Epidermal Growth Factor and Transforming Growth Factor-β Modulation of Follicle-Stimulating Hormone-Induced Deoxyribonucleic Acid Synthesis in Hamster Preantral and Early Antral Follicles1

The interactions of epidermal growth factor (EGF) and transforming growth factor-beta (TGF-beta) in modulating FSH-induced follicular DNA synthesis were studied in isolated intact preantral (stages 1-6) and early antral (stage 7) ovarian follicles from adult hamsters. Follicles were exposed in vitro for 24 h to FSH (100 ng), EGF (50 ng), TGF-beta 1 (1-10 ng), or TGF-beta 2 (1-10 ng), either alone or in combination. The rate of DNA synthesis was assessed by measuring the incorporation of [3H]thymidine into follicular DNA. Both EGF and FSH significantly stimulated follicular DNA synthesis compared with that in controls. Both isoforms of TGF-beta significantly increased follicular [3H]thymidine incorporation in a dose-dependent manner; the effect was greater for small preantral follicles, such as those of stages 1-4. Interestingly, TGF-beta significantly inhibited EGF-induced follicular DNA synthesis, but the rates of DNA synthesis for most of the stages were still higher than that of the control follicles. Specificity of the TGF-beta action on follicular DNA synthesis was evident from the ability of isoform-specific anti-TGF-beta antibodies to neutralize the effect. These antibodies also reversed the TGF-beta inhibition of EGF-induced DNA synthesis. Surprisingly, although TGF-beta attenuated EGF-induced DNA synthesis, it synergized with FSH to stimulate follicular DNA synthesis. Interestingly, FSH-induced DNA synthesis remained unaffected by the anti-TGF-beta antibodies, indicating that TGF-beta may not mediate FSH action on follicular DNA synthesis. These studies suggest that a critical interaction of EGF and TGF-beta modulates granulosa cell proliferation during folliculogenesis in the hamster.(ABSTRACT TRUNCATED AT 250 WORDS)