Hypogonadotropic hypogonadism (IGD) and constitutional delayed puberty (DP) share a common pathophysiologic process, i.e. GnRH deficiency. Both conditions are heterogenous and exhibit different grades of GnRH deficiency. To discern whether these disorders of GnRH deficiency are associated with altered melatonin secretion profiles, we compared untreated young males IGD (n = 7) and DP (n = 7) to normal pubertal male controls (n = 6). Serum samples for melatonin, LH, and prolactin concentrations were obtained every 15 min from 1900 h to 0700 h in a controlled light-dark environment with simultaneous sleep recordings. Mean (+/- SD) darktime nocturnal melatonin levels were significantly higher in IGD (259 +/- 73 pmol/L) and DP (217 +/- 29 pmol/L) compared with 182 +/- 69 pmol/L in controls (P < 0.02). So were the mean (+/- SD) peak melatonin levels (410 +/- 117, 327 +/- 97 and 298 +/- 95 pmol/L in IGD, DP, and controls, respectively (P < 0.05). Integrated nocturnal melatonin secretion values (AUC) were also higher in IGD and DP (168 +/- 45 and 134 +/- 28) compared with 119 +/- 45 pmol/min.1 x 10(3) in controls (P < 0.02). The time of melatonin peak and the time of onset of the nocturnal melatonin rise were observed earlier in IGD and DP. Light-time mean (+/- SD) serum melatonin levels were similar in all three groups. No correlations were found between melatonin and LH levels, nor between melatonin and prolactin levels. These data indicate that melatonin secretion is increased in male patients with GnRH deficiency. The lack of correlations between melatonin and LH suggest that circulating sex steroids, rather than LH, modulate melatonin secretion in a reverse fashion.

Recently, we demonstrated that melatonin secretion is increased in untreated male patients with GnRH deficiency. As testosterone (T) can be aromatized to estradiol (E2), and both T and E2 increase during T enanthate treatment, we were interested in determining whether T treatment (when T and E2 levels were well matched with pubertal control values) has an effect on melatonin levels in these patients. We measured nocturnal serum melatonin levels during the administration of 250 mg testosterone enantale/month for 4 months in 12 male patients with idiopathic hypogonadotropic hypogonadism (IGD; n = 6) and delayed puberty (DP; n = 6). Serum samples for melatonin and LH determinations were obtained every 15 min from 1900-0700 h in a controlled light-dark environment. The results of melatonin profiles were compared with the pretreatment values in each group and with values obtained in six normal pubertal male controls. After 4 months of testosterone treatment, all patients attained normal serum testosterone (19.5 +/- 3.7 in IGD vs. 20.8 +/- 4.1 nmol/L in DP) and E2 levels (83 +/- 12 in IGD vs. 84 +/- 9 pmol/L in DP). Serum LH levels were suppressed in all patients during T treatment (0.12 +/- 0.1 in IGD vs. 0.12 +/- 0.2 IU/L in DP). Before T treatment, patient melatonin levels were greater than those in age-matched pubertal controls. Melatonin levels were equal in patients and controls when T and E2 levels were well matched. Mean (+/- SD) dark-time melatonin levels decreased from 286 +/- 23 to 157 +/- 36 pmol/L in IGD and from 217 +/- 32 to 133 +/- 47 pmol/L in DP (vs. 183 +/- 64 pmol/L in controls). The integrated melatonin values decreased to normal (from 184 +/- 16 to 102 +/- 21 in IGD and from 142 +/- 19 to 90 +/- 26 pmol/min.L x 10(3) in DP vs. 119 +/- 61 pmol/min.L x 10(3) in controls). The intraindividual variations in melatonin levels ranged from 7.2-14.5%. These data indicate that male patients with GnRH deficiency have increased nocturnal melatonin secretion. T treatment decreased melatonin secretion to normal levels. The results suggest that in GnRH-deficient male patients, sex steroids, rather than LH, modulate pineal melatonin in a reverse fashion.

To examine the role of melatonin in pathological hyperprolactinemia we compared untreated young females (N = 5) with hyperprolactinemic amenorrhea owing to pituitary microadenoma to healthy female controls (N = 6). Serum samples for melatonin, prolactin, and luteinizing hormone (LH) concentrations were obtained every 15 min from 1900 hr to 0700 hr in a controlled light-dark environment with simultaneous sleep recordings. The mean (+/- SD) light-time period, dark-time period, and the integrated nocturnal melatonin secretion values (area under the curve, or AUC) in patients (51 +/- 11 pmol/L, 157 +/- 33 pmol/L, and 102 +/- 19 pmol/min.L x 10(3), respectively) were similar to the values obtained in controls (79 +/- 39, 165 +/- 44, 111 +/- 31, respectively). The onset of the nocturnal melatonin rise, peak level, and peak time were similar in the two groups. A significant nocturnal prolactin rise was observed in patients (112 +/- 9 vs. 65 +/- 11 micrograms/L, P < 0.006) and controls (19 +/- 2 vs. 10 +/- 3 micrograms/L, P < 0.006). The time of prolactin peak was similar in patients and controls (0424 +/- 3:36 vs. 0350 +/- 2:21) and paralleled that of melatonin (0354 +/- 1:46 vs. 0337 +/- 1:30). The mean +/- SD light-time period, dark-time period, and the AUC values of LH were similar in patients and controls. The number of LH pulses in patients (7.2 +/- 1.9 per 12 hr) were not different from those in controls (7.7 +/- 2.1). The LH pulse interval was 100 +/- 22 min in patients compared with 94 +/- 23 min in controls. The mean (+/- SD) nocturnal estradiol (E2) levels were significantly lower in patients (84 +/- 15 pmol/L) than in controls (224 +/- 77) (P < 0.005). Analysis of LH and melatonin secretory profiles revealed significant pulses for both hormones. No significant relationship was observed between the LH and melatonin pulses. However, a negative correlation between LH pulse amplitude and the number of melatonin pulses (P < 0.04) and a positive correlation between LH amplitude and duration of melatonin pulses (P < 0.04) were observed. Taken together, these data suggest that the suppression of normal ovarian cycles in women with hyperprolactinemic amenorrhea owing to pituitary microadenoma may be mediated by blocking of gonadotropin action by prolactin at the ovarian level; yet it remains possible that chronically elevated prolactin might prevent the LH surge and thus lead to amenorrhea. Pulsatile melatonin secretion is unaltered in these patients, and frequent occurrence of amenorrhea in this population is not mediated by melatonin.