Melatonin signalling in male reproductive tissues

Abstract

Melatonin, an evolutionarily conserved photoperiodic signalling molecule secreted by the pineal gland of vertebrates, including humans, is important in the physiological regulation of reproductive fertility in mammals, especially the seasonal breeders. In fact, melatonin is also known as nature’s contraceptive for some seasonal animals. Although humans are non-seasonal breeders, seasonality of human natural conception and birth rates are evident. In humans, as in other species, melatonin possibly plays a critical role in determining a seasonal rhythm of conception by interfering with the reproductive axis. Given that male reproductive research has, until recently, received less attention than studies on female reproductive biology, it may not be surprising that the effect of melatonin on the male reproductive system has not been extensively investigated. Notwithstanding that most of the reported actions of melatonin on the mammalian reproductive functions have been ascribed to modulation of the hypothalamic-pituitary gonadotrophin secretion by the pineal neurohormone, direct action of melatonin on male gonadal cells or peripheral reproductive tissues is supported by recent radio-receptor binding and/or recombinant DNA studies, which demonstrated the existence of specific and functional melatonin receptors in testicular Leydig cells, spermatozoa, prostatic and epididymal epithelial cells. Melatonin signalling in epididymis constitutes an active research area of our group. High affinity 2-[125I] iodomelatonin binding sites, satisfying the pharmacokinetic properties of a specific receptor, are localized in the corpus epididymidis of rats. Testosteroneinduced changes in 2-[125I] iodomelatonin binding to rat epididymis suggest functional interaction between androgen and melatonin signalling in the regulation of epididymal physiology. These high affinity binding sites in rat epididymis have been identified by cDNA cloning to be G protein-coupled MEL1a and MEL1b receptors. In situ hybridization studies have demonstrated that both MEL1a and MEL1b receptor mRNAs are expressed by epithelial cells of rat epididymis. Melatonin receptors expressed by rat epididymal epithelial cells are coupled to pertussis toxin-sensitive Gi proteins. Inhibitory effects of melatonin on forskolinstimulated cAMP accumulation were potentiated by 5•-dihydrotestosterone. Opposing interactions between melatonin and ß-adrenergic receptor signaling in rat epididymal epithelial cells were observed with melatonin inhibiting norepinephrine- and isoproterenol-stimulated cAMP accumulation. To date, our data support a novel modulatory action of melatonin, mediated via androgen-responsive and pertussis toxinsensitive Gi-coupled MEL1a and MEL1b receptors, in adrenergic regulation of rat corpus epididymal epithelial cell functions. We would like to propose that unravelling the mechanisms of melatonin signalling in the regulation of male reproductive physiology may provide us with new leads in the search for a male contraceptive, targeted at the signal transduction pathways of melatonin, for humans in the twenty-first century.