Multiple levels of melatonin action on the reproductive system: evidence contributed by recent melatonin receptor studies

Abstract

Melatonin synchronizes seasonal reproduction in animals. In some mammals, melatonin also plays an important role on pubertal development. It has been hypothesized that melatonin acts on multiple sites in the hypothalamic-pituitary-gonadal-reproductive tract axis. The best documented site of melatonin action is the hypothalamus. Melatonin receptors have been demonstrated consistently in the suprachiasmatic nuclei (SCN) of almost all animals studied. In the rat, SCN has the mt1 (Mel1a) melatonin receptor subtype. These receptors link to adenylyl cyclase and cross-talk with GABA and vasoactive intestinal peptide. Whether these molecular mechanisms are related to melatonin modulation of GnRH release remains to be determined. The pituitary is another major site of melatonin action. However, in many animal species, melatonin receptors appeared to localize in the pars tuberalis and not in the anterior pituitary. The function of the pars tuberalis awaits investigation. Recently, MT2 (Mel1b) receptor subtype was demonstrated in anterior pituitary cells from neonatal rats. In addition to the modulation of LH release in neonatal pituitary cells, melatonin also inhibited TRH-induced prolactin release from rat anterior pituitary cell cultures. The intracellular mechanism of melatonin action on anterior pituitary cells involves cAMP and [Ca2+]i pathways. This modulatory action of melatonin on the neonatal anterior pituitary may be important on the pubertal development of some animals. In gonads, melatonin receptors of both MT2 and mt1 receptor subtypes have been demonstrated in preliminary studies. These receptors may be important in the modulation of steroidogenesis in ovaries and testes reported earlier. Melatonin receptors are also present in the epididymis, vas deferens and prostate in the male and the uterus and mammary gland in the female. With the exception of the mammary gland where low affinity melatonin receptors have been reported, high affinity melatonin receptor, mt1 and/or MT2 subtypes have been demonstrated in male or female reproductive tracts. In the epididymis and uterus, high affinity melatonin receptors are linked to Gi-protein and adenylyl cyclase. In addition epididymal and uterine melatonin receptors are modulated by sex steroids and/or cross-talk with catecholamines. It appears that melatonin receptors are expressed in the hypothalamic-pituitary-gonadalreproductive tract axis during different stages of development in many animal species. The above findings are consistent with the hypothesis of multiple levels of melatonin action on the reproductive system. Further studies on the molecular mechanisms of melatonin action at different levels on the hypothalamic-pituitary-gonadal-reproductive tract axis may provide important insights on the physiological control of pubertal development and/or seasonal reproduction in animals.