Paracrine mechanisms involved in granulosa cell differentiation

Since the heterogeneous development of individual follicles in a given ovary cannot be accounted for by changes in circulating gonadotropin levels, local modulatory factors play an important role in the paracrine control of follicular development. The important paracrine role of ovarian steroids has been well established. Oestrogen is important in the augmentation of gonadotropin action. High local concentration of oestrogens enhances the gonadotropin stimulation of aromatase activity, resulting in further increases in oestrogen production. The elevated local oestrogens in the follicular fluid are also capable of enhancing the FSH induction of LH receptors. Similar to oestrogens, local high concentrations of progesterone may enhance the gonadotropin stimulation of progesterone biosynthesis in granulosa and luteal cells. This positive autofeedback mechanism is believed to be important for the autonomy of luteal cell steroidogenesis. Ovarian actions of androgens are diverse. In the absence of FSH, androgens exert mainly negative effects at the follicular level by causing atresia and granulosa cell death, whereas in the presence of FSH, androgens augment FSH stimulation of progesterone and oestrogen biosynthesis. Since androgen and oestrogen appear to antagonize each other's actions, the ratio of these two steroids is important in determining the fate of an individual follicle. In contrast to ovarian steroids, the role of ovarian peptides as paracrine signals is less clear. In vitro studies clearly demonstrated that GnRH exerts both stimulatory and inhibitory actions on follicular functions, while IGF-I and VIP stimulate ovarian steroidogenesis. The actions of these peptides are presumably mediated through specific granulosa cell receptors that have been tentatively identified. It is presumed that GnRH and IGF-I may be produced by ovarian cells, while VIP may be derived from ovarian nerves. It is anticipated that new methodologies will be developed to study individual follicles as independent units, capable of synthesizing hormones, releasing them, and exerting local paracrine functions.