FSH及其受体基因多态性与男性精子发生相关性

卵泡刺激素(FSH)是一种由脑垂体合成并分泌的激素,与支持细胞膜上的FSH受体(FSHR)结合,提高支持细胞合成雄激素结合蛋白的水平,同时分泌抑制素,在生精过程中起到至关重要的作用。随着DNA测序技术的发展,检测到FSH基因单核苷酸多态性(SNP)rs10835638和FSHR基因SNPs rs6165,rs6166,rs1394205,这些SNPs可能直接影响FSH表达水平和FSHR的活性,在男性主要表现为精子发生障碍。本文综述FSH及FSHR基因多态性与男性精子发生的相关性。     

卵泡刺激素受体研究进展

卵泡刺激素 (FSH)是哺乳动物重要的生殖激素 ,其生理作用是通过其受体 (FSHR)介导的。FSHR属于G蛋白偶联受体超家族中的糖蛋白亚家族成员 ,它的细胞外域具有FSH特异性结合位点 ,细胞外域有 3或 4个潜在的糖基化位点 ,这些糖基对受体的折叠及转运激素至膜表面是必须的 ;其跨膜域参与蛋白激酶A(PKA)介导的信号转导 ,启动受体活化后的胞内事件 ;受体的脱敏可导致受体解偶联和受体数量下调。大多数哺乳动物FSHRcDNA开放阅读框由 2 0 85个核苷酸构成 ,人和大鼠FSHR基因为单拷贝基因 ,它包含 1 0个外显子和 9个内含子 ,其 5’侧翼区缺乏规则的TAT或CCAAT启动子元件 ,在 3’末端非翻译区含有 2个推断的多聚腺苷酸信号。FSHR存在活性突变和非活性突变 ,FSHR不足可导致原发性不育     

卵巢早衰小鼠中抗苗勒管激素与卵泡刺激素受体相关性的研究

目的探讨卵巢早衰(POF)小鼠中抗苗勒管激素(AMH)与卵泡刺激素受体(FSHR)的关系。方法以小鼠透明带3(ZP3)的第330～342个氨基酸序列所合成的透明带多肽为免疫原,免疫SPF级Balb/c雌性小鼠,皮下多点注射建立POF模型。放射免疫法测定模型组及对照组小鼠外周血FSH、雌二醇(E_2)的水平,酶联免疫法测定外周血AMH、抗透明带抗体(AzpAb)的水平,HE染色观察卵巢组织的变化,并用免疫组化方法分析卵巢颗粒细胞中FSHR的表达。结果 POF小鼠较正常小鼠外周血的FSH升高,E_2值降低,AMH值降低,AzpAb值升高。POF小鼠卵巢的HE染色病理切片见卵泡闭锁,正常发育的卵泡甚少。免疫组化分析,FSHR仅在颗粒细胞上表达,且POF小鼠卵巢上FSHR的表达明显少于正常组。结论 FSHR仅在颗粒细胞上表达,POF小鼠中各级卵泡的FSHR表达均降低,POF小鼠伴低浓度AMH,且FSHR的表达随AMH降低亦降低。     

精子发生的激素调节

长期以来一致公认 ,垂体促性腺激素——卵泡刺激素 ( FSH)和黄体生成素 ( L H)所介导的睾酮 ( T)是所有哺乳动物和人类精子发生的主要调节物。然而 ,近年来大量的动物实验和一些临床研究结果对上述观点提出了至少两方面的挑战。一方面 ,睾丸产生的相当数量的雌激素也是精子发生和成熟的必须激素。因为敲除雌激素两种受体基因 ( ERαKO、ERβKO)或敲除芳香化酶基因 ( Ar KO)的雄性小白鼠均出现多种生殖功能障碍或不育。临床上也出现了因 ERα基因突变而不育的个别报道 ;另一方面 ,发现了至少已有 5例因 FSH受体 ( FSHR)基因或FSH…     

卵泡刺激素受体主动免疫对雄性小鼠生育力影响的初步研究

探索卵泡刺激素受体 (FSHR)作为男性免疫避孕疫苗的可能性。利用分子生物学方法克隆表达卵泡刺激素受体 -谷胱甘肽转硫酶 (FSHR- GST)融合蛋白 ,以此作为免疫原免疫雄性小鼠 ,观察免疫应答反应及其对生育力的影响。结果表明 ,在大肠杆菌中表达出 FSHR- GST融合蛋白 ,免疫家兔及小鼠后均产生免疫应答 ,免疫后的雄性小鼠仍具生育能力 ,免疫小鼠睾丸精曲小管出现生精细胞减少现象。提示 FSHR主动免疫对雄性小鼠生育力无影响     

控制性超排卵中低LH的发生及其结局与特殊类型病例LH添加治疗

<正> 在女性的卵巢周期中,卵泡的正常发育是由垂体分泌的卵泡刺激素(FSH)和黄体生成素(LH)两种激素控制的,两者对于正常卵泡雌二醇(E_2)的生物合成均有重要作用,也就是所谓的"两种细胞,两种促性腺激素"学说,即FSH刺激卵泡发育,LH结合于卵泡膜细胞上的受体,激发雄激素前体从膜细     

促性腺激素释放激素激动剂降调对垂体内外的影响

降调是促激素下调自身的受体以调节靶组织对激素的反应性,是促激素调节其自身作用的机制之一.除受体的升调和降调外,促激素还可通过自分泌/旁分泌、激素的异质性来调节自身的作用.降调的机制是通过受体与调节亚单位G蛋白解耦联、受体内在化进入细胞、以及腺苷酸环化酶的调节和催化亚单位解耦联3种途径来实现的.降调对卵泡刺激素(FSH)和黄体生成素(LH)的直接作用是使40％～60％的FSH分泌受到抑制,而90％的LH分泌受到抑制,目的是抑制过早内源性LH峰.降调对FSH、LH旁分泌调节的作用需要通过FSH和LH发挥作用,旁分泌调节因子本身并没有促使卵泡发育的作用.由于类固醇激素的负反馈是通过下丘脑垂体发挥作用,而降调是在促性腺激素释放激素(GnRH)的受体水平,因此取消了类固醇激素正常的正负反馈.由于卵巢颗粒细胞、膜细胞、黄体细胞均有GnRH受体,理论上推测GnRH对卵巢可能有直接作用.动物实验及体外试验均提示GnRH对卵巢颗粒细胞有直接作用,体现在类固醇的合成和卵泡的发育两方面.因此,促性腺激素释放激素激动剂(GnRH-a)提高妊娠率的作用除了来自于抑制过早LH峰,降低过高LH的不利作用外,还可能来自GnRH-a对卵泡发育、卵母细胞成熟、子宫内膜的容受性等直接作用,但目前的研究方法尚无法证实.     

卵泡中期黄体生成素水平对体外受精-胚胎移植治疗中卵巢反应和妊娠结局的影响

正常卵泡发育受垂体分泌的黄体生成素(LH)、卵泡刺激素(FSH)调控,LH在诱导卵泡生长和发育的相对重要性目前仍存争议。促性腺激素正常妇女在体外受精-胚胎移植(IVF-ET)周期用促性腺激素释放激素激动剂(GnRH-a)降调节后予重组人卵泡刺激素(rhFSH)超促排卵过程中卵泡中期LH水平是否影响IVF-ET结果,是否需添加外源性LH是当前研究的热点。本研究回顾性分析120例患者卵泡中期LH水平,报道如下。一、资料和方法1·对象:为2003年5月至2005年4月在我院生殖医学中心行IVF-ET或卵胞浆内单精子注射(ICSI)治疗患者共120例。纳入标准:患者…     

不同剂量FSH进行控制性卵巢刺激的结局

<正> 控制性卵巢刺激(controlled ovarian stimulation,COS)是通过适当的刺激方案和促性腺激素(Gn)的剂量达到理想的卵巢反应和妊娠结局,这是体外受精-胚胎移植(IVF-ET)技术的重要部分。COS的目的是期望获得理想的卵泡数、成熟卵母细胞数,增加可供移植胚胎数及胚胎冻存的机会,最终达到提高临床妊娠率的目的。Gn中的卵泡刺激素(FSH)在卵泡选择和优势卵泡的发育过程中起重     

促排卵中卵泡刺激素的最大值

在促排卵过程中,卵泡的发育不仅取决于卵泡刺激素(FSH)的剂量,还取决于基础窦卵泡数,窦卵泡中颗粒细胞数量,颗粒细胞表面FSH受体的质量以及卵母细胞的质量.当FSH剂量达到阈值后,卵泡发育的关键就取决于窦卵泡数和卵泡发育的内在因素.窦卵泡在正常范围内,增加剂量可能增加获卵数,但并不增加妊娠率,因此促性腺激素(Gn)剂量只要超过需要卵泡数的阈值即可,一般建议为150～225 IU;而卵巢反应不良的患者,由于卵巢内能对FSH发生反应的小窭卵泡数减少,而且卵泡颗粒细胞和FSH受体数量下降,对FSH反应不敏感,因此增加剂量不能增加获卵数.系统综述、前瞻对照研究和回顾性研究结果均提示,FSH＞300 IU不能增加获卵数和妊娠率,因此对卵巢反应不良患者建议的最大FSH剂量为300 IU/d.     

胰岛素对卵巢颗粒细胞黄体生成素/绒毛膜促性腺激素受体表达的影响

目的 :研究胰岛素 ( INS)对猪卵巢颗粒细胞黄体生成素 /绒毛膜促性腺激素( L H/ CG)受体表达的影响 ,探讨高胰岛素血症可能在多囊卵巢综合征 ( PCOS)卵泡发育停滞中的作用。方法 :采用逆转录聚合酶链反应 ( RT-PCR)及其蛋白免疫印迹 ( Westernblot)法分别对加药处理的 4组猪卵巢颗粒细胞检测 LH/ CG受体的 m RNA及其蛋白表达。结果 :RT-PCR结果表明卵泡刺激素 ( FSH) +INS组 ( 0 .2 47± 0 .0 44)与 FSH组( 0 .1 61± 0 .0 2 3 )相比 L H/ CG受体 m RNA表达明显增强 ( P<0 .0 5) ;FSH+L H+INS组( 0 .2 40± 0 .0 3 0 )与 FSH+L H组 ( 0 .1 2 1± 0 .0 1 3 )相比 ,L H/ CG受体 m RNA表达明显增强 ( P <0 .0 1 )。 Western blot结果表明 FSH +INS组 ( 570 2 .3± 81 5.9)、与 FSH组( 3 81 3 .0± 3 48.5)相比 L H/ CG受体蛋白表达明显增强 ( P<0 .0 5) ;FSH+L H+INS组( 5898.8± 93 3 .8)与 FSH+L H组 ( 2 42 1 .0± 3 41 .5)相比 L H/ CG受体蛋白表达明显增强 ( P<0 .0 1 )。结论 :INS可以协同 FSH及 L H增强卵巢颗粒细胞 L H/ CG受体的表达 ,推测高胰岛素可能通过增强 L H+CG受体表达使 PCOS患者发育至窦状卵泡阶段的卵泡颗粒细胞过早黄素化 ,导致卵泡发育停滞。     

不同日龄小鼠卵丘颗粒细胞对卵泡刺激素/缺氧诱导因子-1信号通路的影响

目的研究不同日龄小鼠颗粒细胞对卵泡刺激素(FSH)诱导的缺氧诱导因子-1/血管内皮细胞生长因子(HIF-1/VEGF)信号通路的影响。方法超排卵方法取出卵母细胞和颗粒细胞,进行体外受精;荧光素酶报告基因实验检测常氧和低氧培养条件下,不同日龄小鼠卵丘颗粒细胞对FSH诱导的HIF-1/VEGF信号通路的应答;蛋白质免疫印迹技术检测FSH受体的表达水平。结果雌性小鼠超排卵数和卵母细胞体外受精能力与小鼠日龄数呈负相关;FSH上调小鼠卵丘颗粒细胞HIF-1α的转录活性;免疫印迹结果显示小鼠颗粒细胞中FSH受体的表达水平随着日龄数的增加呈下降趋势。结论小鼠卵丘颗粒细胞对FSH诱导的HIF-1/VEGF信号通路的应答反应随小鼠天日龄数增加而下降,与颗粒细胞表面FSH受体的表达下降相一致。雌性小鼠随着年龄增加引起的生殖能力下降可能与颗粒细胞表面FSH受体表达减少有关。     

Identification of a potential FSH modulatory protein in human testis and seminal plasma

A variety of factors capable of inhibiting the in vitro binding of FSH to its receptor have been identified in gonadal tissues from males and females. Interest in these factors has been stimulated because of their potential role as local modulators of gonadotropin action. Studies reported here were undertaken to determine if proteins having antigenic homologies with human FSH or an "FSH-like" protein isolated from porcine follicular fluid were present in human testicular tissue or seminal plasma. Polyclonal antibodies were generated against fractions of porcine follicular fluid containing FSH receptor binding inhibitory activity, FSH agonist activity in vitro, and a 58,000 Mr protein recognized by human FSH antiserum. Antiserum against this fraction of porcine follicular fluid and antiserum against human FSH were used to probe Western blots of proteins from human testis homogenates or seminal plasma. A 58,000 Mr protein was identified in both human testis extract and seminal plasma. This protein appears to be related antigenically to both human FSH and the 58,000 Mr "FSH-like" protein in porcine follicular fluid. It does not appear to be a metabolic degradatory product of human FSH since the protein is larger than FSH, does not dissociate into subunits under reducing conditions and is recognized by the antiserum to FSH-like protein that does not recognize human FSH. These data identify a 58,000 Mr protein in human testis and seminal plasma that may represent a local modulator of FSH action in the testis.     

猪卵巢周期中卵泡刺激素和黄体生成素受体mRNA的定位及表达

以周期化的猪卵巢为标本，进行Ｎｏｒｔｈｅｒｎ和原位杂交，观察周期第０、４、７、１２和１６天猪卵泡刺激素（ＦＳＨ）和黄体生成素（ＬＨ）受体ｍＲＮＡ的分布和表达。结果：ＦＳＨ受体ｍＲＮＡ的转录模式在周期第０、４、７、１２和１６天中均为３个片段（４．２、３．５和２．４ｋｂ）；ＬＨ受体ｍＲＮＡ表达多个共同片段（１０．０、６．８、５．９、４．７、３．８、２．５和１．５ｋｂ）。ＦＳＨ受体ｍＲＮＡ的表达在未成熟和成熟卵泡仅定位于卵巢颗粒细胞和卵丘细胞；促性腺激素峰值期，在未成熟卵泡颗粒细胞中的表达强于成熟卵泡；在卵泡退化过程中，闭锁卵泡中呈不同程度的减少而在黄体细胞则无表达。ＬＨ受体ｍＲＮＡ在成熟卵泡的颗粒细胞和卵泡膜细胞中均有表达，不成熟卵泡仅在卵泡膜细胞中表达，退化的卵泡表达逐渐减少；在峰值后的第４和第７天的少许黄体细胞中可见，在第１２天达高峰，继而逐渐消失。表明在猪动情周期的不同阶段，ＦＳＨ和ＬＨ受体ｍＲＮＡ在卵泡细胞中的表达呈多样性和细胞特异性。成熟黄体细胞仅表达ＬＨ受体ｍＲＮＡ而不表达ＦＳＨ受体ｍＲＮＡ。     

Testicular FSH and hCG receptors in Sertoli-cell-only syndrome

Testicular FSH and hCG receptors were measured in patients with Sertoli-cell-only syndrome (SCOS), and the value of Bmax for each hormone was compared with the value in subjects with normal testes. FSH receptor was detectable in only four of 10 patients, and the mean value of Bmax in four of the 10 patients was clearly lower than that in normal testes (p less than 0.005). On the other hand, hCG receptors were detected in all of six tested patients, and the mean value of Bmax was lower, but not remarkably so, than that in the normal testes. The function of Sertoli cells was remarkably impaired in most men with SCOS, whereas the function of Leydig cells was relatively preserved.     

Humoral mechanisms in prostate cancer:: A role for FSH

The natural history of prostate cancer has long been related to the male hormone testosterone, and treatment has focused on depletion of this androgen to slow or prevent growth of prostate cancer tissue. It has become clear recently, however, that more than androgens influence the progression of prostate cancer, with recent interest focusing on the gonadotropin, follicle-stimulating hormone (FSH). Research of the last decade has found that FSH is produced in and FSH receptors are expressed in the prostate. Investigators have found as well that production of FSH is altered in prostate cancer: FSH levels are increased and receptor production raised in the cancerous prostate. It also has been shown that there are endogenous compounds such as prostatic inhibin peptin that can modulate FSH levels. All of these findings are outlined in this paper, and suggest that FSH may affect the pathogenesis and progression of prostate cancer and that altering FSH production may prove to be an active therapeutic maneuver.     

Cell-based evidence regarding the role of FSH in prostate cancer

Introduction

Conversion of androgen-responsive prostate cancer (CaP) to castration-resistant CaP is associated with an acceleration of the disease that often requires treatment modalities other than androgen deprivation therapy only. Recently, follicle-stimulating hormone (FSH) has been shown to play a role in CaP growth, and clinical data showed that high serum concentration of FSH in chemically castrated CaP patients was associated with a shorter time of progression to castration-resistant CaP. In this study, we sought to investigate if FSH could have direct effects on CaP cells, possibly through the androgen receptor and androgen receptor regulated genes, such as prostate-specific antigen (PSA).

Effects of follicular fluid administration on serum bioactive and immunoreactive FSH concentrations and compensatory testosterone secretion in hemicastrated adult rats

In adult rats, removal of one testis (hemicastration) results in an elevation of serum follicle-stimulating hormone (FSH) concentrations and a compensation in testosterone secretion by the remaining testis without a corresponding increase in testis size. To determine whether changes in FSH secretion and compensatory androgen production are related, serum testosterone concentrations were measured after inhibin-rich porcine follicular fluid was administered twice daily for 4 days to block the hemicastration-induced rise in FSH. Both serum immunoreactive FSH (immuno-FSH) and bioactive FSH (bio-FSH) concentrations were increased 4 days after hemicastration. The significant increase in serum immuno-FSH in hemicastrated animals was prevented by follicular fluid administration, whereas the serum bio-FSH activity and biologic to immunologic (B/I) ratios were increased in follicular fluid-treated animals. The follicular fluid-induced reduction in serum immuno-FSH had no effect on serum testosterone secretion in hemicastrated rats. Serum inhibin concentrations were reduced 27% in hemicastrated rats compared with intact controls, while administration of exogenous follicular fluid increased serum inhibin concentrations. An elevation in serum immuno-FSH secretion after hemicastration apparently is not required for the compensatory testosterone response. However, the observation of increased bio-FSH in hemicastrated and follicular fluid-treated animals raises questions about the importance of FSH quality (bioactivity), rather than quantity, for controlling testicular steroidogenic activity.     

Clinical studies in an adult male patient with "isolated follicle stimulating hormone (FSH) deficiency"

Previous reports concerning isolated follicle stimulating hormone (FSH) deficiency and its possible pathogenesis have been conflicting. Both "normal" and "abnormal" FSH response to luteinizing hormone releasing hormone (LHRH) infusion have been described. We studied a 22-year-old man with normal basal serum testosterone and luteinizing hormone (LH) levels but undetectable levels of serum FSH. His serum LH titers showed one secretory spike during a 40-hour sampling at 20-minute intervals, whereas his serum FSH titers remained undetectable (less than 0.4 IU/l). Infusion of LHRH, 0.2 microgram/minute for 4 hours, induced the expected rise in the serum LH levels, but serum FSH levels remained low and only at one point reached 0.9 IU/l (normal adult male basal range 0.9-10.3 IU/l). The patient received LHRH, 100 micrograms/day, for three days. A second LHRH infusion, 0.2 microgram/minute for 4 hours, induced a normal rise in both the serum LH and FSH titers. The serum sex steroid binding globulin level was 10.3 ng DHT bound/ml (normal adult male level 8.0 +/- 0.3 ng DHT bound/ml). Presence of circulating auto-antibodies to the serum FSH was excluded by determining the binding of [125I] FSH with the patient's serum and comparing it with sera obtained from two normal male adult volunteers. Pituitary function tests were otherwise intact. Presence of a pituitary tumor was excluded by computerized axial tomography and x-ray studies of the pituitary fossa and normal visual fields. Clinically, the patient demonstrated cryptorchidism, hypospadias, surgically repaired omphalocele, and bilateral hearing loss.(ABSTRACT TRUNCATED AT 250 WORDS)     

Spermatogenic onset. II. FSH modulates mitotic activity of germ and Sertoli cells in immature rats

By using high doses of testosterone propionate (TP) endogenous FSH was lowered to non-detectable levels in immature rats of different ages. Combined administration of TP and human menopausal gonadotrophin (hMG) or purified human FSH (hFSH) restored circulating FSH to normal or supranormal levels. This experimental model was used to investigate the influences of hormones on the proliferation of Sertoli and germ cells. Mitoses in seminiferous tubules were counted after being blocked by administration of colchicine. The mitotic index so determined showed a reduction with FSH withdrawal and a significant increase when the hormone levels were restored. Testicular DNA content was determined in testicular homogenates and showed similar changes. Autoradiographs were prepared and 3H-thymidine incorporation into germ and Sertoli cells was quantified. It was found that hFSH induced a significant increase in the labelling indices of gonocytes, type A-spermatogonia and Sertoli cells. All of these changes were effective in rats younger than 10 days but no modifications in any of the parameters under study were observed after 20 days. It is concluded that FSH exerts a stimulatory effect on the proliferation of spermatogonia, Sertoli cells and testicular DNA content during the first 10 days of life.