The goal of this project was to dissect the mechanisms by which the brain and gonads interact to control gonadotropin secretion and reproductive function. We concentrated on the role of inhibin as a feedback regulator of luteinizing hormone (LH). Stimulation of ovarian function through exogenous FSH administration suppresses the preovulatory surges of both LH and fSH in a number of species including humans. This phenomenon was demonstrated to be the result of an unknown ovarian factor designated gonadotropin surge-inhibiting factor (GnSIF). Inhibin immunoreactivity was found to be significantly elevated in rats receiving an FSH treatment protocol known to increase GnSIf activity. FSH-stimulation of female rats was observed to completely prevent the preovulatory LH and FSH surges; however, in FSH-stimulated rats subsequently treated with anti-inhibin serum, normal preovulatory surges were observed. The results indicate that inhibin is the factor responsible for the suppression of the preovulatory gonadotropin surges in FSH-stimulated rats and may be the long sought, clinically important GnSIF. In related studies, we demonstrated that FSH-stimulation suppressed the development of LHRH self-priming of the pituitary which occurs on proestrus following multiple LHRH exposures. Immunoneutralization of endogenous inhibin eliminated LHRH self-priming in both FSH-stimulated and normal proestrous females by increasing pituitary sensitivity to LHRH to a maximal level prior to the first exposure to exogenous LHRH. These results demonstrate the importance of inhibin as a modulator of LH secretion during the female estrous cycle and shatter the concept of inhibin as a selective regulator of FSH secretion. Other studies demonstrated that the newly isolated peptide. pituitary adenylate cyclase-activating peptide (PACAP), enhances the gonadotropin-releasing activity of LHRH in cultured pituitary cells. This suggests intriguing possibilities for PACAP both as a modulator of gonadotropin secretion and as a possible probe of intracellular cross-talk within the gonadotrophs. We demonstrated the ability of PACAP to both stimulate cAMP production and regulate a number of secretory functions in cultured Sertoli and ovarian granulosa cells, thus further establishing PACAP as a modulator of reproductive function.
