GONADOTROPIN-RELEASING-HORMONE PULSE FREQUENCY REGULATES EXPRESSION OF PITUITARY FOLLISTATIN MESSENGER-RIBONUCLEIC-ACID - A MECHANISM FOR DIFFERENTIAL GONADOTROPE FUNCTION

Follistatin (FS) is a monomeric glycoprotein that selectively inhibits both secretion of FSH and expression of FSH beta messenger RNA (mRNA), presumably via its ability to bind activin. FS mRNA and protein are present in the gonadotrope, suggesting a local action in regulating FSH beta. Pituitary FS mRNA increases after gonadectomy and at the midcycle gonadotropin surge of the estrous cycle, times of increased GnRH secretion. Thus, the purpose of the present studies was to assess the role of GnRH secretion on the regulation of pituitary FS. To confirm GnRH regulation of FS and to study the role of gonadal steroids, adult male rats were gonadectomized (2-36 h), with some animals receiving either testosterone (T) replacement, LRF-147 (a GnRH antagonist, AC-DTrp(1)-pCl-DPhe(2)-DTrp(3)-Ser(4) Tyr(5)-DArg(6) Leu(7)-Arg(8)-Pro(9)-DAla(10)), or both for 36 h (from the time of castration). Pituitary FS mRNA increased rapidly after castration, with levels rising 3-fold by 12 h and 4-fold by 36 h when compared to intact animals (P < 0.05). This rise was completely abolished by administration of LRF-147 and prevented by T replacement. Because GnRH pulse frequency can selectively regulate FSH beta mRNA expression, we next examined the effect of GnRH pulse interval (8-480 min) on FS mRNA expression. Fast frequency GnRH pulses (8 min), which did not increase FSH beta mRNA, were associated with an increase in FS mRNA (2.5-fold). The 30-min interval increased FS and gonadotropin subunit mRNAs. Slower pulse frequencies (greater than or equal to 120 min), which selectively stimulated a rise in FSH beta mRNA, did not increase FS mRNA. These results indicate that pituitary FS mRNA is regulated by GnRH. In addition, GnRH frequency modulation of pituitary FS provides a mechanism whereby a single hypothalamic GnRH can differentially regulate the gonadotropins, LH and FSH.