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It has become increasingly evident that disturbances of the hypothalamic-pituitary-testicular axis account for only a small percentage of male infertility cases (Bartlett et al., 1989). A number of factors have been associated to testicular paracrine regulation but their physiological significance must be examined. In the last decades, the major topics on testicular research have been focused on regulation of steroidogenesis. Particularly, the fine tunning exerted by local substances at the cellular level has been taking into account. In the last years, it has been described the presence and influence of neurotransmitters (N-T) on the gonadal activity at the different stages of sexual development. In addition to the well established actions of different N-T and neuropeptides in the vertebrate central and peripheral nervous systems (Gershon et al., 1977), recent data indicate that significant levels of these compounds are also found in many non neural tissues including sexual organs (Verbeuren, 1989; Zhu et al., 1995). In this context, serotonin (5-HT) has been described in the gonads and accessory reproductive organs of several species (Sowerbutts et al., 1986). Our laboratory initially demonstrated the presence of 5-HT and its main metabolite 5-hydroxyindoleacetic acid (5-HIAA) in rat testes, the influence of 5-HT on rat testicular steroidogenesis, and the existence of 5-HT specific binding sites (Campos et al., 1988). 5-HT was found in rat testicular capsule, interstitial cells as well as in the interstitial fluid, but not in the tubular compartment (Campos et al., 1990). The golden (Syrian) hamster is a seasonal breeder and consequently the pituitary-testicular axis undergoes annual cyclic variations (Desjardins et al., 1971; Bartke, 1985). Thus, the golden hamster represents a versatile experimental model where changes in the photoperiod can greatly alter male gonadal function. It is well known that when golden hamsters are exposed to short-day photoperiods (SP less than 12.5 h light/day) undergo a morphological and physiological testicular regression followed by a spontaneous recrudescence phase. The SP-induced gonadal regression is accompanied by a marked decrease in serum levels of FSH, LH and prolactin (Bex et al., 1978; Frungieri et al., 1996) as well as a decrease of serum and intratesticular androgen concentrations (Chandrashekar et al., 1989; Frungieri et al., 1996). We have demonstrated that levels of 5-HT and 5-HIAA in hamster testicular parenchyma and capsule are significantly elevated at ages of 36 and 60-90 days, but decreased markedly during their exposure to SP. Thus, testicular 5-HT concentration increases at prepubertal and adult ages when high circulating levels of 3a-androstane,17b-diol (3a-Diol) and testosterone are detected (Frungieri et al., 1999). In addition, we have demonstrated that in vitro basal and hCG-stimulated testosterone production is significantly inhibited in presence of physiological concentrations of 5-HT via its binding to 5-HT2 and 5-HT1A receptors. This mechanism also involves induction of CRH secretion by 5-HT. In fact, CRH via CRH-R1 receptors has inhibitory actions on testicular steroidogenesis since incubation of hamster Leydig cells with the a-helical CRH antagonist partially or totally reverted the modulatory action of CRH, 5-HT and 5-HT1A / 5-HT2 agonists on the production of cAMP and testosterone (Frungieri et al., 2002). Therefore, the previous results in rat testes (Tinajero et al., 1992) and our data in hamsters, suggest that 5-HT acts as a regulator of the steroidogenesis during sexual development and the photoperiodic induced regression / recrudescence transition of the golden hamster. It is known that mast cells contain 5-HT in their secretory granules. Frungieri et al. (1999) have shown that, in the golden hamster testes, mast cells are localized mainly in the capsule near to the blood vessels. Furthermore, the number of testicular mast cells increases in an age-dependent manner concomitantly with sexual maturation processes. On the other hand, the exposure to SP significantly decreased testicular mast cells number in the capsule. In addition, we also detected immunoreactivity of 5-HT and its key biosynthetic enzyme, tryptophan hydroxylase, in hamster Leydig cells supporting a role of this amine in the regulation of testicular steroidogenesis. Nerve endings in the testicular capsule and the spermatic arteries that penetrate into testicular parenchyma have also been postulated as testicular sources of 5-HT (Dufau et al., 1993; Setchell et al., 1994). The pineal hormone melatonin (Mel) mediates the influence of photoperiod on the reproduction of many mammalian species. Whether the day-light signal is interpreted as anti- or pro-gonadotropic will depend on a) the species, b) the duration of night Mel peak, c) the magnitude of the night Mel peak, and / or d) the window of sensitivity to Mel (Arendt, 1988). Since the Syrian hamster is a seasonal breeder, Mel plays a key role in the regulation of the reproductive function (Bartke, 1985) through the hypothalamic-pituitary axis. The pineal Mel is released into the circulation almost entirely at night and reaches peripheral tissues including the testes. Moreover, there are evidences for the local synthesis of Mel in testes (Tijmes et al., 1996). We have investigated the role of Mel on testicular steroidogenesis in hamsters. Those studies showed an inhibitory effect of Mel on camp and androgen production via its binding to Mel1a receptors and its interactions with the local CRH system (Frungieri et al., 2005). Previously, Mel binding sites have been found in rat and avian testes (Valenti et al., 2001). Furthermore, the effect of Mel on testicular testosterone synthesis involves down-regulation of StAR and steroidogenic enzymes expression (P450scc, 3b-HSD, 17b-HSD) (Frungieri et al., 2005). N-T receptors are often co-localized on neuron membranes with other receptors, an activation of one receptor can either amplify or antagonize the response involving a co-localized receptor (Wang et al., 1999). In this context, the behavioural and biochemical effects of central 5-HT2A receptor activation are modulated by other 5-HT receptor subtypes (5-HT1A) as well as by stimulation of receptors of other N-T and hormones such as norepinephrine (b-adrenergic) and melatonin (Eison et al., 1995). Our studies have demonstrated for the first time a similar cross talk between N-T, hormones and factors at the testicular level. In this context, we have found that the serotoninergic and melatonergic inhibition of camp and testosterone production is exerted though specific receptors (5-HT2 and Mel1a, respectively) localized on Leydig cells by cross-interaction with the testicular CRH /CRH-R1 system (see details in Fig. 1) (Frungieri et al., 2002; Frungieri et al., 2005). Nevertheless, more studies are required before the biological relevance of our results and, consequently the role of local action of 5-HT, melatonin and CRH in the hamster testis can be placed in its proper perspective. We have also identified the expression of all components of those systems in human testes (Frungieri et al., 2005) but whether their role in the seasonal breeder golden hamster can be extended to non seasonal reproductive mammalian species including man remains to be clarified.