Molecular endocrinological study on the local regulatory mechanism of the proliferation, differentiation and apoptosis of female reproductive cells

甲状腺激素、IGF-I、EGF、TGF β和TNF α等生长因子在颗粒细胞增殖、分化和凋亡过程中的调节作用被评估。在培养的颗粒细胞中，甲状腺激素、胰岛素、IGF-I和EGF可上调FSH的作用，而TGF β和TNF α可下调FSH的作用。DNA 3′端标记法显示FSH、IGF-I和FGF抑制颗粒细胞凋亡DNA片段化，而TGF β和TNF α刺激细胞凋亡DNA片段化。这表明，卵泡生存因子如FSH、IGF-I和EGF的显性暴露可能是对生长卵泡的选择负责，而显性暴露于致闭锁因子如TGF β和TNF α可能是对卵泡闭锁负责。颗粒细胞是已知生长最快的正常细胞类型之一。事实上，c-myc mRNA在欠成熟卵泡颗粒细胞中大量表达。未成熟颗粒细胞中c-myc的分期特异性表达可能提示c-myc参与未成熟卵泡的自主生长。erb-A在小滤泡颗粒细胞中的表达量也高于在大滤泡颗粒细胞中的表达量。因此，这些癌基因的表达，无论是单独的还是联合的，都可能在卵泡发育早期的自主颗粒细胞增殖中发挥作用。此外，根据最近的证据，Fas抗原介导凋亡信号，Fas抗原在退行性黄体和闭锁卵泡中大量表达，提示Fas抗原通过凋亡过程参与黄体退行和卵泡闭锁。

The roles of growth factors, such as thyroid hormone, IGF-I,EGF,TGF beta and TNF alpha were evaluated for their potential as regulators of granulosa cell proliferation, differentiation and apoptotic process. Thyroid hormone, insulin, IGF-I and EGF were found to act as up-regulators of FSH actions in cultured granulosa cells, whereas TGF beta and TNF alpha were shown to act as down-regulators of FSH actions in the cells. The use of DNA 3'-end labeling method revealed that FSH,IGF-I and FGF suppressed apoptotic DNA fragmentation of granulosa cells, whereas TGF beta and TNF alpha stimulated apoptotic DNA fragmentation of the cells. This suggests that dominant exposure to follicle survival factors such as FSH,IGF-I,and EGF may be responsible for the selection of growing follicles, while dominant exposure to atretogenic factors such as TGF beta and TNF alpha may be responsible for follicle atresia. The granulosa cell is one of the most rapidly growing normal cell types known. Actually, c-myc mRNA was expressed abundantly in the granulosa cells of less-mature follicles. The stage-specific expression of the c-myc in immature granulosa cells may suggest c-myc participation in the autonomous growth of immature follicles. erb-A was also expressed more abundantly in small-follicle granulosa cells than in large-follicle granulosa cells. Thus, the expression of these oncogenes, either alone or in combination, may play a role in the autonomous granulosa cell proliferation early in follicular development. Furthermore, on the basis of the recent evidence, that the Fas antigen mediates an apoptotic signal, abundant expression of the Fas antigen in the regressing corpora lutea and atretic follicles suggests that the Fas antigen participates in luteal regression and follicular atresia through the apoptotic process.