多囊卵巢综合征患者颗粒细胞FSHR、LHR、mRNA的表达
摘要
目的:多囊卵巢综合征( polycystic ovarian syndrome,PCOS)是一种常见的生殖功能异常,也是无排卵性不孕的主要病因之一,其主要内分泌特征为高雄激素血症、高胰岛素血症、黄体生成素(LH)水平升高、LH与卵泡刺激素( FSH)比值升高。临床上常表现闭经或月经稀发,无排卵和不孕。患者须通过药物诱导排卵方能解决生育问题。在药物促排卵过程中,卵巢的反应性存在明显的个体差异,与卵巢功能正常者相比,同样剂量的促排卵药物,PCOS患者更有可能出现OHSS,其原因尚不明了。本研究通过观察在我院接受体外受精与胚胎移植(invitro fertilization-embryo transfer, IVF- ET )的PCOS患者与卵巢功能正常者在应用促排卵药物后,卵巢颗粒细胞中促卵泡激素受体(FSHR)、黄体生成素受体(LHR)mRNA的表达,并结合基础血清、垂体降调节后月经第2天、HCG日血清中性激素水平及及卵泡液中促卵泡激素(FSH)、黄体生成素(LH)、雌二醇(E_2)、睾酮(T)水平变化,进一步探讨PCOS患者颗粒细胞中促性腺激素受体与对促排卵药物反应的关系。
方法:
1研究对象:
1.1 PCOS组(实验组):选择2007年5月-2007年10月在河北医科大学第二医院生殖中心接受IVF- ET治疗的多囊卵巢综合征患者24例,平均年龄在28.83±3.16岁。
1.2对照组:随机选择同期在本生殖中心接受IVF-ET治疗的不孕患者20例,月经规律,不孕原因为输卵管因素,且基础血(月经第三天) FSH、LH、E_2、T、催乳素(PRL)在正常范围内,平均年龄在30.17±3.21岁。
所有患者均为初次进入周期,空腹血糖均正常,无全身性及其他内分泌性疾病,男方精液正常。
2研究方法和测定内容:
2.1标本采集:PCOS组和对照组均采用口服避孕药(达英-35)控制性超促排卵长方案治疗,根据阴道B超和血清中LH、E_2水平检测卵泡发育。当B超显示下有一个卵泡平均直径≥18mm,两个卵泡平均直径≥17mm,或者三个卵泡平均直径≥16mm时,于当日21:00给予肌肉注射绒促性素(HCG)5000– 10000 iu,36小时后在阴道超声引导下行采卵术。取未被血染的穿刺液经2000 r/min离心10 min,上清液置-20℃冰箱保存。收集所有的卵泡穿刺液, Ficoll分离获得颗粒细胞,加入Trizol(Invitrogen),置1.5ml EP管中,经液氮快速冷冻后于-70℃冰箱保存。
2.2标本测定:RT-PCR测定颗粒细胞FSHR及LHR mRNA相对表达量。
2.3内分泌激素测定:化学发光法测定基础血清FSH,LH,T,E_2,空腹胰岛素水平(INS),垂体降调节后月经第2天血清FSH、LH,HCG日血清LH,E_2以及卵泡液FSH,LH,T,E_2。
结果:
1 PCOS组和对照组间颗粒细胞FSHR、LHRmRNA相对表达量的比较
1.1 PCOS组颗粒细胞FSHRmRNA相对表达量(0.675±0.106)较对照组颗粒细胞FSHRmRNA (0.567±0.132)增高,两组之间比较有统计学意义(P<0.05)。
1.2 PCOS组颗粒细胞LHRmRNA相对表达量(0.647±0.123)较对照组颗粒细胞LHRmRNA (0.519±0.156)增高,两组之间比较有统计学意义(P<0.05)。
2各指标之间的直线相关关系
通过多元线性回归分析,显示获卵数与FSHRmRNA相对表达量呈正相关,与LHRmRNA相对表达量无明显直线相关关系。回归方程分别为PCOS组:Y=-22.18+50.51X, R~2=0.66, F=20.36, P=0.0001;对照组:Y=-0.11+26.32X, R~2=0.773, F=61.36, P=0.0001
3 PCOS组和对照组血清性激素浓度的比较
基础血清中,LH、T、空腹胰岛素水平在PCOS组高于对照组,FSH,E_2两组无统计学差异;垂体降调节后月经第2天血清FSH、LH在进行rhFSH治疗前无统计学差异。与对照组相比,PCOS组HCG日血清LH增高, E_2两组相近。
4 PCOS组和对照组卵泡液中性激素浓度的比较
PCOS组患者卵泡液中FSH浓度(4.80±1.44 mIU/ml),与对照组(6.47±0.95 mIU/ml)相比,明显降低(P =0.003),而LH浓度、T水平明显升高( P值分别为0.004,0.005),有统计学意义。同时,两组患者卵泡液中E_2浓度相近。
5 PCOS组和对照组IVF周期特征比较
两组患者rhFSH治疗总用量和时间无明显差异,hCG日最大血浆E_2水平相近。然而PCOS组获卵数(21±8)高于对照组(15±4),且平均卵泡直径PCOS组(18.02±1.80 mm)小于对照组(19.41±2.32mm),P<0.05,有统计学意义。
结论:1与对照组患者相比,PCOS患者基础血清睾酮(T)和胰岛素(INS)增高,超促排卵过程中总卵泡数增加而卵泡直径下降;PCOS卵泡液中FSH、P浓度明显降低,而LH浓度、T水平明显升高,同时,两组患者卵泡液中E_2浓度相近,提示PCOS患者存在多种内分泌异常和卵泡发育异常。
2超排卵过程中,颗粒细胞FSHR mRNA表达在PCOS组高于对照组,获卵数与颗粒细胞FSHRmRNA表达均成正相关,提示FSHRmRNA表达量与卵巢对外源性促性腺激素反应有关,FSHRmRNA的表达增高可能引起卵巢反应性增高,PCOS组获卵数及FSHRmRNA的表达高于对照组,推测FSHRmRNA的表达增高可能是PCOS患者易发生卵巢过度刺激的原因之一;而卵巢反应性与颗粒细胞LHR表达量无明显相关性。
3超排卵过程中,颗粒细胞LHRmRNA表达在PCOS组高于对照组,推测PCOS卵泡可能存在提早的黄素化。
Objective: Polycystic ovarian syndrome(PCOS) is a common reproductive syndrome of women characterized by ovarian hyper-androgenism, hyperinsulinemia , high LH level and LH/FSH. It is also one of the main causes of anovulatory infertility. It is characterized by a myriad of symptoms including oligomenorrhea or amenorrhea, anovulation or infertility, and so on. Drug-induced ovulation was effective in treatment of such infertility. Through controlled-ovarian hyper-stimulation process, ovarian response has obvious individual difference. Compared with normal ovary,patients with PCOS are more likely to OHSS. The mechanism still remains unknown. This study tested the levels of FSHR、LHR mRNA expression on ovarian granulosa cells after ovulatory induction ovarian by RT-PCR .The sexual hormone levels in serum at the day 3、the day 2 after pituitary down-regulation、the day of HCG administered and in follicular fluid were all measured by chemiluminescent method.The aim was to investigate the correlation between the levels of FSHR、LHR mRNA expression on ovarian granulosa cells after ovulatory induction ovarian and ovarian response to exogenous gonadotropins.
Methods:
1 The study subject
1.1 The PCOS group (The study group): To select 24 patients with polycystic ovarian syndrome who undergone IVF-ET because of infertility in the Second Hospital of HeBei Medical University from May 2007 to October 2007.Their mean ages were 28.83±3.16 years old.
1.2 The control group: To random select 20 patients with eumenorrhea who undergone IVF-ET because of infertility, from May 2007 to October 2007.The patients were tubal infertility and their elementary hormone FSH、LH、E_2、PRL、T(MC:3day) were within normal limits. Their mean ages were 30.17±3.21 years old.
The patients of PCOS group and control group should be the first time to receive controlled ovarian hyper- stimulation (COH). No woman had systemic diseases, galactorrhea, endometriomas and other endocrine diseases. They all have normal blood sugar and husbands'sperm condition in control group and PCOS group.
2 Methods and Contents:
2.1 Collecte the sample: All women receive OC long down-regulated protocols and controlled ovarian hypers- timulation (COH), GnRH-a / Gonal-F /HMG/HCG. Serial LH、E_2 levels and two-dimensional TVUS follicle measurements were performed until at least one dominant follicles reached at least 18mm or two dominant follicles reached at least 17mm or three dominant follicles reached at least 16mm in diameter. Then HCG 5000-10000iu was administered, followed by trans- vaginal oocyte retrieval 36h later. Follicular fluid uncontami- nated by blood was selected.They was centrifuged at 2000r for 10min (ordinary temperature), and the supernatant liquid were storaged at -20℃with refrigerator.
At oocyte retrieval, all follicular fluid was collected. Granulosa cells were separated from follicular fluid by Ficoll density gradient centrifugation .They were stored in 1.5 ml Eppendorf tubes in Trizol (Invitrogen). Samples were snapping frozen in liquid nitrogen and were stored at -70℃for later RNA extraction.
2.2 Mensurate the sample: FSHR and LHR mRNA were determined by RT-PCR .
2.3 Hormone assays : Baseline serum FSH、LH、T、E_2、insulin as well as serum FSH、LH at pituitary down- regulation, LH、E_2 at the day of HCG administered , and follicular fluid FSH、LH、T、E_2 were all measured by chemiluminescent method.
Results:
1 The relative expression level of FSHRmRNA、LHRmRNA on ovarian granulosa cells from PCOS patients and control women
1.1 The relative expression level of FSHRmRNA on ovarian granulosa cells from PCOS patients (0.675±0.106) was higher than that from control women (0.567±0.132). There were remarkably statistical significance (P<0.05).
1.2 The relative expression level of LHRmRNA on ovarian granulosa cells from PCOS patients (0.647±0.123) was higher than that from control women (0.519±0.156). There were remarkably statistical significance (P<0.05).
2 Multivariate linear regression analysis on data showed that there was a positive correlation between the number retrieved oocyte with the expression of FSHRmRNA on ovarian granulosa cells, but not with the expression of LHRmRNA. The regression equations in two groups were as followes: the PCOS group:Y=-22.18+50.51X, R~2=0.66, F=20.36, P=0.0001;the control group:Y=-0.11+26.32X, R~2=0.773, F=61.36, P=0.0001
3 To compare outcomes of serum sex hormone levels of the patients of PCOS group and control group
The mean of baseline serum LH、T、insulin in PCOS group was higher than that in the control group,while FSH and T was similar. At day 2 after pituitary down-regulation, serum FSH、LH levels in two groups were similar. At the day of HCG administered, the mean of serum LH in PCOS group was higher than that in the control group, while E_2 levels in two groups were similar.
4 To compare outcomes of follicular fluid sex hormone levels of the patients of PCOS group and control group:
The mean of the FSH level in follicular fluid in PCOS group was lower than that in the control group (4.80±1.44 mIU/ml vs. 6.47±0.95 mIU/ml, P =0.003), while LH and T levels higher (P =0.004,P =0.005). There was remarkably statistical significance. The E_2 levels in follicular fluid in two groups were similar.
5 IVF cycle characteristics of control women and PCOS patients undergoing GnRH analog/rhFSH
The amount of rhFSH administered and the duration of rhFSH treatment were similar in control women and PCOS patients, causing comparable maximum serum E_2 levels on the day of hCG administration. Total number of oocytes retrieved was greater (21±8 vs. 15±4), whereas average follicle diameter was smaller, in PCOS patients vs. control women (18.02±1.80mm vs. 19.41±2.32mm). There were remarkably statistical significance (P<0.05).
Conclusion: 1 The patients with PCOS existe more than one kinds of endocrine abnormality and abnormal growth of follicles.
2 There was a positive correlation between the number retrieved oocyte with the expression of FSHRmRNA on ovarian granulosa cells in two groups,and the relative expression level of FSHRmRNA on ovarian granulosa cells from PCOS patients was higher than that from control women. The increase of the level of the expression FSHR may cause enhancement of ovarian response to exogenous gonado- tropins.This may be one of the cause that patient with PCOS are easy to occour OHSS.At the same time there was no correlation between ovarian response with the expression level of LHR.
3 The relative expression level of LHRmRNA on ovarian granulosa cells from PCOS patients was higher than that from control women. To hint that PCOS follicles exposed to GnRH analog/FSH stimulation for IVF may exist abnormal luteinization.
方法:
1研究对象:
1.1 PCOS组(实验组):选择2007年5月-2007年10月在河北医科大学第二医院生殖中心接受IVF- ET治疗的多囊卵巢综合征患者24例,平均年龄在28.83±3.16岁。
1.2对照组:随机选择同期在本生殖中心接受IVF-ET治疗的不孕患者20例,月经规律,不孕原因为输卵管因素,且基础血(月经第三天) FSH、LH、E_2、T、催乳素(PRL)在正常范围内,平均年龄在30.17±3.21岁。
所有患者均为初次进入周期,空腹血糖均正常,无全身性及其他内分泌性疾病,男方精液正常。
2研究方法和测定内容:
2.1标本采集:PCOS组和对照组均采用口服避孕药(达英-35)控制性超促排卵长方案治疗,根据阴道B超和血清中LH、E_2水平检测卵泡发育。当B超显示下有一个卵泡平均直径≥18mm,两个卵泡平均直径≥17mm,或者三个卵泡平均直径≥16mm时,于当日21:00给予肌肉注射绒促性素(HCG)5000– 10000 iu,36小时后在阴道超声引导下行采卵术。取未被血染的穿刺液经2000 r/min离心10 min,上清液置-20℃冰箱保存。收集所有的卵泡穿刺液, Ficoll分离获得颗粒细胞,加入Trizol(Invitrogen),置1.5ml EP管中,经液氮快速冷冻后于-70℃冰箱保存。
2.2标本测定:RT-PCR测定颗粒细胞FSHR及LHR mRNA相对表达量。
2.3内分泌激素测定:化学发光法测定基础血清FSH,LH,T,E_2,空腹胰岛素水平(INS),垂体降调节后月经第2天血清FSH、LH,HCG日血清LH,E_2以及卵泡液FSH,LH,T,E_2。
结果:
1 PCOS组和对照组间颗粒细胞FSHR、LHRmRNA相对表达量的比较
1.1 PCOS组颗粒细胞FSHRmRNA相对表达量(0.675±0.106)较对照组颗粒细胞FSHRmRNA (0.567±0.132)增高,两组之间比较有统计学意义(P<0.05)。
1.2 PCOS组颗粒细胞LHRmRNA相对表达量(0.647±0.123)较对照组颗粒细胞LHRmRNA (0.519±0.156)增高,两组之间比较有统计学意义(P<0.05)。
2各指标之间的直线相关关系
通过多元线性回归分析,显示获卵数与FSHRmRNA相对表达量呈正相关,与LHRmRNA相对表达量无明显直线相关关系。回归方程分别为PCOS组:Y=-22.18+50.51X, R~2=0.66, F=20.36, P=0.0001;对照组:Y=-0.11+26.32X, R~2=0.773, F=61.36, P=0.0001
3 PCOS组和对照组血清性激素浓度的比较
基础血清中,LH、T、空腹胰岛素水平在PCOS组高于对照组,FSH,E_2两组无统计学差异;垂体降调节后月经第2天血清FSH、LH在进行rhFSH治疗前无统计学差异。与对照组相比,PCOS组HCG日血清LH增高, E_2两组相近。
4 PCOS组和对照组卵泡液中性激素浓度的比较
PCOS组患者卵泡液中FSH浓度(4.80±1.44 mIU/ml),与对照组(6.47±0.95 mIU/ml)相比,明显降低(P =0.003),而LH浓度、T水平明显升高( P值分别为0.004,0.005),有统计学意义。同时,两组患者卵泡液中E_2浓度相近。
5 PCOS组和对照组IVF周期特征比较
两组患者rhFSH治疗总用量和时间无明显差异,hCG日最大血浆E_2水平相近。然而PCOS组获卵数(21±8)高于对照组(15±4),且平均卵泡直径PCOS组(18.02±1.80 mm)小于对照组(19.41±2.32mm),P<0.05,有统计学意义。
结论:1与对照组患者相比,PCOS患者基础血清睾酮(T)和胰岛素(INS)增高,超促排卵过程中总卵泡数增加而卵泡直径下降;PCOS卵泡液中FSH、P浓度明显降低,而LH浓度、T水平明显升高,同时,两组患者卵泡液中E_2浓度相近,提示PCOS患者存在多种内分泌异常和卵泡发育异常。
2超排卵过程中,颗粒细胞FSHR mRNA表达在PCOS组高于对照组,获卵数与颗粒细胞FSHRmRNA表达均成正相关,提示FSHRmRNA表达量与卵巢对外源性促性腺激素反应有关,FSHRmRNA的表达增高可能引起卵巢反应性增高,PCOS组获卵数及FSHRmRNA的表达高于对照组,推测FSHRmRNA的表达增高可能是PCOS患者易发生卵巢过度刺激的原因之一;而卵巢反应性与颗粒细胞LHR表达量无明显相关性。
3超排卵过程中,颗粒细胞LHRmRNA表达在PCOS组高于对照组,推测PCOS卵泡可能存在提早的黄素化。
Objective: Polycystic ovarian syndrome(PCOS) is a common reproductive syndrome of women characterized by ovarian hyper-androgenism, hyperinsulinemia , high LH level and LH/FSH. It is also one of the main causes of anovulatory infertility. It is characterized by a myriad of symptoms including oligomenorrhea or amenorrhea, anovulation or infertility, and so on. Drug-induced ovulation was effective in treatment of such infertility. Through controlled-ovarian hyper-stimulation process, ovarian response has obvious individual difference. Compared with normal ovary,patients with PCOS are more likely to OHSS. The mechanism still remains unknown. This study tested the levels of FSHR、LHR mRNA expression on ovarian granulosa cells after ovulatory induction ovarian by RT-PCR .The sexual hormone levels in serum at the day 3、the day 2 after pituitary down-regulation、the day of HCG administered and in follicular fluid were all measured by chemiluminescent method.The aim was to investigate the correlation between the levels of FSHR、LHR mRNA expression on ovarian granulosa cells after ovulatory induction ovarian and ovarian response to exogenous gonadotropins.
Methods:
1 The study subject
1.1 The PCOS group (The study group): To select 24 patients with polycystic ovarian syndrome who undergone IVF-ET because of infertility in the Second Hospital of HeBei Medical University from May 2007 to October 2007.Their mean ages were 28.83±3.16 years old.
1.2 The control group: To random select 20 patients with eumenorrhea who undergone IVF-ET because of infertility, from May 2007 to October 2007.The patients were tubal infertility and their elementary hormone FSH、LH、E_2、PRL、T(MC:3day) were within normal limits. Their mean ages were 30.17±3.21 years old.
The patients of PCOS group and control group should be the first time to receive controlled ovarian hyper- stimulation (COH). No woman had systemic diseases, galactorrhea, endometriomas and other endocrine diseases. They all have normal blood sugar and husbands'sperm condition in control group and PCOS group.
2 Methods and Contents:
2.1 Collecte the sample: All women receive OC long down-regulated protocols and controlled ovarian hypers- timulation (COH), GnRH-a / Gonal-F /HMG/HCG. Serial LH、E_2 levels and two-dimensional TVUS follicle measurements were performed until at least one dominant follicles reached at least 18mm or two dominant follicles reached at least 17mm or three dominant follicles reached at least 16mm in diameter. Then HCG 5000-10000iu was administered, followed by trans- vaginal oocyte retrieval 36h later. Follicular fluid uncontami- nated by blood was selected.They was centrifuged at 2000r for 10min (ordinary temperature), and the supernatant liquid were storaged at -20℃with refrigerator.
At oocyte retrieval, all follicular fluid was collected. Granulosa cells were separated from follicular fluid by Ficoll density gradient centrifugation .They were stored in 1.5 ml Eppendorf tubes in Trizol (Invitrogen). Samples were snapping frozen in liquid nitrogen and were stored at -70℃for later RNA extraction.
2.2 Mensurate the sample: FSHR and LHR mRNA were determined by RT-PCR .
2.3 Hormone assays : Baseline serum FSH、LH、T、E_2、insulin as well as serum FSH、LH at pituitary down- regulation, LH、E_2 at the day of HCG administered , and follicular fluid FSH、LH、T、E_2 were all measured by chemiluminescent method.
Results:
1 The relative expression level of FSHRmRNA、LHRmRNA on ovarian granulosa cells from PCOS patients and control women
1.1 The relative expression level of FSHRmRNA on ovarian granulosa cells from PCOS patients (0.675±0.106) was higher than that from control women (0.567±0.132). There were remarkably statistical significance (P<0.05).
1.2 The relative expression level of LHRmRNA on ovarian granulosa cells from PCOS patients (0.647±0.123) was higher than that from control women (0.519±0.156). There were remarkably statistical significance (P<0.05).
2 Multivariate linear regression analysis on data showed that there was a positive correlation between the number retrieved oocyte with the expression of FSHRmRNA on ovarian granulosa cells, but not with the expression of LHRmRNA. The regression equations in two groups were as followes: the PCOS group:Y=-22.18+50.51X, R~2=0.66, F=20.36, P=0.0001;the control group:Y=-0.11+26.32X, R~2=0.773, F=61.36, P=0.0001
3 To compare outcomes of serum sex hormone levels of the patients of PCOS group and control group
The mean of baseline serum LH、T、insulin in PCOS group was higher than that in the control group,while FSH and T was similar. At day 2 after pituitary down-regulation, serum FSH、LH levels in two groups were similar. At the day of HCG administered, the mean of serum LH in PCOS group was higher than that in the control group, while E_2 levels in two groups were similar.
4 To compare outcomes of follicular fluid sex hormone levels of the patients of PCOS group and control group:
The mean of the FSH level in follicular fluid in PCOS group was lower than that in the control group (4.80±1.44 mIU/ml vs. 6.47±0.95 mIU/ml, P =0.003), while LH and T levels higher (P =0.004,P =0.005). There was remarkably statistical significance. The E_2 levels in follicular fluid in two groups were similar.
5 IVF cycle characteristics of control women and PCOS patients undergoing GnRH analog/rhFSH
The amount of rhFSH administered and the duration of rhFSH treatment were similar in control women and PCOS patients, causing comparable maximum serum E_2 levels on the day of hCG administration. Total number of oocytes retrieved was greater (21±8 vs. 15±4), whereas average follicle diameter was smaller, in PCOS patients vs. control women (18.02±1.80mm vs. 19.41±2.32mm). There were remarkably statistical significance (P<0.05).
Conclusion: 1 The patients with PCOS existe more than one kinds of endocrine abnormality and abnormal growth of follicles.
2 There was a positive correlation between the number retrieved oocyte with the expression of FSHRmRNA on ovarian granulosa cells in two groups,and the relative expression level of FSHRmRNA on ovarian granulosa cells from PCOS patients was higher than that from control women. The increase of the level of the expression FSHR may cause enhancement of ovarian response to exogenous gonado- tropins.This may be one of the cause that patient with PCOS are easy to occour OHSS.At the same time there was no correlation between ovarian response with the expression level of LHR.
3 The relative expression level of LHRmRNA on ovarian granulosa cells from PCOS patients was higher than that from control women. To hint that PCOS follicles exposed to GnRH analog/FSH stimulation for IVF may exist abnormal luteinization.
引文
1 Fauser B C JM,Devroey P,Yen S S C,et al.Minimal ovarian-stimulation for IVF:appraisal of potential benefits and drawbacks. Human Reprod, 1999, 14 (1):2681~2686
2 Elchalal U,Schenker J.The pathophysiology of ovarian hyperstimulation syndrome-views and ideas. Human Reprod, 1997, 12 (6): 1129~1137
3 Cai J,Lou HY,Dong MY,et al.Poor ovarian response to gonadotropin stimulation is associated with low expre- ssion of follicle stimulating hormone receptor in granulosa cells. Fertil Steril, 2007, 87(6):1350~1356
4 O’Shaughnessy PJ,Dudley K, Rajapaksha WR.Expression of follicle stimulating hormone receptor mRNA during gonadal development. Mol Cell Endocrinol, 1996, 125 (122): 169~ 175
5 Rice S,Ojha K,Whitehead S,et al.Stage-specific expression of androgen receptor, follicle stimulating hormone receptor, and anti-Müllerian hormone type II receptor in single, isolated, human preantral follicles: relevance to polycystic ovaries. J Clin Endocrinol Metab, 2007, Mar, 92(3): 1034~ 1040
6 SimoniM,Gromoll J,Nieschlag E.The follicle stimulating hormone receptor: biochemistry,molecular biology,physio- logy, and pathophysiology. Endocr Rev, 1997,18(6):739~ 773
7 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 Endocrinol Invest, 2006,29 (11):975~982
8 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 pre- mature ovarian failure and polycystic ovary syndrome. Horm Metab Res,2001,33(4):221~226
9 Sudo S,Kudo M,Wada S,et al.Genetic and functional analyses of polymorphisms in the human FSH receptor gene.Mol Hum Reprod, 2002, 8 (10): 893~899
10 Ota H, Wakizaka A, Fukushima M,et al. Enhanced Ovari- an Gonadotropin Receptors in the Testosterone- Induced Polycystic Ovary in Rats .Tohoku J. exp. Med., 1986, 148, 313-325
11 Maritza PM, Jorg G, HermannM B, et al. Ovarian response to follicle-stimulating hormone stimulating depends on the FSH receptor genotype . J Clin Endocrinol Metab, 2000, 85 (9): 3365~ 3369
12 ZHAO Hai-bo, LUO Li-lan,LIU Yi. The effect of insulin- like grow th factor-I on stero idogenesis and ultrastructures of culutured human granulosa cells in vitro. Chinese Journal of Obstetrics and Gynecology, 1998, 33(9): 546~548
13 Damario M A, Bogovich K, Liu H G, et al. Synergistic effects of insulin-like growth factor-I and human cho rionicgonadotropin in the rat ovary. Metabolism, 2000, 49 (3): 314~ 320
14 CHEN Dan-qing, SHI Yi-fu,CHEN Huai-zeng. Relation- ship between follicle development and insulin like growth factor I receptor in stimulated cycles. Chinese Journal of Obstetrics and Gynecology, 2001, 36 (2): 98~100
15 Weil S, Vendola K, Zhou J, et al. Androgen and follicle- stimulating hormone interactions in primate ovarian follicle development. J Clin Endocrinol Metab, 1999, 84(8): 2951~2956
16 Willis DS, Watson H, Mason HD, et al. Premature response to LH of granulosa cells from anovulatory women with polycystic ovaries: relevance to mechanism of anovulation. J Clin Endocrinol Metab 1998, 83 (11): 3984 ~3991
17 Jakimiuk AJ, Weitsman SR, Navab A, et al. Luteinizing hormone receptor, steroidogenesis acute regulatory protein, and steroidogenic enzyme messenger ribonucleic acids are overexpressed in thecal and granulosa cells from polycystic ovaries. J Clin Endocrinol Metab, 2001,86(3):1318~1323
18 Jakimiuk AJ, Weitsman SR, Brzechffa PR, et al. Aroma- tase messenger ribonucleic acid expression in individual follicles from polycystic ovaries. Mol Hum Reprod, 1998 ,4: 1~8
19 Foong SC, Abbott DH, Zschunke MA, et al. Follicle luteinization in hyperandrogenic follicles of polycystic ovary syndrome patients undergoing gonadotropin therapyfor in Vitro fertilization. J Clin Endocrinol Metab, 2006, 91(6):2327~2333
20 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 Hum Genet, 2006, 51(8):665~670
21 Loutradis D, Patsoula E, Minas V, et al. FSH receptor gene polymorphisms have a role for different ovarian response to stimulation in patients entering IVF/ICSI-ET programs. J Assist Reprod Genet, 2006, 23(4):177~184
22 Teissier MP, Chable H, Paulhac S, et al. Comparison of follicle steroidogenesis from normal and polycystic ovaries in women undergoing IVF: relationship between steroid concentrations, follicle size, oocyte quality and fecundability. Hum Reprod, 2000,15(12):2471~2477
23 Lambert Messerlian G, Taylor A, Leykin L,et al. Charac- terization of intrafollicular steroid hormones, inhibin, and follistatin in women with and without polycystic ovarian syndrome following gonadotropin stimulation. Biol Reprod, 1997, 57(5):1211~1216
24 Nelson VL, Legro RS, Strauss JF 3rd, et al. Augmented androgen production is a stable steroidogenic phenotype of propagated theca cells from polycysitc ovaries. Mol Endocrinol, 1999(6), 13:946~957
25 Nelson VL, Qin K, Rosenfield RL, et al. The biochemical basis for increased testosterone production in theca cellspropagated from patients with polycystic ovary syndrome. J Clin Endocrinol Metab, 2001, 86(12): 5925~5933
26 Willis D, Mason H, Gilling-Smith C, et al.Modulation by insulin of follicle-stimulating hormone and luteinizing hormone actions in human granulosa cells of normal and polycystic ovaries. J Clin Endocrinol Metab, 1996, 81(1): 302~309
27 Franks S, Mason H, Willis D.Follicular dynamics in the polycystic ovary syndrome. Mol Cell Endocrinol,2000,163:49~52
28 Willis D, Mason H, Watson H, et al. Raised follicular fluid progesterone levels in polycystic ovaries (PCO). Program of the 79th Annual Meeting of the Endocrine Society, Minneapolis, MN, 1997, 221
29 Eden JA, Jones J, Carter GD, et al. Follicular fluid concentrations of insulin-like growth factor 1, epidermal growth factor, transforming growth factor- and sex-steroids in volume matched normal and polycystic human follicles.Clin Endocrinol, 1990, 32(4): 395~405
30 Erickson GF, Magoffin DA, Garzo VG, et al. Granulosa cells of polycystic ovaries: are they normal or abnormal? Hum Reprod, 1992, 7(3): 293~299
31 Welt CK, Taylor AE, Fox J, et al. Follicular arrest in poly- cystic ovary syndrome is associated with deficient inhibin A and B biosynthesis. J Clin Endocrinol Metab, 2005, 90(10):5582~5587
32 Wada Y, Tsuiki A, Uehara S, et al. Effects of androgen in 17B-estradiol and progesterone secretion by cultured human granulosa cells. Nippon Sanka Fujinka Gakkai Zasshi, 1988, 40(3):331~337
33 Greisen S, Ledet T, Ovesen P Effects of androstenedione, insulin and luteinizing hormone on steroidogenesis in human granulosa luteal cells. Hum Reprod, 2001,16(10):2061~2065
34 Hickey TE, Marrocco DL, Gilchrist RB, et al. Interactions between androgen and growth factors in granulosa cell subtypes of porcine antral follicles. Biol Reprod, 2004, 71(1):45~52
35 Pradeep PK, Li X, Peegel H, et al. Dihydrotestosterone inhibits granulosa cell proliferation by decreasing the cyclin D2 mRNA expression and cell cycle arrest at G1 phase. Endocrinology, 2002, 143(8):2930~2935
1 Vassart G , Pardo L , Costagliola S. A molecular dissection of the glycoprotein hormone receptors. Trends Biochem Sci, 2004, 29(3): 119~226
2 Davia D, Lin X, Segaloff DL. Identification of the sitea of N-linded glycosylation on the follicle-stimulating hormone (FSH) receptor and assessment of their role in FSH receptor function [J].Mol Endocrinol, 1995, 9(2):159~170
3 Fan QR, Hendrickson WA. Structure of human follicle -stimulating hormone in complex with its receptor. Nature, 2005, 433(7023):269~277
4 Thomas RM, Nechamen CA, Mazurkiewicz JE, Muda M, Palmer S, Dias JA.Follice-stimulating hormone receptor forms oligomers and shows evidence of carboxyl-terminal proteolytic processing. Endocrinology,2007,148(5): 1987~ 1995
5 Meno KM,Mnushi UM,Clouser CL,etal. Regluation ofluteinizing hormone/human chorionic gonadotropin receptor expression: a perspective.Biol Reprod,2004,70(4): 861~866
6 Oktay K, Briggs D ,Gosden R G. Ontogeny of follicle stimulating hormone receptor gene expression in isolated human ovarian follicles. J Clin Endocrinol Metab, 1997, 82 (11):3748~3751
7 Meduri G ,Charnaux N ,Driancourt MA,et al. Follicle-stimulating hormone receptors in oocytes? J Clin Endocrinol Metab,2002, 87 (5):2266~2276
8 Patsoula E ,Loutradis D ,Drakakis P ,et al. Messenger RNA expression for the follicle-stimulating hormone receptor and luteinizing hormone receptor in human oocytes and preimplantation-stage embryos. Fertil Steri1, 2003, 79(5): 1187~1193
9 Koo YB, Ji I, Ji TH. Characterization of different sizes of rat luteinizing hormone/chorionic gonadotropin receptor messenger ribonucleic acids.Endocrinology,1994,134(1): 19~26
10 Atger M, Misrahi M, et al. Structure of the human luteinizing hormone-choriogonadotropin receptor gene: unusual promoter and 5' non-coding regions.Mol Cell Endocrinlo, 1995, 111(2): 113~123.
11 Jun JK, Yoon JS, Ku SY, et al. Follicle-stimulating hormone receptor gene polymorphism and ovarian responses to controlled ovarian hyperstimulation for IVF-ET. Hum Genet, 2006, 51(8): 665~670.
12 Loutradis D, Patsoula E, Minas V, et al.FSH receptor gene polymorphisms have a role for different ovarian response to stimulation in patients entering IVF/ICSI-ET programs. Assist Reprod Genet, 2006 , 23(4):177~184
13 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 theovarian response to FSH: a pharmacogenetic approach to controlled ovarian hyperstimulation.Pharmacogenet Genomics, 2005, 15 (7):451~456
14 Laven JS, Mulders AG, Suryandari DA, et al. Follicle stimulating hormone receptor polymorphisms in women with normogonadotropic anovulatory infertility.Fertil Steril, 2003, 80 (4):986~992
15 Klinkert ER, te Velde ER, Weima S, et al. FSH receptor genotype is associated with pregnancy but not with ovarian response in IVF. Reprod Biomed Online, 2006,13 (5): 687~ 695
16 de Castro F, Morón FJ, Montoro L, et al.Human controlled ovarian hyperstimulation outcome is a polygenic trait. Pharmacogenetics, 2004 ,14(5):285~293
17 Cai J, Lou HY, Dong MY, et al.Poor ovarian response to gonadotropin stimulation is associated with low expression of follicle-stimulating hormone receptor in granulosa cells. Fertil Steril, 2007 ,87(6):1350~1356
18 Timossl C, Maldonado D, Vizcaino A,et al. Structural determinants in the second intracellular loop of the human follicle-stimulating hormone receptor are involved in G(s) pmtein activation. Mol Cell Endocrimol,2002,189(1-2): 157~168
19 Smits G , Olatunbosun O, Delbaere A ,et al. Ovarian hyper- stimulation syndorme due to a mutation in the follicle- stimulating hormone receptor.N Engl J Med,2003, 349 (8):760~766
20 Vasseur C, Rodien P, Beau I, et al. A chorionic gonadotopin- sensitive mutation in the follicle- stimulating hormone receptor as a cause of familial gestational spontaneous ovarian hyper-stimulation syndorme. N Engl J Med, 2003, 349 (8): 753~759
21 Montanelli L, Delbaere A, Di-Carlo C, et al. A mutation in the follicle-stimulating hormone receptor as a cause of familial spontaneous ovarian hyperstimulation syndorme.J Clin Endocirnol Metab , 2004, 89 (4): 1255~1258
22 Kerkel? 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. Fertil Steirl, 2007,87(3): 603~606
23 d'Alva CB, Serafini P, Motta E, et al.Absence of follicle- stimulating hormone receptor activating mutations in women with iatrogenic ovarian hyperstimulation syndrome. Fertil Steril, 2005,83(6):1695~1699
24 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 Clin Endocirnol Metab , 2004, 89(12):6310~6315
25 Shelling AN, Burton KA,Chard AL,et al. Inhibin:a candidate gene for premature ovarian failuer. Hum Reprod, 2000, 15(12): 2644~2649
26 Takakura K, Takebayashi K, Wang HQ, et al. Follicle- stimulating hormone receptor gene mutations are rare in Japanese women with prematuer ovarian failuer and polycystic ovary syndorme. Fertil Steirl, 2001, 75 (1):207~220
27 Puett D, Li Y,Angelova K,et al. Structure-function relationships of the luteinizing homorne receptor.Ann N Y Acad Sci,2005,1061(2): 41~54
28 Nair AK, Peegel H, Menon KM.The role of luteinizing hormone/human chorionic gonadotropin receptor-specific mRNA binding protein in regulating receptor expression in human ovarian granulosa cells. J Clin Endocirnol Metab, 2006 ,91(6):2239~2243
29 Menon KM, Nair AK, Wang L, Peegel H.Regulation of luteinizing hormone receptor mRNA expression by a specific RNA binding protein in the ovary.Mol Cell Endocrinol, 2007, 260~262:109~116
30 Nair AK, Menon KM.Isolation and characterization of a novel trans -factor for luteinizing hormone receptor mRNA from ovary. J Biol Chem, 2004,279(15):14937~14944
31 Wang L, Nair AK, Menon KM. Ribonucleic acid binding protein- mediated regulation of luteinizing hormone receptor expression in granulosa cells: relationship to sterol metabolism. Mol Endocrinol, 2007,21(9):2233~2241
2 Elchalal U,Schenker J.The pathophysiology of ovarian hyperstimulation syndrome-views and ideas. Human Reprod, 1997, 12 (6): 1129~1137
3 Cai J,Lou HY,Dong MY,et al.Poor ovarian response to gonadotropin stimulation is associated with low expre- ssion of follicle stimulating hormone receptor in granulosa cells. Fertil Steril, 2007, 87(6):1350~1356
4 O’Shaughnessy PJ,Dudley K, Rajapaksha WR.Expression of follicle stimulating hormone receptor mRNA during gonadal development. Mol Cell Endocrinol, 1996, 125 (122): 169~ 175
5 Rice S,Ojha K,Whitehead S,et al.Stage-specific expression of androgen receptor, follicle stimulating hormone receptor, and anti-Müllerian hormone type II receptor in single, isolated, human preantral follicles: relevance to polycystic ovaries. J Clin Endocrinol Metab, 2007, Mar, 92(3): 1034~ 1040
6 SimoniM,Gromoll J,Nieschlag E.The follicle stimulating hormone receptor: biochemistry,molecular biology,physio- logy, and pathophysiology. Endocr Rev, 1997,18(6):739~ 773
7 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 Endocrinol Invest, 2006,29 (11):975~982
8 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 pre- mature ovarian failure and polycystic ovary syndrome. Horm Metab Res,2001,33(4):221~226
9 Sudo S,Kudo M,Wada S,et al.Genetic and functional analyses of polymorphisms in the human FSH receptor gene.Mol Hum Reprod, 2002, 8 (10): 893~899
10 Ota H, Wakizaka A, Fukushima M,et al. Enhanced Ovari- an Gonadotropin Receptors in the Testosterone- Induced Polycystic Ovary in Rats .Tohoku J. exp. Med., 1986, 148, 313-325
11 Maritza PM, Jorg G, HermannM B, et al. Ovarian response to follicle-stimulating hormone stimulating depends on the FSH receptor genotype . J Clin Endocrinol Metab, 2000, 85 (9): 3365~ 3369
12 ZHAO Hai-bo, LUO Li-lan,LIU Yi. The effect of insulin- like grow th factor-I on stero idogenesis and ultrastructures of culutured human granulosa cells in vitro. Chinese Journal of Obstetrics and Gynecology, 1998, 33(9): 546~548
13 Damario M A, Bogovich K, Liu H G, et al. Synergistic effects of insulin-like growth factor-I and human cho rionicgonadotropin in the rat ovary. Metabolism, 2000, 49 (3): 314~ 320
14 CHEN Dan-qing, SHI Yi-fu,CHEN Huai-zeng. Relation- ship between follicle development and insulin like growth factor I receptor in stimulated cycles. Chinese Journal of Obstetrics and Gynecology, 2001, 36 (2): 98~100
15 Weil S, Vendola K, Zhou J, et al. Androgen and follicle- stimulating hormone interactions in primate ovarian follicle development. J Clin Endocrinol Metab, 1999, 84(8): 2951~2956
16 Willis DS, Watson H, Mason HD, et al. Premature response to LH of granulosa cells from anovulatory women with polycystic ovaries: relevance to mechanism of anovulation. J Clin Endocrinol Metab 1998, 83 (11): 3984 ~3991
17 Jakimiuk AJ, Weitsman SR, Navab A, et al. Luteinizing hormone receptor, steroidogenesis acute regulatory protein, and steroidogenic enzyme messenger ribonucleic acids are overexpressed in thecal and granulosa cells from polycystic ovaries. J Clin Endocrinol Metab, 2001,86(3):1318~1323
18 Jakimiuk AJ, Weitsman SR, Brzechffa PR, et al. Aroma- tase messenger ribonucleic acid expression in individual follicles from polycystic ovaries. Mol Hum Reprod, 1998 ,4: 1~8
19 Foong SC, Abbott DH, Zschunke MA, et al. Follicle luteinization in hyperandrogenic follicles of polycystic ovary syndrome patients undergoing gonadotropin therapyfor in Vitro fertilization. J Clin Endocrinol Metab, 2006, 91(6):2327~2333
20 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 Hum Genet, 2006, 51(8):665~670
21 Loutradis D, Patsoula E, Minas V, et al. FSH receptor gene polymorphisms have a role for different ovarian response to stimulation in patients entering IVF/ICSI-ET programs. J Assist Reprod Genet, 2006, 23(4):177~184
22 Teissier MP, Chable H, Paulhac S, et al. Comparison of follicle steroidogenesis from normal and polycystic ovaries in women undergoing IVF: relationship between steroid concentrations, follicle size, oocyte quality and fecundability. Hum Reprod, 2000,15(12):2471~2477
23 Lambert Messerlian G, Taylor A, Leykin L,et al. Charac- terization of intrafollicular steroid hormones, inhibin, and follistatin in women with and without polycystic ovarian syndrome following gonadotropin stimulation. Biol Reprod, 1997, 57(5):1211~1216
24 Nelson VL, Legro RS, Strauss JF 3rd, et al. Augmented androgen production is a stable steroidogenic phenotype of propagated theca cells from polycysitc ovaries. Mol Endocrinol, 1999(6), 13:946~957
25 Nelson VL, Qin K, Rosenfield RL, et al. The biochemical basis for increased testosterone production in theca cellspropagated from patients with polycystic ovary syndrome. J Clin Endocrinol Metab, 2001, 86(12): 5925~5933
26 Willis D, Mason H, Gilling-Smith C, et al.Modulation by insulin of follicle-stimulating hormone and luteinizing hormone actions in human granulosa cells of normal and polycystic ovaries. J Clin Endocrinol Metab, 1996, 81(1): 302~309
27 Franks S, Mason H, Willis D.Follicular dynamics in the polycystic ovary syndrome. Mol Cell Endocrinol,2000,163:49~52
28 Willis D, Mason H, Watson H, et al. Raised follicular fluid progesterone levels in polycystic ovaries (PCO). Program of the 79th Annual Meeting of the Endocrine Society, Minneapolis, MN, 1997, 221
29 Eden JA, Jones J, Carter GD, et al. Follicular fluid concentrations of insulin-like growth factor 1, epidermal growth factor, transforming growth factor- and sex-steroids in volume matched normal and polycystic human follicles.Clin Endocrinol, 1990, 32(4): 395~405
30 Erickson GF, Magoffin DA, Garzo VG, et al. Granulosa cells of polycystic ovaries: are they normal or abnormal? Hum Reprod, 1992, 7(3): 293~299
31 Welt CK, Taylor AE, Fox J, et al. Follicular arrest in poly- cystic ovary syndrome is associated with deficient inhibin A and B biosynthesis. J Clin Endocrinol Metab, 2005, 90(10):5582~5587
32 Wada Y, Tsuiki A, Uehara S, et al. Effects of androgen in 17B-estradiol and progesterone secretion by cultured human granulosa cells. Nippon Sanka Fujinka Gakkai Zasshi, 1988, 40(3):331~337
33 Greisen S, Ledet T, Ovesen P Effects of androstenedione, insulin and luteinizing hormone on steroidogenesis in human granulosa luteal cells. Hum Reprod, 2001,16(10):2061~2065
34 Hickey TE, Marrocco DL, Gilchrist RB, et al. Interactions between androgen and growth factors in granulosa cell subtypes of porcine antral follicles. Biol Reprod, 2004, 71(1):45~52
35 Pradeep PK, Li X, Peegel H, et al. Dihydrotestosterone inhibits granulosa cell proliferation by decreasing the cyclin D2 mRNA expression and cell cycle arrest at G1 phase. Endocrinology, 2002, 143(8):2930~2935
1 Vassart G , Pardo L , Costagliola S. A molecular dissection of the glycoprotein hormone receptors. Trends Biochem Sci, 2004, 29(3): 119~226
2 Davia D, Lin X, Segaloff DL. Identification of the sitea of N-linded glycosylation on the follicle-stimulating hormone (FSH) receptor and assessment of their role in FSH receptor function [J].Mol Endocrinol, 1995, 9(2):159~170
3 Fan QR, Hendrickson WA. Structure of human follicle -stimulating hormone in complex with its receptor. Nature, 2005, 433(7023):269~277
4 Thomas RM, Nechamen CA, Mazurkiewicz JE, Muda M, Palmer S, Dias JA.Follice-stimulating hormone receptor forms oligomers and shows evidence of carboxyl-terminal proteolytic processing. Endocrinology,2007,148(5): 1987~ 1995
5 Meno KM,Mnushi UM,Clouser CL,etal. Regluation ofluteinizing hormone/human chorionic gonadotropin receptor expression: a perspective.Biol Reprod,2004,70(4): 861~866
6 Oktay K, Briggs D ,Gosden R G. Ontogeny of follicle stimulating hormone receptor gene expression in isolated human ovarian follicles. J Clin Endocrinol Metab, 1997, 82 (11):3748~3751
7 Meduri G ,Charnaux N ,Driancourt MA,et al. Follicle-stimulating hormone receptors in oocytes? J Clin Endocrinol Metab,2002, 87 (5):2266~2276
8 Patsoula E ,Loutradis D ,Drakakis P ,et al. Messenger RNA expression for the follicle-stimulating hormone receptor and luteinizing hormone receptor in human oocytes and preimplantation-stage embryos. Fertil Steri1, 2003, 79(5): 1187~1193
9 Koo YB, Ji I, Ji TH. Characterization of different sizes of rat luteinizing hormone/chorionic gonadotropin receptor messenger ribonucleic acids.Endocrinology,1994,134(1): 19~26
10 Atger M, Misrahi M, et al. Structure of the human luteinizing hormone-choriogonadotropin receptor gene: unusual promoter and 5' non-coding regions.Mol Cell Endocrinlo, 1995, 111(2): 113~123.
11 Jun JK, Yoon JS, Ku SY, et al. Follicle-stimulating hormone receptor gene polymorphism and ovarian responses to controlled ovarian hyperstimulation for IVF-ET. Hum Genet, 2006, 51(8): 665~670.
12 Loutradis D, Patsoula E, Minas V, et al.FSH receptor gene polymorphisms have a role for different ovarian response to stimulation in patients entering IVF/ICSI-ET programs. Assist Reprod Genet, 2006 , 23(4):177~184
13 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 theovarian response to FSH: a pharmacogenetic approach to controlled ovarian hyperstimulation.Pharmacogenet Genomics, 2005, 15 (7):451~456
14 Laven JS, Mulders AG, Suryandari DA, et al. Follicle stimulating hormone receptor polymorphisms in women with normogonadotropic anovulatory infertility.Fertil Steril, 2003, 80 (4):986~992
15 Klinkert ER, te Velde ER, Weima S, et al. FSH receptor genotype is associated with pregnancy but not with ovarian response in IVF. Reprod Biomed Online, 2006,13 (5): 687~ 695
16 de Castro F, Morón FJ, Montoro L, et al.Human controlled ovarian hyperstimulation outcome is a polygenic trait. Pharmacogenetics, 2004 ,14(5):285~293
17 Cai J, Lou HY, Dong MY, et al.Poor ovarian response to gonadotropin stimulation is associated with low expression of follicle-stimulating hormone receptor in granulosa cells. Fertil Steril, 2007 ,87(6):1350~1356
18 Timossl C, Maldonado D, Vizcaino A,et al. Structural determinants in the second intracellular loop of the human follicle-stimulating hormone receptor are involved in G(s) pmtein activation. Mol Cell Endocrimol,2002,189(1-2): 157~168
19 Smits G , Olatunbosun O, Delbaere A ,et al. Ovarian hyper- stimulation syndorme due to a mutation in the follicle- stimulating hormone receptor.N Engl J Med,2003, 349 (8):760~766
20 Vasseur C, Rodien P, Beau I, et al. A chorionic gonadotopin- sensitive mutation in the follicle- stimulating hormone receptor as a cause of familial gestational spontaneous ovarian hyper-stimulation syndorme. N Engl J Med, 2003, 349 (8): 753~759
21 Montanelli L, Delbaere A, Di-Carlo C, et al. A mutation in the follicle-stimulating hormone receptor as a cause of familial spontaneous ovarian hyperstimulation syndorme.J Clin Endocirnol Metab , 2004, 89 (4): 1255~1258
22 Kerkel? 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. Fertil Steirl, 2007,87(3): 603~606
23 d'Alva CB, Serafini P, Motta E, et al.Absence of follicle- stimulating hormone receptor activating mutations in women with iatrogenic ovarian hyperstimulation syndrome. Fertil Steril, 2005,83(6):1695~1699
24 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 Clin Endocirnol Metab , 2004, 89(12):6310~6315
25 Shelling AN, Burton KA,Chard AL,et al. Inhibin:a candidate gene for premature ovarian failuer. Hum Reprod, 2000, 15(12): 2644~2649
26 Takakura K, Takebayashi K, Wang HQ, et al. Follicle- stimulating hormone receptor gene mutations are rare in Japanese women with prematuer ovarian failuer and polycystic ovary syndorme. Fertil Steirl, 2001, 75 (1):207~220
27 Puett D, Li Y,Angelova K,et al. Structure-function relationships of the luteinizing homorne receptor.Ann N Y Acad Sci,2005,1061(2): 41~54
28 Nair AK, Peegel H, Menon KM.The role of luteinizing hormone/human chorionic gonadotropin receptor-specific mRNA binding protein in regulating receptor expression in human ovarian granulosa cells. J Clin Endocirnol Metab, 2006 ,91(6):2239~2243
29 Menon KM, Nair AK, Wang L, Peegel H.Regulation of luteinizing hormone receptor mRNA expression by a specific RNA binding protein in the ovary.Mol Cell Endocrinol, 2007, 260~262:109~116
30 Nair AK, Menon KM.Isolation and characterization of a novel trans -factor for luteinizing hormone receptor mRNA from ovary. J Biol Chem, 2004,279(15):14937~14944
31 Wang L, Nair AK, Menon KM. Ribonucleic acid binding protein- mediated regulation of luteinizing hormone receptor expression in granulosa cells: relationship to sterol metabolism. Mol Endocrinol, 2007,21(9):2233~2241