Nongenomic actions of steroids on gonadotropin release

The release of gonadotropins is effected by GnRH and regulated by steroids. The classical mechanism of steroid hormone action, which implies the binding of hormone receptor complexes to regulatory elements of nuclear genes, is derived largely from the well-studied and familiar steroids such as progesterone, testosterone, and estradiol. Their effects on gonadotropin release generally have been examined following hours or days of exposure and therefore cannot account for the rapid effects of steroids on gonadotropin release. Moreover, tissues such as gonad, pituitary, and hypothalamus can produce a variety of hormonally active steroids in addition to these well-studied, traditional ones. The recently discovered allylic steroid, 3 alpha-hydroxy-4-pregnen-20-one (3 alpha HP), is readily interconverted from/to progesterone and is found at appreciable levels in serum, gonads, pituitary, hypothalamus, and other tissues. 3 alpha HP has provided the "missing link" in the progesterone biosynthetic/ metabolic pathways, allowing cyclical 4-pregnene and 5 alpha-pregnane pathways to be described for steroidogenic tissues. Among the functions ascribed to 3 alpha HP is the ability to selectively and rapidly (within seconds or minutes) suppress GnRH-provoked FSH release. In vitro studies using pituitary gonadotropes in culture and in perifusion paradigms suggest that suppression of FSH release by 3 alpha HP occurs as a result of nongenomic mechanisms of action. These mechanisms are discussed and include interaction at the level of receptors in the gonadotrope membrane and the cell-signaling pathway involving protein kinase C, phospholipase C, or IP3-induced Ca2+ mobilization and Ca2+ channels. This may be the first evidence of a gonadal steroid regulating gonadotropin release by nongenomic mechanisms of action. In order to understand the critical role of steroids in the rapid regulation of secretory (and bence, circulating) levels of gonadotropins, other gonadal steroids will need to be examined for their nongenomic action on gonadotropes.