GONADOTROPIN-RELEASING-HORMONE REGULATION OF PITUITARY FOLLISTATIN GENE-EXPRESSION DURING THE PRIMARY FOLLICLE-STIMULATING-HORMONE SURGE

Follistatin is produced in the gonadotrope and folliculostellate cells of the pituitary gland and is thought to indirectly regulate FSH bios ynthesis and secretion through its ability to bind activin. Recent mea surements of follistatin gene expression during the rat estrous cycle revealed a marked increase in pituitary follistatin messenger RNA (mRN A) levels at the time of the preovulatory FSH surge. This finding sugg ests a role for follistatin in the regulation of FSH at this dynamic t ime of the cycle. The aim of the present study was to identify the hor monal control mechanisms responsible for stimulating follistatin gene expression on proestrus. In particular, the roles of estrogen (E) and GnRH were assessed using an in vivo ovariectomized (OVX) animal model in which steroid priming results in daily gonadotropin surges. Follist atin mRNA and serum FSH levels were unchanged throughout the day in un treated OVX rats. E priming of OVX rats elicited a 2-fold elevation in follistatin mRNA levels between 1600-2000 h coincident with the peak of the E-induced FSH surge. To determine whether this effect of E on f ollistatin mRNA levels was the result of the direct or indirect effect s of E on the pituitary, follistatin mRNA levels were examined in E-pr imed OVX rats that had been treated with pentobarbital at 1430 h (to b lock hypothalamic neurosecretion). Pentobarbital treatment prevented t he E-induced increase in follistatin mRNA levels, suggesting that the effects of E are mediated via GnRH or other hypothalamic factors. The effects of GnRH on follistatin gene Expression were examined further u sing an in vitro perifusion model. Proestrous or metestrous pituitarie s were perifused for 8 h with pulsatile GnRH (one pulse per h), contin uous GnRH, or medium only. Continuous GnRH treatment resulted in a sig nificant elevation in follistatin mRNA levels in both proestrous and m etestrous pituitaries, whereas pulsatile GnRH had no effect at either cycle stage. These results suggest that the proestrous GnRH surge is r esponsible at least in part for the elevation in pituitary follistatin mRNA levels that is associated with the primary FSH surge. GnRH-induc ed follistatin production on proestrus probably plays a role in the dy namic regulation of FSH at this time of the ovulatory cycle.