Epidermal growth factor acts directly on the sheep ovary in vivo to inhibit oestradiol-17β and inhibin secretion and enhance progesterone secretion
Authors: Murray J. F. , Downing J. A. , Evans G. , Findlay J. K. , Scaramuzzi R. J. 
Published: December 2008

Epidermal growth factor (EGF) is a potential intra-ovarian modulator of gonadotroph action on differentiated follicular cells. Specific binding sites have been identified in the ovary and functional differentiation in cultured granulosa cells can be modulated by treatment with EGF. The aim of this study was to determine if EGF was capable of altering ovarian function in vivo during the follicular phase of the sheep oestrous cycle. Fourteen cross-bred ewes with ovarian autotransplants were treated with progestagen pessaries for 12 days. Three ewes were infused with murine EGF (mEGF) via the jugular vein (75 μg/kg bodyweight per 12 h) during the 12 h preceding progestagen pessary withdrawal, and received an injection of a prostaglandin analogue at 0 h to induce luteolysis. Over the same time-period, two doses of EGF were administered to other groups of ewes by infusion into the ovarian artery (low: 6 μg/12 h, n = 3 and high: 60 μg/12 h, n = 3). The remaining five ewes were not infused with EGF (controls). Jugular and ovarian venous blood samples were taken at 10-min intervals at two stages during the follicular phase (21–27 h and 38–42 h after pessary withdrawal) and every 2 h from 44 to 76 or 86 h. mEGF, LH, FSH, inhibin, androstenedione, oestradiol-17β and progesterone concentrations in plasma were determined using radioimmunoassays. The secretion rates of androstenedione, oestradiol, progesterone and inhibin by the ovary were calculated.

EGF acted directly on the ovary in a dose-dependent manner. Oestradiol secretion was inhibited following treatment with EGF but androstenedione secretion was unaffected. EGF appears therefore to act within the granulosa cells to inhibit aromatization. Inhibin secretion was also suppressed 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 infusions of EGF, even though a preovulatory LH surge was not observed in these animals during the entire experimental period. Concomitant increases 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 also to inhibit inhibin production. The low levels of oestradiol and inhibin in the presence of high levels of gonadotrophin indicate that atresia may have been induced in medium to large antral follicles. The increase in progesterone secretion following high doses of EGF may be derived from a luteinized follicle. FSH-stimulated functions cease when a follicle luteinizes and progesterone secretion commences. EGF treatment inhibited both oestradiol and inhibin secretion whilst enhancing progesterone which suggests that EGF may also be involved in the induction of functional luteinization. EGF or an EGF-like substance may therefore be an important factor in the induction of functional luteinization, with atresia occurring in antral follicles which are exposed to EGF too early in their development.

Journal of Endocrinology (1993) 137, 253–264