出血风险
代谢调节剂	代谢紊乱者	潜在性	有效性有待证实