Epidermal growth factor inhibits follicular response to human chorionic gonadotropin: Possible role of cell to cell communication in the response to gonadotropin

Epidermal growth factor (EGF) affects follicular steroidogenesis and expression of gonadotropin receptors. The effects of EGF on hCG-induced estradiol and progesterone secretion and ovulation were examined in the in vitro perfused rabbit ovary. We also examined the effects of EGF on hCG-induced progesterone secretion by isolated granulosa cells. In addition, distribution of hCG within the follicle was probed by immunohistochemical means 30 min after its administration to the in vitro perfused ovary. EGF significantly (P < 0.05) reduced hCG-induced secretion of estradiol (control, 117 ± 12 pg/min· follicle; 10 ng/ml EGF, 55 ± 10) and progesterone (control, 18.2 ± 1.2 ng/min·follicle; 10 ng/ml EGF, 11.9 ± 0.8) by the perfused ovary. In contrast, EGF did not inhibit hCG-induced progesterone secretion by isolated granulosa cells. Ovulatory efficiency (number of ovulated ova per number of mature follicles × 100) when EGF was given 30 min before HCG was reduced dose-dependently from 58.2% with no EGF to 8.3% with 10 ng/ml EGF (P < 0.001). Ovulation was not inhibited by EGF when it was given 30 min after hCG. Distribution of hCG in the preovulatory follicle was confined to the basement membrane, thecal cell layer, and a small fraction of the outer granulosa cell layer. These observations suggest that gonadotropin stimulates the follicle through the release of a secondary signal(s) from ligand-bound granulosa cells near the follicle wall to unexposed cells of the inner avascular area. EGF may inhibit the follicular response to hCG by attenuation of this cell to cell communication.