Blood Melatonin Levels Research Articles

Melatonin concentration in the umbilical artery and vein in human preterm and term neonates and neonates with acute fetal distress.

In order to assess the existence of a rhythmic secretion of melatonin (aMT) in newborns and whether this rhythm is affected by neonatal stress, we studied 112 newborns classified in three groups: normal babies delivered at term, preterm infants born before the 38th week, and babies with fetal distress. Melatonin was measured by RIA in the umbilical artery and vein at the time of birth. Melatonin levels in umbilical arterial and venous blood showed a diurnal rhythm in all groups. Melatonin levels in umbilical cord artery and vein were closely related. Nocturnal melatonin levels were increased in newborns with acute fetal distress in comparison with normal term and preterm neonates. These results suggest that (1) a rhythm of aMT secretion exists in newborns, although it cannot be determined whether this rhythm is of maternal or fetal origin and (2) neonatal stress (acute fetal distress) increases aMT production during the night in comparison with normal term and preterm neonates.

Blood levels of melatonin, serotonin, cortisol, and prolactin in relation to the circadian rhythm of platelet serotonin uptake.

Blood levels of melatonin, serotonin, cortisol, prolactin, and serotonin uptake by platelets were measured at 08:00, 14:00, 20:00, 02:00, and 08:00 hours in 10 healthy men who ranged in age from 27 to 35 years. The Km values of serotonin active transport by platelets were significantly correlated with melatonin blood levels. There were no other significant correlations. The secretion of steroid hormones and prolactin showed an increase at 02:00 hours; levels of prolactin decreased at 08:00 hours, but steroid levels continued to rise. This finding suggests either a direct effect of melatonin on serotonin active transport or the influence of the suprachiasmatic nucleus on serotonin uptake by platelets. It is also possible that there is a simultaneous decrease in serotonin uptake and decline from peak levels of melatonin due to the rise in steroid secretion.

Effects of physiological cycles of infused melatonin on circadian rhythmicity in pigeons.

The role of the hormone melatonin in the circadian system of pigeons (Columba livia) was investigated. Using an automatic infusion system, melatonin at physiological levels was delivered for 10 h each day to cannulated, pinealectomized (P-X) pigeons in constant darkness. These cyclic infusions of melatonin entrained feeding rhythms in P-X pigeons while vehicle infusions were ineffective entraining agents. When the retinae of P-X pigeons were removed (E-X), feeding rhythms were abolished in constant darkness. When cyclic melatonin infusions were delivered to these birds (E-X and P-X), feeding rhythmicity was restored whereas vehicle infusions alone did not restore rhythmicity. When melatonin infusions were terminated in E-X/P-X pigeons, feeding rhythms persisted for several days but eventually decayed. Blood melatonin levels were measured in both P-X and E-X/P-X birds infused cyclically with exogenous melatonin and were found to be within the physiological range both in level and pattern. These results strongly suggest that endogenous melatonin, released by the pineal gland and the retinae, regulates the timing of feeding rhythms by entraining other oscillators in the circadian system of the pigeon.

Serum melatonin, 5-HT and tryptophan levels in blood and CSF in the diagnosis of early dementia and depressive pseudodementia

Serum melatonin, 5-HT and tryptophan levels in blood and CSF in the diagnosis of early dementia and depressive pseudodementia

Neuroendocrine effects of light

The light/dark cycle to which animals, and possibly humans, are exposed has a major impact on their physiology. The mechanisms whereby specific tissues respond to the light/dark cycle involve the pineal hormone melatonin. The pineal gland, an end organ of the visual system in mammals, produces the hormone melatonin only at night, at which time it is released into the blood. The duration of elevated nightly melatonin provides every tissue with information about the time of day and time of year (in animals that are kept under naturally changing photoperiods). Besides its release in a circadian mode, melatonin is also discharged in a pulsatile manner; the physiological significance, if any, of pulsatile melatonin release remains unknown. The exposure of animals including man to light at night rapidly depresses pineal melatonin synthesis and, therefore, blood melatonin levels drop precipitously. The brightness of light at night required to depress melatonin production is highly species specific. In general, the pineal gland of nocturnally active mammals, which possess rod-dominated retinas, is more sensitive to inhibition by light than is the pineal gland of diurnally active animals (with cone-dominated retinas). Because of the ability of the light/dark cycle to determine melatonin production, the photoperiod is capable of influencing the function of a variety of endocrine and non-endocrine organs. Indeed, melatonin is a ubiquitously acting pineal hormone with its effects on the neuroendocrine system having been most thoroughly investigated. Thus, in nonhuman photoperiodic mammals melatonin regulates seasonal reproduction; in humans also, the indole has been implicated in the control of reproductive physiology.

Fluctuation of Blood Melatonin Concentrations With Age: Result of Changes in Pineal Melatonin Secretion, Body Growth, and Aging

Melatonin in the systemic circulation of rats fluctuates with age, and the causes for such changes were investigated. Male rats (aged 7 days, 16 days, 18 days, 20 days, 30 days, 48 days, 60 days, and greater than 17 months) were adapted under a lighting regime of 12L:12D for at least 7 days. Pineals and blood samples from the trunk or confluens sinuum were collected in the dark period. Melatonin in tissues was extracted, identified, and determined by gas chromatography-mass spectrometry (GC-MS) and/or radioimmunoassay. Tissue melatonin levels obtained by radioimmunoassay correlated closely with those quantified by GC-MS. Thus, the melatonin radioimmunoassay used is a reliable assay method for melatonin in the plasma and pineal of the rat. Plasma melatonin in the confluens sinuum of rats exhibited episodic release superimposed on a basal release pattern. It was suggested that there are two pools of melatonin in the pineal gland, a readily releasable pool and a bound pool. The mean plasma levels of melatonin in the confluens sinuum of rats increased with age with the highest level recorded at 60 days old and declined to a lower level at greater than 17 months old. The above age-related changes, being similar to the alterations in pineal melatonin levels with growth and aging, suggest that, under our experimental conditions, levels of pineal melatonin increase or decrease with its secretory rate. In developing rats, the age-related increase in the rate of secretion of pineal melatonin as reflected by increases in melatonin levels in the confluens sinuum or pineal melatonin content before adulthood is different from the changes in melatonin levels in the systemic circulation which showed an early developmental rise, followed by an active period and then a prepubertal decline. However, when the body weight was taken into consideration, changes in the levels of pineal melatonin content per 100 gm body weight or the calculated blood melatonin levels (plasma melatonin in the confluens sinuum/body:head ratio) correlated well with the fluctuation of serum melatonin in the systemic circulation. Thus, the developmental changes in the concentrations of melatonin in the general circulation are the result of 1) changes in the rate of pineal melatonin secretion and 2) increase in the dilution factor because of increase in body size. In old rats, levels of plasma melatonin in the confluens sinuum and pineal melatonin content decreased indicating a decline in the rate of pineal melatonin secretion.(ABSTRACT TRUNCATED AT 400 WORDS)

Absence of circadian patterns of secretion of melatonin or cortisol in Weddell seals under continuous natural daylight.

Blood samples were obtained from adult female Weddell seals in McMurdo Sound, Antarctica, utilizing four different seals every 2 h for 24 h on two occasions in November 1987. Plasma levels of melatonin were mostly near zero, whereas the values for cortisol were high (2101 +/- 54 and 1908 +/- 108 (S.E.M.) nmol/l, n = 52). For both hormones there was no evidence of a diurnal pattern of secretion. Juvenile seals sampled in December 1985 also had no evidence of a diurnal secretion pattern of melatonin, but blood levels of melatonin were higher than in adults. The results indicate that secretion of melatonin in adult Weddell seals ceases during the Antarctic summer.

A radiologic study by CT scan of pineal size in cancer patients: correlation to melatonin blood levels.

Alterations in size of the pineal body and melatonin secretion have been observed in cancer patients. The present study was carried out to evaluate pineal dimensions in a group of cancer patients and their relation to melatonin blood levels. The study included 70 oncologic patients. As controls, 41 patients with acute or chronic disease other than cancer entered the study. Melatonin serum levels were measured by radioimmunoassay on venous blood samples collected at 9:00 a.m. Pineal size was determined by brain CT scan, by considering the product of the two longest perpendicular diameters, multiplied by the thickness of the stratum. The volume of the pineal body was found to be enlarged in 12/70 (17%) cancer patients, and its mean value was significantly higher than that observed in controls. Melatonin levels were also significantly higher in oncologic patients than in controls. However, there was no correlation between melatonin levels and pineal size in cancer patients. Finally, cancer patients did not show a higher degree of pineal calcifications than controls. The clinical significance of pineal enlargement in cancer patients remains to be understood.

Endocrine and immune effects of melatonin therapy in metastatic cancer patients

Melatonin, the most important indole hormone produced by the pineal gland, appears to inhibit tumor growth; moreover, altered melatonin secretion has been reported in cancer patients. Despite these data, the possible use of melatonin in human neoplasms remains to be established. The aim of this clinical trial was to evaluate the therapeutic, immunological and endocrine effects of melatonin in patients with metastatic solid tumor, who did not respond to standard therapies. The study was carried out on 14 cancer patients (colon, six; lung, three; pancreas, two; liver, two; stomach, one). Melatonin was given intramuscularly at a daily dose of 20 mg at 3.00 p.m., followed by a maintenance period in an oral dose of 10 mg daily in patients who had a remission, stable disease or an improvement in PS. Before and after the first 2 months of therapy, GH, somatomedin-C, beta-endorphin, melatonin blood levels and lymphocyte subpopulations were evaluated. A partial response was achieved in one case with cancer of the pancreas, with a duration of 18+ months; moreover, six patients had stable disease, while the other eight progressed. An evident improvement in PS was obtained in 8 14 patients. In patients who did not progress, T4 T8 mean ratio was significantly higher after than before melatonin therapy, while it decreased in patients who progressed. On the contrary, hormonal levels were not affected by melatonin administration. This study would suggest that melatonin may be of value in untreatable metastatic cancer patients, particularly in improving their PS and quality of life; moreover, based on its effects on the immune system, melatonin could be tested in association with other antitumor treatments.

Melatonin concentration in the cerebral vascular sinuses of sheep and evidence for its episodic release.

Blood was collected from the cerebral sinuses and from the jugular vein of 5 ewes during both the day and night. Cerebral sinus samples were collected by means of a permanently indwelling cannula (roughly every 5 min) while jugular vein samples were collected by venipuncture (roughly every 10 min). In each of the 5 animals mean nighttime melatonin concentrations were greater at night than during the day. In 2 animals, cerebral sinus plasma melatonin concentrations were greater than in the jugular vein; in 2 animals the sinus and jugular plasma had similar melatonin levels; in 1 ewe jugular vein blood melatonin levels exceeded those in the cerebral sinus plasma. These differences among animals are presumably due to slight positional differences in the cerebral venous cannula placement. In several animals episodic release of melatonin was apparent. Whereas the episodes were most obvious in the cerebral venous blood at night, they were also apparent in 1 case in the jugular vein plasma and in 1 animal during the day. When episodes appeared they occurred about every 15-20 min.

Melatonin increase as predictor for tumor objective response to chemotherapy in advanced cancer patients.

Clinical studies have demonstrated an altered pineal function in cancer patients. Owing to the documented antineoplastic activity of the pineal gland, these anomalies could have a prognostic significance. This study was carried out to monitor changes in blood levels of melatonin, the most important pineal hormone, in relation to the clinical response to chemotherapy in human neoplasms. The study included 42 cancer patients of both sexes (breast cancer, 10; lung cancer, 13; colon cancer, 11; soft tissue sarcoma, 4; testicular cancer, 1; Hodgkin's disease, 1; peritoneal mesothelioma, 2). Melatonin serum levels were measured by radioimmunoassay before and 28 days after each cycle of chemotherapy. The results showed that, irrespectively of the type of tumor and chemotherapeutic regimen, 12/16 patients (75%) whose melatonin markedly enhanced after chemotherapy had an objective regression. In contrast, 2/26 patients only (8%) whose melatonin did not enhance after chemotherapy had a clinical response. The percentage of objective responses was statistically significantly higher in patients with a chemotherapy-induced melatonin increase than in those with no melatonin increase (p less than 0.001). This study seems to demonstrate that melatonin determination can be used as a predictor of the objective response to chemotherapy in cancer patients. Moreover, it suggests that the antineoplastic effect of cytotoxic drugs may require participation of the pineal gland.

Plasma levels of immunoreactive melatonin, estradiol, progesterone, follicle stimulating hormone, and beta-human chorionic gonadotropin during pregnancy and shortly after parturition in humans.

Plasma concentrations of immunoreactive melatonin, estradiol, progesterone, follicle stimulating hormone (FSH), and beta-human chorionic gonadotropin (beta hCG) were studied between 1000 and 1230 h in 105 Chinese females during six periods of normal pregnancy and 1-5 min after normal delivery. We have also examined the midday levels of immunoreactive melatonin in the cord blood of fetuses and plasma collected 1-5 min after and 24 h after delivery from their mothers. Concentrations of hormone immunoreactivities were determined by radioimmunoassay, and distinct fluctuations of all hormones were recorded during pregnancy. In the pregnant females, there were significant negative correlations between melatonin and estradiol, melatonin and progesterone, beta hCG and progesterone, and beta hCG and estradiol, and positive correlations between melatonin and FSH and progesterone and estradiol. Furthermore, plasma melatonin levels in the cord blood demonstrated no sex difference and were significantly lower than and correlated positively with the levels in their mothers. Our results suggest that sex steroids may inhibit and FSH may potentiate circulating melatonin levels in gravid women; changes in the levels of melatonin during pregnancy may affect the in utero development of the human embryo; and circulating melatonin in the mother may be the major source of blood melatonin in the fetus before parturition.

Dose-dependent entrainment of rat circadian rhythms by daily injection of melatonin.

Previous work in our laboratory has shown that daily injection of large doses of the pineal hormone melatonin entrains the free-running locomotor rhythms of rats held in constant darkness and synchronizes the disrupted patterns of rats maintained in constant bright light. The present experiments determined the dose-response characteristics of entrainment to daily melatonin injections and made preliminary biochemical estimates of blood melatonin levels and half-lives after two critical doses of the hormone. The data indicated that the median effective dose for melatonin as an entraining agent in free-running rats was 5.45 +/- 1.33 micrograms/kg, considerably lower than doses previously employed and lower than doses employed in reproductive and metabolic studies in rats and hamsters. The data further indicated that the response to melatonin was quantal; rats either entrained to melatonin or they did not. No "partial entrainment" was evident, nor were there differences in phase angle, activity, or period among all effective doses. Biochemical estimates of blood melatonin after either 1 mg/kg or 1 microgram/kg of melatonin indicated that all effective doses resulted in supraphysiological levels of blood melatonin, although doses of 1 microgram/kg resulted in blood levels that were within one order of magnitude of normal nighttime values. Together, the data suggest that the rat circadian system is sensitive to the pineal hormone melatonin at or below doses required to effect rodent reproduction. Whether this sensitivity reflects a role for the pineal gland in rat circadian organization, however, still remains to be determined.

Enhanced Release of Drugs from Silicone Elastomers (III): Subcutaneous Controlled Administration of Melatonin for Early Onset of Estrus Cycles in Ewes

AbstractImplants were fabricated from swellable silicone elastomers to release hydrophilic melatonin at a controlled rate for the early induction of breeding season in ewes. Both the in vitro and in vitro release profiles of melatonin were observed to follow a linear Q vs. t1/2 relationship. The in vitro/in vivo release flux ratio ranging from 0.415 to 1.452 was obtained depending upon the polyethylene glycol 400 concentration in the aqueous release medium used for in vitro studies. The release flux (Q/t1/2) of melatonin from the implants was observed to increase as a function of the glycerol content in the silicone elastomers. When the ewes were treated with subdermal implants containing 25% w/w of melatonin for up to 49 days, blood melatonin levels above the target level of 450-900 pmole/1 were achieved and maintained for at least 35 days.

Effect of constant-release implants of melatonin on seasonal cycles in reproduction, prolactin secretion and moulting in rams

Seasonal cycles in the size of the testes, blood plasma concentration of testosterone, FSH and prolactin, intensity of the sexual skin flush, timing of rutting behaviour and moulting of the body coat were recorded in Soay rams after s.c. implantation of melatonin contained in a Silastic envelope which increased the circulating blood levels of melatonin to 200-600 pg/ml for many months. Two groups of 8 adult rams were held under alternating periods of short days (8L:16D) and long days (16L:8D) to drive the seasonal cycles and the treatments with melatonin were initiated during the long or short days, and one group of 8 ram lambs was kept out of doors and given implants during the long days of summer (4 melatonin-implanted and 4 control (empty implants) rams per group). The treatments demonstrated that melatonin implants during exposure to long days resulted in a rapid 'switch on' of reproductive redevelopment similar to that produced by exposure to short days melatonin implants prevented the rams from showing the normal responses to changes in the prevailing photoperiod rendering them nonphotoperiodic; and long-term cyclic changes in testicular activity, prolactin secretion and other characteristics occurred in the melatonin-implanted rams; the pattern was similar to that previously observed in rams exposed to prolonged periods of short days. The overall results are consistent with the view that melatonin is the physiological hormone that relays the effects of changing photoperiod on reproduction and other seasonal features, and that continuous exogenous melatonin from an implant interferes with the normal 'signal' and produces an over-riding short-day response.

Melatonin rhythms in the eyes, pineal bodies, and blood of Japanese quail ( Coturnix coturnix japonica)

Melatonin levels in the eyes, pineal bodies, and blood of Japanese quail exposed to 12L:12D show robust daily rhythms with high levels occurring in the night and low levels occurring during the day. Since melatonin is synthesized in both the eyes and pineal bodies of birds, the relative contribution of these structures to the blood melatonin levels was determined. A rhythm of blood melatonin persisted in 12L:12D in birds blinded by complete orbital enucleation and in pinealectomized birds but the nighttime levels were reduced by 33 and 54%, respectively, as compared to melatonin levels in control quail. Only a small melatonin rhythm (13% of control levels) was detected in the blood of pinealectomized, blinded quail. This “residual” rhythm could indicate either the contribution of extrapineal, extraocular sources of melatonin or melatonin secretion from remnants (if any) of pineal body tissue remaining after pinealectomy. Blinding did not obviously affect pineal melatonin levels nor did pinealectomy affect ocular melatonin levels. It was concluded that (1) daily rhythms in melatonin content occur in the pineal bodies, the eyes, and the blood of quail; (2) the blood rhythm is the result of melatonin secretion from both the pineal body and the eyes; (3) extraretinal photoreceptors can mediate entrainment of the pineal melatonin rhythm; and (4) obvious compensatory changes in melatonin levels do not occur in the eye following pinealectomy or in the pineal body following blinding.

Reproductive photorefractoriness in rams and accompanying changes in the patterns of melatonin and prolactin secretion.

Exposure of rams to alternating 16-week cycles of long and short days (16L:8D and 8L:16D) results in periods of testicular regression followed by testicular redevelopment, and there is an inverse relationship between the blood levels of prolactin and testis activity. In this study, two groups of rams were held under long or short day lengths for a period of 94 weeks. When held under either long or short days for more than 16 weeks, the animals showed spontaneous changes in gonadal activity and in the secretion of prolactin, both of which were no longer correlated with the prevailing photoperiod, i.e., they became photorefractory. The photorefractoriness was characterized by cyclical changes in testis function which were independent of day length. The period of these spontaneous cycles was similar during both treatment regimens (long days: 40.9 +/- 1.5 weeks; short days: 38.1 +/- 0.33 weeks), suggesting the presence of an endogenous pacemaker for the reproductive system. The changes in blood prolactin levels during photorefractoriness were no longer correlated with testis activity, and though cyclical, the period lengths differed under the two regimens (long days: 31.8 +/- 1.4 weeks; short days: 48.6 +/- 0.3 weeks). The rates of change in testis function and prolactin secretion were slower during the refractory state than during the photosensitive state. Upon switching the rams to a different photoperiod after the 94 weeks of exposure to fixed day lengths, the rams showed relatively rapid testicular and prolactin responses. Photoperiodic information appears to be relayed to the endocrine system through the daily pattern of melatonin secretion by the pineal. We measured the daily blood levels of melatonin on several occasions during phases of photosensitivity and photorefractoriness in the same group of rams. During the first 21 weeks under both lighting treatments, the rams showed synchronized daily patterns in their blood levels of melatonin, with elevated levels occurring mainly during the daily period of darkness. Similar synchronized daily rhythms were also seen when the rams were switched to a different photoperiod following 94 weeks of exposure to either long or short days. Between Weeks 21 and 94, the daily rhythms of melatonin did not occur consistently in all rams; often, the patterns differed markedly between individual rams held under the same day length and peak levels of melatonin were not always confined to periods of darkness.(ABSTRACT TRUNCATED AT 400 WORDS)

Evidence for pineal gland modulation of the neuroendocrine-thyroid axis.

Experiments with rats and hamsters have provided evidence for an inhibitory action of the pineal gland on the neuroendocrine-thyroid axis. While maintenance of these animals in short photoperiod results in reduced levels of circulating thyroxin (T4), pinealectomy restores the levels to normal. Recent studies suggest that an active pineal gland produces a substance which inhibits thyrotrophin-releasing hormone release from the hypothalamus. Several investigators have concluded that endogenous melatonin, produced in the pineal gland, could account for the inhibitory action of the pineal gland on blood T4 levels. Although melatonin administration has been reported to inhibit blood T4 levels in both rats and hamsters, under certain experimental conditions melatonin administration can be demonstrated to have a counter-antithyrotrophic effect resulting in increased blood levels of T4 and thyrotrophin. Assay of blood levels of melatonin of rats and hamsters under various experimental conditions will be necessary to distinguish physiological from pharmacological effects of melatonin. Lesion studies as well as studies with melatonin implants in the brain, suggest that the site of action is in the anterior hypothalamus. The effects of melatonin on the neuroendocrine-thyroid axis are similar to its effects on the neuroendocrine-gonadal axis, leading to the hypothesis of a common site of action for the thyroid and gonadal effects of melatonin. Although many pineal 'factors' have been postulated to account for the action of this gland, an action of melatonin on the serotonergic system of the brain stem could account for the data.

Entrainment of rhythmic melatonin secretion in man to a 12-hour phase shift in the light/dark cycle

Daily rhythms in melatonin secretion were monitored in four healthy adult males by measuring the melatonin contents of sequential 4-hour urine specimens and of plasma samples collected at 12-hour intervals, or, in one subject, continuously for 24 hours. All subjects exhibited similar diurnal rhythms, with peak urinary melatonin excretion rates and blood melatonin levels occurring during the daily period of darkness and sleep. When the daily light/dark regimen was phase-shifted by 180°, the plasma and urinary melatonin rhythms required 5–7 days (depending on the subject) to re-entrain to the new schedule. Simultaneous measurements of plasma melatonin levels and melatonin excretion rates indicate that urinary melatonin reflects, with remarkable fidelity, circulating melatonin levels.

MELATONIN CONCENTRATION IN HUMAN BLOOD AND CEREBROSPINAL FLUID: TO STRESS.

In 35 daytime paired blood and cerebrospinal fluid (CSF) samples from 15 patients, melatonin levels in CSF were undetectable or detectable but not higher than blood levels. During pneumoencephalography in 6 patients, no significant elevation of blood melatonin levels was observed, whereas cortisol concentration increased.