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Melatonin and growth hormone deficiency: A contribution to the evaluation of neuroendocrine disorders
Abstract
Melatonin, a hormone secreted by the pineal gland, constitutes a landmark in neuroendocrine integration. The relationship between melatonin and different pituitary hormones and sex steroids has been studied; however, the relationship between growth hormone (GH) and melatonin remains unclear. Considering that melatonin is an essential component of the so-called "biological clock", related to circadian rhythm, day-night cycle, and sleep-dependent hormonal alterations, and knowing that physiological GH secretion occurs predominantly at night, we decided to evaluate nocturnal melatonin secretion in a group of GH-deficient children and adults on and off replacement therapy. Patients and Methods: We studied 44 patients with GH deficiency (GHD), duly confirmed by pharmacological tests, divided into 4 groups: Group a (Ga ): untreated GHD children; Group b (Gb): GHD children on GH replacement therapy (0.16 mg/Kg/week, stable dose for at least 6 months); Group c (Gc): untreated GHD adults and Group d (Gd): GHD adults on GH replacement therapy (0.1- 0.8 mg/day, to maintain IGF1 between 0 and +2 SDS, stable dose for at least 6 months). All associated hormonal deficits were adequately replaced. Melatonin production was evaluated by measuring the excretion of its major urinary metabolite: 6-Sulphatoxymelatonin (6-SM). Urinary 6-SM was measured (radioimmunoassay, Stockgrand Ltd, Guildford, UK) in nocturnal samples (6PM to 8AM) in all patients. Results: Nocturnal 6-SM levels expressed as μg/unit of time were (mean ± SEM) for the pediatric group: Ga = 6.50 (± 5.10) and Gb = 8.21 (± 5.31) (Mann Whitney test, p = 0.82). For adults: Gc = 2.99 (± 1.17) and Gd = 6.60 (± 2.00) (Mann Whitney test, p = 0.35). Discussion and Conclusions: It is difficult to characterize the relationship between melatonin and GH in healthy individuals; however, the administration of intravenous melatonin stimulates GH secretion in normal adults. In some hypothalamic-pituitary alterations, changes in the secretory pattern of melatonin have been reported, but possible variations in GHD patients have not been thoroughly characterized yet. This led us to evaluate 6-SM concentrations in GH deficient children and adults on and off adequate replacement therapy. One of the major aspects of this study has been the evaluation of baseline 6-SM concentrations, with no physiological or pharmacological stimulation. Even if under the conditions of this study we found no differences in nocturnal excretion of 6-SM between untreated and treated GHD individuals in both groups, this does not rule out the potential existence of differences that might be detected by studying diurnal melatonin secretion and its difference with nocturnal secretion. Such studies may contribute to an understanding of potential chronobiological disorders involved in GH deficiency. Copyright © 2011 por la Sociedad Argentina de Endocrinología y Metabolismo.
... The higher concentration of growth hormone under red light may probably be as a result of enhanced melatonin level in the rats. Melatonin was reported to enhance growth hormone secretion (Zeman et al 1999;Dˆaz et al 2001;Fideleff, et al 2010). In addition, the activities of animals were reported to increase on exposure to red light, and exercise has also been implicated in increasing growth hormone (Meeking, et al 1999). ...
The study investigated the effect of exposure to monochromatic lights (ambient – control, blue, red, yellow, white) on haematology, plasma electrolytes, growth hormone and weight changes in albino rat (Rattus norvegicus). Albino rats were exposed to lights of varying wavelengths (15 watts energy saving fluorescents) from suckling age to 63 days; the light intensity was regulated to 300 lux. An Inverter was used to ensure uninterrupted power throughout the study-period. At the end of 63 days of exposure, blood samples were collected from anaesthetized rats through cardiac puncture into plain bottles (plasma electrolytes analysis) and EDTA-bottles (haematological parameter analysis). Rats were weighed to the
nearest gram on a top-loading Metler electronic balance. Packed Cell Volume (PCV), Red Blood Cell (RBC), White Blood Cell (WBC) counts, Haemoglobin (Hgb) concentration, Mean Corpuscular Haemoglobin (MCH), Mean Corpuscular Heamoglobin Concentration (MCHC), leukocyte differential and platelet counts were estimated by standard haematological methods. Spectrophotometry method was used to analyse plasma electrolyte and Growth Hormone (GH). Data obtained were expressed as means and standard deviation; means were compared using ANOVA and separated using Duncan’s multiple range test at p<0.05. Rat weights were not significantly (p>0.05) affected by exposure to the lights. PCV (%) was significantly different (p<0.05); rats exposed to ambient, blue and red lights recorded significantly (p<0.05) higher values of 42.35, 40.00 and 36.33 respectively; no significant difference (p>0.05) was recorded in the other blood parameters; plasma electrolyte concentrations showed no significant difference (p>0.05) among the rats. The growth hormone concentration was significantly different (p<0.05) with rats exposed to red light having significantly (p<0.05) higher (14.80 mg/ml) concentration. Exposure of albino rats to monochromatic lights of varying wavelengths for 63 days had significant impact on PCV and growth hormone of albino rats.
Keywords: Light wavelengths; monochromatic; haematology; growth hormone; plasma electrolytes.
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.
An interaction between melatonin and adrenocorticotropin (ACTH) seems to occur in humans and both hormones respond to beta-adrenergic stimulation. As in lower animal species, human pineal gland also contains alpha2-adrenergic receptors as does the hypothalamus-pituitary axis. In this study the response of the pineal gland and of the hypothalamus-pituitary-adrenal axis to alpha2-adrenergic stimulation was assessed. Twenty-nine children (21 males, mean age 11.2 +/- 0.6 yr and eight females, mean age 9.1 +/- 1.1 yr) from the University of Granada Hospital were studied. The children were diagnosed as having growth problems but with a normal response of growth hormone (GH) to clonidine test. Changes in plasma levels of ACTH, cortisol and melatonin were evaluated in these children after oral administration of the alpha2-adrenoceptor agonist clonidine (100 microg/m2) or a placebo. Plasma ACTH, cortisol and melatonin were measured before (basal) and at 30, 60 and 90 min after oral clonidine or placebo administration. Hormonal determinations were carried out by commercial radioimmunoassay kits, previously standardised in our laboratory. The results show a significant decrease in plasma ACTH, cortisol and melatonin 30 min after clonidine administration (P < 0.001), reaching lowest values at 90 min after the drug was administered. The reduction in the levels of these hormones is independent of their normal circadian decay since the control group showed a significantly different pattern of behaviour. These data support the existence of an inhibitory alpha2-adrenergic influence on both the pineal gland and the hypothalamus-pituitary-adrenal in children and further support the presence of alpha2-adrenoceptors in the human pineal gland.
The pineal gland in humans is under both alpha- and beta-adrenergic control, although it seems that beta1-adrenoceptors are mainly implicated in melatonin secretion. In the present study, we evaluated the role of beta-adrenergic innervation on melatonin production and its relation with the production of growth hormone (GH). Thirty-four children (15 males and 19 females, mean age 10.5 +/- 0.8 years) from the University of Granada Hospital were studied. The children were included in a protocol for the evaluation of growth delay using the propranolol + exercise test. This standardized test allowed us to study simultaneously the role of an unspecific beta-adrenergic blocker such as propranolol and of an adrenergic stimulus such as exercise on the pineal production of melatonin. Changes in plasma levels of melatonin and GH were determined at basal, 120 and 140 min after the test was applied. Hormonal determinations were carried out by commercial radioimmunoassay kits previously standardized in our laboratory. The results show a significant decrease in plasma melatonin levels at 120 and 140 min after the test (P < 0.05), whereas GH levels increased significantly at 140 min (P < 0.001). The decrease of melatonin levels was a consequence of the test, since in a control group, the circadian decay of melatonin was significantly less pronounced (P < 0.05). These data suggest an inverse relationship between melatonin and GH after the propranolol + exercise test, and the reduction in melatonin may be related to its depletion by exercise-induced oxidative stress.
We critically evaluated the diagnostic value of IGF-I and IGF-binding protein-3 (IGFBP-3) in GH deficiency (GHD) in children and adults using receiver operating characteristic (ROC) plot analysis. Sixty-six children (chronological age, 1.3-15 yr) were studied: 34 GHD and 32 idiopathic short stature (ISS). Ninety-two adults (chronological age, 18-70 yr) were also evaluated: 72 GHD, 34 of childhood onset (AGHD-CO), and 38 of adult onset (AGHD-AO); and 20 healthy volunteers. The SD score (SDS) for IGF-I was calculated from 596 normal subjects (212 children and 384 adults), and the SDS for IGFBP-3 was calculated from 350 normal subjects (212 children and 138 adults). The ROC plot showed that the best IGF-I SDS cut-off line was -1.65 for children [sensitivity (S), 68%; specificity (Sp), 97%, diagnostic efficiency (DEf), 81%], the cut-off line for AGHD was -1.65 for AGHD-CO (S, 91%; Sp, 100%; DEf, 94%), and the cut-off line for AGHD-AO was -1.80 (S, 81%; Sp, 100%; DEf, 88%). For IGFBP-3 SDS, the best cut-off line was -1.80 for children (S, 90%; Sp, 60%; DEf, 78%); it was -1.45 for AGHD-CO (S, 90%; Sp, 75%; DEf, 82%) and -0.90 for AGHD-AO (S, 90%; Sp, 68%; DEf, 77%). An accurate diagnosis was obtained using IGF-I SDS alone in GHD children 65%; ISS, 97%; AGHD-CO, 92%; AGHD-AO, 86%, with IGFBP-3 SDS alone in GHD children 60%; ISS, 90%; AGHD-CO, 75%; AGHD-AO, 68%. Considering both, an accurate diagnosis was obtained in GHD children 60%; ISS, 87%; AGHD-CO, 71%; AGHD-AO, 64%. In conclusion, our findings support the need to use cut-off lines expressed in SDS obtained using an appropriate statistical methodology for better characterization of the various clinical presentations. IGF-I proved to be more useful because of its good diagnostic efficiency and accuracy in both children and adults, whereas IGFBP-3 did not significantly contribute to the diagnosis of GHD.
6-Sulphatoxymelatonin (aMT6s) has been measured, by a direct radioimmunoassay, in urine from 130 normal volunteers aged 2-80 years. Its relationship to a number of physiological parameters has been assessed. Total urinary excretion of aMT6s did not vary in a group of 40 children aged 2-20 years (24 boys and 16 girls) except when expressed as a function of body weight. In this case, total aMT6s excretion over 24 h decreased as a function of age. In 90 adult volunteers (44 men and 46 women) aged 20-80 years, there was an age-related decline in total 24 h aMT6s excretion with significantly lower values in elderly subjects. In this same adult group no relationships were found between total aMT6s excretion and body weight or height. No sex differences were found either in the 2-20 years or the 20-80 years groups. Pineal calcification was assessed by lateral skull X-ray in 26 adult volunteers (17 men and 9 women) aged 20-50 years. No significant differences in aMT6s excretion were found as a function of pineal calcification. In 16 of these subjects plasma melatonin and aMT6s also showed no relationship to pineal calcification. These studies confirm the usefulness of aMT6s as an index of melatonin secretion in normal volunteers.
Melatonin is synthesized and secreted during the dark period of the light-dark cycle. Thus, melatonin has an obvious association with sleep, at least in diurnal animals. Rhythmic nocturnal melatonin secretion is directly generated by the circadian clock, located in mammals within the suprachiasmatic nuclei (SCN), and is entrained to a 24-h period by the light-dark cycle. The periodic secretion of melatonin may be used as a circadian mediator to any system than can “read” the message. In addition, direct effects of the hormone on the SCN could explain some of melatonin effects on the circadian system. Duration of melatonin nocturnal secretion is directly proportional to the length of the night and it has been demonstrated experimentally to be the critical parameter for photoperiod integration. The two main hypotheses to explain the action of melatonin are the duration hypothesis (supporting that night length is coded by the duration of the melatonin secretory phase) and the coincidence hypothesis (holding that physiological responses are linked to the existence of a diurnal rhythm in sensitivity to melatonin). The sites and mechanisms of action of melatonin for circadian and photoperiodic responses are far from being elucidated, but action through specific membrane receptor sites is well documented. In view of melatonin s lipophilic nature, interactions with specific intracellular proteins like calmodulin or tubulin, or with nuclear receptor sites, have also been considered, whereas the physiological significance of the documented antioxidant effect of melatonin remains to be settled. Melatonin seems to act as an “arm” of the circadian clock, giving a time-related signal to a number of body functions; one of these, the circadian organization of an organism's defence, is discussed in some detail as an example.
The secretion of growth hormone (GH) is regulated through a complex neuroendocrine control system that includes two major hypothalamic regulators, namely GH-releasing hormone (GHRH) and somatostatin (SST) that stimulate and inhibit, respectively, GH release. Classical experiments involving damage and electrical stimulation suggested that the lateral hypothalamic area (LHA) modulated the somatotropic axis, but the responsible molecular mechanisms were unclear. Evidence obtained during the last decade has demonstrated that orexins/hypocretins, a family of peptides expressed in the LHA controlling feeding and sleep, play an important regulatory role on GH, by inhibiting its secretion modulating GHRH and SST neurones. Considering that GH release is closely linked to the sleep-wake cycle and feeding state, understanding orexin/hypocretin physiology could open new therapeutic possibilities in the treatment of sleep, energy homeostasis and GH-related pathologies, such as GH deficiency.
Aging is associated with a decline in immune function (immunosenescence), a condition known to correlate with increased incidence of cancer as well as infectious and degenerative diseases. Innate, cellular and humoral immunity all exhibit increased deterioration with age. Circulating melatonin decreases with age, and in recent years much interest has been focused on its immunomodulatory effect. Melatonin stimulates the production of progenitor cells for granulocytes and macrophages. It also stimulates the production of natural killer cells and CD4+ cells and inhibits CD8+ cells. The production and release of various cytokines from natural killer cells and T helper lymphocytes are enhanced by melatonin. Melatonin has the potential therapeutic value to enhance immune function in aged individuals.
It is well known that the pineal gland can modulate the secretion of pituitary hormones. Melatonin, the main hormone produced by the pineal gland, acts at the hypothalamic site, whereas hypophyseal sensitivity to melatonin seems to change with age. To investigate the influence of pubertal development on the role of the pineal gland in the regulation of the secretion of pituitary hormones, FSH, LH, Prl, TSH and GH responses to melatonin were evaluated in a group of 9 prepubertal and 10 pubertal healthy subjects of both sexes. Melatonin was given im at a dose of 0.2 mg/kg body weight at 3 p.m. Venous blood samples were drawn −20, 0, 20, 40, 60, 90, 120, 180 and 240 min, after melatonin injection. According to the same experimental protocol, venous blood samples were collected during a saline infusion on a separate occasion. FSH, LH, Prl, TSH and GH plasma levels were measured with RIA. In pubertal subjects, a significant rise in the mean Prl levels was seen 90 min after melatonin as compared with those during saline infusion. The Prl melatonin response area was significantly lower in prepubertal treated subjects and significantly higher in pubertal ones compared with the respective controls. The mean GH values showed a significant decrease 120 min after melatonin only in prepubertal subjects; no significant variations were seen in 8 of 10 pubertal subjects, whereas in the last 2 a marked increase was observed. Finally, under these conditions, melatonin did not influence the basal FSH LH and TSH levels.
These results seem to suggest that hypophyseal hormone reponses change with pubertal development.
In order to investigate the role of melatonin on the neuroregulation of GH secretion, eight healthy male volunteers each underwent four separate tests in random order separated by at least 1 week. Following oral administration of melatonin (500 mg at -60 min and at -30 min) plasma GH levels were higher than after placebo at 45 min (mean +/- SEM 2.9 +/- 0.8 vs 0.9 +/- 0.4 ng/ml, P less than 0.01) and 60 min (mean +/- SEM 2.9 +/- 0.4 vs 0.8 +/- 0.1 ng/ml, P less than 0.05). Likewise, after prior administration of melatonin, GH responses to GRF 1-44 (1 micrograms/kg i.v. at 0 min) were greater than placebo plus GRF at 15 min (mean +/- SEM 22.4 +/- 6.1 ng/ml vs 11.3 +/- 2.3 ng/ml, P less than 0.05), 45 min (mean +/- SEM 26.2 +/- 5.3 ng/ml vs 13.3 +/- 2.5 ng/ml, P less than 0.01) and 60 min (mean +/- SEM, 24.7 +/- 7.4 ng/ml vs 11.1 +/- 2.5 ng/ml, P less than 0.05). In contrast we did not observe any effect of either 10(-9)M, 10(-7)M melatonin on in-vitro basal GH release and GH responses to 10(-8)M GRF by rat anterior pituitary cells in monolayer culture. These data suggest that melatonin plays a facilitatory role in the neuroregulation of GH secretion, probably by acting at the hypothalamic level.
Several observations have demonstrated that the opioid system can modulate melatonin secretion from the pineal gland and that the effects of opioids may require a pineal participation. In contrast, the role played by the pineal gland in regulating the synthesis and secretion of endorphins and enkephalins in still obscure. To establish whether the neuroendocrine activity of melatonin are mediated by endogenous opioids and to demonstrate a possible action exerted by the pineal gland on opioid peptides, GH and LH serum mean levels were evaluated by RIA in 12 healthy subjects of both sexes after melatonin injection alone (0.4 mg/kg bw im at 09:00 h) and on a separate occasion after a simultaneous administration of melatonin and naloxone (1.2 mg iv as a bolus, followed by an iv infusion of 1.6 mg/h for 3h). On an other occasion, the study was performed during saline or naloxone infusion alone. In each test, venous blood samples were collected at -20, 0, 30, 60, 90, 120 and 180 min. A significant rise of GH was observed after melatonin injection alone. The simultaneous infusion of naloxone blocked melatonin-induced GH rise. Melatonin did not affected LH serum levels, while it was able to reduce LH increase induced by naloxone. These preliminary results suggest that some neuroendocrine effects of melatonin might be mediated by a modulation on the opioid tone.
The biorhythm of melatonin in human newborns is established later than that of either serotonin or N-acetylserotonin. Towards the end of the first year of life, the melatonin rhythm is a well established phenomenon and its nocturnal increment is equal to that seen in the pre-school children. Following this period the magnitude of nighttime melatonin increment starts declining and is closely associated with advancing skeletal age. This association between the magnitude of nocturnal increment and skeletal age is also noted in pathological subjects, lower skeletal age with greater magnitude of increment or advanced skeletal age with less increment. Although no inverse relationship between plasma melatonin and gonadotropins could be detected in children, there emerged a marked negative association between melatonin and growth hormone. GRF-induced GH stimulation suppressed melatonin in children as well as in adults. Melatonin pretreatment blocked GRF-induced increment of GH in rats. When animals were given either melatonin or growth hormone, one suppressed the other. It is possible that melatonin-induced growth hormone suppression is somatostatin mediated.
The oral administration of melatonin to men has been reported to cause a rapid and significant elevation of serum GH, and to inhibit GH release after stimulation by L-Dopa. We studied the effect of melatonin i.v. on the basal and L-Dopa stimulated GH secretion in four young men. Each subject's control response to L-Dopa was first studied by an oral administration to 500 mg of L-Dopa under a placebo infusion and was followed 2 weeks later by a similar study under melatonin infusion, 2.1 mg/min (total dose of 500 mg). The infusion of melatonin was given for a 4-hour period, 2 hours before and 2 hours after the L-Dopa stimulation. Blood samples for GH were obtained at 30-min intervals. Basal values of serum GH did not rise under the melatonin infusion and peak GH values following L-Dopa stimulation during the control infusion and the melatonin infusion also did not differ (2 +/- 0.5 to 22 +/- 6 and 2 +/- 0.8 to 25 +/- 4 ng/ml respectively). Our data suggest that under an acute constant infusion melatonin does not stimulate GH secretion, nor does it interfere with the L-Dopa stimulated GH response in men.
Melatonin was recently reported to be an effective free radical scavenger and antioxidant. Melatonin is believed to scavenge the highly toxic hydroxyl radical, the peroxynitrite anion, and possibly the peroxyl radical. Also, secondarily, it reportedly scavenges the superoxide anion radical and it quenches singlet oxygen. Additionally, it stimulates mRNA levels for superoxide dismutase and the activities of glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase (all of which are antioxidative enzymes), thereby increasing its antioxidative capacity. Also, melatonin, at least at some sites, inhibits nitric oxide synthase, a pro-oxidative enzyme. In both in vivo and in vitro experiments melatonin has been shown to reduce lipid peroxidation and oxidative damage to nuclear DNA. While these effects have been observed primarily using pharmacological doses of melatonin, in a small number of experiments melatonin has been found to be physiologically relevant as an antioxidant as well. The efficacy of melatonin in inhibiting oxidative damage has been tested in a variety of neurological disease models where free radicals have been implicated as being in part causative of the condition. Thus, melatonin has been shown prophylactically to reduce amyloid beta protein toxicity of Alzheimer's disease, to reduce oxidative damage in several models of Parkinson's disease (dopamine auto-oxidation, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine), to protect against glutamate excitotoxicity, to reduce ischemia-reperfusion injury, to lower neural damage due to gamma-aminolevulinic acid (phorphyria), hyperbaric hyperoxia and a variety of neural toxins. Since endogenous melatonin levels fal 1 markedly in advanced age, the implication of these findings is that the loss of this antioxidant may contribute to the incidence or severity of some age-associated neurodegenerative diseases.
There is evidence that melatonin may play a role in modulating pituitary secretion, although the mechanisms are unclear. We examined the effects of a single dose of oral melatonin (5mg) on exercise-induced GH secretion. In a randomised, double-blind, placebo-controlled study, seven healthy male subjects undertook an initial period of graded bicycle ergometric exercise to determine maximum workload and oxygen uptake (VO(2max)). Subjects were subsequently studied on two further occasions, receiving either melatonin or placebo in random order at the onset of each study (-60min). At 0 min a period of bicycle exercise was performed for 8 min at a workload corresponding to 70% of that achieved at VO(2max). Serum GH and IGF-binding protein-1 (IGFBP-1) concentration was measured at 15-min intervals from the onset of the study until 120 min post-exercise. Blood was also sampled for the measurement of plasma glucose, insulin, non-esterified fatty acids, IGFBP-3, melatonin and vasopressin concentration. There was an exercise-induced increase in GH concentration following melatonin which was greater compared with placebo as assessed by both area under the curve (P<0.01) and peak increase in GH levels (P<0.01). The peak increase in IGFBP-1 levels post-exercise was also significantly greater following melatonin compared with placebo (P<0. 01) but did not quite reach levels of significance as measured by area under the curve (P=0.07). Since exercise-induced GH secretion is thought to be mediated predominantly through a hypothalamic pathway, it seems likely that melatonin facilitates GH secretion at a hypothalamic level.
The paper presents the data concerning the in vivo effects of melatonin on experimentally-induced tumors in animals and the in vitro effects on animal and human tumor cells. The majority of experimental tumors responded to the melatonin treatment with growth inhibition. However, some negative or opposite results (i.e. stimulation of tumor instead of inhibition) were also reported. Some of the negative results can be attributed to the improper timing of melatonin administration. Melatonin was also shown to inhibit the growth of several animal and human tumor cell lines in vitro. On the basis of these experiments, a hypothesis of the oncostatic action of melatonin was put forward. The mechanism of the postulated action is complex and probably includes: 1) modulation of the endocrine system; 2) modulation of the immune system; 3) the direct oncostatic action of melatonin on tumor cells. The latter includes the recently discovered anti-oxidative action which probably plays an important role in the countering the DNA damage during the radiation challenge or the exposure to chemical carcinogens. It also includes the antiproliferative and pro-apoptotic effects exerted via melatonin receptors expressed by tumor cells. The involvement of the membrane melatonin receptors is mainly assumed. However, the recent data from our and other laboratories suggest also the involvement of RZR/ROR receptors (the putative melatonin nuclear receptors) in both melatonin-induced proliferation inhibition and apoptosis.
Descriptions of the pineal gland date back to antiquity, but its functions in humans are still poorly understood. In both diurnal and nocturnal vertebrates, its main product, the hormone melatonin, is synthesized and released in rhythmic fashion, during the dark portion of the day-night cycle. Melatonin production is controlled by an endogenous circadian timing system and is also suppressed by light. In lower vertebrates, the pineal gland is photosensitive, and is the site of a self-sustaining circadian clock. In mammals, including humans, the gland has lost direct photosensitivity, but responds to light via a multisynaptic pathway that includes a subset of retinal ganglion cells containing the newly discovered photopigment, melanopsin. The mammalian pineal also shows circadian oscillations, but these damp out within a few days in the absence of input from the primary circadian pacemaker in the suprachiasmatic nuclei (SCN). The duration of the nocturnal melatonin secretory episode increases with nighttime duration, thereby providing an internal calendar that regulates seasonal cycles in reproduction and other functions in photoperiodic species. Although humans are not considered photoperiodic, the occurrence of seasonal affective disorder (SAD) and its successful treatment with light suggest that they have retained some photoperiodic responsiveness. In humans, exogenous melatonin has a soporific effect, but only when administered during the day or early evening, when endogenous levels are low. Some types of primary insomnia have been attributed to diminished melatonin production, particularly in the elderly, but evidence of a causal link is still inconclusive. Melatonin administration also has mild hypothermic and hypotensive effects. A role for the pineal in human reproduction was initially hypothesized on the basis of clinical observations on the effects of pineal tumors on sexual development. More recent data showing an association between endogenous melatonin levels and the onset of puberty, as well as observations of elevated melatonin levels in both men and women with hypogonadism and/or infertility are consistent with such a hypothesis, but a regulatory role of melatonin has yet to be established conclusively. A rapidly expanding literature attests to the involvement of melatonin in immune function, with high levels promoting and low levels suppressing a number of immune system parameters. The detection of melatonin receptors in various lymphoid organs and in lymphocytes suggests multiple mechanisms of action. Melatonin has been shown to be a powerful antioxidant, and has oncostatic properties as well, both direct and indirect, the latter mediated by its effects on reproductive hormones. Finally, there are reports of abnormal daily melatonin profiles in a number of psychiatric and neurological disorders, but the significance of such abnormalities is far from clear.
Melatonin is a methoxyindole synthesized and secreted principally by the pineal gland at night under normal environmental conditions. The endogenous rhythm of secretion is generated by the suprachiasmatic nuclei and entrained to the light/dark cycle. Light is able to either suppress or synchronize melatonin production according to the light schedule. The nycthohemeral rhythm of this hormone can be determined by repeated measurement of plasma or saliva melatonin or urine sulfatoxymelatonin, the main hepatic metabolite. The primary physiological function of melatonin, whose secretion adjusts to night length, is to convey information concerning the daily cycle of light and darkness to body physiology. This information is used for the organisation of functions, which respond to changes in the photoperiod such as the seasonal rhythms. Seasonal rhythmicity of physiological functions in humans related to possible alteration of the melatonin message remains, however, of limited evidence in temperate areas in field conditions. Also, the daily melatonin secretion, which is a very robust biochemical signal of night, can be used for the organisation of circadian rhythms. Although functions of this hormone in humans are mainly based on correlative observations, there is some evidence that melatonin stabilises and strengthens coupling of circadian rhythms, especially of core temperature and sleep-wake rhythms. The circadian organisation of other physiological functions could depend on the melatonin signal, for instance immune, antioxidative defences, hemostasis and glucose regulation. Since the regulating system of melatonin secretion is complex, following central and autonomic pathways, there are many pathophysiological situations where the melatonin secretion can be disturbed. The resulting alteration could increase predisposition to disease, add to the severity of symptoms or modify the course and outcome of the disorder.
Melatonin, the hormone of the pineal gland, received a great deal of attention in the last decade because of its availability as over-the-counter drug or food supplement in some countries and suggested role in many vital physiological processes. Melatonin secretion is not restricted to mammals but is also produced in nonmammalian vertebrates, in some invertebrates, and in many plants, with the same molecular structure. The synthesis of melatonin is strictly controlled by lighting conditions and shows a clear circadian rhythm with low values during the daytime and significant increase at night. In this survey the basic data on melatonin significance in human physiology and in pathological processes as well as its possible therapeutic significance are reviewed and discussed.
A relationship between melatonin and growth hormone (GH) is poorly understood. We compare circadian melatonin rhythms in short children with normal and decreased GH secretion. The analysis included 22 children (20 boys and 2 girls) aged 11.1-16.9 yr (mean +/- S.E.M. = 14.1 +/- 0.3 yr) with short stature (height SDS below -2.0). Based on the GH peak in stimulation tests patients were divided into two groups: idiopathic short stature (ISS, n = 11; GH peak > or = 10 ng/mL) and GH deficiency (GHD, n = 11; GH peak < 10 ng/mL). In all patients the circadian melatonin rhythm was assessed on the basis of nine blood samples, collected in 4-hr intervals during the daytime and 2-hr intervals at night, with dark period lasting from 22:00 to 06:00 hr. Magnetic resonance imaging examination excluded organic abnormalities in central nervous system in all patients. Melatonin concentration at 24:00, 02:00 and 04:00 hr as well as the area under curve of melatonin concentrations (AUC) were significantly higher in the patients with GHD than in individuals with ISS. Significant correlations between GH secretion and melatonin concentrations at 24:00, 02:00 and 04:00 hr, and AUC were also observed. On the basis of these data it seems that the assessment of nocturnal melatonin secretion might be a valuable diagnostic tool used for the improvement of the difficult diagnosis of short stature in children.
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