DURATION OF ESTROGEN EXPOSURE PRIOR TO FOLLICLE-STIMULATING-HORMONE STIMULATION IS CRITICAL TO GRANULOSA-CELL GROWTH AND DIFFERENTIATION INRATS

Estrogens have been reported to exert both stimulatory and inhibitory effects on granulosa cell function, Previous studies from our laborato ry 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 stimul ation 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 folli cles. The present study was designed 1) to confirm that the duration o f estrogen pre-exposure determines the way granulosa cells respond to FSH and 2) to investigate the underlying mechanisms involved. While DE S was used in preliminary experiments, the majority of the studies wer e conducted with estradiol, a natural estrogen, in order to conform as closely as possible to the normal physiology, In the experimental pro tocol, 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 granulo sa cells collected at the end of the FSH treatment period. The results demonstrate that exposure to either of these estrogens for 12 h allow ed the subsequent FSH stimulation to produce high cellular proliferati on, high aromatase enzyme activity, and large amounts of FSH receptor and aromatase mRNA. Estrogen exposure for 36 h, however, resulted in s ignificantly 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 t o estrogen exposure could help explain how dominant follicles survive to ovulate while others are lost to atresia during ovarian cycles.