Ovarian folliculogenesis is a dynamic and complex process during which follicles undergo tremendous growth and maturation. Beginning as a single layer of pregranulosa cells surrounding the immature oocyte, granulosa cells actively proliferate and differentiate until the time of ovulation. The proliferation of granulosa cells is necessary not only for follicular growth but also for creation of the unique micro-environment for oocyte maturation. Although the primary role of follicle-stimulating hormone (FSH) in granulosa cell growth and function is well established, detailed mechanisms regulating folliculogenesis are not understood. Thus, in this study the role of several growth factors, such as thyroid hormone, insulin, insulin-like growth factor-I (IGF-I), epidermal growth factor (EGF), transforming growth factor-beta (TGF beta) and tumor necrosis factor-alpha (TNF alpha) were evaluated for their potential as endocrine, paracrine and/or autocrine regulators of granulosa cell proliferation and differentiation. Furthermore, the granulosa cell is one of the most rapidly growing normal cell types known, so a possible participation of the myc oncogene in granulosa cell proliferation was assumed. Actually, we have found that myc oncoprotein is expressed in granulosa cells in a stage-limited manner during follicular growth and regression. Abundant expression of myc oncoprotein in granulosa cells was apparent only at the preantral follicle stage. Moreover, c-myc mRNA was expressed abundantly only in the granulosa cells of the less-mature, small follicles. The stage-specific expression of c-myc oncogene in immature granulosa cells early in follicular growth may suggest the intriguing possibility of c-myc oncogene participation in the autonomous growth of the immature follicles during the early stage of folliculogenesis. We have also shown that erb-A oncogene, which encodes a thyroid hormone receptor, was expressed more abundantly in small-follicle granulosa cells than in large-follicle granulosa cells. Thus, it is possible that the expression of these oncogenes, either alone or in combination, may play a role in autonomous granulosa cell proliferation early in follicular development. On the other hand, thyroid hormone, insulin, IGF-I and EGF were found to be act as biological amplifiers (up-regulators) of FSH actions in granulosa cells, whereas TGF beta and TNF alpha were shown to act as down-regulators of FSH actions in granulosa cells. Greater than 99% of ovarian follicles undergo atresia during reproductive life. It has been shown that apoptotic cell death is the molecular mechanism underlying follicle atresia.(ABSTRACT TRUNCATED AT 400 WORDS)