Gonadotropin-releasing hormone as a paracrine hormone and neurotransmitter in extra-pituitary sites

Gonadotropin-releasing hormone (GnRH), in addition to its classical releasing action at the pituitary level, acts on multiple extrapituitary sites to regulate various reproductive functions. In the rat ovary, specific high affinity GnRH receptors have been identified in granulosa and theca cells. These binding sites mediate the inhibitory effects of GnRH and its agonists on gonadotropin-stimulated estrogen, progestin and androgen biosynthesis. At the granulose cell level, GnRH treatment decreases aromatase activity as well as the biosynthesis of pregnenolone and progesterone via inhibition of cholesterol side-chain cleavage and 3 beta-hydroxysteroid dehydrogenase enzymes. High concentrations of GnRH also stimulate low but significant levels of various steroids. In addition, treatment with high concentrations of GnRH induces ovulation and oocyte maturation in hypophysectomized rats. This is associated with the ability of GnRH to stimulate plasminogen activator activity in cultured granulosa cells. In the rat testis, GnRH receptors have been identified in Leydig but not Sertoli cells. Treatment with GnRH inhibits gonadotropin-stimulated androgen biosynthesis by the cultured Leydig cells. The inhibitory effect of GnRH on testicular androgen production occurs at sites distal to the formation of cyclic AMP and pregnenolone and may be due to decreases in the activity of the enzyme 17 alpha-hydroxylase and 17-20 desmolase. Since hypothalamic GnRH is unlikely to act at the gonadal level, several laboratories have attempted to isolate gonadal GnRH-like peptide which may serve as the ligand for specific gonadal GnRH receptors. Although the presence of ovarian GnRH-like substance still remains elusive, testicular GnRH-like substance has been identified. This gonadal peptide(s) may be an important local paracrine hormone. In addition to its action at the gonadal level, GnRH or GnRH-like peptides may play an important role as a neurotransmitter in the central nervous system. Exogenous administration of GnRH in selected brain areas has been shown to modulate sexual behavior in experimental animals, while neural pathways containing GnRH-like immunoreactive substances have been identified in several brain areas. We have recently synthesized a bioluminescent GnRH analog capable of serving as a specific GnRH ligand for a bioluminescent ligand receptor assay which is more sensitive than classical 125I-ligand assays. We have identified GnRH receptors in small, discrete brain regions. Thus, GnRH and GnRH-like peptides may play important paracrine and neurotransmitter roles in the regulation of various reproductive functions in extra-pituitary sites.