INHIBITION OF OESTRADIOL PRODUCTION BY EPIDERMAL GROWTH FACTOR IN HUMAN GRANULOSA CELLS OF NORMAL AND POLYCYSTIC OVARIES

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Abstract
Anovulation in women with polycystic ovary syndrome results from a disorder of FSH-mediated follicular maturation which may involve paracrine modulation of FSH action by intra-ovarian factors. Epidermal growth factor (EGF) is a potent inhibitor of FSH-stimulated oestradiol production in the rat and has also been shown to inhibit aromatase activity in human granulosa cells obtained after superovulation. The purpose of this study was to investigate the action of EGF on granulosa cell function in human ovaries which had not been previously exposed to treatment with exogenous gonadotrophins and to compare the responses in tissue obtained from normal and from polycystic ovaries. Granulosa cells were obtained from antral follicles < 10 mm in diameter after dissection of unstimulated normal or polycystic ovaries (PCO). Cells were pooled, washed, plated and incubated for 48 h in the presence of 10-7 M testosterone and various doses of human FSH. FSH dose responses were obtained with or without the addition of purified EGF (50 pg/ml). Testosterone in the absence of FSH resulted in a fourfold (range 2-7.5) increase in oestradiol accumulation in the medium after incubation of granulosa cells from both normal and polycystic ovaries. This increase was reversed by addition of EGF. FSH treatment stimulated a dose-related increase in oestradiol regardless of the origin of the granulose cells. The peak E2 response to FSH, obtained at a dose of 1-2.5 ng/ml was a 20-fold increase above testosterone alone (range 4-55) in cells from PCO compared to sixfold (2.5-13) in cells from normal ovaries. The concurrent addition of EGF at 50 pg/ml caused an average 57% inhibition of the peak response to FSH. EGF also caused a dose-dependent inhibition of oestradiol production stimulated by a fixed dose of FSH in cells from both normal and PCO. These data indicate that EGF inhibits FSH-induced oestradiol production by granulosa cells of both normal and polycystic ovaries and suggest that EGF, or its analogue, transforming growth factor .alpha., which is known to be synthesized by theca cells, may have a role in human ovarian function.