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 biosynthesis and secretion through its ability to bind activin. Recent measurements of follistatin gene expression during the rat estrous cycle revealed a marked increase in pituitary follistatin messenger RNA (mRNA) levels at the time of the preovulatory FSH surge. This finding suggests a role for follistatin in the regulation of FSH at this dynamic time of the cycle. The aim of the present study was to identify the hormonal 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. Follistatin mRNA and serum FSH levels were unchanged throughout the day in untreated 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 follistatin mRNA levels was the result of the direct or indirect effects of E on the pituitary, follistatin mRNA levels were examined in E-primed OVX rats that had been treated with pentobarbital at 1430 h (to block hypothalamic neurosecretion). Pentobarbital treatment prevented the 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 using an in vitro perifusion model. Proestrous or metestrous pituitaries were perifused for 8 h with pulsatile GnRH (one pulse per h), continuous GnRH, or medium only. Continuous GnRH treatment resulted in a significant elevation in follistatin mRNA levels in both proestrous and metestrous pituitaries, whereas pulsatile GnRH had no effect at either cycle stage. These results suggest that the proestrous GnRH surge is responsible at least in part for the elevation in pituitary follistatin mRNA levels that is associated with the primary FSH surge. GnRH-induced follistatin production on proestrus probably plays a role in the dynamic regulation of FSH at this time of the ovulatory cycle.