肿瘤坏死因子-α与卵子生成

肿瘤坏死因子-α(TNF-α)是一种多效的细胞因子,与相应受体结合后通过一系列的信号传导通路,在体内发挥着重要的调节作用,是卵巢局部微环境重要的组成成分之一。它的作用涉及卵子发生的每一个环节,如卵泡发育、排卵、卵泡闭锁等,调控着卵巢细胞的生死平衡。     

卵泡膜细胞与卵巢功能的调控

卵泡膜细胞作为卵巢中组成卵泡的3种主要细胞之一,在卵巢的各项功能如甾体合成、卵泡发育和卵泡闭锁中都发挥了一定的作用。卵泡膜细胞起源于卵巢中类似成纤维细胞样的基质细胞,其可分泌雄激素,与卵泡刺激素(FSH)相互作用促进颗粒细胞增殖,促进卵泡的发育。有研究认为应当把卵泡膜细胞在基底膜外开始分化作为卵泡生长的起点。某些卵泡膜细胞源性生长因子可促进有丝分裂,阻止颗粒细胞凋亡,在卵泡闭锁过程中发挥重要的调控作用。故探讨卵泡膜细胞在卵巢功能调控中的作用有临床实际意义。     

参与调控始基卵泡激发过程的细胞信号通路

始基卵泡占卵巢所有卵泡的99%以上,人卵巢组织中最后一批由初级卵母细胞分化形成的始基卵泡的寿命可长达50余年。始基卵泡的有序激活受多种信号通路的调控作用。许多细胞因子可以通过PI3K-AKT信号通路,激活叉头蛋白转录因子O3a(Fox O3a),促进始基卵泡的启动,而该作用可以被抑癌基因PTEN编码的蛋白所抑制;结节性硬化综合征(TSC)蛋白能够负向调节哺乳动物雷帕霉素靶蛋白复合体1(m TORC1),在始基卵泡保持静止状态的过程中发挥重要作用;转化生长因子-β(TGF-β)家族成员众多,对始基卵泡的激活作用存在争议,主要通过蛋白分子Smads控制靶基因的转录;近期有研究表明,Hippo信号通路在卵泡激活调节过程中有重要作用,对卵巢组织进行机械切割,可以抑制Hippo信号通路,促进卵泡激活。上述不同的信号通路之间存在频繁的交叉对话。对多种信号通路之间进行联系,能够为整体理解始基卵泡的激活机制提供新的思路。     

转化生长因子β及其受体与卵泡发育

转化生长因子β(TGF-β)是一类具有多种生物学活性的细胞因子,而卵巢中的卵泡发育是一动态和复杂的过程.对不同标本进行研究证明,TGF-β及其受体在卵巢不同发育阶段中均可表达,通过自分泌/旁分泌机制参与调控卵巢功能,对维持卵巢内环境稳定发挥重要作用.     

胰岛素增加猪卵泡膜细胞黄体生成素刺激的类固醇生物合成

近来一些研究表明胰岛素可增加人、猪和大鼠的卵巢粒层细胞。猪卵巢的卵泡膜细胞合成和分泌的雄激素对粒层细胞合成雌激素起重要作用,胰岛素对卵泡生物合成类固醇的作用和机理用粒层细胞已广泛进行研究,发现猪粒层细胞有胰岛素特异性受体,在猪粒层细胞的培养基中加入胰岛素起促进作用并引起细胞形态特征不同变化和增加类固醇激素的合成率。另外通过培养猪卵泡组织发现胰岛素还可增加黄体生成素(LH)刺激的雄激素的产     

转化生长因子β及其受体与卵泡发育

转化生因子β（TGF－β）是一类具有多种生物学活性的细胞因子，而卵巢中的卵泡发育是一动态和复杂的过程。对不同标本进行研究证明，TGF－β及其受体在卵巢不同发育阶段中均可表达，通过自分泌／旁分泌机制参与调控卵巢功能，对维持卵巢内环境稳定发挥重要作用。     

雄激素致无排卵大鼠卵巢转化生长因子β1及其受体的变化

目的:探讨雄激素致无排卵大鼠卵泡发育的影响。方法:建立雄激素致无排卵大鼠模型,并设正常对照组,放免法测定血清睾酮(T),HE染色观察卵巢组织形态学变化,免疫组化法检测卵巢转化生长因子β1及其受体(TGFβ1/TGFβ1R)的表达。结果:①模型组血清T水平明显高于对照组;②模型组大鼠卵巢中卵泡囊状扩张,颗粒细胞层极薄;而对照组可见发育期各级卵泡及黄体形成;③模型组卵巢颗粒细胞、卵泡膜细胞、间质细胞TGFβ1/TGFβ1R的表达明显高于对照组。结论:雄激素致无排卵大鼠卵巢颗粒细胞、卵泡膜细胞、间质细胞TGFβ1/TGFβ1R的表达明显增高可能是导致卵泡发育障碍、无排卵的因素之一。     

卵巢颗粒细胞中卵泡刺激素的受体后信号传导通路

卵泡刺激索(FSH)是下丘脑-垂体-性腺轴中的关键激素,通过与颗粒细胞的FSH受体(FSHR)结合,发挥卵泡募集、促卵泡生长和卵母细胞成熟的作用,并与黄体生成素(LH)一起,介导排卵过程,促进和维持正常的性腺发育和生殖功能.研究颗粒细胞中FSH与FSHR结合后的信号传导通路(即受体后信号传导通路)机制,对了解颗粒细胞在卵泡发育过程中的作用以及对治疗不孕、不育药物的研制具有重要意义.本文将对颗粒细胞中FSH的受体后信号传导及功能调节的分子学机制的研究进展做一综述.     

雄激素在女性生殖内分泌疾病发生及治疗中的作用

雄激素在女性生殖系统健康的维持中发挥重要作用,过量或缺乏雄激素都可能导致女性发生生殖内分泌疾病。高雄激素血症是多囊卵巢综合征(PCOS)的重要特征和致病因素之一,可能通过影响表观遗传学、下丘脑神经内分泌、卵泡发育、卵巢功能和代谢发挥致病作用。雄激素在复发性自然流产中的作用机制主要是影响子宫内膜容受性和胚胎植入。早发性卵巢功能不全的妇女常表现为睾酮水平低,雄激素缺乏可能与颗粒细胞凋亡以及卵巢功能降低有关。降低雄激素的相关治疗是PCOS临床治疗的重要部分,而雄激素补充治疗可用于早发性卵巢功能不全妇女,但其疗效和长期用药的安全性尚需进一步研究。     

白细胞介素6对雄激素活性的影响及在多囊卵巢综合征发病机制中的作用

目的探讨白细胞介素6(IL-6)对雄激素活性的影响及在多囊卵巢综合征(PCOS)发病机制中的作用。方法在体外培养的猪卵泡内膜细胞和颗粒细胞培养液中分别加入IL-6(10ng/L、100ng/L、1000ng/L),观察IL-6对卵泡内膜细胞睾酮分泌及卵巢颗粒细胞雄激素受体(AR)mRNA表达的影响。结果在24h、48h、72h三个时间点分别与空白对照组(0ng/L)相比,加入IL-6后卵泡内膜细胞睾酮分泌无明显变化;在72h时通过Real-timePCR检测发现,IL-6(100ng/L、1000ng/L)对卵巢颗粒细胞AR-mRNA的表达具有上调作用。结论IL-6虽然没有直接促进卵巢睾酮分泌的作用,但却可以上调卵巢组织AR-mRNA的表达,间接增强雄激素活性,此可能与慢性亚临床炎症可引发PCOS的机制有关。     

Androgen receptor in hirsutism and acne

Hyperandrogenism may result in acne and hirsutism. On the other hand, acne and hirsutism may occur without elevated androgen serum levels. An important point of androgen action is the target organ sensitivity at the receptor level. In the present study, androgen receptor (AR) determinations by saturation analysis were performed in 36 hirsute as well as in 11 female and 52 male acne patients. A small group of endocrine healthy patients served as control group. For AR analysis, the predilection sites of the disease were chosen. In acne, also nonlesional skin served as control. 26% of the hirsute patients were AR-positive, with mean AR levels of 68 fmol/mg protein. Male acne patients were 50% AR-positive in acne lesions and 60% positive in their nonlesional skin. The mean AR levels were 25 and 38 fmol/mg protein, respectively. The control group was 27% AR-positive, with mean AR levels of 15 fmol/mg protein. Female acne patients were 3/11 positive in lesional and 1/11 positive in nonlesional skin. The mean AR levels were 25 and 35 fmol/mg protein, respectively. The female control group was in 3/13 cases AR-positive, with a mean level of 8 fmol/mg protein. Comparison of the AR levels indicates hirsutism as the mostly androgen-dependent dermatosis. No correlation between AR and androgen serum levels was demonstrated. This finding suggests that androgen action at the target organ level in both dermatoses may be independent of peripheral serum levels of hormones.     

Molecular pathology of the androgen receptor in male (in)fertility

Idiopathic male infertility, accounting for 40% of all male infertility cases, is postulated to have a genetic basis. The androgen receptor (AR) plays a crucial post-meiotic role during male germ cell differentiation, which includes terminal differentiation of spermatids and their release from the seminiferous epithelium. Mutations in the AR gene result in a condition known as androgen insensitivity syndrome (AIS) affecting normal male morphogenesis. Depending on the severity of the syndrome, the external phenotype can range from normal female to normal male. In almost all cases affected individuals are infertile. In seven reported cases individuals appeared to suffer primarily or solely from male infertility, suggesting these AR mutations specifically cause male infertility. Three of these mutations are possibly population specific. Longer CAG repeats present in exon 1 of the AR have been studied as a possible risk factor for male infertility. Results are contradictory, with a trend to significance (Asian populations) and non-significance (European populations). Recent advances in protein modelling techniques may result in a much better understanding of the mechanism of action of the known infertility mutations. The determination of the significance of longer CAG repeats is likely to require studies that examine CAG repeat lengths in spermatozoa as well as patients' blood.     

雄激素在女性生殖内分泌疾病发生及治疗中的作用

雄激素在女性生殖系统健康的维持中发挥重要作用，过量或缺乏雄激素都可能导致女性发生生殖内分泌疾病。高雄激素血症是多囊卵巢综合征（PCOS）的重要特征和致病因素之一，可能通过影响表观遗传学、下丘脑神经内分泌、卵泡发育、卵巢功能和代谢发挥致病作用。雄激素在复发性自然流产中的作用机制主要是影响子宫内膜容受性和胚胎植入。早发性卵巢功能不全的妇女常表现为睾酮水平低，雄激素缺乏可能与颗粒细胞凋亡以及卵巢功能降低有关。降低雄激素的相关治疗是PCOS临床治疗的重要部分，而雄激素补充治疗可用于早发性卵巢功能不全妇女，但其疗效和长期用药的安全性尚需进一步研究     

Concentrations of steroid receptors in normal human endometrium in relation to the day of the menstrual cycle

Concentrations of receptors for estrogen (ER), progestin (PR) and androgen (AR) were measured in the cytoplasm and nucleus of human endometrium, throughout the normal menstrual cycle. Endometrial cellular ER and PR levels gradually increased during the preovulatory and immediate postovulatory phases, remained constant at the maximal level during the mid-secretory phase and gradually decreased to the lowest level at the end of the cycle. There was a difference between ER and PR nuclear levels in the mid-secretory endometrium, where maximum levels of PR and low levels of ER were noted. This PR abundance indicates the necessity of progesterone action for implantation. During the menstrual cycle, AR sites did not change noticeably and far fewer were found than those of the other receptors. This finding indicates that androgen plays a less important role in female reproduction.     

Insulin-like growth factors and their binding proteins: Potential relevance to reproductive physiology

Cyclic ovarian follicular development is a complex process that involves proliferation, differentiation, and death of follicle cells. Gonadotropins produced by the pituitary gland have a central role in the regulation of these processes. In addition, a wide range of paracrine and autocrine factors produced in the reproductive organs have been proposed as regulators of reproductive functions. Components of the insulin-like growth factors (IGF) system are widely expressed in the female reproductive tract. The IGFs and their binding proteins play a significant role in several processes of reproductive physiology, including ovarian follicular development, oogenesis and oocyte maturation, ovulation, luteal function, follicular atresia, and testicular function. The majority of these physiological actions of the IGFs are believed to occur via activation of the IGF-I receptor, although the IGF-I effects are modulated by IGF binding proteins (IGFBPs). As much of the data obtained to date have been in the rodent reproductive organs, it may not be possible to directly extrapolate the results to the primate organs. There is a distinct species-difference in the gene expression and functional roles of the IGF-IGFBP system in reproductive organs. However, the disturbance of the IGF-IGFBP system in human reproductive physiology may lead to anovulation, disorders of androgen excess, infertility associated with implantation failure, and male infertility. Further research is needed in domestic animals to determine if manipulation of the IGF-IGFBP system may result in improved reproductive efficiency. As our understanding of the IGF-IGFBP system increases, the uses of human recombinant IGF peptides and IGFBPs as clinical therapy for disease states is becoming a reality. (Reprod Med Biol 2003; 2 : 1–24)     

Impact of androgens on fertility - physiological, clinical and therapeutic aspects

Ovarian androgen synthesis and regulation are essential to ensure adequate steroidogenesis and folliculogenesis. In primates, there is evidence for a direct impact on the number of small antral follicles and on the process of chronic anovulation. Therefore, serum androgen should be more carefully assessed in infertile women. Accurate measurements of serum androgen are required to better identify patients with androgen excess or deficiency. Medical or surgical interventions are able to decrease ovarian androgen excess and to reduce the risk of hyperstimulation. Conversely, androgen supplementation should be considered in women at risk of low ovarian response to gonadotrophins, related to androgen deficiency. This review supports a specific and broad role of androgen in reproductive physiology.     

Endometrial steroid receptor during normal menstrual cycle and physiopathology of nidation

Human uterine endometrial steroid receptor [estrogen (ER), progestin (PR) and androgen (AR) receptors] in the normal menstrual cycle were determined at the cellular level. Endometria with pathological out-of-phase findings or with hypoplastic uterus were evaluated for the concentration of steroid receptors, for a better understanding of their pathophysiology. ER and PR levels gradually rose toward the early secretory phase, remained at the maximum level during the mid-secretory phase and dropped to the lowest level during the late secretory phase. Especially nuclear PR reached the maximum level during the mid-secretory phase. These results indicate that the endometrial ER and PR, especially the endometrial nuclear PR, is kept in the maximum level at implantation. AR showed only a slight change in a very low level throughout the menstrual cycle. This indicates that androgen may not play so important a role in endometrial physiology. Endometria with out-of-phase or with hypoplastic uterus contained significantly low levels of endometrial ER and PR, while serum hormones levels were normal. This indicates indigenous reduction of ER and PR synthesis in such endometria.     

Androgen, estrogen and progesterone receptor expression in the human uterus during the menstrual cycle

Cyclic changes in steroid receptor expression in endometrial cells are considered a reflection of its differential functions. Besides estrogen and progestogens, androgens have also been suggested to affect the biological function of the female reproductive tract. We investigated the distribution and intensity of immuno-cytochemical estrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) staining in the various cell types of human endometrium and myometrium during the different menstrual cycle phases in 30 paraffin-embedded sections.AR expression in endometrial stromal cells decreased gradually from early proliferative till mid secretory phase. In the late secretory phase, AR expression in all cell types distinguished. Staining of epithelial cells was moderate. The disappearance of AR expression before cyclic separation of endometrial tissue may be causally related or just an epiphenomenon. Due to local competition for 5alpha-reduction of testosterone and the excess of progesterone in the secretory phase, the level of dihydrotestosterone (DHT) will be diminished. Hypothetically, if AR synthesis in endometrium would be DHT-dependent, it would explain the lack of AR expression in the late secretory phase.     

CAG repeat polymorphism of androgen receptor gene and X-chromosome inactivation in daughters of women with polycystic ovary syndrome (PCOS): relationship with endocrine and metabolic parameters

Background: The polycystic ovary syndrome (PCOS) is a hyperandrogenic disorder that arise from a combination of genetic and environmental factors. Aim: To assess the role of the androgen receptor (AR) CAG repeat polymorphism in the metabolic and reproductive features in daughters of women with PCOS (PCOSd). Methods: Sixty-seven PCOSd and 60 daughters of control women (Cd) were studied in early stages of sexual development. Sex steroids, glucose, insulin and lipids were determined. The AR CAG repeat sizes and X-chromosome inactivation (XCI) were analyzed. Results: PCOSd and Cd had similar mean number of CAG repeats and XCI pattern. In PCOSd and Cd, methylation-weighted biallelic means CAGn (mwCAGn) was not associated with androgen levels. In infants and pubertal PCOSd, mwCAGn was associated with a low concentration of HDL-cholesterol. Conclusions: AR CAG repeat polymorphism appears to be unrelated with serum androgen levels. However, the short mwCAGn variant may have a possible impact on the lipid profile in PCOSd.     

Discovery of dachshund 2 protein as a novel biomarker of poor prognosis in epithelial ovarian cancer

The aim of this study was to elucidate the regulatory role of androgen in the follicular development of wild female ground squirrels. Immunohistochemical staining of FSHR, LHR, P450c17, P450arom, androgen receptor (AR), estrogen receptors (ERa and ERb) were executed in ovaries of female ground squirrels from both breeding and nonbreeding seasons. In addition, total ovarian proteins were extracted from the ovaries of squirrels from breeding and nonbreeding seasons, and Western blot analysis were performed in order to probe for FSHR, LHR, P450c17, P450arom, AR, ERa and ERb. The results of immunohistochemical staining and Western blotting of P450c17 showed that there was no significant difference between the breeding and nonbreeding seasons. It was found that granulosa cells expressed P450arom during the breeding season. In contrast, there was no positive staining of P450arom in the nonbreeding season. There was no significant difference in immunoreactivity of AR between the breeding and nonbreeding seasons. However, the immunoreactivities of ERa and ERb were both significantly reduced in the nonbreeding season compared to the breeding season. The positive stains of FSHR and LHR were found in the granulosa cells and theca cells of the ovaries of the breeding and nonbreeding seasons. In addition, the Western blotting results of FSHR and LHR showed a significant reduction in the nonbreeding season compared with the breeding season. These findings suggested that androgen might be predominantly converted into estrogen in order to regulate the follicular development via binding of estrogen receptors during the breeding season, whereas androgen might predominantly directly bind androgen receptor to regulate the follicular development during the nonbreeding season in the ovaries of wild female ground squirrels.