Potential Harmful Effects of Melatonin
Significant Findings:
"Acute melatonin administration in humans impairs glucose tolerance in both the morning and evening. When administering melatonin, the proximity to meal timing may need to be considered, particularly in those at risk for glucose intolerance."
Abstract:
To study the effect of melatonin administration on glucose metabolism in humans in the morning and evening.
Placebo-controlled, single-blind design.
Laboratory assessments.
21 healthy women (24 ± 6 y; body mass index: 23.0 ± 3.3 kg/m2).
Glucose tolerance was assessed by oral glucose tolerance tests (OGTT; 75 g glucose) on 4 occasions: in the morning (9 AM), and evening (9 PM); each occurring 15 minutes after melatonin (5 mg) and placebo administration on 4 non-consecutive days.
Melatonin administration impaired glucose tolerance. When administered in the morning, melatonin significantly increased the incremental area under the curve (AUC) and maximum concentration (Cmax) of plasma glucose following OGTT by 186% and 21%, respectively, as compared to placebo; while in the evening, melatonin significantly increased glucose AUC and Cmax by 54% and 27%, respectively. The effect of melatonin on the insulin response to the OGTT depended on the time of day (P < 0.05). In the morning, melatonin decreased glucose tolerance primarily by decreasing insulin release, while in the evening, by decreasing insulin sensitivity.
Acute melatonin administration in humans impairs glucose tolerance in both the morning and evening. When administering melatonin, the proximity to meal timing may need to be considered, particularly in those at risk for glucose intolerance.
Full Study: https://academic.oup.com/sleep/article/37/10/1715/2416885?
Influence of Melatonin Administration on Glucose Tolerance and Insulin Sensitivity of Postmenopausal Women
Significant Findings:
"The present results indicate that in aged women administration of 1 mg of melatonin reduces glucose tolerance and insulin sensitivity."
Abstract:
The effect of melatonin on human carbohydrate metabolism is not yet clear. We investigated whether melatonin influences glucose tolerance and insulin sensitivity in aged women.
Twenty-two postmenopausal women of whom 14 were on hormone replacement therapy.
After an overnight fast, at 0800 hours on two nonconsecutive days, placebo or melatonin (1 mg) were administered randomly and in a double blind fashion. Forty-five minutes later, an oral glucose tolerance test (75 g; OGTT) was performed in 13 women. In another nine women insulin-dependent (Si) and -independent (Sg) glucose utilization was tested by a frequently sampled intravenous glucose tolerance test (FSIGT).
Areas under the response curve to OGTT (AUC) for glucose (1420 ± 59 vs. 1250 ± 55 mmol × min/l; P < 0·01), and C-peptide (420980 ± 45320 vs. 33528 ± 15779 pmol × min/l; P < 0·02) were higher following melatonin than placebo, while Si values were lower (2·6 ± 0·28 units vs. 3·49 ± 0·4 units; P < 0·03). Si modifications induced by melatonin were inversely related to Si values of the placebo day (r2 = 0·538; P < 0·025).
The present results indicate that in aged women administration of 1 mg of melatonin reduces glucose tolerance and insulin sensitivity. The present data may have both physiological and clinical implications.|
Full Study: https://onlinelibrary.wiley.com/doi/abs/10.1046/j.1365-2265.2001.01232.x
Loss of Response to Melatonin Treatment is Associated With Slow Melatonin Metabolism
Significant Findings:
"We hypothesize that loss of response to melatonin treatment can be caused by slow metabolization of exogenous melatonin. In patients with loss of response to melatonin, a melatonin clearance test should be considered and a considerably dose reduction is advised."
Abstract:
Background
In some of our patients with intellectual disability (ID) and sleep problems, the initial good response to melatonin disappeared within a few weeks after starting treatment, while the good response returned only after considerable dose reduction. The cause for this loss of response to melatonin is yet unknown. We hypothesise that this loss of response is associated with slow melatonin metabolism.
Method
In this study, we determined melatonin clearance in two female (aged 61 and 6 years) and one male (aged 3 years) patients who had chronic insomnia, late melatonin onset and mild ID, and whose sleep quality worsened a few weeks after initial good response to melatonin treatment, suggesting melatonin tolerance. After a 3-week washout period, patients received melatonin 1.0, 0.5 or 0.1 mg, respectively. Salivary melatonin level was measured just before melatonin administration, and 2 and 4 h thereafter. After this melatonin clearance test, melatonin treatment was resumed with a considerably lower dose.
Results
In all patients melatonin concentrations remained >50 pg/mL at 2 and 4 h after melatonin administration. After resuming melatonin treatment sleep problems disappeared. The same procedure was followed in three patients who did not show loss of response to melatonin after 6 months of treatment. In all patients in the control group melatonin concentrations decreased between 2 and 4 h after melatonin administration with a mean of 83%.
Conclusion
We hypothesise that loss of response to melatonin treatment can be caused by slow metabolisation of exogenous melatonin. As melatonin is metabolised in the liver almost exclusively by cytochrome P450 enzyme CYP1A2, this slow melatonin metabolism is probably due to decreased activity/inducibility of CYP1A2. In patients with loss of response to melatonin, a melatonin clearance test should be considered and a considerably dose reduction is advised.
Full Study: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2788.2010.01283.x
Inhibitory Effect of Melatonin on Testosterone Synthesis is Mediated Via GATA-4/SF-1 Transcription Factors
Significant Findings:
" Overall, the data suggest that the inhibitory effects of melatonin on testosterone production are mediated via down-regulation of GATA-4 and SF-1 expression."
Abstract:
The aim of the present study was to elucidate whether the GATA-4/SF-1 signalling pathway is involved in the inhibitory effects of melatonin on testosterone production in both the TM3 Leydig cell line and in C57BL/6J mice. In-vitro experiments demonstrated that melatonin treatment significantly reduced testosterone levels in cell culture medium (P < 0.05 or P < 0.01); and decreased intracellular cyclic adenosine monophospha accumulation (P < 0.05 or P < 0.01) and mRNA/protein expression of GATA-4, SF-1 (NR5A1), StAR, P450SCC (CYP11A1) and 3β-HSD (P < 0.05 or P < 0.01). These effects were blocked by N-acetyl-2-benzyltryptamin, a melatonin receptor antagonist. Similar effects of melatonin on testosterone production (P < 0.05 or P < 0.01) and down-regulation of transcription factors GATA-4 and SF-1 (P < 0.01) were also observed in mice treated with intratesticular injections of melatonin. Overall, the data suggest that the inhibitory effects of melatonin on testosterone production are mediated via down-regulation of GATA-4 and SF-1 expression.
Full Study:
https://www.sciencedirect.com/science/article/abs/pii/S1472648315003740
A Novel Mechanism for the Melatonin Inhibition of Testosterone Secretion by Rat Leydig Cells: Reduction of GnRH-induced Increase in Cytosolic Ca2+
Significant Findings:
" We conclude that melatonin reduces GnRH-induced testosterone secretion by 1) decreasing [Ca(2+)](i), through impairment of the GnRH-dependent release of Ca(2+) from intracellular stores and 2) blocking 17-20 desmolase enzymatic activity, an effect that occurs irrespective of changes in [Ca(2+)](i)"
Abstract:
The site of inhibition, by melatonin, of GnRH-dependent testosterone secretion was investigated in adult rat Leydig cells cultured in vitro. The various effects downstream of the binding of GnRH to its own receptor were isolated and mimicked by specific drugs. Testosterone secretion was then evaluated after 3 h stimulation with GnRH, thapsigargin (1 microM), phorbol-12-myristate-13-acetate (100 nM), arachidonic acid (20 microM), and ionomycin (1 microM) in the presence or absence of melatonin (215 nM). The effect of melatonin on the GnRH-induced changes in cytoplasmic calcium concentration ([Ca(2+)](i)) was also studied, using Fura-2 as fluorescent Ca(2+) indicator. Melatonin attenuated the increase in [Ca(2+)](i) and inhibited the testosterone secretion induced by GnRH, but not that induced by ionomycin. Both ionomycin and thapsigargin potentiated GnRH-induced testosterone secretion; however, ionomycin, but not thapsigargin, partially prevented the inhibitory effect of melatonin on cells stimulated with GnRH. The effect of melatonin was probably dependent on the binding of melatonin to its Gi-protein-coupled receptor, as the inhibitory effect on GnRH-induced secretion was supressed in cells pretreated with pertussis toxin in a concentration of 180 ng/ml for 20 h. Assay of 17-hydroxy-progesterone showed that, irrespective of the treatment, cells cultured with melatonin secreted greater amounts than controls. We conclude that melatonin reduces GnRH-induced testosterone secretion by 1) decreasing [Ca(2+)](i), through impairment of the GnRH-dependent release of Ca(2+) from intracellular stores and 2) blocking 17-20 desmolase enzymatic activity, an effect that occurs irrespective of changes in [Ca(2+)](i).
Full Study: https://pubmed.ncbi.nlm.nih.gov/10601975/