Discussions

Previous researchers failed to document an effect of melatonin on reproductive axis of adult rats(9,16). Moreover, the studied day/night moments, different from those we used, may have determined melatonin's failure to influence testosterone and gona-dotropin secretion. In our study, after melatonin treatment, the plasma testosterone concentrations at 10 a.m. were similar to control group (Figure 1), while at 10 p.m. and 2 a.m., were significantly changed. Melatonin treatment induced a biphasic response of testosterone secretion; at 10 p.m., 2 hours after the onset of darkness, the high testosterone levels were significantly reduced by melatonin treatment, while at 2 a.m. the low testosterone levels were significantly stimulated. Our studies on adult rats,

Figure 5. Urinary LH (mIU/h) values in sexual dysfunction.
Figure 6. Urinary FSH (mIU/h) values in sexual dysfunction.

have shown that the selected moments of the light/dark cycle are critical for the evidence of melatonin action, suggesting an interaction between the light/dark cycle, melatonin secretion and the responsiveness to melatonin. The biphasic response to exogenous melatonin after the onset of night could be related with endogenous melatonin nocturnal activity.

This progonadal or antigonadal influence of melatonin suggests that melatonin is able to modulate reproductive activity. However, the mechanism by which melatonin modulates testosterone secretion cannot be explained by a simple down-regulation of melatonin receptors.

Our previous studies have shown that melatonin administration in the morning did not alter the testosterone and raised levels of LH and FSH induced by GnRH treatment (3). The present study showed that melatonin administration 2 h after the onset of darkness and at l a.m. significantly decreased the high LH and FSH levels induced by GnRH treatment. The antigonadotropic effect of melatonin was dose-dependent.

These results support the hypothesis that melatonin acts at hypothalamic and/or pituitary level (5,7,11,13). Melatonin treatment during the juvenile and pubertal periods decrease the hypothalamic GnRH and suppress the pubertal peak of pituitary GnRH receptor number. It also reduces pituitary LH content and almost completely suppresses the pubertal peak of FSH secretion (5,7,9,13).

However, an additive direct action of melatonin on gonadal steroidogenesis cannot be excluded. Our studies on castrated and testosterone treated rats have shown changes in pineal melatonin levels. At 62 hours after castration, the pineal melatonin concentrations were significantly decreased, nocturnal values were close to those measured during the day. Testosterone administration significantly reduced the inhibitory effect of castration upon melatonin production. The melatonin concentrations returned to the melatonin levels in sham-castrated rats. Interestingly, the pineal melatonin was lower in sham-castrated rats as compared to intact rats but the circadian pattern was preserved. The decrease of melatonin production in sham castrated rats supports the findings that stress induces changes in melatonin production.

Our data confirm the existence of a reciprocal modulation between the hypo-thalamic-pituitary-gonadal axis and pineal gland. Also, they show that the timing of studied points within the light/dark cycle is critical for the evidence of melatonin action in adult male rats and also suggest an interaction between the light/dark cycle, melatonin secretion and responsiveness to MLT.

As regarding the clinical studies, our results support the evidence of correlations between melatonin and the reproductive system status in humans. Considering our results regarding the sexual maturation and the present results, melatonin production seems to be an important hormonal signal for the reproductive system. In addition, the oral treatment with 2.5 mg of melatonin taken before bedtime (10-11 p.m.) for a month, yielded the improvement of sexual dynamics and spermatogenesis in subjects with sleep disorders.

Taken together these studies again convincingly establish that the reproductive system is pineal dependent. These results support the concept that melatonin is an evolutionary stable timing signal to which each species has adapted the timing of physiological processes.

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