卵泡刺激素受体基因多态性对女性卵巢功能影响的研究进展

摘要/Abstract

摘要： 卵泡刺激素(FSH)是人类重要的生殖激素,被广泛应用于体外受精超促排卵。然而,在临床上发现使用FSH进行卵巢刺激的不孕症患者其卵巢反应不一。FSH通过与卵泡刺激素受体(FSHR)结合介导其生理功能,目前在卵泡刺激素受体基因中发现超过900个SNP位点,其中一些SNP位点可能与FSH刺激引起的卵巢反应差异相关,在辅助生殖超促排卵过程中应该考虑这些SNPs对于卵巢功能的影响。通过预测疾病的遗传因素,为即将进行卵巢刺激的患者测定其基因多态性,以此制定个体化的卵巢刺激方案,达到优化不孕症治疗的临床目的。本文从遗传药理学角度,综述卵泡刺激素受体基因多态性对女性生殖功能的影响,探讨其临床意义。

关键词: 卵泡刺激素受体, 基因多态性, 控制性超促排卵, 卵巢过度刺激综合征, 多囊卵巢综合症

Abstract: Follicle stimulating hormone (FSH) is a glycoprotein hormone played an essential role in reproduction and widely used in the treatment of infertility. However, in the assisted reproductive technology programs, the response of ovulating women to exogenous FSH is quite variable in individuals. FSH action is mediated by the FSH receptor (FSHR). More than 900 polymorphisms of FSHR gene are known, it has been previously reported that SNPs of FSHR may be related to the response of the patients to FSH stimulation and should, therefore, be considered in assessment of efficacy in controlled ovarian hyperstimulation during assisted reproduction techniques in women. The aim of these studies would be the prediction of the genetic causes of diseases to enable an individual clinical setting according to the patient's genetic background undergoing FSH stimulation. In this review we discuss the latest information about the effects of polymorphisms of the FSHR genes on reproductive functions of female, and discuss their clinical implications.

Key words: Follicle stimulating hormone receptor, Polymorphism, Controlled ovarian hyperstimulation, Ovarian hyperstimulation syndrome, Polycystic ovary syndrome

中图分类号:

R968

颜元良, 龚志成. 卵泡刺激素受体基因多态性对女性卵巢功能影响的研究进展[J]. 中国临床药理学与治疗学, 2013, 18(8): 944-949.

YAN Yuan-liang, GONG Zhi-cheng. Effects of polymorphisms in follicle stimulating hormone receptor genes on female reproductive function[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2013, 18(8): 944-949.

参考文献

[1] Polyzos NP, Devroey P. A systematic review of randomized trials for the treatment of poor ovarian responders: is there any light at the end of the tunnel [J]? Fertil Steril, 2011, 96(5): 1058-1061.
[2] Humaidan P, Quartarolo J, Papanikolaou EG. Preventing ovarian hyperstimulation syndrome: guidance for the clinician [J]. Fertil Steril, 2010, 94(2): 389-400.
[3] Perez Mayorga M, Gromoll J, Behre HM, et al. Ovarian response to follicle-stimulating hormone (FSH) stimulation depends on the FSH receptor genotype [J]. J Clin Endocrinol Metab, 2000, 85(9): 3365-3369.
[4] Du J, Zhang W, Guo L, et al. Two FSHR variants, haplotypes and meta-analysis in Chinese women with premature ovarian failure and polycystic ovary syndrome [J]. Mol Genet Metab, 2010, 100 (3): 292-295.
[5] Casarini L, Pignatti E, Simoni M. Effects of polymorphisms in gonadotropin and gonadotropin receptor genes on reproductive function [J]. Rev Endocr Metab Disord, 2011, 12 (4): 303-321.
[6] Lussiana C, Guani B, Mari C, et al. Mutations and polymorphisms of the FSH receptor (FSHR) gene: clinical implications in female fecundity and molecular biology of FSHR protein and gene [J]. Obstet Gynecol Surv, 2008, 63 (12): 785-795.
[7] Ulloa-Aguirre A, Zariñán T, Pasapera AM, et al. Multiple facets of follicle-stimulating hormone receptor function [J]. Endocrine, 2007, 32 (3): 251-263.
[8] Levallet J, Pakarinen P, Huhtaniemi IT. Follicle - stimulating hormone ligand and receptor mutations and gonadal dysfunction [J]. Arch Med Res, 1999, 30 (6): 486-494.
[9] Kene PS, Nalavadi VC, Dighe RR, et al. Identification of the structural and functional determinants of the extracellular domain of the human follicle stimulating hormone receptor [J]. J Endocrinol, 2004, 182 (3): 501-508.
[10] 陈洋,陈娟,杨永梅,等. 促卵泡素受体基因的研究概况 [J]. 中国畜牧兽医, 2010, 37 (2): 108-111.
[11] Themmen APN, Huhtaniemi IT. Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and pathophysiology of pituitary-gonadal function [J]. Endocr Rev, 2000, 21 (5): 551-583.
[12] Gromoll J, Pekel E, Nieschlag E. The structure and organization of the human follicle-stimulating hormone receptor (FSHR) gene [J]. Genomics, 1996, 35 (2): 308-311.
[13] Minegishi T, Nakamura K, Takakura Y, et al. Cloning and sequencing of human FSH receptor cDNA [J]. Biochem Biophys Res Commun, 1991, 175 (3): 1125-1130.
[14] George JW, Dille EA, Heckert LL. Current concepts of follicle-stimulating hormone receptor gene regulation [J]. Biol Reprod, 2011, 84 (1): 7-17.
[15] 夏良斌. 卵泡刺激素受体基因与卵巢功能的研究进展 [J]. 国外医学计划生育/生殖健康分册, 2007, 4: 198-201.
[16] 张晓静,黄荷凤. 卵巢颗粒细胞中卵泡刺激素懂得受体后信号传导通路 [J]. 中华妇产科杂志, 2009, 4 (44): 309-312.
[17] 陈悦群. 颗粒细胞增殖分化中卵泡刺激素的cAMP-PKA通路 [J]. 国际生殖健康/ 计划生育杂志, 2011, 1 (30): 65-68.
[18] Jun JK, Yoon JS, Ku SY, et al. Follicle-stimulating hormone receptor gene polymorphism and ovarian responses to controlled ovarian hyperstimulation for IVF-ET [J]. J Hum Genet, 2006, 51(8): 665-670.
[19] Yao Y, Ma CH, Tang HL, et al. Influence of follicle-stimulating hormone receptor (FSHR) Ser680Asn polymorphism on ovarian function and in-vitro fertilization outcome: a meta-analysis [J]. Mol Genet Metab, 2011, 103(4): 388-393.
[20] Behre HM, Greb RR, Mempel A, et al. Significance of a common single nucleotide polymorphism in exon 10 of the follicle-stimulating hormone (FSH) receptor gene for the ovarian response to FSH: a pharmacogenetic approach to controlled ovarian hyperstimulation [J]. Pharmacogenet Genomics, 2005, 15 (7): 451-456.
[21] Klinkert ER, te Velde ER, Weima S, et al. FSH receptor genotype is associated with pregnancy but not with ovarian response in IVF [J]. Reprod Biomed Online, 2006, 13 (5): 687 - 695.
[22] Achrekar SK, Modi DN, Desai SK, et al. Follicle-stimulating hormone receptor polymorphism (Thr307Ala) is associated with variable ovarian response and ovarian hyperstimulation syndrome in Indian women [J]. Fertil Steril, 2009, 91 (2): 432-439.
[23] Achrekar SK, Modi DN, Meherji PK, et al. Follicle stimulating hormone receptor gene variants in women with primary and secondary amenorrhea [J]. J Assist Reprod Genet, 2010, 27 (6): 317-326.
[24] Achrekar SK, Modi DN, Desai SK, et al. Poor ovarian response to gonadotrophin stimulation is associated with FSH receptor polymorphism [J]. Reprod Biomed Online, 2009, 18 (4): 509-515.
[25] Nastri CO, Ferriani RA, Rocha IA, et al. Ovarian hyperstimulation syndrome: pathophysiology and prevention [J]. J Assist Reprod Genet, 2010, 27 (2/3): 121-128.
[26] Daelemans C, Smits G, de Maertelaer V, et al. Prediction of severity of symptoms in iatrogenic ovarian hyperstimulation syndrome by follicle-stimulating hormone receptor Ser680Asn polymorphism [J]. J Clin Endocrinol Metab, 2004, 89 (12): 6310-6315.
[27] D'Alva CB,Serafini P,Motta E. Absence of follicle-stimulating hormone receptor activating mutations in women with iatrogenic ovarian hyperstimulation syndrome [J]. Fertil Steril, 2005, 83(6): 1695-1699.
[28] Kerkela E, Skottman H, Friden B, et al. Exclusion of coding-region mutations in luteinizing hormone and follicle-stimulating hormone receptor genes as the cause of ovarian hyperstimulation syndrome [J]. Fertile Steril, 2007, 87(3): 603-606.
[29] Tong Y, Liao WX, Roy AC, et al. Absence of mutations in the coding regions of follicle-stimulating hormone receptor gene in Singapore Chinese women with premature ovarian failure and polycystic ovary syndrome [J]. Horm Metab Res, 2001, 33 (4): 221-226.
[30] Orio F Jr, Ferrarini E, Cascella T, et al. Genetic analysis of the follicle stimulating hormone receptor gene in women with polycystic ovary syndrome [J]. J Endocrinol Invest, 2006, 29 (11): 975-982.
[31] Unsal T, Konac E,Yesilkaya E,et al.Genetic polymorphisms of FSHR, CYP17, CYP1A1, CAPN10, INSR, SERPINE1 genes in adolescent girls with polycystic ovary syndrome[J]. J Assist Reprod Genet, 2009, 26 (4): 205-216.
[32] Valkenburg O, Uitterlinden AG, Piersma D, et al. Genetic polymorphisms of GnRH and gonadotrophic hormone receptors affect the phenotype of polycystic ovary syndrome [J]. Hum Reprod,2009, 24 (8): 2014-2022.
[33] Gu BH, Park JM, Baek KH. Genetic variations of follicle stimulating hormone receptor are associated with polycystic ovary syndrome [J]. Int J Mol Med, 2010, 26 (1): 107-112.
[34] Overbeek A, Kuijper EA, Hendriks ML, et al. Clomiphene citrate resistance in relation to follicle-stimulating hormone receptor Ser680Ser-polymorphism in polycystic ovary syndrome [J]. Hum Reprod, 2009, 24 (8): 2007-2013.
[35] Rodini GP, Genro VK, Matte U, et al. There is no complete linkage between the polymorphisms N680S and T307A of the follicular stimulating hormone receptor gene in fertile women [J]. J Assist Reprod Genet, 2011, 28 (3): 221-224.