INTERACTIONS BETWEEN FSH, ESTRADIOL-17-BETA AND TRANSFORMING GROWTH-FACTOR-BETA REGULATE GROWTH AND DIFFERENTIATION IN THE RAT GONAD
INTERACTIONS BETWEEN FSH, ESTRADIOL-17-BETA AND TRANSFORMING GROWTH-FACTOR-BETA REGULATE GROWTH AND DIFFERENTIATION IN THE RAT GONAD
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DOI：
10.1016/0960-0760(93)90248-u
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发表时间：
1993-03-01
影响因子：
4.1
通讯作者：
KHAN, SA
中科院分区：
文献类型：
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作者：
DORRINGTON, JH;BENDELL, JJ;KHAN, SA
雌二醇-17 β（E2）是一种促有丝分裂剂，在体内可促进大鼠卵巢颗粒细胞增殖。排卵前卵泡通过一系列促性腺激素依赖性事件合成E2：LH刺激卵泡膜细胞合成雄激素（雄烯二酮和睾酮），雄激素是颗粒细胞中FSH诱导芳构化为雌激素的底物。最近，我们发现转化生长因子-β（TGF-β）在体外刺激大鼠颗粒细胞的DNA合成，FSH增强了这种作用。由于E2在体内是促分裂剂，而TGF-β是唯一已知的刺激体外增殖的生长因子，因此检查了E2和TGF-β作用之间的可能联系。E2刺激培养的大鼠颗粒细胞分泌TGF-β样因子，并随着时间的推移刺激DNA合成。促有丝分裂作用的E2在FSH的存在下增强，并减弱了中和抗体TGF-β。后者的观察结果已经确定TGF-β是E2对大鼠颗粒细胞的促有丝分裂作用中的“缺失环节”。除了TGF-β和FSH的促生长作用外，TGF-β还增强了FSH诱导的芳香酶活性。因此，FSH加TGF-β刺激大鼠颗粒细胞的增殖和芳构化能力。我们认为FSH、E2和TGF-β之间的相互作用导致了在周期的卵泡期发生的血清E2水平的指数增加。类似地，FSH刺激从未成熟大鼠睾丸分离的支持细胞将外源性雄激素芳构化为雌激素，并且FSH诱导的芳构化与有丝分裂活性之间存在相关性。我们已经证明FSH加TGF-β刺激支持细胞的DNA合成。由于E2增加支持细胞分泌TGF-β，FSH、E2和TGF-β之间的相互作用可能在青春期前为支持细胞提供促有丝分裂刺激。总之，我们的研究结果表明，雌激素诱导的大鼠颗粒细胞的生长是通过TGF-β的产生介导的，TGF-β是一种自分泌的增殖调节因子。我们还提出，促生长作用的FSH支持细胞可能取决于一系列级联事件，涉及雌激素和TGF-β。
Estradiol-17beta (E2) is a mitogen in vivo for the proliferation of granulosa cells in the rat ovary. E2 is synthesized by the preovulatory follicle through a series of gonadotrophin-dependent events: LH stimulates thecal cells to synthesize androgens (androstenedione and testosterone) which are substrates for FSH-induced aromatization to estrogens in granulosa cells. More recently, we have found that transforming growth factor-beta (TGF-beta) stimulates DNA synthesis in rat granulosa cells in vitro and this effect is augmented by FSH. Since E2 is a mitogen in vivo and TGF-beta is the only known growth factor to stimulate proliferation in vitro, the possible link between the actions of E2 and TGF-beta were examined. E2 stimulated the secretion of a TGF-beta-like factor by rat granulosa cells in culture, and with time DNA synthesis was stimulated. The mitogenic action of E2 was enhanced in the presence of FSH, and attenuated by a neutralizing antibody to TGF-beta. The latter observations have identified TGF-beta as the ''missing-link'' in the mitogenic actions of E2 on rat granulosa cells. In addition to the growth-promoting actions of TGF-beta plus FSH, TGF-beta enhanced FSH-induced aromatase activity. Consequently, FSH plus TGF-beta stimulates both the proliferation and aromatization capacity of rat granulosa cells. We propose that interactions between FSH, E2 and TGF-beta lead to the exponential increase in serum E2 levels that occurs during the follicular phase of the cycle. Similarly, FSH stimulates the aromatization of exogenous androgens to estrogen by Sertoli cells isolated from immature rat testes, and there is a correlation between FSH-induced aromatization and mitotic activity. We have shown that FSH plus TGF-beta stimulates DNA synthesis in Sertoli cells. Since E2 increases the secretion of TGF-beta by Sertoli cells, interactions between FSH, E2 and TGF-beta may provide the mitogenic stimulus for Sertoli cells during the prepubertal period. In summary, our findings suggest that the estrogen-induced growth of rat granulosa cells is mediated through the production of TGF-beta, which acts as an autocrine regulator of proliferation. We also propose that the growth-promoting actions of FSH on Sertoli cells may depend upon a cascade series of events involving estrogens and TGF-beta.