EPIDERMAL GROWTH-FACTOR ACTS DIRECTLY ON THE SHEEP OVARY INVIVO TO INHIBIT ESTRADIOL-17-BETA AND INHIBIN SECRETION AND ENHANCE PROGESTERONESECRETION

Epidermal growth factor (EGF) is a potential intraovarian modulator of gonadotroph action on differentiated follicular cells. Specific bindi ng sites have been identified in the ovary and functional differentiat ion in cultured granulosa cells can be modulated by treatment with EGF . The aim of this study was to determine if EGF was capable of alterin g ovarian function in vivo during the follicular phase of the sheep oe strous cycle. Fourteen cross-bred ewes with ovarian autotransplants we re treated with progestagen pessaries for 12 days. Three ewes were inf used with murine EGF (mEGF) via the jugular vein (75 mug/kg bodyweight per 12 h) during the 12 h preceding progestagen pessary withdrawal, a nd received an injection of a prostaglandin analogue at 0 h to induce luteolysis. Over the same time-period, two doses of EGF were administe red to other groups of ewes by infusion into the ovarian artery (low: 6 mug/12 h, n = 3 and high: 60 mug/12 h, n = 3). The remaining five ew es were not infused with EGF (controls). Jugular and ovarian venous bl ood samples were taken at 10-min intervals at two stages during the fo llicular phase (21-27 h and 38-42 h after pessary withdrawal) and ever y 2 h from 44 to 76 or 86 h. mEGF, LH, FSH, inhibin, androstenedione, oestradiol-17beta and progesterone concentrations in plasma were deter mined using radioimmunoassays. The secretion rates of androstenedione, oestradiol, progesterone and inhibin by the ovary were calculated. EG F acted directly on the ovary in a dose-dependent manner. Oestradiol s ecretion was inhibited following treatment with EGF but androstenedion e secretion was unaffected. EGF appears therefore to act within the gr anulosa cells to inhibit aromatization. Inhibin secretion was also sup pressed by treatment with EGF, though it was not possible to determine if this was caused by a direct or indirect action of EGF on granulosa cells. The rate of progesterone secretion increased in ewes receiving systemic (i.e. via the jugular vein) and high-dose intra-arterial inf usions of EGF, even though a preovulatory LH surge was not observed in these animals during the entire experimental period. Concomitant incr eases in both LH and FSH secretion were associated with these effects of EGF on ovarian function. In conclusion, EGF appears to act directly on the granulosa cells of the follicle to inhibit aromatization and a lso to inhibit inhibin production. The low levels of oestradiol and in hibin in the presence of high levels of gonadotrophin indicate that at resia may have been induced in medium to large antral follicles. The i ncrease in progesterone secretion following high doses of EGF may be d erived from a luteinized follicle. FSH-stimulated functions cease when a follicle luteinizes and progesterone secretion commences. EGF treat ment inhibited both oestradiol and inhibin secretion whilst enhancing progesterone which suggests that EGF may also be involved in the induc tion of functional luteinization. EGF or an EGF-like substance may the refore be an important factor in the induction of functional luteiniza tion, with atresia occurring in antral follicles which are exposed to EGF too early in their development.