生长激素预测体外受精-胚胎移植结局的价值及其改善卵巢反应的作用机理
|
摘要
研究背景
多囊卵巢综合征(polycystic ovary syndrome,PCOS)是导致育龄妇女无排卵性不孕的常见原因,发病率约4%~12%。其临床表现呈高度异质性,常表现为月经不规律,肥胖、多毛,伴胰岛素抵抗及高胰岛素血症。PCOS的特点由其发生机制所决定,该机制导致下丘脑—垂体—卵巢—肾上腺各部位功能的异常,并伴有代谢异常。相关的代谢功能失调包括:胰岛素抵抗、血脂异常以及日益增加的肥胖问题。正常排卵周期是由性腺以及卵巢内、外的各种生长因子所调节,这些因子的异常被推测在PCOS病理生理中起重要作用。生长激素(growth hormone,GH)及其相关因子对下丘脑—垂体—卵巢轴具有重要的调节作用,影响卵巢的成熟及卵泡的周期性发育。近年国外有研究认为PCOS患者GH-IGF轴功能混乱,学者们对PCOS患者相对正常对照组基础GH分泌有降低、正常、升高,观点不一,但大部分研究认为PCOS患者对左旋多巴及GHRH刺激的反应迟钝,分泌受损,可能与肥胖、胰岛素抵抗、高雄激素血症有关,确切机制尚不清楚。生长激素具有促进细胞增殖、蛋白质合成、调理免疫功能等作用,已在辅助生殖领域应用已久,常用于卵巢反应不良患者辅助治疗,有助于改善助孕结局。因此,探讨PCOS及卵巢反应不良患者GH及IGF-1的水平与妊娠结局的关系及其对预测卵巢反应的价值具有重要的临床指导意义。
目的
检测GH、IGF-1在PCOS及卵巢反应不良患者表达水平,并结合临床指标评价GH、IGF-1对PCOS及卵巢反应不良患者行体外受精-胚胎移植(in vitro fertilization-embryo transfer, IVF-ET)结局的影响,探讨GH、IGF-1对预测卵巢反应的价值。
方法
对2010年3月至2010年10月于广州医学院第三附属医院生殖中心行体外受精-胚胎移植的65名患者进行前瞻性病例对照研究。将PCOS患者作为研究组,共29例,同期的输卵管因素不孕患者作为对照组,共36例,另根据获卵数分成低反应(≤4)及正常反应(>4)两个亚组。没有一例获卵数超过30个。所有患者均采用黄体期长方案降调节促排卵,于取卵日收集两组患者外周静脉血及卵泡液,采用时间分辨免疫荧光法(time-resolved fluoroimmunoassay,TRFIA)和酶联免疫吸附法(enzyme linked immunosorbent assay,ELISA)分别测定两组患者血清及卵泡液中GH,IGF-1的浓度。对三组间的IVF-ET结局:获卵数、受精率、优质胚胎率、种植率、临床妊娠率进行比较,并结合GH、IGF-1水平进行相关性分析。
结果
1、所有患者血清GH及IGF-1水平较卵泡液高( GH 9.01+1.33 VS.2.97±1.75;P=0.000, IGF-1 111.89±28.54VS.90.19±19.65;P=0.000),PCOS患者血清GH显著高于低反应组(P<0.001),与正常反应组无差异,卵泡液GH在各组无显著性差异;血清及卵泡液IGF-1水平三组间两两比较均有显著性差异,PCOS患者高于正常反应组,正常反应组高于低反应组(P<0.001);
2、三组间子宫内膜厚度无统计学差异(P>0.05);HCG日E2、Gn用量、获卵数、2PN胚胎数及卵裂数在三组间两两比较均有显著性差异(P<0.05),PCOS组高于正常反应组,正常反应组高于低反应组;PCOS组优质胚胎数高于正常反应组及低反应组,均有统计学差异(P<0.05);三组间种植率有显著性差异(P<0.05),正常反应组最高,低反应组最低;受精率、妊娠率、临床妊娠率、继续妊娠率、流产率、OHSS发生率及周期取消率均无统计学差异(P>0.05)。
3、血清和卵泡液中IGF-1水平与Gn用量呈负相关趋势,与获卵数、受精数、卵裂数、优质胚胎数、2PN数、种植率呈正相关趋势,卵泡液GH与种植率呈正相关趋势,均有统计学差异(P<0.05);血清和卵泡液中GH水平与获卵数、受精数、卵裂数、优质胚胎数、2PN数呈正相关趋势,但均无统计学差异(P>0.05)。
4、血清和卵泡液GH及血清IGF-1水平在妊娠组和非妊娠组比较无统计学差异(P>0.05);卵泡液IGF-1在妊娠组明显高于非妊娠组,差异有统计学意义(P<0.05)。
结论
血清GH、IGF-1水平较卵泡液高,PCOS患者取卵日GH、IGF-1与对照组比较并无降低,但低反应组血清及卵泡液GH、IGF-1水平均较低,血清和卵泡液中IGF-1水平与Gn用量呈负相关趋势,与获卵数、受精数、卵裂数、优质胚胎数、2PN数、种植率呈正相关趋势,卵泡液GH与种植率呈正相关趋势,血清和卵泡液中GH水平与获卵数、受精数、卵裂数、优质胚胎数、2PN数无相关性,妊娠组卵泡液IGF-1水平高于非妊娠组。表明PCOS患者在促排卵过程中并无GH、IGF-1分泌减少,卵泡液中的GH、IGF-1主要由循环分泌渗透而来,由于GH的易受其他因素影响,其作为预测卵巢反应的价值有待进一步研究,IGF-1稳定性较好,可以作为预测卵巢反应的指标之一。
目的了解人卵泡黄素化颗粒细胞中生长激素(GH)和胰岛素样生长因子-1(IGF-1)受体的表达,GH在体外对人卵泡黄素化颗粒细胞产生雌、孕激素的影响。方法采用免疫细胞化学染色法,测定24例行体外受精-胚胎移植治疗患者的卵泡黄素化颗粒体细胞的GH和IGF-1受体表达,并将黄素化颗粒细胞在不同浓度的GH(0、0.1、0.2、0.4mg/m1)作用下单独及与促卵泡素(FSH,浓度为75U/ml)共同培养72h,采用酶联免疫吸附法测定黄素化颗粒细胞培养液中的IGF-1和化学发光法测定雌二醇和孕酮含量。结果80%以上黄素化颗粒细胞GH和IGF-1受体阳性;黄素化颗粒细胞在基础状态下能自分泌一定量的IGF-1(140.00±27.13ng/ml),E_2 444.67±67.25(pg/ml),和P(655.00±70.07ng/ml),GH不能直接刺激黄素化颗粒细胞合成IGF-1,E_2和P,但能直接或间接通过IGF-1协同FSH进一步促进E_2和P的合成,且呈剂量依赖性。
Background
PCOS is one of the most common endocrine disorders in women of reproductive age, with prevalence ranging from 4% to 12%.Polycystic ovary syndrome is a heterogeneous clinical condition, characterized by hirsutism, irregular menstrual cycles, infertility, and endocrine abnormalities such as hyperandrogenism. Moreover, a considerable percentage of women with PCOS present insulin resistance and compensatory hyperinsulinemia. Women with PCOS have a disturbance of normal GH kinetics. Serum GH baseline concentrations in women with PCOS have been variously described as low,normal or elevated, while the diurnal GH secretion was found to be impaired. It has been shown that women with PCOS have a relative deficiency or reduction in GH reserve after oral L-dopa stimulation. The GH concentrations after GHRH administration were found to be impaired in women with PCOS. A number of recent clinical studies have also suggested alterations in the GH/IGF-I system in women with PCOS.
Therefore,The purpose of the present study was to evaluate the serum and intrafollicular concentrations of GH and IGF-1 and its relationship with the outcomes of women with polycystic ovary syndrome and low ovrian responders undergoing IVF-ET. To determine if these factors are predictive of IVF outcome.
Objective
To evaluate the serum and intrafollicular concentrations of GH and IGF-1 and its relationship with the outcomes of women with polycystic ovary syndrome and low ovrian responders undergoing IVF-ET. Investigate if these factors are predictive of IVF outcome.
Methods
A prospective case-control study was conducted on 65 patients who were submitted to ovulation induction for IVF-ET. These patients were divided into the study group(29 patients with endometriosis) and the control group(36 patients with tubal factor infertility).The control patients were subgroup as low and norm ovarian response according to the number of oocytes retrieved. Whose numbers of oocytes retrieval was less than 4 was defined as low responders.No one in norm ovarian response group had more than 30 oocytes retrieved. All patients underwent a long GnRH agonist protocol for pituitary downregulation followed by controlled ovarian hyperstimulation. Peripheral blood and follicular-fluid samples were collected on the day of oocyte retrieval. Growth hormone(GH), Insulin-like growth factor-1(IGF-1) were measured by time-resolved fluoroimmunoassay (TRFIA) and enzyme linked immunosorbent assay (ELISA) respectively. Compare the outcome of IVF-ET between the three groups: include retrieved oocytes, fertilization rates, good-embryo rates, implantation rates and clinical pregnancy rates, and analysis the correlation between the levels of above growth factors and the outcome of IVF-ET.
Results
1.The concentrations of GH and IGF-1 in serum was significantly higher than follicular fruid(9.01+1.33 VS.2.97±1.75;P=0.000, 111.89±28.54VS.90.19±19.65;P=0.000,respectively).Serum GH level in PCOS patients was higher than low ovarian responsers(P=0.000),but norm ovarian responsers had no significantly differences comparing with the other two groups. Follicular fruid GH levels were no significantly differences among three groups.The serum and follicular fruid IGF-1 levels had significantly differences between each other in the three groups(P<0.001).
2.Endometrial thickness had no significantly differences between each other(P>0.05). Peak E2 levels on the day of HCG injection, doses of gonadotropin requirement,the number of oocytes retrieved,cleavage embroys and 2PN were significantly differences between each other(P<0.05). PCOS womem had more high-quailty embryos than normal and low ovarian responsers. Implantation rates was differences among three groups(P=0.007),implantation rate in low ovarian responsers was lowest ,while the fertilization rates,the pregnancy rates,clinical pregnancy rates,ongoing pregnancy rates,cancellation rates and OHSS rates were lower and spontaneous abortion rate was higher in poor ovarian responsers but had no significantly differences among three groups.
3. No relationship was found between the concentration of GH in serum or follicular fruid and the number of oocytes retrieved,high-quailty embryos,fertilizaton,cleavage embroys , as well as 2PN embroys (P>0.05), However, follicular fruid GH was correlated with implantation rates,while serum and follicular fruid IGF-1 levels were correlated with oocytes retrieved,high-quailty embryos,fertilizaton rate,cleavage embroys,2PN embroys and implantation rates (P>0.05).
4. GH in serum or follicular fruid as well as IGF-1 in serum had no significantly differences between pregnancy group and non pregnancy group,but IGF-1 in follicular fruid had significantly differences between the two groups.
Conclusions
Serum GH and IGF-1 concentrations were statistically significantly higher than in follicular fruid. It is thought that the origin of follicular fruid GH and IGF-1 is through transudation of serum GH and IGF-1 derived from an extraovarian source and through local production in the granulosa cells.Our result fail to show there was difference in the concentrations of GH in serum and follicular fruid between PCOS and normal response patient on day of oocytes retrieved,but these factors were lowest in poor ovarian responsers. No relationship was found between the concentration of GH in serum or follicular fruid and the number of oocytes retrieved,high-quailty embryos,fertilizaton,cleavage embroys , as well as 2PN embroys . However, follicular fruid GH was correlated with implantation rates,while serum and follicular fruid IGF-1 levels were correlated with oocytes retrieved,high-quailty embryos,fertilizaton rate,cleavage embroys,2PN embroys and implantation rates.It means the patients with PCOS didn’t have the diurnal GH、IGF-1 secretion impaired on day of oocyte retrieval,IGF-1 is a good predictor of the ovarian response to COH and IVF outcome.Due to GH secrete characteristic, we need further research to investigate its value as predictor of the ovarian response to COH and IVF outcome.
Objective The aim of this study was to determine whether there were differences in the dose-dependent effects of growth hormone(GH) on estradiol(E_2),progesterone(P),insulin-like growth factor-1(IGF-1) production by luteinized granulosa cells and to detect GH and IGF-1 receptors in human luteinized granulosa cells. Methods Human luteinized granulosa cells(LGC) were isolated from 24 women undergoing in vitro fertilization and embryo transfer (IVF-ET) .Some of the LGCs were used for detecting GH and IGF-1 receptors by immunocytochemistry(SABC method).Most of them were cultured in DMEM/F12 medium with 10% fetal bovine serum(FCS), after 2 days the medium was removed and the cells were incubated with various concentration of GH (0,0.1,0.2 and 0.4mg/ml) in the presence or absence of follicle stimulating hormone( FSH 75IU/ml).Media were collected after 72 hours and E_2,P in media were measured with chemiluminescence immune assay(CLIA)while IGF-1 was measured with enzyme linked immunosorbent assay(ELISA). Results More than 80% of the LGCs were positively stained for GH and IGF-1 receptors . LGCs can autocrine IGF-1,E_2,P at the level of 140.00±27.13ng/ml, 444.67±67.25pg/ml, 655.00±70.07ng/ml without GH or FSH co-culture,GH alone can’t directly stimulate LGCs biosynthesis IGF-1,E_2,and P. However, the combination of GH and FSH can enhance gonadotropin-stimulated steroidogenesis in a significant dose-dependent manner. Conclusions: The main function of GH appeared to synergize with FSH and amplify gonadotropin action and thereby facilitation of granulosa cell replication, differentiation and steroidogenesis directly or indirectly via IGF-1.
多囊卵巢综合征(polycystic ovary syndrome,PCOS)是导致育龄妇女无排卵性不孕的常见原因,发病率约4%~12%。其临床表现呈高度异质性,常表现为月经不规律,肥胖、多毛,伴胰岛素抵抗及高胰岛素血症。PCOS的特点由其发生机制所决定,该机制导致下丘脑—垂体—卵巢—肾上腺各部位功能的异常,并伴有代谢异常。相关的代谢功能失调包括:胰岛素抵抗、血脂异常以及日益增加的肥胖问题。正常排卵周期是由性腺以及卵巢内、外的各种生长因子所调节,这些因子的异常被推测在PCOS病理生理中起重要作用。生长激素(growth hormone,GH)及其相关因子对下丘脑—垂体—卵巢轴具有重要的调节作用,影响卵巢的成熟及卵泡的周期性发育。近年国外有研究认为PCOS患者GH-IGF轴功能混乱,学者们对PCOS患者相对正常对照组基础GH分泌有降低、正常、升高,观点不一,但大部分研究认为PCOS患者对左旋多巴及GHRH刺激的反应迟钝,分泌受损,可能与肥胖、胰岛素抵抗、高雄激素血症有关,确切机制尚不清楚。生长激素具有促进细胞增殖、蛋白质合成、调理免疫功能等作用,已在辅助生殖领域应用已久,常用于卵巢反应不良患者辅助治疗,有助于改善助孕结局。因此,探讨PCOS及卵巢反应不良患者GH及IGF-1的水平与妊娠结局的关系及其对预测卵巢反应的价值具有重要的临床指导意义。
目的
检测GH、IGF-1在PCOS及卵巢反应不良患者表达水平,并结合临床指标评价GH、IGF-1对PCOS及卵巢反应不良患者行体外受精-胚胎移植(in vitro fertilization-embryo transfer, IVF-ET)结局的影响,探讨GH、IGF-1对预测卵巢反应的价值。
方法
对2010年3月至2010年10月于广州医学院第三附属医院生殖中心行体外受精-胚胎移植的65名患者进行前瞻性病例对照研究。将PCOS患者作为研究组,共29例,同期的输卵管因素不孕患者作为对照组,共36例,另根据获卵数分成低反应(≤4)及正常反应(>4)两个亚组。没有一例获卵数超过30个。所有患者均采用黄体期长方案降调节促排卵,于取卵日收集两组患者外周静脉血及卵泡液,采用时间分辨免疫荧光法(time-resolved fluoroimmunoassay,TRFIA)和酶联免疫吸附法(enzyme linked immunosorbent assay,ELISA)分别测定两组患者血清及卵泡液中GH,IGF-1的浓度。对三组间的IVF-ET结局:获卵数、受精率、优质胚胎率、种植率、临床妊娠率进行比较,并结合GH、IGF-1水平进行相关性分析。
结果
1、所有患者血清GH及IGF-1水平较卵泡液高( GH 9.01+1.33 VS.2.97±1.75;P=0.000, IGF-1 111.89±28.54VS.90.19±19.65;P=0.000),PCOS患者血清GH显著高于低反应组(P<0.001),与正常反应组无差异,卵泡液GH在各组无显著性差异;血清及卵泡液IGF-1水平三组间两两比较均有显著性差异,PCOS患者高于正常反应组,正常反应组高于低反应组(P<0.001);
2、三组间子宫内膜厚度无统计学差异(P>0.05);HCG日E2、Gn用量、获卵数、2PN胚胎数及卵裂数在三组间两两比较均有显著性差异(P<0.05),PCOS组高于正常反应组,正常反应组高于低反应组;PCOS组优质胚胎数高于正常反应组及低反应组,均有统计学差异(P<0.05);三组间种植率有显著性差异(P<0.05),正常反应组最高,低反应组最低;受精率、妊娠率、临床妊娠率、继续妊娠率、流产率、OHSS发生率及周期取消率均无统计学差异(P>0.05)。
3、血清和卵泡液中IGF-1水平与Gn用量呈负相关趋势,与获卵数、受精数、卵裂数、优质胚胎数、2PN数、种植率呈正相关趋势,卵泡液GH与种植率呈正相关趋势,均有统计学差异(P<0.05);血清和卵泡液中GH水平与获卵数、受精数、卵裂数、优质胚胎数、2PN数呈正相关趋势,但均无统计学差异(P>0.05)。
4、血清和卵泡液GH及血清IGF-1水平在妊娠组和非妊娠组比较无统计学差异(P>0.05);卵泡液IGF-1在妊娠组明显高于非妊娠组,差异有统计学意义(P<0.05)。
结论
血清GH、IGF-1水平较卵泡液高,PCOS患者取卵日GH、IGF-1与对照组比较并无降低,但低反应组血清及卵泡液GH、IGF-1水平均较低,血清和卵泡液中IGF-1水平与Gn用量呈负相关趋势,与获卵数、受精数、卵裂数、优质胚胎数、2PN数、种植率呈正相关趋势,卵泡液GH与种植率呈正相关趋势,血清和卵泡液中GH水平与获卵数、受精数、卵裂数、优质胚胎数、2PN数无相关性,妊娠组卵泡液IGF-1水平高于非妊娠组。表明PCOS患者在促排卵过程中并无GH、IGF-1分泌减少,卵泡液中的GH、IGF-1主要由循环分泌渗透而来,由于GH的易受其他因素影响,其作为预测卵巢反应的价值有待进一步研究,IGF-1稳定性较好,可以作为预测卵巢反应的指标之一。
目的了解人卵泡黄素化颗粒细胞中生长激素(GH)和胰岛素样生长因子-1(IGF-1)受体的表达,GH在体外对人卵泡黄素化颗粒细胞产生雌、孕激素的影响。方法采用免疫细胞化学染色法,测定24例行体外受精-胚胎移植治疗患者的卵泡黄素化颗粒体细胞的GH和IGF-1受体表达,并将黄素化颗粒细胞在不同浓度的GH(0、0.1、0.2、0.4mg/m1)作用下单独及与促卵泡素(FSH,浓度为75U/ml)共同培养72h,采用酶联免疫吸附法测定黄素化颗粒细胞培养液中的IGF-1和化学发光法测定雌二醇和孕酮含量。结果80%以上黄素化颗粒细胞GH和IGF-1受体阳性;黄素化颗粒细胞在基础状态下能自分泌一定量的IGF-1(140.00±27.13ng/ml),E_2 444.67±67.25(pg/ml),和P(655.00±70.07ng/ml),GH不能直接刺激黄素化颗粒细胞合成IGF-1,E_2和P,但能直接或间接通过IGF-1协同FSH进一步促进E_2和P的合成,且呈剂量依赖性。
Background
PCOS is one of the most common endocrine disorders in women of reproductive age, with prevalence ranging from 4% to 12%.Polycystic ovary syndrome is a heterogeneous clinical condition, characterized by hirsutism, irregular menstrual cycles, infertility, and endocrine abnormalities such as hyperandrogenism. Moreover, a considerable percentage of women with PCOS present insulin resistance and compensatory hyperinsulinemia. Women with PCOS have a disturbance of normal GH kinetics. Serum GH baseline concentrations in women with PCOS have been variously described as low,normal or elevated, while the diurnal GH secretion was found to be impaired. It has been shown that women with PCOS have a relative deficiency or reduction in GH reserve after oral L-dopa stimulation. The GH concentrations after GHRH administration were found to be impaired in women with PCOS. A number of recent clinical studies have also suggested alterations in the GH/IGF-I system in women with PCOS.
Therefore,The purpose of the present study was to evaluate the serum and intrafollicular concentrations of GH and IGF-1 and its relationship with the outcomes of women with polycystic ovary syndrome and low ovrian responders undergoing IVF-ET. To determine if these factors are predictive of IVF outcome.
Objective
To evaluate the serum and intrafollicular concentrations of GH and IGF-1 and its relationship with the outcomes of women with polycystic ovary syndrome and low ovrian responders undergoing IVF-ET. Investigate if these factors are predictive of IVF outcome.
Methods
A prospective case-control study was conducted on 65 patients who were submitted to ovulation induction for IVF-ET. These patients were divided into the study group(29 patients with endometriosis) and the control group(36 patients with tubal factor infertility).The control patients were subgroup as low and norm ovarian response according to the number of oocytes retrieved. Whose numbers of oocytes retrieval was less than 4 was defined as low responders.No one in norm ovarian response group had more than 30 oocytes retrieved. All patients underwent a long GnRH agonist protocol for pituitary downregulation followed by controlled ovarian hyperstimulation. Peripheral blood and follicular-fluid samples were collected on the day of oocyte retrieval. Growth hormone(GH), Insulin-like growth factor-1(IGF-1) were measured by time-resolved fluoroimmunoassay (TRFIA) and enzyme linked immunosorbent assay (ELISA) respectively. Compare the outcome of IVF-ET between the three groups: include retrieved oocytes, fertilization rates, good-embryo rates, implantation rates and clinical pregnancy rates, and analysis the correlation between the levels of above growth factors and the outcome of IVF-ET.
Results
1.The concentrations of GH and IGF-1 in serum was significantly higher than follicular fruid(9.01+1.33 VS.2.97±1.75;P=0.000, 111.89±28.54VS.90.19±19.65;P=0.000,respectively).Serum GH level in PCOS patients was higher than low ovarian responsers(P=0.000),but norm ovarian responsers had no significantly differences comparing with the other two groups. Follicular fruid GH levels were no significantly differences among three groups.The serum and follicular fruid IGF-1 levels had significantly differences between each other in the three groups(P<0.001).
2.Endometrial thickness had no significantly differences between each other(P>0.05). Peak E2 levels on the day of HCG injection, doses of gonadotropin requirement,the number of oocytes retrieved,cleavage embroys and 2PN were significantly differences between each other(P<0.05). PCOS womem had more high-quailty embryos than normal and low ovarian responsers. Implantation rates was differences among three groups(P=0.007),implantation rate in low ovarian responsers was lowest ,while the fertilization rates,the pregnancy rates,clinical pregnancy rates,ongoing pregnancy rates,cancellation rates and OHSS rates were lower and spontaneous abortion rate was higher in poor ovarian responsers but had no significantly differences among three groups.
3. No relationship was found between the concentration of GH in serum or follicular fruid and the number of oocytes retrieved,high-quailty embryos,fertilizaton,cleavage embroys , as well as 2PN embroys (P>0.05), However, follicular fruid GH was correlated with implantation rates,while serum and follicular fruid IGF-1 levels were correlated with oocytes retrieved,high-quailty embryos,fertilizaton rate,cleavage embroys,2PN embroys and implantation rates (P>0.05).
4. GH in serum or follicular fruid as well as IGF-1 in serum had no significantly differences between pregnancy group and non pregnancy group,but IGF-1 in follicular fruid had significantly differences between the two groups.
Conclusions
Serum GH and IGF-1 concentrations were statistically significantly higher than in follicular fruid. It is thought that the origin of follicular fruid GH and IGF-1 is through transudation of serum GH and IGF-1 derived from an extraovarian source and through local production in the granulosa cells.Our result fail to show there was difference in the concentrations of GH in serum and follicular fruid between PCOS and normal response patient on day of oocytes retrieved,but these factors were lowest in poor ovarian responsers. No relationship was found between the concentration of GH in serum or follicular fruid and the number of oocytes retrieved,high-quailty embryos,fertilizaton,cleavage embroys , as well as 2PN embroys . However, follicular fruid GH was correlated with implantation rates,while serum and follicular fruid IGF-1 levels were correlated with oocytes retrieved,high-quailty embryos,fertilizaton rate,cleavage embroys,2PN embroys and implantation rates.It means the patients with PCOS didn’t have the diurnal GH、IGF-1 secretion impaired on day of oocyte retrieval,IGF-1 is a good predictor of the ovarian response to COH and IVF outcome.Due to GH secrete characteristic, we need further research to investigate its value as predictor of the ovarian response to COH and IVF outcome.
Objective The aim of this study was to determine whether there were differences in the dose-dependent effects of growth hormone(GH) on estradiol(E_2),progesterone(P),insulin-like growth factor-1(IGF-1) production by luteinized granulosa cells and to detect GH and IGF-1 receptors in human luteinized granulosa cells. Methods Human luteinized granulosa cells(LGC) were isolated from 24 women undergoing in vitro fertilization and embryo transfer (IVF-ET) .Some of the LGCs were used for detecting GH and IGF-1 receptors by immunocytochemistry(SABC method).Most of them were cultured in DMEM/F12 medium with 10% fetal bovine serum(FCS), after 2 days the medium was removed and the cells were incubated with various concentration of GH (0,0.1,0.2 and 0.4mg/ml) in the presence or absence of follicle stimulating hormone( FSH 75IU/ml).Media were collected after 72 hours and E_2,P in media were measured with chemiluminescence immune assay(CLIA)while IGF-1 was measured with enzyme linked immunosorbent assay(ELISA). Results More than 80% of the LGCs were positively stained for GH and IGF-1 receptors . LGCs can autocrine IGF-1,E_2,P at the level of 140.00±27.13ng/ml, 444.67±67.25pg/ml, 655.00±70.07ng/ml without GH or FSH co-culture,GH alone can’t directly stimulate LGCs biosynthesis IGF-1,E_2,and P. However, the combination of GH and FSH can enhance gonadotropin-stimulated steroidogenesis in a significant dose-dependent manner. Conclusions: The main function of GH appeared to synergize with FSH and amplify gonadotropin action and thereby facilitation of granulosa cell replication, differentiation and steroidogenesis directly or indirectly via IGF-1.
引文
1.Jacoba A.M.de Boer, Cornelis B.Lambalk, Heleen H.Hendriks,et.al. Growth hormone secretion is impaired but not related to insulin sensitivity in non-obese patients with polycystic ovary syndrome. Human Reproduction 2004,19: 504-509
2.Orio F Jr, Palomba S, Colao A, GH release after GHRH plus arginine administration in obese and overweight women with polycystic ovary syndrome. J Endocrinol Invest. 2003 Feb;26(2):117-22.
3.Guido M, Romualdi D, Mancini A, Effect of the opioid blockade on the feeding-induced growth hormone response to growth hormone-releasing hormone in women with polycystic ovary syndrome. Fertil Steril. 2002;78(5):994-1000.
4.Lee EJ,Park KH,Lee BS,et,al.Growth hormone response to L-dopa and pyridostigmine in women with policystic ovarian syndrome[J].Fertil Steril,1993,60(2):53-57.
5.王颖,李美芝,杨池荪,等.生长激素在多囊卵巢综合征促排卵中的作用.中华妇产科杂志,2001,36(1),36-39
6.Kaltsas T, Pontikides N, Krassas GE, Effect of gonadotrophin-releasing hormone agonist treatment on growth hormone secretion in women with polycystic ovarian syndrome. Hum Reprod. 1998 13(1):22-6.
7.Iwata H,Ohota M,Hashimoto S,et a1.Stage-specific effect of growth hormone on developmental competence of bovine embryos produced in- vitro.J Reprod Dev,2003,49(6):493-499.
8. Hideya Kodama1,Jun Fukuda,Hiroko Karube,et,al.High incidence of embryo transfer cancellations in patients with polycystic ovarian syndrome.Human Reproduction, 1995,10 :1962-1967,
9.Kucuk T. Growth hormone co-treatment within a GnRH agonist long protocol in patients with poor ovarian response: a prospective, randomized, clinical trial. J Assist Reprod Genet ,2008,25(4): 123-127
10.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,实用医学杂志,2004,20(8):883-884
11.刘冬娥,李艳萍,邬伶仟,等.生长激素辅助促排卵对卵巢低反应患者体外受精-胚胎移植结果的影响,医学临床研究,2006(8) ): 1219-1220
12.Kolle S,Stojkovic M,Reese S,et a1.Effects of growth hormone on the uhrastructure of bovine preimplantation embryos.[J] Cell Tissue Res, 2004,317(1):101—108.
13.Hull KL,Harvey S. Growth hormone:roles in femal reproduction.J Endocrinol,2001,168:1-23 .
14.赵海波,罗丽兰,刘义.胰岛素样生长因子-1在体外对人卵巢颗粒细胞雌二醇和孕酮产生量及超微结构的影响.中华妇产科杂志1998,33(9)546-548.
15.杨雪,周从容.胰岛素样生长因子-Ⅱ对人颗粒细胞分泌功能的影响.中国计划生育学杂志2006,9:541-543.
16.Katherine D. Schoyer, Hung-Ching Liu, Steven Witkin,et,al.Serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) in IVF patients with polycystic ovary syndrome: correlations with outcome. Fertil Steril,2007;88:139–44.
17.Mendoza C, Ruiz-Requena E, Ortega E, Cremades N, Martinez F,Bernabeu R. Follicular fluid markers of oocyte developmental potential. Hum Reprod 2002;17:1017–22.
18.Kolibianakis, Venetis, Diedrich,et,al.Addition of growth hormone to gonadotrophins in ovarian stimulation of poor responders treated by in vitro fertilization: a systematic review and meta-analysis. Human Reproduction Update, 2009,15(6) 613–622.
19.Kyrou D, Kolibianakis EM, Venetis CA, Papanikolaou EG, Bontis J,Tarlatzis BC. How to improve the probability of pregnancy in poor responders undergoing in vitro fertilization: a systematic review and meta-analysis. Fertil Steril 2009;91:749–766.
20.Adashi EY, Reznick CE, May JV, Knecht M, Svoboda ME, Van WykJJ. Somatomedin C/insulin-like growth factor I as an amplifier of follicle-stimulating hormone action: studies on mechanism(s) and site(s) of action in cultured granulosa cells. Endocrinology 1988;122:1583–92.
21.Demeestere I, Gervy C, Centner J, et al. Effect of insulin-like growth factor-I during preantral follicular culture on steroidogenesis, in vitro oocyte maturation, and embryo development in mice. Biol Reprod, 2004; 70:1664-9.
22.Pellegrini S, Fuzzi B, Pratesi S, Mannelli M, Criscuoli L, Messeri G et,al. In-vivo studies on ovarian insulin-like growth factor I concentrations in human preovulatory follicles and human ovarian circulation. Hum Reprod 1995;10:1341–5.
23.Rabinovici J, Dandekar P, Angle MJ, Rosenthal S, Martin MC. Insulin-like growth factor I (IGF-I) levels in follicular ?uid from human revelatory follicles: correlation with serum IGF-I levels. Fertil Steril,1990;54:428–33.
24.Erickson GF, Garzo VG, Magoffin DA. Insulin-like factor-1 regulates aromatase activity in human granulosa and granulosa luteal cells. J Clin Endocrinol Metab 1989; 69:716-24.
25.Mason HD, Martikainen H, Beard RW, Anyaoku V, Franks S. Direct gonadotropic effect of growth hormone on oestradiol production by the human granulosa cell in vitro. J Endocrinol 1990; 126:R1-4.
1.Hull KL,Harvey S. Growth hormone:roles in femal reproduction.J Endocrinol,2001,168:1-23 .
2.Gregoraszeczuk E L,Bylica A,Gertler A.Response of porcine theca and granulosa cells to GH during short-time in vitro culture [J].Anim Reprod Sci.2000,28:58(1-2):113-125.
3. Slot K A,Kastelijn J,Bachelot A,et al.Reduced recruitment and survival of primordial and growing follicles in GH receptor-deficient mice[J].Reproduction,2006,131(3):525-532
4.Mendoza C, Cremades N,Ruiz-Requena E,et,al.Relationship between fertilization results after intracytoplasmic sperm injection,and intrafoliicular steroid,pituitary hormone and cytokine concentration[J].Human Reprod,1999,14:628-635
5.Anne B . Pllilippe M . Growth hormone is required for ovarian folliculiar growth[J].Endocrinology,2000,143(10):4104-4112.
6.Jacoba A.M.de Boer, Cornelis B.Lambalk, Heleen H.Hendriks,et.al. Growth hormone secretion is impaired but not related to insulin sensitivity in non-obese patients with polycystic ovary syndrome. Human Reproduction 2004,19: 504-509
7.Orio F Jr, Palomba S, Colao A, GH release after GHRH plus arginine administration in obese and overweight women with polycystic ovary syndrome. J Endocrinol Invest. 2003 Feb;26(2):117-22.
8.Guido M, Romualdi D, Mancini A, Effect of the opioid blockade on the feeding-induced growth hormone response to growth hormone-releasing hormone in women with polycystic ovary syndrome. Fertil Steril. 2002;78(5):994-1000.
9.Lee EJ,Park KH,Lee BS,et,al.Growth hormone response to L-dopa and pyridostigmine in women with policystic ovarian syndrome[J].Fertil Steril,1993,60(2):53-57.
10.王颖,李美芝,杨池荪,等.生长激素在多囊卵巢综合征促排卵中的作用.中华妇产科杂志,2001,36(1),36-39
11.Kirsimarja Sallinen,Xiao-ke Wu,Shan-ying Zhou,et,al.Androgen excess contributes to altered growth hormone/insulin-like growth factor-1 axis in nonobese women with policystic ovary syndrome[J]Fertil Steril,1000,73(4):730-734.
12.Kaltsas T, Pontikides N, Krassas GE, Effect of gonadotrophin-releasing hormone agonist treatment on growth hormone secretion in women with polycystic ovarian syndrome. Hum Reprod. 1998 13(1):22-6.
13.赵海波,罗丽兰,刘义.胰岛素样生长因子-1在体外对人卵巢颗粒细胞雌二醇和孕酮产生量及超微结构的影响.中华妇产科杂志1998,33(9)546-548.
14.杨雪,周从容.胰岛素样生长因子-Ⅱ对人颗粒细胞分泌功能的影响.中国计划生育学杂志2006,9:541-543.
15.Kucuk T. Growth hormone co-treatment within a GnRH agonist long protocol in patients with poor ovarian response: a prospective, randomized, clinical trial. J Assist Reprod Genet ,2008,25(4): 123-127
16.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,实用医学杂志,2004,20(8):883-884
17.刘冬娥,李艳萍,邬伶仟,等.生长激素辅助促排卵对卵巢低反应患者体外受精-胚胎移植结果的影响,医学临床研究,2006(8) ): 1219-1220
18.Kolle S,Stojkovic M,Reese S,et a1.Effects of growth hormone on the uhrastructure of bovine preimplantation embryos.[J] Cell Tissue Res, 2004,317(1):101—108.
19.Tesarik J,Hazout A,Mendoza C. Improvement of delivery and live birth rates after ICSI in women aged>40 years by ovarian costimulation with growth hormone [J].Hum Reprod,2005,2O(9):2536- 2541
20.Tansu Kucuk, Hakan Kozinoglu, Ayten Kaba.Growth hormone co-treatment within a GnRH agonist long protocol in patients with poor ovarian response:a prospective, randomized, clinical trial.J Assist Reprod Genet (2008) 25:123–127
1. Buyalos,R.P.(1995)Insulin-like growth factors:clinical experience in ovarian function.Am,J.Med.,98(SUPPL.1A),1A-55S-1A-66S.
2. Sharara,F,I and Nieman,L,K, Identification and cellular localization of growth hormone receptor gene expression in the human ovary.J.Clin.Endocrinol,Metab. (1994),79,670-672.
3. Davoren,J.B. and Hsueh,A.J.W.Growrh hormone increase levels of immunoreactiv smatomdin C/insulin-like growth factor in vivo.Endocrinology,1986,118,888-890.
4. Daughaday,W.H. and Rotwein,P. Insulin-like growth factors I and II.Peptide,messenger ribonucleic acid and gene structures,serum and tissue concentration.Endocr.Rev.1989,10,68-92.
5. Per Ovesen. Synergistic effects of growth hormone and insulin-like growth factor-I on differentiation and replication of cultured human luteinized granulosa cells. Acta Obstet Gynecol Scand 1998; 77: 487–491.
6. Joana Penarrubia,Juan Balasch,Mercedes Garcia-Bermudez,et al.Growth hormone does not increase the expression of insulin-like growth factors and their receptor genes in the pre-menppausal human ovary.Human Reproduction,2000,15,1241-1246.
7. Ben-Ami I, Freimann S, Armon L, Dantes A, Ron-El R, Amsterdam A.Novel function of ovarian growth factors: combined studies by DNA microarray, biochemical and physiological approaches. Molecular Hum Reprod 2006;12:413–9.
8. Fleming JM, Desury G, Polanco TA, CohickWS. Insulin growth factor-I and epidermal growth factor receptors recruit distinct upstream signaling molecules to enhanceAKTactivation inmammary epithelial cells. Endocrinology 2006;147:6027–35.
9.Akira Iwase,Maki Goto,Toko Harata,et,al.Insulin Attenuates the Insulin-like Growth Factor-1-Akt Pathway,not IGF-1-Extracelluarly Regulated Kinase Pathway,in Luteinized Granulosa Cell with an incease in PTEN.U Clin Endocrine Metab,2009,94:2184-2191.
10.Hu CL,Cowan RG,Harman Rmet,al.Cell cycle progression and activation of Akt kinase are required for insulin-like growth factor-1 mediated supression of apoptosis ingranulose cells.Mol Endocrinol,2004,18:326-338.
11.Bergh C, Nilsson L, Hillensjo T, Borg G,WiklandM, Hamberger L. Adjuvant growth hormone treatment during in vitro fertilization: a randomized, placebo-controlled study. Fertil Steril 1994;62:113–20.
12. Rabinovici J, Cataldo NA, Dandekar P, Rosenthal SM, Gargosky SE,Gesundheit N, et al. Adjunctive growth hormone during ovarian hyperstimulation increases levels of insulin-like growth factor binding proteinsin follicular ?uid: a randomized, placebo-controlled, cross-over study.J Clin Endocrinol Metab 1997;82:1171–6.
13.Penarrubia J, Balasch J, Garcia-BermudezM, Casamitjana R, Vanrell JA,Hernandez ER. Growth hormone does not increase the expression of insulin-like growth factors and their receptor genes in the pre-menopausal human ovary. Hum Reprod 2000;15:1241–6.
14.Spiliotis B. Growth hormone insufficiency and its impact on ovarian function. Ann NYAcad Sci 2003;997:77–84.
15.Toshiaki Taketani,Yoshiaki Yamagata,Akihisa Takasaki,et,al. Effects of growth hormone and insulin-like growth factor 1 on progesterone production in human luteinized granulosa cells. Fertil Steril,2008;90:744–8.
16.Villavicencio A, IniguezG, JohnsonMC, Gabler F, PalominoA, VegaM.Regulation of steroid synthesis and apoptosis by insulin-like growth factor I and insulin-like growth factor binding protein 3 in human corpus luteum during the midluteal phase. Reproduction 2002;124:501–8.
17.Barreca A, Artini PG, Monte PD, Ponzani P, Pasquini P, Cariola G, et al.In vivo and in vitro effect of growth hormone on estradiol secretion by human granulosa cells. J Clin Endocrinol Metab 1993;77:61–7.
2.Orio F Jr, Palomba S, Colao A, GH release after GHRH plus arginine administration in obese and overweight women with polycystic ovary syndrome. J Endocrinol Invest. 2003 Feb;26(2):117-22.
3.Guido M, Romualdi D, Mancini A, Effect of the opioid blockade on the feeding-induced growth hormone response to growth hormone-releasing hormone in women with polycystic ovary syndrome. Fertil Steril. 2002;78(5):994-1000.
4.Lee EJ,Park KH,Lee BS,et,al.Growth hormone response to L-dopa and pyridostigmine in women with policystic ovarian syndrome[J].Fertil Steril,1993,60(2):53-57.
5.王颖,李美芝,杨池荪,等.生长激素在多囊卵巢综合征促排卵中的作用.中华妇产科杂志,2001,36(1),36-39
6.Kaltsas T, Pontikides N, Krassas GE, Effect of gonadotrophin-releasing hormone agonist treatment on growth hormone secretion in women with polycystic ovarian syndrome. Hum Reprod. 1998 13(1):22-6.
7.Iwata H,Ohota M,Hashimoto S,et a1.Stage-specific effect of growth hormone on developmental competence of bovine embryos produced in- vitro.J Reprod Dev,2003,49(6):493-499.
8. Hideya Kodama1,Jun Fukuda,Hiroko Karube,et,al.High incidence of embryo transfer cancellations in patients with polycystic ovarian syndrome.Human Reproduction, 1995,10 :1962-1967,
9.Kucuk T. Growth hormone co-treatment within a GnRH agonist long protocol in patients with poor ovarian response: a prospective, randomized, clinical trial. J Assist Reprod Genet ,2008,25(4): 123-127
10.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,实用医学杂志,2004,20(8):883-884
11.刘冬娥,李艳萍,邬伶仟,等.生长激素辅助促排卵对卵巢低反应患者体外受精-胚胎移植结果的影响,医学临床研究,2006(8) ): 1219-1220
12.Kolle S,Stojkovic M,Reese S,et a1.Effects of growth hormone on the uhrastructure of bovine preimplantation embryos.[J] Cell Tissue Res, 2004,317(1):101—108.
13.Hull KL,Harvey S. Growth hormone:roles in femal reproduction.J Endocrinol,2001,168:1-23 .
14.赵海波,罗丽兰,刘义.胰岛素样生长因子-1在体外对人卵巢颗粒细胞雌二醇和孕酮产生量及超微结构的影响.中华妇产科杂志1998,33(9)546-548.
15.杨雪,周从容.胰岛素样生长因子-Ⅱ对人颗粒细胞分泌功能的影响.中国计划生育学杂志2006,9:541-543.
16.Katherine D. Schoyer, Hung-Ching Liu, Steven Witkin,et,al.Serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) in IVF patients with polycystic ovary syndrome: correlations with outcome. Fertil Steril,2007;88:139–44.
17.Mendoza C, Ruiz-Requena E, Ortega E, Cremades N, Martinez F,Bernabeu R. Follicular fluid markers of oocyte developmental potential. Hum Reprod 2002;17:1017–22.
18.Kolibianakis, Venetis, Diedrich,et,al.Addition of growth hormone to gonadotrophins in ovarian stimulation of poor responders treated by in vitro fertilization: a systematic review and meta-analysis. Human Reproduction Update, 2009,15(6) 613–622.
19.Kyrou D, Kolibianakis EM, Venetis CA, Papanikolaou EG, Bontis J,Tarlatzis BC. How to improve the probability of pregnancy in poor responders undergoing in vitro fertilization: a systematic review and meta-analysis. Fertil Steril 2009;91:749–766.
20.Adashi EY, Reznick CE, May JV, Knecht M, Svoboda ME, Van WykJJ. Somatomedin C/insulin-like growth factor I as an amplifier of follicle-stimulating hormone action: studies on mechanism(s) and site(s) of action in cultured granulosa cells. Endocrinology 1988;122:1583–92.
21.Demeestere I, Gervy C, Centner J, et al. Effect of insulin-like growth factor-I during preantral follicular culture on steroidogenesis, in vitro oocyte maturation, and embryo development in mice. Biol Reprod, 2004; 70:1664-9.
22.Pellegrini S, Fuzzi B, Pratesi S, Mannelli M, Criscuoli L, Messeri G et,al. In-vivo studies on ovarian insulin-like growth factor I concentrations in human preovulatory follicles and human ovarian circulation. Hum Reprod 1995;10:1341–5.
23.Rabinovici J, Dandekar P, Angle MJ, Rosenthal S, Martin MC. Insulin-like growth factor I (IGF-I) levels in follicular ?uid from human revelatory follicles: correlation with serum IGF-I levels. Fertil Steril,1990;54:428–33.
24.Erickson GF, Garzo VG, Magoffin DA. Insulin-like factor-1 regulates aromatase activity in human granulosa and granulosa luteal cells. J Clin Endocrinol Metab 1989; 69:716-24.
25.Mason HD, Martikainen H, Beard RW, Anyaoku V, Franks S. Direct gonadotropic effect of growth hormone on oestradiol production by the human granulosa cell in vitro. J Endocrinol 1990; 126:R1-4.
1.Hull KL,Harvey S. Growth hormone:roles in femal reproduction.J Endocrinol,2001,168:1-23 .
2.Gregoraszeczuk E L,Bylica A,Gertler A.Response of porcine theca and granulosa cells to GH during short-time in vitro culture [J].Anim Reprod Sci.2000,28:58(1-2):113-125.
3. Slot K A,Kastelijn J,Bachelot A,et al.Reduced recruitment and survival of primordial and growing follicles in GH receptor-deficient mice[J].Reproduction,2006,131(3):525-532
4.Mendoza C, Cremades N,Ruiz-Requena E,et,al.Relationship between fertilization results after intracytoplasmic sperm injection,and intrafoliicular steroid,pituitary hormone and cytokine concentration[J].Human Reprod,1999,14:628-635
5.Anne B . Pllilippe M . Growth hormone is required for ovarian folliculiar growth[J].Endocrinology,2000,143(10):4104-4112.
6.Jacoba A.M.de Boer, Cornelis B.Lambalk, Heleen H.Hendriks,et.al. Growth hormone secretion is impaired but not related to insulin sensitivity in non-obese patients with polycystic ovary syndrome. Human Reproduction 2004,19: 504-509
7.Orio F Jr, Palomba S, Colao A, GH release after GHRH plus arginine administration in obese and overweight women with polycystic ovary syndrome. J Endocrinol Invest. 2003 Feb;26(2):117-22.
8.Guido M, Romualdi D, Mancini A, Effect of the opioid blockade on the feeding-induced growth hormone response to growth hormone-releasing hormone in women with polycystic ovary syndrome. Fertil Steril. 2002;78(5):994-1000.
9.Lee EJ,Park KH,Lee BS,et,al.Growth hormone response to L-dopa and pyridostigmine in women with policystic ovarian syndrome[J].Fertil Steril,1993,60(2):53-57.
10.王颖,李美芝,杨池荪,等.生长激素在多囊卵巢综合征促排卵中的作用.中华妇产科杂志,2001,36(1),36-39
11.Kirsimarja Sallinen,Xiao-ke Wu,Shan-ying Zhou,et,al.Androgen excess contributes to altered growth hormone/insulin-like growth factor-1 axis in nonobese women with policystic ovary syndrome[J]Fertil Steril,1000,73(4):730-734.
12.Kaltsas T, Pontikides N, Krassas GE, Effect of gonadotrophin-releasing hormone agonist treatment on growth hormone secretion in women with polycystic ovarian syndrome. Hum Reprod. 1998 13(1):22-6.
13.赵海波,罗丽兰,刘义.胰岛素样生长因子-1在体外对人卵巢颗粒细胞雌二醇和孕酮产生量及超微结构的影响.中华妇产科杂志1998,33(9)546-548.
14.杨雪,周从容.胰岛素样生长因子-Ⅱ对人颗粒细胞分泌功能的影响.中国计划生育学杂志2006,9:541-543.
15.Kucuk T. Growth hormone co-treatment within a GnRH agonist long protocol in patients with poor ovarian response: a prospective, randomized, clinical trial. J Assist Reprod Genet ,2008,25(4): 123-127
16.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,实用医学杂志,2004,20(8):883-884
17.刘冬娥,李艳萍,邬伶仟,等.生长激素辅助促排卵对卵巢低反应患者体外受精-胚胎移植结果的影响,医学临床研究,2006(8) ): 1219-1220
18.Kolle S,Stojkovic M,Reese S,et a1.Effects of growth hormone on the uhrastructure of bovine preimplantation embryos.[J] Cell Tissue Res, 2004,317(1):101—108.
19.Tesarik J,Hazout A,Mendoza C. Improvement of delivery and live birth rates after ICSI in women aged>40 years by ovarian costimulation with growth hormone [J].Hum Reprod,2005,2O(9):2536- 2541
20.Tansu Kucuk, Hakan Kozinoglu, Ayten Kaba.Growth hormone co-treatment within a GnRH agonist long protocol in patients with poor ovarian response:a prospective, randomized, clinical trial.J Assist Reprod Genet (2008) 25:123–127
1. Buyalos,R.P.(1995)Insulin-like growth factors:clinical experience in ovarian function.Am,J.Med.,98(SUPPL.1A),1A-55S-1A-66S.
2. Sharara,F,I and Nieman,L,K, Identification and cellular localization of growth hormone receptor gene expression in the human ovary.J.Clin.Endocrinol,Metab. (1994),79,670-672.
3. Davoren,J.B. and Hsueh,A.J.W.Growrh hormone increase levels of immunoreactiv smatomdin C/insulin-like growth factor in vivo.Endocrinology,1986,118,888-890.
4. Daughaday,W.H. and Rotwein,P. Insulin-like growth factors I and II.Peptide,messenger ribonucleic acid and gene structures,serum and tissue concentration.Endocr.Rev.1989,10,68-92.
5. Per Ovesen. Synergistic effects of growth hormone and insulin-like growth factor-I on differentiation and replication of cultured human luteinized granulosa cells. Acta Obstet Gynecol Scand 1998; 77: 487–491.
6. Joana Penarrubia,Juan Balasch,Mercedes Garcia-Bermudez,et al.Growth hormone does not increase the expression of insulin-like growth factors and their receptor genes in the pre-menppausal human ovary.Human Reproduction,2000,15,1241-1246.
7. Ben-Ami I, Freimann S, Armon L, Dantes A, Ron-El R, Amsterdam A.Novel function of ovarian growth factors: combined studies by DNA microarray, biochemical and physiological approaches. Molecular Hum Reprod 2006;12:413–9.
8. Fleming JM, Desury G, Polanco TA, CohickWS. Insulin growth factor-I and epidermal growth factor receptors recruit distinct upstream signaling molecules to enhanceAKTactivation inmammary epithelial cells. Endocrinology 2006;147:6027–35.
9.Akira Iwase,Maki Goto,Toko Harata,et,al.Insulin Attenuates the Insulin-like Growth Factor-1-Akt Pathway,not IGF-1-Extracelluarly Regulated Kinase Pathway,in Luteinized Granulosa Cell with an incease in PTEN.U Clin Endocrine Metab,2009,94:2184-2191.
10.Hu CL,Cowan RG,Harman Rmet,al.Cell cycle progression and activation of Akt kinase are required for insulin-like growth factor-1 mediated supression of apoptosis ingranulose cells.Mol Endocrinol,2004,18:326-338.
11.Bergh C, Nilsson L, Hillensjo T, Borg G,WiklandM, Hamberger L. Adjuvant growth hormone treatment during in vitro fertilization: a randomized, placebo-controlled study. Fertil Steril 1994;62:113–20.
12. Rabinovici J, Cataldo NA, Dandekar P, Rosenthal SM, Gargosky SE,Gesundheit N, et al. Adjunctive growth hormone during ovarian hyperstimulation increases levels of insulin-like growth factor binding proteinsin follicular ?uid: a randomized, placebo-controlled, cross-over study.J Clin Endocrinol Metab 1997;82:1171–6.
13.Penarrubia J, Balasch J, Garcia-BermudezM, Casamitjana R, Vanrell JA,Hernandez ER. Growth hormone does not increase the expression of insulin-like growth factors and their receptor genes in the pre-menopausal human ovary. Hum Reprod 2000;15:1241–6.
14.Spiliotis B. Growth hormone insufficiency and its impact on ovarian function. Ann NYAcad Sci 2003;997:77–84.
15.Toshiaki Taketani,Yoshiaki Yamagata,Akihisa Takasaki,et,al. Effects of growth hormone and insulin-like growth factor 1 on progesterone production in human luteinized granulosa cells. Fertil Steril,2008;90:744–8.
16.Villavicencio A, IniguezG, JohnsonMC, Gabler F, PalominoA, VegaM.Regulation of steroid synthesis and apoptosis by insulin-like growth factor I and insulin-like growth factor binding protein 3 in human corpus luteum during the midluteal phase. Reproduction 2002;124:501–8.
17.Barreca A, Artini PG, Monte PD, Ponzani P, Pasquini P, Cariola G, et al.In vivo and in vitro effect of growth hormone on estradiol secretion by human granulosa cells. J Clin Endocrinol Metab 1993;77:61–7.