Acute modifications in the levels of daytime melatonin do not influence leptin in postmenopausal women

Melatonin shows a clear circadian rhythm with peak values at night, and may act directly with fat cells. Leptin, the anorexic hormone synthesized mainly by adipocytes, is produced in a circadian fashion, similar to that of melatonin. Accordingly, in the present study, we investigated whether melatonin may contribute to the rise in circulating leptin. The study was performed in postmenopausal women with 2 months of treatment with placebo or estradiol (50 microg/day). Melatonin was administered in doses of 1 mg by mouth versus placebo. In experiment 1, melatonin was administered at 08:30 hr. In experiment 2, at 08:30 hr and 10:30 hr, and in experiment 3 at 15:30 hr. Three blood samples, one every 15 min, were collected prior to the administration of melatonin and 2 hr after the administration of the single melatonin dose or the second melatonin administration (experiment 2). Following its administration, circulating melatonin reached pharmacological levels. In the three experiments, levels of leptin were not modified by the daytime administration of melatonin. These data indicate that, at least in daytime hours, acute modifications in daytime melatonin levels do not influence levels of leptin of postmenopausal women either without or with estradiol replacement. Accordingly, the metabolic, endocrine, reproductive and biological modifications induced by acute daytime melatonin in women do not seem to be mediated by modifications in circulating leptin.     

Different circulatory response to melatonin in postmenopausal women without and with hormone replacement therapy

In young men and women, melatonin influences vascular reactivity and reduces blood pressure and norepinephrine levels. Herein, we investigated whether these effects are conserved in postmenopausal women without and with hormone replacement therapy (HRT). Oral melatonin (1 mg) or placebo was randomly and in double blind fashion administered to 18 untreated and 13 postmenopausal women who were treated continuously with transdermal estradiol (50 microg/day) plus cyclic medroxyprogesterone acetate (5 mg/day x 12 days every 28 days). Internal carotid artery pulsatility index (PI), an index of downstream resistance to blood flow, blood pressure and catecholamine levels were evaluated. In untreated postmenopausal women, melatonin was ineffective, while in HRT-treated women, studied during the only estrogenic phase, melatonin reduced, within 90 min, systolic (-8.1 +/- 9.9 mmHg; P = 0.054), diastolic (-5.0 +/- 7.0 mmHg; P = 0.049) and mean (- 6.0 +/- 6.6 mmHg; P = 0.037) blood pressure. Norepinephrine (-50.1 +/- 66.7 pg/mL; P = 0.019), but not epinephrine levels, were also significantly reduced. Similarly, resistance to blood flow in the internal carotid artery, as evaluated by the PI, decreased (-0.190 +/- 0.15; P = 0.0006) in a way that was linearly related to pre-existing PI values (r2 = 0.5; P = 0.0059). These data show that the circulatory response to melatonin is conserved in postmenopausal women on HRT but not in untreated postmenopausal women. Possible physiological and pharmacological implications of these data on the cardiovascular risk of postmenopausal women can be envisioned.     

Pulsatile luteinizing hormone release in postmenopausal women: effect of chronic bromocriptine administration

Pulsatile LH release was studied in 28 healthy postmenopausal women by obtaining blood samples every 5 min for 4 h either basally or after 30 days of bromocriptine (BCT; 3.75 mg/day; n = 14) or placebo (n = 14) administration. Basally, mean plasma LH levels were 46.3 +/- 3.5 (+/- SE) and 53.4 +/- 4.6 mIU/mL in the BCT and placebo groups, respectively. Mean LH pulse frequencies were 4.2 +/- 0.3 and 4.0 +/- 0.4 pulses/4 h, mean pulse amplitudes were 19.2 +/- 1.9 and 20.1 +/- 1.5 mIU/mL, and mean interpulse intervals were 54.3 +/- 3.1 and 54.6 +/- 3.2 min in the two groups, respectively. BCT administration induced no significant changes in mean plasma LH levels, but it significantly (P less than 0.01) decreased LH pulse frequency (1.7 +/- 0.3 pulses/4 h) and amplitude (12.7 +/- 0.8 mIU/mL) and significantly (P less than 0.01) increased mean interpulse interval (126.1 +/- 17.5 min). Placebo administration did not induce any significant changes in pulsatile LH release. These results demonstrate that in postmenopausal women LH secretion is circhoral, and BCT administration can blunt LH pulsatility, suggesting dopaminergic regulation of the GnRH-LH pulse generator.     

Altered neuroendocrine regulation of luteinizing hormone secretion in postmenopausal women with Parkinson's disease.

The secretion of gonadotropins and the role exerted by the endogenous opioid system on luteinizing hormone (LH) secretion were investigated in 6 postmenopausal women affected by idiopathic Parkinson's disease (PD) as well as in 6 age- and weight-matched normal postmenopausal women as controls. The mean plasma follicle-stimulating hormone (FSH) and LH levels were evaluated both under basal conditions and after 20 days of conjugated estrogen administration (1.25 mg/day). At the same time, the activity of the endogenous opioid system was evaluated, as well as the LH response to the 4-hour infusion of the opioid antagonist naloxone (1.6 mg i.v. bolus followed by 1.6 mg/h). Both before and during estrogen administration, plasma FSH levels were similar in the two groups of subjects, whereas plasma LH levels were significantly lower (p less than 0.01) in parkinsonian than in control women. In each subject estrogen administration significantly blunted (p less than 0.01) plasma FSH levels. Plasma LH levels were reduced only in controls (p less than 0.05), but not in women with PD. In each subject, before estrogen administration, the plasma LH levels did not vary during naloxone infusion. In control women after 20 days of estrogen administration, the plasma LH levels significantly increased during naloxone infusion (p less than 0.01). By contrast, in women with PD, conjugated estrogens failed to restore the LH response to naloxone. The present results suggest that the neurotransmitter mechanisms, which regulate LH secretion, are altered, and, in particular, the activity of the endogenous opioid system is deficient in women with PD.     

Effects of transdermal 17 beta-estradiol treatment and naloxone infusion on gonadotropin response to gonadotropin-releasing hormone in postmenopausal women

Estrogens exert both inhibitory and stimulatory effects on the secretion of GnRH and gonadotropins in women. The endogenous opioid peptides seem to mediate, at least in part, the inhibitory action exerted by estrogens on LH secretion. However, the mechanisms that mediate the stimulatory effect of estrogens on LH secretion are still unclear. The present study was performed to evaluate whether the endogenous opioid peptides could also participate in the stimulatory effect that estrogens exert on the gonadotropin response to GnRH. In postmenopausal women, a GnRH test was performed both under basal conditions and during the second month of treatment with transdermal 17 beta-estradiol (E2). In untreated postmenopausal women, two different doses of naloxone infusion failed to modify the LH and FSH responses to GnRH stimulation. During treatment with transdermal E2, the LH response to GnRH was significantly increased, while the FSH response was similar to that before treatment. Naloxone completely counteracted the enhanced LH response to GnRH observed during E2 treatment. On the other hand, naloxone did not significantly modify the FSH response to GnRH. The present results confirm that E2 exerts a sensitizing effect on the pituitary LH response to GnRH and suggest that the endogenous opioid system could be involved in this effect.     

Melatonin: a major regulator of the circadian rhythm of core temperature in humans.

The circadian rhythm of core body temperature (BTc), with maxima during the day and minima at night, is normally coupled with the sleep-wake cycle. Pineal melatonin secretion occurs contemporaneously during the nighttime hours and is mediated by the activation of beta-adrenergic receptors during darkness. The hypothesis that nocturnal melatonin secretion may be involved in the regulation of the human circadian BTc rhythm was examined. The temporal relationship between melatonin and the circadian BTc rhythm was characterized in 12 young women, normally entrained to the light-dark cycle. Melatonin levels were manipulated through the administration of exogenous melatonin (2.5 mg, orally) during the daytime (n = 6) or suppression of endogenous nocturnal melatonin secretion by the beta-adrenergic antagonist atenolol (100 mg; n = 6) in double blind placebo-controlled experiments conducted during 2 consecutive days. Serum melatonin levels and BTc were monitored at 20- and 10-min intervals, respectively. In a nightshift worker the temporal relationship between the circadian rhythm of melatonin and BTc was investigated before and after entrainment to a reversed wake-sleep cycle. Our data show that in normally entrained subjects, the time course and amplitude of nocturnal melatonin secretion were temporally coupled with the decline of BTc (r = 0.97; P less than 0.00001). The same occurred in the nightshift worker, both during the dissociation and after entrainment to the reversed sleep-wake cycle. Compared with placebo, administration of melatonin significantly reduced daytime BTc (P less than 0.01), and the suppression of melatonin (by atenolol) attenuated the nocturnal decline of BTc (P less than 0.01). Cosinor analysis showed that the amplitude of the circadian BTc rhythm was reduced by about 40% in response to both daytime melatonin administration (P less than 0.05) and nocturnal melatonin suppression (P less than 0.02). In conclusion, circadian rhythms of melatonin and BTc are inversely coupled. The demonstrated hypothermic properties of melatonin are accountable for the generation of at least 40% of the amplitude of the circadian BTc rhythm. Manipulation of melatonin levels might be clinically useful to resynchronize the BTc rhythm under conditions of BTc rhythm desynchronization.     

Sex steroids modulate prolactin response to naloxone in postmenopausal women

To evaluate whether ovarian steroids modify the prolactin (PRL) response to opioid receptor blockade, the effects of naloxone infusion (1.6 mg/h for 4 h) on PRL secretion were studied in 5 postmenopausal women. Naloxone infusion was performed in basal conditions and after chronic oral treatment with conjugated estrogens (CE) (1.25 mg/day, for 20 days) or CE plus medroxyprogesterone acetate (MPA) (10 mg/day, for 20 days). Under basal conditions, 17 beta-estradiol, estrone, gonadotropin, and PRL plasma levels were in the normal range for postmenopausal women, and naloxone failed to affect PRL secretion. Naloxone induced a significant PRL increase after CE treatment alone (p less than 0.001) or in combination with MPA (p less than 0.001). The increase was significantly higher (p less than 0.05) after CE + MPA treatment than after CE treatment alone. These data suggest that steroids modulate the stimulatory effect of naloxone on PRL secretion in postmenopausal women.     

Amplification of pulsatile LH secretion by exogenous melatonin in women

The effect of melatonin on pulsatile LH secretion was investigated in early follicular phase women (days 2-5). During two consecutive days, at 0800 hrs., subjects received placebo or oral melatonin in a random double-blind fashion. Two doses of melatonin were used; 100 mg single dose (N = 6) or 2.5 mg in three divided doses (N = 5), (1 mg at 0800 hrs., 0.75 mg at 1000 and 1200 hrs.). Blood samples were collected every 10 minutes, between 0900-1700 hrs. Compared with placebo, melatonin administration augmented LH pulse amplitude (p less than 0.01) without changing LH pulse frequency. The integrated LH secretion was significantly increased (p less than 0.01) after melatonin, independent of doses administered. Serum FSH and ovarian steroids were not altered. It is concluded that exogenous melatonin enhances LH pulse amplitude in women, without modifying FSH and ovarian steroid levels.     

Chronic bromocriptine administration restores luteinizing hormone response to naloxone in postmenopausal women

To evaluate whether dopaminergic treatment may modify endogenous opioid activity at the hypothalamic-pituitary level, the effects of naloxone infusion (1.6 mg/h for 4 h) on luteinizing hormone (LH) secretion were studied in 5 postmenopausal women either before or after chronic administration of the dopaminergic drug bromocriptine (BCT; 5 mg/day for 30 days). BCT administration did not modify mean plasma LH levels. Before treatment naloxone infusion did not induce any significant modification of LH secretion. Conversely, after chronic BCT administration naloxone induced a significant (p less than 0.05) increase in plasma LH levels. The LH response to naloxone was significantly (p less than 0.001) higher than that observed before BCT. The present data show that chronic BCT administration restores the LH response to naloxone in postmenopausal women. Therefore, these results seem to demonstrate that BCT administration can enhance opioid activity, suggesting an involvement of the endogenous opioid system in dopaminergic modulation of gonadotropin release.