生长激素对卵巢储备功能低下患者IVF-ET治疗结局的影响
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摘要
随着社会竞争压力、环境污染、心理压力等因素的影响，妇女生育年龄在推迟,不孕症的发病率逐年升高。尤其由于年龄、手术、免疫、环境理化因子等因素的影响卵巢储备功能低下导致的不孕患者越来越多。在体外授精-胚胎移植(in vitro fertilization-embryo transfer,IVF-ET)助孕过程中卵巢储备功能低下患者表现为卵巢反应不良和卵子质量下降,从而影响IVF-ET结局。目前卵巢储备功能低下患者发生的卵巢反应不良是困扰辅助生殖临床医生的难题之一。如何有效改善卵巢储备功能低下患者的卵巢反应及IVF-ET结局是目前研究的热点之一。目前国内外多数学者研究认为生长激素(growth hormon,GH)对卵泡的发生、生长起营养作用,有助于改善卵巢功能。GH对卵巢储备功能低下患者的卵巢反应是否有改善,目前探讨很少。
目的
本研究通过对卵巢储备功能低下患者在IVF-ET助孕治疗中应用GH,来探讨GH对卵巢储备功能低下患者是否有影响,从而为临床应用提供理论依据。
方法
自2010年1月至2011年2月在郑州大学第一附属医院生殖医学中心就诊行IVF-ET的卵巢储备功能低下(基础内分泌FSH>10.0mIU/ml)的不孕患者240例,按照不同年龄分两部分：年龄<35岁部分171例,年龄≥35岁部分69例；按照是否应用GH分：实验组为应用GH组,对照组为未用GH组。年龄<35岁部分实验组81例,对照组90例；年龄≥35岁部分实验组39例,对照组30例。所有患者均在我中心采用普通长方案降调节,于月经黄体中期采用促性腺激素释放激素激动剂(gonadotrophin releasing hormone agonist, GnRH-a)开始降调节,皮下注射0.1mg/日*14天,降调节达标后,于卵泡晚期开始应用果纳芬(Gn,serono)启动至卵泡成熟,GnRH-a改为0.05mg/日至HCG日,Gn启动日应用GH(注射用重组生长激素,塞增)4.5IU/日*5天为实验组、未用GH为对照组,观察卵巢反应的各项指标。采用SPSS13.0统计学软件对实验数据进行统计学分析。
结果
1.生长激素(GH)对年轻(年龄<35岁)卵巢储备功能低下患者的卵巢反应及IVF-ET的影响。两组不孕症患者的各项临床基本资料比较包括年龄、不孕年限、bFSH、AFC,结果均无统计学差异(P>0.05)。两组不孕症患者的各项实验室及治疗结局资料比较,结果Gn天数、Gn支数、HCG日E2、获卵数、2PN受精率、优胚率、种植率、妊娠率,这些观察指标,均无统计学差异(P>0.05)。
2.生长激素(GH)对高龄(年龄≥35岁)卵巢储备功能低下患者的卵巢反应及IVF-ET的的影响。两组不孕症患者的各项临床基本资料比较包括年龄、不孕年限、bFSH、AFC,结果均无统计学差异(P>0.05)。两组不孕症患者的各项实验室及治疗结局资料比较：Gn用量(Gn支数)实验组显著低于对照组,有统计学差异(P<0.05)；HCG日E2水平、获卵数实验组显著高于对照组,有统计学差异(P<0.05)。用药时间(Gn天数)比较在数值上实验组低于对照组,但无统计学差异(P>0.05)；2PN受精率、优胚率、种植率、妊娠率比较实验组均高于对照组,但是这些观察指标无统计学差异(P>0.05)。
结论
1.生长激素(GH)对年龄<35岁卵巢储备功能低下患者的卵巢反应及IVF-ET治疗结局无影响。
2.生长激素(GH)对年龄≥35岁卵巢储备功能低下患者的卵巢反应及IVF-ET治疗结局有影响,可减少Gn使用量,提高HCG日的E2水平,增加获卵数。
3.在辅助生殖技术临床应用中对年龄≥35岁卵巢储备功能低下患者可通过应用生长激素改善卵巢的反应性。
Under the increasingly heavy pressure of social competition, more and more women tend to postpone their gestational plan, thus the rate of infertility is gradually elevated. Especially, due to the effect of advanced maternal age, surgery, immune and environmental factors, the number of infertile patients with diminished ovary reserve increases. In the process of in vitro fertilization and embryo transfer, manifestations of declined ovary reserve include low ovarian response and decreased quality of ovum, which are both linked to poor outcome of IVF-ET. Nowadays, poor ovarian responder is one of the issues that bother clinicians most. And how to improve the ovarian response and IVF outcome become one of the focuses in research field. Many scholars stated that growth hormone (GH), to some extent, may improve the ovarian response. So we use the data in our Reproductive Medical Centre to illustrate whether GH functions or not.
Objective:
To discuss whether GH positively affect the IVF outcome of patients, thus to provide theoretical proof for clinical application.
Methods:
Two hundred and forty infertile patients with decreased ovarian reserve (basal FSH>10.0mIU/ml), admitted to the Reproductive Medical Centre of the First Affiliated Hospital of Zhengzhou University from January,2011 to February,2011, were enrolled into our study. They were divided in terms of age:171 patients under 35 years old and 69 patients equal to or above 35 years old. And both groups were further divided into two groups by having used GH in their cycles or not. Patients received GH were taken as the experimental group, while those didn't were taken as the control group. The group less than 35 years old included experimental group with 81 cases and control group with 90 cases. The group equals to or more than 35 years old included experimental group with 39 cases and control group with 30 cases. All the patients in this study had been down regulated according to the conventional long protocol in our centre. Use of GnRHa started from the midluteal phase of the menstrual cycle, with a daily injection of 0.1mg for about 14 days. After achieving the standard of down regulation, GnRHa was continued with a dosage of 0.05mg daily while Gn (Gonal-F, Merck Serono) was given for superovulation, till the day of HCG injection. The experimental group was given GH (Jintropin, Gensci, China) since the beginning of Gn,4.5IU daily for consecutive 5 days. The control group were not given GH. Ovarian response and outcome of IVF were observed in both groups. We use SPSS 13.0 Software to perform statistical analysis.
Result:
1.Effect of GH on patients under 35 years old with diminished ovarian reserve: No significantly difference was observed between the basic informations of the two groups, such as age, duration of infertility, basal FSH, AFC (all P>0.05). The dosage of Gn was lower, and its duration was shorter in the experimental group than those in the control groups. The level of estradiol, the number of retrieved ovum,2PN fertilization rate, good quality embryo rate, implantation rate and clinical rate were all higher in the control groups. But for all the above items, no significant differences were found (all P>0.05).
2. Effect of GH on patients equals to or more than 35 years old with diminished ovarian reserve:No significantly difference was observed between the basic informations of the two groups, such as age, duration of infertility, basal FSH, AFC (all P>0.05). The dosage of Gn was significantly lower(P<0.05), and its duration was shorter in the experimental group than those in the control groups. The level of estradiol and the number of retrieved ovum were significantly higher(P<0.05) in the control groups.2PN fertilization rate, good quality embryo rate, implantation rate and clinical rate were all higher in the control group. But for all the above items, no significant differences were found (all P>0.05).
Conclusions
1. Growth hormone has no significant effect on the ovarian response and IVF outcome for the patients less than 35 years old with decreased ovarian reserve.
2. Growth hormone may diminish the dosage of Gn, elevate the level of estradiol on the day of HCG injection and increase the number of ovum for the patients equal to or more than 35 years old with decreased ovarian reserve.
3. In the clinical application of assisted reproductive technologies, the patients who are equal to or more than 35 years old with decreased ovarian reserve improve the ovarian response by having used GH.
目的
本研究通过对卵巢储备功能低下患者在IVF-ET助孕治疗中应用GH,来探讨GH对卵巢储备功能低下患者是否有影响,从而为临床应用提供理论依据。
方法
自2010年1月至2011年2月在郑州大学第一附属医院生殖医学中心就诊行IVF-ET的卵巢储备功能低下(基础内分泌FSH>10.0mIU/ml)的不孕患者240例,按照不同年龄分两部分：年龄<35岁部分171例,年龄≥35岁部分69例；按照是否应用GH分：实验组为应用GH组,对照组为未用GH组。年龄<35岁部分实验组81例,对照组90例；年龄≥35岁部分实验组39例,对照组30例。所有患者均在我中心采用普通长方案降调节,于月经黄体中期采用促性腺激素释放激素激动剂(gonadotrophin releasing hormone agonist, GnRH-a)开始降调节,皮下注射0.1mg/日*14天,降调节达标后,于卵泡晚期开始应用果纳芬(Gn,serono)启动至卵泡成熟,GnRH-a改为0.05mg/日至HCG日,Gn启动日应用GH(注射用重组生长激素,塞增)4.5IU/日*5天为实验组、未用GH为对照组,观察卵巢反应的各项指标。采用SPSS13.0统计学软件对实验数据进行统计学分析。
结果
1.生长激素(GH)对年轻(年龄<35岁)卵巢储备功能低下患者的卵巢反应及IVF-ET的影响。两组不孕症患者的各项临床基本资料比较包括年龄、不孕年限、bFSH、AFC,结果均无统计学差异(P>0.05)。两组不孕症患者的各项实验室及治疗结局资料比较,结果Gn天数、Gn支数、HCG日E2、获卵数、2PN受精率、优胚率、种植率、妊娠率,这些观察指标,均无统计学差异(P>0.05)。
2.生长激素(GH)对高龄(年龄≥35岁)卵巢储备功能低下患者的卵巢反应及IVF-ET的的影响。两组不孕症患者的各项临床基本资料比较包括年龄、不孕年限、bFSH、AFC,结果均无统计学差异(P>0.05)。两组不孕症患者的各项实验室及治疗结局资料比较：Gn用量(Gn支数)实验组显著低于对照组,有统计学差异(P<0.05)；HCG日E2水平、获卵数实验组显著高于对照组,有统计学差异(P<0.05)。用药时间(Gn天数)比较在数值上实验组低于对照组,但无统计学差异(P>0.05)；2PN受精率、优胚率、种植率、妊娠率比较实验组均高于对照组,但是这些观察指标无统计学差异(P>0.05)。
结论
1.生长激素(GH)对年龄<35岁卵巢储备功能低下患者的卵巢反应及IVF-ET治疗结局无影响。
2.生长激素(GH)对年龄≥35岁卵巢储备功能低下患者的卵巢反应及IVF-ET治疗结局有影响,可减少Gn使用量,提高HCG日的E2水平,增加获卵数。
3.在辅助生殖技术临床应用中对年龄≥35岁卵巢储备功能低下患者可通过应用生长激素改善卵巢的反应性。
Under the increasingly heavy pressure of social competition, more and more women tend to postpone their gestational plan, thus the rate of infertility is gradually elevated. Especially, due to the effect of advanced maternal age, surgery, immune and environmental factors, the number of infertile patients with diminished ovary reserve increases. In the process of in vitro fertilization and embryo transfer, manifestations of declined ovary reserve include low ovarian response and decreased quality of ovum, which are both linked to poor outcome of IVF-ET. Nowadays, poor ovarian responder is one of the issues that bother clinicians most. And how to improve the ovarian response and IVF outcome become one of the focuses in research field. Many scholars stated that growth hormone (GH), to some extent, may improve the ovarian response. So we use the data in our Reproductive Medical Centre to illustrate whether GH functions or not.
Objective:
To discuss whether GH positively affect the IVF outcome of patients, thus to provide theoretical proof for clinical application.
Methods:
Two hundred and forty infertile patients with decreased ovarian reserve (basal FSH>10.0mIU/ml), admitted to the Reproductive Medical Centre of the First Affiliated Hospital of Zhengzhou University from January,2011 to February,2011, were enrolled into our study. They were divided in terms of age:171 patients under 35 years old and 69 patients equal to or above 35 years old. And both groups were further divided into two groups by having used GH in their cycles or not. Patients received GH were taken as the experimental group, while those didn't were taken as the control group. The group less than 35 years old included experimental group with 81 cases and control group with 90 cases. The group equals to or more than 35 years old included experimental group with 39 cases and control group with 30 cases. All the patients in this study had been down regulated according to the conventional long protocol in our centre. Use of GnRHa started from the midluteal phase of the menstrual cycle, with a daily injection of 0.1mg for about 14 days. After achieving the standard of down regulation, GnRHa was continued with a dosage of 0.05mg daily while Gn (Gonal-F, Merck Serono) was given for superovulation, till the day of HCG injection. The experimental group was given GH (Jintropin, Gensci, China) since the beginning of Gn,4.5IU daily for consecutive 5 days. The control group were not given GH. Ovarian response and outcome of IVF were observed in both groups. We use SPSS 13.0 Software to perform statistical analysis.
Result:
1.Effect of GH on patients under 35 years old with diminished ovarian reserve: No significantly difference was observed between the basic informations of the two groups, such as age, duration of infertility, basal FSH, AFC (all P>0.05). The dosage of Gn was lower, and its duration was shorter in the experimental group than those in the control groups. The level of estradiol, the number of retrieved ovum,2PN fertilization rate, good quality embryo rate, implantation rate and clinical rate were all higher in the control groups. But for all the above items, no significant differences were found (all P>0.05).
2. Effect of GH on patients equals to or more than 35 years old with diminished ovarian reserve:No significantly difference was observed between the basic informations of the two groups, such as age, duration of infertility, basal FSH, AFC (all P>0.05). The dosage of Gn was significantly lower(P<0.05), and its duration was shorter in the experimental group than those in the control groups. The level of estradiol and the number of retrieved ovum were significantly higher(P<0.05) in the control groups.2PN fertilization rate, good quality embryo rate, implantation rate and clinical rate were all higher in the control group. But for all the above items, no significant differences were found (all P>0.05).
Conclusions
1. Growth hormone has no significant effect on the ovarian response and IVF outcome for the patients less than 35 years old with decreased ovarian reserve.
2. Growth hormone may diminish the dosage of Gn, elevate the level of estradiol on the day of HCG injection and increase the number of ovum for the patients equal to or more than 35 years old with decreased ovarian reserve.
3. In the clinical application of assisted reproductive technologies, the patients who are equal to or more than 35 years old with decreased ovarian reserve improve the ovarian response by having used GH.
引文
[1]Keay SD,Lunenfeld B,Eshel A,etal. Assisted conception following poor ovarian responses to gonadotrophin stimulation.Br J Obstet Gynaecol,1997,14:521-527.
[2]周毛婴,周馥贞等.不孕症妇女卵巢储备监测及意义[J].国外医学计划生育分册,2001,20(2)：94-97.
[3]Yong PY, Baird DT,ThongKJ,et a.l Prospective analysis of the relationships between the ovarian follicle cohort and basal FSH concentration, the inhibin response to exogenous FSH and ovarian follicle tuitary down-regulation[J].Hum Reprod,2003,18(1):35-44.
[4]朱小明,蔡婕,黄荷凤.卵巢反应不良的诊断标准和预测[J].中国实用妇科与产科杂志,2006,22(5)：388-389.
[5]黄晓卉,王华,胡明玥等.小剂量生长激素对卵巢低反应患者超促排卵的影响[J].实用诊断与治疗杂志,2007,21(12)：939-940.
[6]hao J, TaverneM A,Van derWeijden GC,et al. Immunohistochemical localization of growth hormone(GH), GH receptor(GHR), insulin-like growth factor Ⅰ(IGF-I) and Type IGF-I receptor, and gene expression of GH and GHR in rat pre-antral follicles [J]. Zygote,2002, 10(1):85-94.
[7]NishiyamaK, SugimotoT, KajiH, etal. Stimulatory effeet of growth hormone on bone resorption and osteoclast differentiation [J].Endocrinology,1996,137(1):35-41.
[8]吴效科,苏延华等PCOS患者血清生长激素和泌乳素对左旋多巴反应的研究[J].中华妇产科杂志,1997,32(8)：489-491.
[9]丁国莲,黄荷凤等.生长激素在辅助生殖技术中的应用及作用机制[J].国际生殖健康/计划生育杂志,2008,27(6)：351-354.
[10]傅薇,韩金兰.IVF超促排卵过程中对卵巢反应性的预测[J].生殖与避孕,2004,24(4)：236-239.
[11]庄广伦,翁世湘,周灿权.小剂量生长激素在体外受精超排卵周期中的作用[J].中华妇产科杂志,1994,29(8)：471-474.
[12]赵红岩,孙莹璞,苏迎春等.两种降调节方案在控制性超排卵中的效果比较[J].生殖与避孕,2010,30(1)：32-36.
[13]苏迎春,陈慧,孙莹璞.影响冷冻胚胎着床因素回顾性分析[J].生殖医学杂志,2007,16(3)：196-198.
[14]Tamura M,Sasano H,Suzuki T.1994 Immunohistochemical localization of gowth hormone receptor in cyclic human ovaries. Hum Reprod,1994;9:2259-62.
[15]李雪梅,朱文杰,陈秀敏等.生长激素在体外受精周期中的应用初探[J].实用医学杂志,2004,20(8)：883-884.
[16]陈华,孙海翔,胡娅莉等生长激素在体外受精胚胎移植的作用[J].江苏医药,2006,32(5)：479-480.
[17]孙莹璞,王芳.降调节对卵子质量的影响[J].生殖医学,2007,16(5)：327-328.
[18]吴效科,顾秋善,苏延华.生长激素轴与女性生殖.国外医学妇产科学分 册,1995,22(5)：262-262.
[19]王增艳,何方方等内科内分泌疾病与闭经[J].中国实用妇科与产科杂志,2008,24(12)：895-897.
[20]Homburg R,Eshel A,Abdalla HI. Growth hormone facilitates ovulation induction by gonadotropins[J]. Clin Endocrinol,1988,29(1):113-117.
[21]孙伟,崔薇,闻姬等.两种不同剂量生长激素在体外受精超排卵中作用比较[J].中国优生与遗传杂志,2002,10：9-10.
[22]刘冬娥,李艳萍,邬伶仟等.生长激素辅助促排卵对卵巢反应不良患者体外受精-胚胎移植结果的影响[J].医学临床研究,2006,23(8)：1219-1224.
[23]TesarikJ, HazoutA, MendozaC..Improvement of delivery and live birth rates after ICSI in women aged>40years by ovarian costimulation with growth hormone[J]. Hum ReProd, 2005,20(9):2536-2541.
[24]Abdalla H,Thum MY. An elevated basal FSH reflects a quantita-tive rather than qualitative decline of the ovarian reserve [J]. Hum-Reprod,2004,19(4):893-898.
[25]李柳铭,张红玉,李慕军等.体外受精-胚胎移植中预测卵巢储备功能指标的临床研究[J]广西医程大学学报,2007,24(5)：680-683.
[26]Danilovich NA, Bartke A, Winters TA. Ovarian follicle apoptosis in bovine gro-wth hormone transgenic mice. Biol Reprod,2000,62(1):103-107.
[27]Izadyar F,Hage W,Colenbrander B.The Promotory effect of growth hormone on the developmental competence of in vitro matured bovine oocytes is due to improved cytoplasmic maturation[J].Moleeular ReProduction and Development,1998,49:444-453.
[28]OvesenP. Synergistic effetes of growth hormone and insulin-like growth faetor-I on differentiation and replication of cultured human luteinized granulose cells[J].Acta Obstetriea et Gynecologica Seandinavica.1998(77) 487-491
[29]徐慧灵.体外受精-胚胎移植中卵巢反应不良的临床初步研究[D].[硕十学位论文].广州.中山大学.2009.
[30]Owen EJ, Ostergard H. Cotreatment with growth hormone after pituitary supper- sion for ovarian stimulation in vitro fertilization:Arandomized, double-blind, place control trial [J]. Fertile Steril,1991,56:1104-1110.
[31]Sirotkin AV, Makarevich AV.Growth hormone eanregulate funetions of porcine ovarian granulose cells through the eAMP/Proteink inase Asystem [J].Anim ReProd Sei,2002, 70(1-2):111-126.
[32]欧蕾.卵巢及子宫内膜血流参数在辅助生殖技术中的应用价值[D].[硕十学位论文].郑州：郑州大学,2010.
[33]庄广伦等主编.现代辅助生育技术[M].北京：人民卫生出版社,2005,15-17.
[34]Tamura M,Sasano H,Suzuki T.Immunohistoehemical localization of growthHormone receptor in cyclic human ovaries[J]. Hum ReProd,1994Dec;9(12):2259-62.
[35]Zucchini S,Pirazzoli P,Baronio F,et al. Effect on adult height of pubertal growthhormone retesting and withdrawal of therapy in patients with previously diagnosedgrowth hormone deficiency[J].J Clin Endocrinol Metab,2006,91(11):4271-4276.
[36]Keene DE,Suescun MO,Bostwick MG,et al. Puberty is delayed in male growth hormone receptor gene-disrupted mice[J].J Androl,2002,23(5):661-668.
[37]Peng F,Stefan R,Serge A,et al. Primary growth hormone (GH)in sensitivity and insulin-like growth factor deficiency caused by novel compound heterozygous mutations of the gh receptor gene:genetic and functional studies of simpl and compound heterozygousstates [J].J ClinEndocrinolMetab,2007,92(6):2223-2231.
[38]ShararaFI, GiudieeLC.Role of growth hormone in ovarian physiology and onset puberty [J]. Journal of the soeiety for Gyneeologic investigation,1997(4):2-7.
[39]吴效科,苏延华等PCOS患者血清生长激素和泌乳素对左旋多巴反应的研究[J].中华妇产科杂志,1997,32(8)：489-491.
[40]王增艳,何方方等.内科内分泌疾病与闭经[J].中国实用妇科与产科杂志,2008,24(12)：895-897.
[41]Zhao J, TaverneM A,Van derWeijden G C,et al. Immunohistochemical localizationof growth hormone(GH), GH receptor(GHR), insulin-like growth factor I(IGF-I) and type I IGF-I receptor, and gene expression of GH and GHR in rat preantral follicles [J].Zygote, 2002,10(1):85-94.
[42]Lebedeva IY, LebedevV A, GrossmannR,etal. Characterization of growth hormone Binding sites in granulosa and theca layers at different stages of follicular maturation and ovulatory cycle in the domestic hen[J].Biol Reprod,2004,71(4):1174-1181.
[43][10]Marcha,l MaudC, AlainM,etal. Effectofgrowth hormone (GH) on in vitro nuclear and cytoplasmic oocyte maturation, cumulus expansion, hyaluronan synthases, and Connexins 32 and 43 expression, and GH receptormessenger RNA expression in equine and porcine species[J]. Biology of Reproduction,2003,69:1013-1022.
[44]Hastie P M, HaresignW. Expression ofmRNAs encoding insulin- like growth factor (IGF) ligands, IGF receptors and IGF binding proteins during follicular growth and atresia in the ovine ovary throughout the oestrous cycle[J].Anim Reprod Sc,i2006,92(3-4):284-299.
[45]Kolodziejczk J, Gregoraszcuk E L, Leibovich H,et al. Different action of ovine GH on porcine theca and gr anulose cells proliferation and insulin-like growth factors-I and II-stimulated estradiol production [J].Reprod Bio,12001,1(1):33-41.
[46]Samaras SE,Hagen DR,Bryan KA.Effect of growth hormone and gonadotroPinon the insulin-like growth hormone faetor systemin the Porcin ovary[J].Biology of ReProduction. 1994(50):178-186.
[47]Chase CC,Kirby CJ,Hammond AC.Patterns of ovarian growth and devel of ment-In cattle with a growth hormone receptor deficiency[J] Journal of Animal Scienee.1998(76): 212-219.
[48]YuanW,Luey MC.Effeets of growthhormone,Prolactin,insulin-like growth factors and gonadotropins on progester on eseeretion by poreineluteal cells [J].Journal of Animal Seienee.1996(74):866-872.
[49]TaPanainen J,MartikainenH,VoutilainenR.Effect of growth hormone administera- tion on human ovarian function and steroidogenic gene expression in granulose-luteal cells[J]. Fertility and sterility.1992(58):726-732.
[50]Andrade LP, Wright IA,Rhind SM.Effects of bovine somatotrophin on ovarian function in Post-partum beef cows[J]. Reproduction,Fertility and Devel Pment.1996(8):951-960.
[51]Doldi N, Bassan M, Bonzi V. Effects of growth hormone and growth hormone-releasing hormone on steroid synihesis in eultured humanl uteinizing granulose cells [J]. Gynecological Endocrinology.1996(10):101-108.
[52]Adashi EY, Thorner MO, Jaffe RB. The somatotrophic axis and there productive process in health and disease[J]. Fertility and Sterility 1994(61):1014-1015
[53]OvesenP. Synergistic effetes of growth hormone and insulin-like growth faetor-I on differentiation and replieation of cultured human luteinized granulose cells[J].Acta Obstetriea et Gynecologica Seandinavica.1998(77)487-491.
[54]Quesnel H 1999 Loealization of binding sites for IGF-I, insuin and GH in the sow ovary[J].J Endocrinol,163:363-372
[55]JoyeeIM, KhalidM, HaresignW The effect of reeombinant GH treatmenton ovarian growth and atresiainsheeP[J].Theriogenology,2000Jul 15;54(2):327-338.
[56]Gong Jq McBride D, BramleyTA, Effeets of Recombinant bovine somatocropin, insulin-like growth faetor-1 and insulin on the proliferationofbovinegranulosa cells invitro[J].J Endoerinol.1993(139):67-75.
[57]DaniloviehN, BartkeA, WintersTA. Ovarian folliele apoptosis in bovine growth-hormone transgenic mice[J]. Biology of Reproduction.2000,62:103-107.
[58]MendozaC, Ruiz-Requena, CremadesN. Relationship between fertilization resuits after intraeytoplasmies Perm injection, and intrafollieular steroid, Pituitary hormone and cytokine coneeniration[J]. Human Reproduction.1999,14(3):628-635.
[59]IzadyarF,HageWJ,ColenbranderB.The Promotory effect of growth hormone on the developmental competenee of in vitro matured bovine oocytes is due to improved cytoplasmic maturation[J].Moleeular ReProduction and Development,1998,49:444-453.
[60]Sirotkin AV, Makarevich AV.Growth hormone eanregulate funetions of porcine ovarian granulose cells through the eAMP/Proteink inase Asystem [J].Anim ReProd Sei,2002, 70(1-2):111-126.
[61]吴瑞英,邹淑花,张全等生长激素对IVF-ET周期中子宫内膜的影响.生殖与避孕[J].2007,27(3)：222-223.
[62]沈永年.生长激素的临床应用[J].中国新药与临床,1998,17(6)：377-378.
[63]孙荪,朱尚权.生长激素的结构和功能[J].国外医学生理,病理科学与临床分册,1999,19(1)：5-9.
[64]Lanzone A,Fulghesu AM,Simone ND,et al.Human growth hormone enhance progesterone production by human luteal cells in vitro:evidence of a synergistic effect with human chorionic gonadortopin[J],Fertil Steril,1992,57(1):92-96.
[65]项云改,谭丽,董方莉等生长激素对小鼠子宫内膜VE G F、LIF、MMP-9及TIMP-1表达的影响.生殖与避孕[J].2007,27(10)：639-642.
[66]Halder JB, Zhao X, Soker S, et al. Differential expression of VEGF is of orms and VEGF (164)-specific receptor neuropilinl in the mouse uterus suggests a role for VEGF(164) in vascular rpermeability and angiogenesis during implantation[J]. Genesis,2000,26(3): 213-24.
[67]Fata JE, Ho AT, Leco KJ, et al. Cellular turnover and extrace llular matrix remodeling infemale reproductive tissues:functions of metall oproteinases and their in hibitors[J]. CellMol Life Sci,2000,57(1):77-95.
[68]Das SK,Yano S,Wang J, et al. Expression of matrix metall oprotein-ases and tissue inhibitor so fmetall oproteinases in the mouse uterus during the periimplanta- tion period[J]. Dev Genet,1997,21(1):44-54.
[69]Hull KL,Harvey S.etal.Growth hormone:roles in female reproduction [J].J Endocrinol, 2001,168(1):1-23.
[70]Sbracia M,Poverini R.Scarpellini F.etal. Immunol is tochemical localization of the growth hormone in human endometrium and deciduas [J]. Am J Reprod Immunol,2004, 51(2):112-116.
[2]周毛婴,周馥贞等.不孕症妇女卵巢储备监测及意义[J].国外医学计划生育分册,2001,20(2)：94-97.
[3]Yong PY, Baird DT,ThongKJ,et a.l Prospective analysis of the relationships between the ovarian follicle cohort and basal FSH concentration, the inhibin response to exogenous FSH and ovarian follicle tuitary down-regulation[J].Hum Reprod,2003,18(1):35-44.
[4]朱小明,蔡婕,黄荷凤.卵巢反应不良的诊断标准和预测[J].中国实用妇科与产科杂志,2006,22(5)：388-389.
[5]黄晓卉,王华,胡明玥等.小剂量生长激素对卵巢低反应患者超促排卵的影响[J].实用诊断与治疗杂志,2007,21(12)：939-940.
[6]hao J, TaverneM A,Van derWeijden GC,et al. Immunohistochemical localization of growth hormone(GH), GH receptor(GHR), insulin-like growth factor Ⅰ(IGF-I) and Type IGF-I receptor, and gene expression of GH and GHR in rat pre-antral follicles [J]. Zygote,2002, 10(1):85-94.
[7]NishiyamaK, SugimotoT, KajiH, etal. Stimulatory effeet of growth hormone on bone resorption and osteoclast differentiation [J].Endocrinology,1996,137(1):35-41.
[8]吴效科,苏延华等PCOS患者血清生长激素和泌乳素对左旋多巴反应的研究[J].中华妇产科杂志,1997,32(8)：489-491.
[9]丁国莲,黄荷凤等.生长激素在辅助生殖技术中的应用及作用机制[J].国际生殖健康/计划生育杂志,2008,27(6)：351-354.
[10]傅薇,韩金兰.IVF超促排卵过程中对卵巢反应性的预测[J].生殖与避孕,2004,24(4)：236-239.
[11]庄广伦,翁世湘,周灿权.小剂量生长激素在体外受精超排卵周期中的作用[J].中华妇产科杂志,1994,29(8)：471-474.
[12]赵红岩,孙莹璞,苏迎春等.两种降调节方案在控制性超排卵中的效果比较[J].生殖与避孕,2010,30(1)：32-36.
[13]苏迎春,陈慧,孙莹璞.影响冷冻胚胎着床因素回顾性分析[J].生殖医学杂志,2007,16(3)：196-198.
[14]Tamura M,Sasano H,Suzuki T.1994 Immunohistochemical localization of gowth hormone receptor in cyclic human ovaries. Hum Reprod,1994;9:2259-62.
[15]李雪梅,朱文杰,陈秀敏等.生长激素在体外受精周期中的应用初探[J].实用医学杂志,2004,20(8)：883-884.
[16]陈华,孙海翔,胡娅莉等生长激素在体外受精胚胎移植的作用[J].江苏医药,2006,32(5)：479-480.
[17]孙莹璞,王芳.降调节对卵子质量的影响[J].生殖医学,2007,16(5)：327-328.
[18]吴效科,顾秋善,苏延华.生长激素轴与女性生殖.国外医学妇产科学分 册,1995,22(5)：262-262.
[19]王增艳,何方方等内科内分泌疾病与闭经[J].中国实用妇科与产科杂志,2008,24(12)：895-897.
[20]Homburg R,Eshel A,Abdalla HI. Growth hormone facilitates ovulation induction by gonadotropins[J]. Clin Endocrinol,1988,29(1):113-117.
[21]孙伟,崔薇,闻姬等.两种不同剂量生长激素在体外受精超排卵中作用比较[J].中国优生与遗传杂志,2002,10：9-10.
[22]刘冬娥,李艳萍,邬伶仟等.生长激素辅助促排卵对卵巢反应不良患者体外受精-胚胎移植结果的影响[J].医学临床研究,2006,23(8)：1219-1224.
[23]TesarikJ, HazoutA, MendozaC..Improvement of delivery and live birth rates after ICSI in women aged>40years by ovarian costimulation with growth hormone[J]. Hum ReProd, 2005,20(9):2536-2541.
[24]Abdalla H,Thum MY. An elevated basal FSH reflects a quantita-tive rather than qualitative decline of the ovarian reserve [J]. Hum-Reprod,2004,19(4):893-898.
[25]李柳铭,张红玉,李慕军等.体外受精-胚胎移植中预测卵巢储备功能指标的临床研究[J]广西医程大学学报,2007,24(5)：680-683.
[26]Danilovich NA, Bartke A, Winters TA. Ovarian follicle apoptosis in bovine gro-wth hormone transgenic mice. Biol Reprod,2000,62(1):103-107.
[27]Izadyar F,Hage W,Colenbrander B.The Promotory effect of growth hormone on the developmental competence of in vitro matured bovine oocytes is due to improved cytoplasmic maturation[J].Moleeular ReProduction and Development,1998,49:444-453.
[28]OvesenP. Synergistic effetes of growth hormone and insulin-like growth faetor-I on differentiation and replication of cultured human luteinized granulose cells[J].Acta Obstetriea et Gynecologica Seandinavica.1998(77) 487-491
[29]徐慧灵.体外受精-胚胎移植中卵巢反应不良的临床初步研究[D].[硕十学位论文].广州.中山大学.2009.
[30]Owen EJ, Ostergard H. Cotreatment with growth hormone after pituitary supper- sion for ovarian stimulation in vitro fertilization:Arandomized, double-blind, place control trial [J]. Fertile Steril,1991,56:1104-1110.
[31]Sirotkin AV, Makarevich AV.Growth hormone eanregulate funetions of porcine ovarian granulose cells through the eAMP/Proteink inase Asystem [J].Anim ReProd Sei,2002, 70(1-2):111-126.
[32]欧蕾.卵巢及子宫内膜血流参数在辅助生殖技术中的应用价值[D].[硕十学位论文].郑州：郑州大学,2010.
[33]庄广伦等主编.现代辅助生育技术[M].北京：人民卫生出版社,2005,15-17.
[34]Tamura M,Sasano H,Suzuki T.Immunohistoehemical localization of growthHormone receptor in cyclic human ovaries[J]. Hum ReProd,1994Dec;9(12):2259-62.
[35]Zucchini S,Pirazzoli P,Baronio F,et al. Effect on adult height of pubertal growthhormone retesting and withdrawal of therapy in patients with previously diagnosedgrowth hormone deficiency[J].J Clin Endocrinol Metab,2006,91(11):4271-4276.
[36]Keene DE,Suescun MO,Bostwick MG,et al. Puberty is delayed in male growth hormone receptor gene-disrupted mice[J].J Androl,2002,23(5):661-668.
[37]Peng F,Stefan R,Serge A,et al. Primary growth hormone (GH)in sensitivity and insulin-like growth factor deficiency caused by novel compound heterozygous mutations of the gh receptor gene:genetic and functional studies of simpl and compound heterozygousstates [J].J ClinEndocrinolMetab,2007,92(6):2223-2231.
[38]ShararaFI, GiudieeLC.Role of growth hormone in ovarian physiology and onset puberty [J]. Journal of the soeiety for Gyneeologic investigation,1997(4):2-7.
[39]吴效科,苏延华等PCOS患者血清生长激素和泌乳素对左旋多巴反应的研究[J].中华妇产科杂志,1997,32(8)：489-491.
[40]王增艳,何方方等.内科内分泌疾病与闭经[J].中国实用妇科与产科杂志,2008,24(12)：895-897.
[41]Zhao J, TaverneM A,Van derWeijden G C,et al. Immunohistochemical localizationof growth hormone(GH), GH receptor(GHR), insulin-like growth factor I(IGF-I) and type I IGF-I receptor, and gene expression of GH and GHR in rat preantral follicles [J].Zygote, 2002,10(1):85-94.
[42]Lebedeva IY, LebedevV A, GrossmannR,etal. Characterization of growth hormone Binding sites in granulosa and theca layers at different stages of follicular maturation and ovulatory cycle in the domestic hen[J].Biol Reprod,2004,71(4):1174-1181.
[43][10]Marcha,l MaudC, AlainM,etal. Effectofgrowth hormone (GH) on in vitro nuclear and cytoplasmic oocyte maturation, cumulus expansion, hyaluronan synthases, and Connexins 32 and 43 expression, and GH receptormessenger RNA expression in equine and porcine species[J]. Biology of Reproduction,2003,69:1013-1022.
[44]Hastie P M, HaresignW. Expression ofmRNAs encoding insulin- like growth factor (IGF) ligands, IGF receptors and IGF binding proteins during follicular growth and atresia in the ovine ovary throughout the oestrous cycle[J].Anim Reprod Sc,i2006,92(3-4):284-299.
[45]Kolodziejczk J, Gregoraszcuk E L, Leibovich H,et al. Different action of ovine GH on porcine theca and gr anulose cells proliferation and insulin-like growth factors-I and II-stimulated estradiol production [J].Reprod Bio,12001,1(1):33-41.
[46]Samaras SE,Hagen DR,Bryan KA.Effect of growth hormone and gonadotroPinon the insulin-like growth hormone faetor systemin the Porcin ovary[J].Biology of ReProduction. 1994(50):178-186.
[47]Chase CC,Kirby CJ,Hammond AC.Patterns of ovarian growth and devel of ment-In cattle with a growth hormone receptor deficiency[J] Journal of Animal Scienee.1998(76): 212-219.
[48]YuanW,Luey MC.Effeets of growthhormone,Prolactin,insulin-like growth factors and gonadotropins on progester on eseeretion by poreineluteal cells [J].Journal of Animal Seienee.1996(74):866-872.
[49]TaPanainen J,MartikainenH,VoutilainenR.Effect of growth hormone administera- tion on human ovarian function and steroidogenic gene expression in granulose-luteal cells[J]. Fertility and sterility.1992(58):726-732.
[50]Andrade LP, Wright IA,Rhind SM.Effects of bovine somatotrophin on ovarian function in Post-partum beef cows[J]. Reproduction,Fertility and Devel Pment.1996(8):951-960.
[51]Doldi N, Bassan M, Bonzi V. Effects of growth hormone and growth hormone-releasing hormone on steroid synihesis in eultured humanl uteinizing granulose cells [J]. Gynecological Endocrinology.1996(10):101-108.
[52]Adashi EY, Thorner MO, Jaffe RB. The somatotrophic axis and there productive process in health and disease[J]. Fertility and Sterility 1994(61):1014-1015
[53]OvesenP. Synergistic effetes of growth hormone and insulin-like growth faetor-I on differentiation and replieation of cultured human luteinized granulose cells[J].Acta Obstetriea et Gynecologica Seandinavica.1998(77)487-491.
[54]Quesnel H 1999 Loealization of binding sites for IGF-I, insuin and GH in the sow ovary[J].J Endocrinol,163:363-372
[55]JoyeeIM, KhalidM, HaresignW The effect of reeombinant GH treatmenton ovarian growth and atresiainsheeP[J].Theriogenology,2000Jul 15;54(2):327-338.
[56]Gong Jq McBride D, BramleyTA, Effeets of Recombinant bovine somatocropin, insulin-like growth faetor-1 and insulin on the proliferationofbovinegranulosa cells invitro[J].J Endoerinol.1993(139):67-75.
[57]DaniloviehN, BartkeA, WintersTA. Ovarian folliele apoptosis in bovine growth-hormone transgenic mice[J]. Biology of Reproduction.2000,62:103-107.
[58]MendozaC, Ruiz-Requena, CremadesN. Relationship between fertilization resuits after intraeytoplasmies Perm injection, and intrafollieular steroid, Pituitary hormone and cytokine coneeniration[J]. Human Reproduction.1999,14(3):628-635.
[59]IzadyarF,HageWJ,ColenbranderB.The Promotory effect of growth hormone on the developmental competenee of in vitro matured bovine oocytes is due to improved cytoplasmic maturation[J].Moleeular ReProduction and Development,1998,49:444-453.
[60]Sirotkin AV, Makarevich AV.Growth hormone eanregulate funetions of porcine ovarian granulose cells through the eAMP/Proteink inase Asystem [J].Anim ReProd Sei,2002, 70(1-2):111-126.
[61]吴瑞英,邹淑花,张全等生长激素对IVF-ET周期中子宫内膜的影响.生殖与避孕[J].2007,27(3)：222-223.
[62]沈永年.生长激素的临床应用[J].中国新药与临床,1998,17(6)：377-378.
[63]孙荪,朱尚权.生长激素的结构和功能[J].国外医学生理,病理科学与临床分册,1999,19(1)：5-9.
[64]Lanzone A,Fulghesu AM,Simone ND,et al.Human growth hormone enhance progesterone production by human luteal cells in vitro:evidence of a synergistic effect with human chorionic gonadortopin[J],Fertil Steril,1992,57(1):92-96.
[65]项云改,谭丽,董方莉等生长激素对小鼠子宫内膜VE G F、LIF、MMP-9及TIMP-1表达的影响.生殖与避孕[J].2007,27(10)：639-642.
[66]Halder JB, Zhao X, Soker S, et al. Differential expression of VEGF is of orms and VEGF (164)-specific receptor neuropilinl in the mouse uterus suggests a role for VEGF(164) in vascular rpermeability and angiogenesis during implantation[J]. Genesis,2000,26(3): 213-24.
[67]Fata JE, Ho AT, Leco KJ, et al. Cellular turnover and extrace llular matrix remodeling infemale reproductive tissues:functions of metall oproteinases and their in hibitors[J]. CellMol Life Sci,2000,57(1):77-95.
[68]Das SK,Yano S,Wang J, et al. Expression of matrix metall oprotein-ases and tissue inhibitor so fmetall oproteinases in the mouse uterus during the periimplanta- tion period[J]. Dev Genet,1997,21(1):44-54.
[69]Hull KL,Harvey S.etal.Growth hormone:roles in female reproduction [J].J Endocrinol, 2001,168(1):1-23.
[70]Sbracia M,Poverini R.Scarpellini F.etal. Immunol is tochemical localization of the growth hormone in human endometrium and deciduas [J]. Am J Reprod Immunol,2004, 51(2):112-116.