Reilly C M, Cannady W E, Mahesh V B, Stopper V S, De Sevilla L M, Mills T M
Department of Physiology and Endocrinology, Medical College of Georgia, Augusta 30912-3000, USA.
Biol Reprod. 1996 Jun;54(6):1336-42. doi: 10.1095/biolreprod54.6.1336.
Estrogens have been reported to exert both stimulatory and inhibitory effects on granulosa cell function. Previous studies from our laboratory showed that 12 h after administration of diethylstilbestrol (DES; a synthetic estrogen), FSH-stimulated granulosa cell proliferation and aromatase activity were increased; however, 48 h after DES, FSH stimulation of both parameters was inhibited. In other experiments, exposure of rats to DES for a period of 26 h blocked ovulation in response to eCG and hCG administration, whereas the same treatment regimen without DES caused ovulation in all treated rats. Thus, DES may in some cases actually interfere with maturation and development of ovulatory follicles. The present study was designed 1) to confirm that the duration of estrogen pre-exposure determines the way granulosa cells respond to FSH and 2) to investigate the underlying mechanisms involved. While DES was used in preliminary experiments, the majority of the studies were conducted with estradiol, a natural estrogen, in order to conform as closely as possible to the normal physiology. In the experimental protocol, immature female rats received injections of DES or implants of estradiol pellets 12 h (short exposure) or 36 h (long exposure) before 36 h of FSH treatment. Rats were killed, ovaries removed, and granulosa cells collected at the end of the FSH treatment period. The results demonstrate that exposure to either of these estrogens for 12 h allowed the subsequent FSH stimulation to produce high cellular proliferation, high aromatase enzyme activity, and large amounts of FSH receptor and aromatase mRNA. Estrogen exposure for 36 h, however, resulted in significantly decreased FSH stimulation of all these parameters. These findings confirm that short exposure to estrogen enhances the response of granulosa cells to FSH while longer exposure makes granulosa cells refractory to FSH. This differential sensitivity of granulosa cells to estrogen exposure could help explain how dominant follicles survive to ovulate while others are lost to atresia during ovarian cycles.
据报道，雌激素对颗粒细胞功能具有刺激和抑制两种作用。我们实验室之前的研究表明，在给予己烯雌酚（DES；一种合成雌激素）12小时后，促卵泡激素（FSH）刺激的颗粒细胞增殖和芳香化酶活性增加；然而，在给予DES 48小时后，FSH对这两个参数的刺激作用受到抑制。在其他实验中，大鼠暴露于DES 26小时会阻断对促性腺激素释放激素（eCG）和人绒毛膜促性腺激素（hCG）给药的排卵反应，而相同的治疗方案但不使用DES会使所有接受治疗的大鼠排卵。因此，DES在某些情况下实际上可能会干扰排卵卵泡的成熟和发育。本研究旨在：1）确认雌激素预先暴露的持续时间决定颗粒细胞对FSH的反应方式；2）研究其中涉及的潜在机制。虽然在初步实验中使用了DES，但大多数研究是使用天然雌激素雌二醇进行的，以便尽可能贴近正常生理状态。在实验方案中，未成熟雌性大鼠在接受36小时FSH治疗前12小时（短时间暴露）或36小时（长时间暴露）接受DES注射或雌二醇丸植入。在FSH治疗期结束时处死大鼠，取出卵巢并收集颗粒细胞。结果表明，暴露于这两种雌激素中的任何一种12小时后，随后的FSH刺激会产生高细胞增殖、高芳香化酶活性以及大量的FSH受体和芳香化酶信使核糖核酸（mRNA）。然而，雌激素暴露36小时会导致FSH对所有这些参数的刺激作用显著降低。这些发现证实，短期暴露于雌激素会增强颗粒细胞对FSH的反应，而长期暴露会使颗粒细胞对FSH产生不应性。颗粒细胞对雌激素暴露的这种差异敏感性有助于解释在卵巢周期中优势卵泡如何存活至排卵，而其他卵泡则闭锁退化。
