Increased melatonin concentrations in children with growth hormone deficiency

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.     

Qualitative and quantitative changes of melatonin levels in physiological and pathological aging and in centenarians

Melatonin secretion is an endogenous synchronizer, and it may possess some anti-aging properties. Thus we examined melatonin levels in physiological aging, in extreme senescence and in senile dementia. In healthy old (age 66-94 yr) and young subjects (age 23-39 yr) and in demented patients (age 68-91 yr) plasma melatonin was measured by radioimmunoassay in eight serial blood samples. In centenarians (age 100-107 yr) melatonin levels were estimated by assaying urinary 6-hydroxymelatonin sulfate (aMT6s) in two different urine samples collected from 08:00 to 20:00 hours and from 20:00 to 08:00 hours. These data were compared with the aMT6s excretion of old and young controls. Elderly subjects, demented or not, exhibited a flattened circadian profile of plasma melatonin, because of the suppression of the nocturnal peak. An age-related decline of the circadian amplitude of the melatonin rhythm occurred in old subjects, especially in demented individuals. Furthermore, the melatonin nocturnal peak was significantly correlated with the severity of the cognitive impairment. aMT6s urinary excretion also declined with age. However, as in young controls, in centenarians the aMT6s excretion was significantly higher at night than during the day. In conclusion, pineal melatonin secretion is affected by age and by the degree of cognitive impairment. In centenarians the maintenance of the circadian organization of melatonin secretion may suggest that the amplitude of the nocturnal peak and/or the persistence of a prevalent nocturnal secretion may be an important marker of biological age and of health status.     

Decreased nocturnal synthesis of melatonin in patients with coronary artery disease

In human beings, cardiovascular activity has a distinct circadian variation: Heart rate, blood pressure, and vascular tone decrease at night. Nocturnal cardiovascular blunting is at least partially linked to the autonomic activity and increased risk of cardiac and cerebral events. To assess whether decreased nocturnal melatonin synthesis and secretion in coronary artery disease (CAD), we investigated nocturnal secretion pattern of melatonin in patients with CAD and healthy subjects. The present study performed in 16 patients with angiographically documented CAD (aged 46-71 years) and in nine healthy controls (aged 36-66 years). Blood samples were collected every 2 h between 22:00 and 08:00 h. Melatonin levels were measured with a commercially available radioimmunoassay kit. We found large interindividual variation in the pattern of melatonin secretion in both groups. Patients with CAD secreted less nocturnal melatonin at 02:00, 04:00 and 08:00 h than control subjects (P=0.014, P=0.04 and P=0.025, respectively). Peak and Delta melatonin (peak-lowest melatonin) were found lower in patients with CAD (48.6 [19.1-75.4] vs. 131.4 [67.8-137.2] pg/ml, P=0.006 and 43 [10.5-68.5] vs. 107.6 [55.7-113.1] pg/ml, P=0.002, respectively). Peak time of melatonin secretion was observed earlier in patients with CAD (02:00 h [23:00-02:00 h] vs. 03:45 h [02:00-05:00 h], P=0.04). Our study provides useful and preliminary information about decreased nocturnal melatonin synthesis and release in patients with CAD might help physicians in managing these patients.     

Estimation of frequently sampled nocturnal melatonin production in humans by deconvolution analysis: evidence for episodic or ultradian secretion

In order to investigate nocturnal melatonin production and clearance rates, we applied deconvolution analysis to plasma melatonin concentration time series obtained every 20 min for 12 hr from 20:00 h to 08:00 h in two groups of healthy subjects at rest (group 1, 12 male subjects, 22-26 yr; group 2, ten female subjects, 31-42 yr). The estimated melatonin production rate from group 1 (0.55 +/- 0.21 microg/kg/night) was significantly higher than that of group 2 (0.26 +/- 0.19 microg/kg/night), as well as the mass of melatonin released per burst (275 +/- 110 vs. 145 +/- 130 pg/mL for groups 1 and 2, respectively), the amplitude of secretory bursts (7.8 +/- 3.2 vs. 4.7 +/- 3.5 pg/mL/min), and the pulsatile melatonin production rate (2.76 +/- 1.14 vs. 1.27 +/- 0.97 ng/mL/night). These differences could reflect alterations related to age and or gender. No differences were observed between the two groups in the secretory burst half-duration and frequency and the interburst interval. Melatonin production rates, as estimated by deconvolution analysis, are in agreement with other independent estimates, especially the isotopic method, and disclose an ultradian rhythmicity.     

老年人血清褪黑素水平变化的探讨

目的　探讨老年人血清褪黑素 (松果腺主要在夜间分泌的一种吲哚胺类激素 )水平变化。方法　用放射免疫法检测了 14 4例济南市人 (31～ 110岁 )夜间 (0 2 :0 0 )及白天 (0 8:0 0 )血清褪黑素水平。结果　夜间血清褪黑素水平随着年龄增长呈下降趋势 ,与成年人组比较 70岁组和 >80岁组的褪黑素水平明显降低 (P <0 .0 1) ;女性的褪黑素水平略高于男性 (P <0 .0 5 ) ;健康老年人与老年患者 (主要为心血管系统疾病 )比较褪黑素水平差异无显著性意义(P >0 .0 5 ) ,年龄、性别和健康状况对白天血清褪黑素水平无明显影响。结论　年龄与性别是影响老年人夜间血清褪黑素水平的主要因素 ,研究结果未能显示健康状况对老年人血清褪黑素水平的影响。     

Melatonin levels decrease in type 2 diabetic patients with cardiac autonomic neuropathy

The present study has been designed to determine melatonin levels in type 2 diabetic patients and test the relationship between the autonomic nervous system and melatonin dynamics. Thirty-six type 2 diabetic patients and 13 age-matched healthy subjects were recruited for the study. Circadian rhythm of melatonin secretion was assessed by measuring serum melatonin concentrations between 02:00-04:00 and 16:00-18:00 hr. Melatonin dynamics were re-evaluated with respect to autonomic nervous system in diabetic patients with autonomic neuropathy who were diagnosed by the cardiovascular reflex tests, heart rate variability (HRV), and 24-hr blood pressure monitoring. Nocturnal melatonin levels and the nocturnal melatonin surge were low in the diabetic group (P = 0.027 and 0.008 respectively). Patients with autonomic neuropathy revealed decreased melatonin levels both at night and during day when compared with healthy controls (P < 0.001 and 0.004 respectively) while the melatonin dynamics were similar to controls in patients without autonomic neuropathy. Nocturnal melatonin level was positively correlated with nocturnal high and low frequency components of HRV (P = 0.005 and 0.011 respectively) and systolic and diastolic blood pressures at night (P = 0.002 and 0.004 respectively) in patients with autonomic neuropathy. We found a negative correlation between nocturnal melatonin levels and the degree of systolic blood pressure decrease at night (r = -0.478, P = 0.045). As a conclusion this study has shown that circadian rhythm of melatonin secretion is blunted in type 2 diabetic patients and there is a complex relationship between various components of autonomic nervous system and melatonin secretion at night. Among the patients with autonomic neuropathy those with more preserved HRV and the systolic nondippers (<10% reduction in blood pressure during the night relative to daytime values) have more pronounced melatonin surge at night.     

Circadian variation of beta-adrenoceptor binding sites in the pineal gland of the Syrian hamster and prevention of the nocturnal reduction by light exposure or propranolol treatment

Radioreceptor assays with (-) [125I]-iodopindolol (IPIN) were used to describe circadian variations of beta-adrenoceptors in the pineal gland of male Syrian hamsters (Mesocricetus auratus). Single-point experiments (200 pM IPIN, 8-9 pineals pooled per time point) showed a significant circadian variation (p less than 0.01) with maximal values (28.9 +/- 1.8 fmol/mg protein, means +/- SEM, n = 7) between 07:00 and 02:30 h, and minimal values at 04:00 (7.2 +/- 2.9 fmol/mg protein, n = 3), 8 h after darkness onset. Either exposure of animals to light at night or treating dark exposed hamsters with a beta-adrenergic receptor blocker, propranolol, prevented the nocturnal drop in the number of beta-adrenoceptors. Scatchard analysis of saturation isotherms at 02:30, 04:00 and 08:00 h (30-600 pM IPIN, one saturation experiment with 25 pineals pooled per time point) confirmed the circadian variation.     

Light Suppression of Melatonin in the Squirrel Monkey (Saimiri sciureus)

This study examined plasma melatonin levels and the suppressant effect of light on melatonin production in the squirrel monkey. Monkeys were maintained on a 12:12 light-dark cycle (LD 12:12) with lights on from 07:00 to 19:00. Plasma levels of melatonin were determined by gas chromatography negative chemical ionization mass spectrometry. Melatonin levels at 00:00 (99.5 +/- 18.9 pg/ml) were significantly higher than at 02:00 (57.21 +/- 7.7 pg/ml; Student's t = 2.859; P less than or equal to 0.021). Baseline values at 02:00 were compared with levels at the same time of day after exposure to 2 hours of 200 lux of light (30.6 +/- 13.1 pg/ml), which caused an average suppression of 54.8% in melatonin levels. One animal did not show light suppression. Results indicated that the squirrel monkey suppressant response to light, as well as baseline values of melatonin, varied between animals.     

Nocturnal melatonin plasma levels in patients with OSAS: the effect of CPAP.

Melatonin is a pineal hormone that regulates the human cycle of sleep and wakefulness. Plasma melatonin levels were investigated in patients with obstructive sleep apnoea syndrome (OSAS). In total, 20 patients with OSAS and 11 healthy controls were studied. OSAS patients were tested twice: on the night of diagnostic polysomnography and the night of continuous positive airway pressure (CPAP) titration. Controls were tested on one occasion. Plasma melatonin levels were determined at 23:00 h (light period), at 02:00 h (dark period) and at 06:00 h (light period) in patients and control subjects using the radioimmunoassay method. The control subjects showed a nocturnal melatonin peak value at 02:00 h (70.6+/-14 pg.mL(-1)). However, this nocturnal melatonin peak was absent in the OSAS patients. The highest melatonin value was found in OSAS patients on the night of diagnosis, at 06:00 h (49.3+/-36.8 pg.mL(-1)). It was found that the melatonin level in OSAS patients at 06:00 h was significantly lower in the night of titration (35.6+/-37.9 pg.mL(-1)) than in the diagnosis night. However, the melatonin levels at either 23:00 h or 02:00 h in OSAS patients did not differ significantly when comparing levels in the night of diagnostic polysomnography (23:00 h: 31.6+/-29.8 pg.mL(-1); 02:00 h: 47.4+/-33.8 pg.mL(-1)) with levels in the night of CPAP titration (23:00 h: 20.2+/-10.3 pg.mL(-1); 02:00 h: 37.7+/-27.5 pg.mL(-1)). Patients with obstructive sleep apnoea syndrome have an abnormal melatonin secretion pattern. The absence of a nocturnal serum melatonin peak could be partially related to the difficulty that these patients have in achieving a normal sleep-wakefulness pattern.     

Effect of estradiol on plasma melatonin levels

Melatonin levels were determined in plasma samples obtained at 15 minute intervals during a 4-hour period (08:00 - 12:00 hours) from a normal adult male on 5 consecutive days. On days 1, 2, and 3, the subject was given estradiol valerate (E2) 10 micrograms/kg at the end of each sampling period. An episodic pattern of melatonin secretion was found. Post E2 mean estradiol levels per 4 hours increased and mean melatonin and testosterone levels per 4 hours decreased significantly. A decrease in melatonin levels post E2 is the reverse of the response expected based on nonhuman animal experimental data.     

Circadian rhythm of melatonin, corticosterone and phagocytosis: effect of stress

Melatonin has a functional connection with the immune system. Phagocyte function is altered by extirpation of the pineal gland, one source of melatonin, or by in vitro incubation of phagocytes with pharmacological concentrations of melatonin. Given that its synthesis by pinealocytes is under the control of the noradrenaline released by the sympathetic postganglionaric nerve endings, the present work was aimed at evaluating the circadian rhythm of melatonin, corticosterone, and phagocytosis in BALB/c mice in basal and stress situations. Peritoneal macrophages were used as phagocytes, latex beads as the particles to be ingested, and forced swimming to exhaustion as the stress situation. Radioimmunoassay was used to determine the animals' serum hormone levels. Samples were taken every 3 hr in the period from 04:00 to 22:00 hr, and every 30 min during the remaining period from 22:00 to 04:00 hr. Control mice presented a short-term melatonin peak at 23:30 hr, while the maximum inert-particle ingestion capacity of the peritoneal macrophages also occurred during the night but at 03:30 hr. The corticosterone levels in control mice presented a circadian rhythm with a day-time maximum peak (16:00 hr). Compared with the controls, the animals subjected to stress maintained, although at lower values, the melatonin peak at 23:30 hr, but they presented a loss of the rhythm of serum corticosterone levels, and the corticosterone levels and the macrophage phagocytic capacity were greater at all hours of the day.     

Seasonality of psychopathology and circannual melatonin rhythm

The association of seasonal changes in health and disease has been known for centuries. The prevalence of psychopathological symptoms with seasonal fluctuations and the use of melatonin as a biological marker of circadian and circannual rhythms is well documented. The aim of this work was to study the variability of melatonin secretion between summer and winter in our geographical area (28 degrees N, 16 degrees W) and relate the changes to the level of psychopathology. Ten drug-free, nonsmoker, healthy subjects were studied in summer (August) and winter (December). Blood samples for melatonin assays were collected every hour at night for 5 hr, from 22:00 to 02:00 hr, and next day at noon. Melatonin was assayed by an ELISA technique. Psychopathology was evaluated by means of the 28-item version of the General Health Questionnaire (GHQ-28). All subjects had a circadian rhythm of melatonin secretion in summer and winter. There was a seasonal rhythm with melatonin levels being significantly higher at night in winter than in summer. Melatonin levels at 22:00, 23:00, 24:00 and 01:00 hr and mean melatonin area under the curve (AUC) were significantly higher in winter than in summer. Melatonin AUC increased 80% in winter compared with summer. The GHQ-28 somatic and anxiety subscales and the total GHQ-28 score were significantly higher in winter than summer. Psychopathology scores were significantly and negatively correlated with melatonin production in summer and winter. Our data strongly suggest that melatonin production and psychopathology levels present seasonal fluctuations and these variations should be taken into account when conducting research in this field.     

Light/dark patterns of soluble vascular cell adhesion molecule-1 in relation to melatonin in patients with ST-segment elevation myocardial infarction

Elevated levels of soluble cellular adhesion molecules have been reported in patients with acute coronary syndromes. Likewise, a relation between decreased nocturnal melatonin levels and coronary artery disease has been suggested. The aim of the present study was to investigate the day-night variations in the concentration of soluble vascular cell adhesion molecule-1 (sVCAM-1) in patients with ST-segment elevation myocardial infarction (STEMI) in relation to the light/dark melatonin pattern. Ninety consecutive patients with STEMI who were admitted to the Coronary Care Unit of our institution were studied. We also recruited 70 age- and gender-matched healthy normal subjects. Blood samples were drawn at 09:00 and 02:00 hr, while patients were at rest, for the assessment of sVCAM-1 and melatonin, which were measured using commercially available ELISA. In STEMI patients, melatonin concentrations maintained a diurnal variation, but the difference between nocturnal and diurnal levels was less than that in healthy subjects (P < 0.0001). In contrast to findings with melatonin, sVCAM-1 levels showed no diurnal variations in control subjects. In the STEMI group, however, sVCAM-1 concentration at 02:00 hr was significantly higher than that during the light phase (09:00 hr; 1391 +/- 38 versus 1200 +/- 43 ng/mL, P < 0.05). The results suggest that diurnal variations in endogenous sVCAM-1 production in STEMI patients might be related to an attenuated circadian secretion of melatonin.     

Impaired nocturnal melatonin secretion in non-dipper hypertensive patients

BACKGROUND: Melatonin plays a role in the biologic regulation of circadian rhythms, including sleep. Melatonin has also been shown to modulate vascular smooth muscle tone and to induce hemodynamic effects in humans. OBJECTIVE: To evaluate whether melatonin plays a role in the circadian rhythm of blood pressure in hypertensive patients. METHODS: Sixteen elderly patients with essential hypertension were evaluated. Patients were defined as either dippers (DIP, n = 8) or non-dippers (NDIP, n = 8) according to the nocturnal change in the mean arterial pressure (MAP). 6-Sulfatoxymelatonin (6-SMT), the main melatonin metabolite, was determined by enzyme-linked immunosorbent assay (ELISA) in two separate urine collections, one in the daytime and one during the night. RESULTS: Both groups of DIP and NDIP hypertensives were comparable in regard to age and sex. During the night, the mean arterial pressure decreased by 10.3 +/- 2.2% in the DIP and increased by 7.5 +/- 1.7% in the NDIP group (p < 0.01). Daily 6-SMT was comparable in DIP (3.28 +/- 0.87 microg/12 h) and NDIP (2.31 +/- 0.68 microg/12 h) (p = 0.39). However, while the DIP presented the physiological nocturnal increase in urinary 6-SMT (mean 8.19 +/- 1.68 microg/ 12 h), this surge of melatonin production was missing in NDIP in whom nocturnal urinary 6-SMT concentrations were not significantly different from daily levels (mean 2.56 +/- 0.79 microg/12 h). The nocturnal change in urinary 6-SMT excretion was positively correlated to the nocturnal change in MAP (R = 0.54; p = 0.031). CONCLUSIONS: NDIP hypertensive patients differ from DIP hypertensives by having an impaired nocturnal melatonin secretion. Thus, melatonin may play a role in the circadian rhythm of blood pressure in hypertensive patients.     

A study of melatonin levels and stress in female shift workers

The aim of this study was to determine the relationship between saliva melatonin and stress levels in Thai female shift workers. Five older (38.4 +/- 1.82) and five younger (21.4 +/- 0.55) female workers voluntarily participated in this study. All participants worked both morning and night shifts at a glass manufacturing factory. Saliva was collected every three hours at the workplace and at the subjects' houses to examine melatonin profiles. The Mann-Whitney U test and the Wilcoxon signed ranks test were used. There was a significant (p < 0.05) difference between melatonin levels in younger and older subjects when measured during the night shift at 19:00. Differences between melatonin levels during the morning and night shifts in the older group were significant at 07:00 and at 19:00 in younger subjects (p < 0.05). Normal stress and mild stress were found. No significant differences in melatonin levels were found between workers with normal and mild stress levels. The onset time of increasing saliva melatonin was at 19:00, both in women working the morning shift and in those working the night shift. Peak melatonin production occurred at 22:00 for the night shift in both groups. During the morning shifts, the peak times were at 04:00 and 01:00 (in the younger and older groups, respectively), usually between 02:00 and 04:00. These findings show that melatonin levels in female shift workers adapted according to the shift worked, especially in the older group. Health surveillance programs should therefore be established to prevent further negative health effects for female shift workers.     

Low urinary 6-sulphatoxymelatonin levels in patients with coronary artery disease

A decrease in nocturnal serum melatonin levels was reported in patients with clinically uncharacterized coronary artery disease. To assess whether there was a correlation between melatonin production and disease stage, we measured the nocturnal urinary excretion of 6-sulphatoxymelatonin (an index of blood melatonin concentration) in patients with chronic stable or unstable coronary disease and in a group of age-matched controls. Three groups of individuals were studied: a) 24 healthy subjects (mean age: 63 +/- 13 yr); b) 32 patients with chronic, stable, coronary disease (62 +/- 11 yr); and c) 27 patients with unstable angina (62 +/- 12 yr). For 6-sulphatoxymelatonin measurement, urine was collected from 18:00 to 06:00 hr, within 48 hr of hospitalization in the case of unstable angina. 6-Sulphatoxymelatonin was measured by a specific radioimmunoassay. Urinary 6-sulphatoxymelatonin excretion was significantly lower in unstable angina patients than in healthy subjects or in patients with stable angina. 6-Sulphatoxymelatonin correlated negatively with age in healthy subjects, but not in coronary patients. 6-Sulphatoxymelatonin excretion in patients treated with beta-adrenoceptor blockers did not differ significantly from coronary patients not receiving beta-blockers. The results indicate that patients with coronary disease have a low melatonin production rate, with greater decreases in those with higher risk of cardiac infarction and/or death.     

DNA synthesis in human bone marrow is circadian stage dependent

Fraction of human bone marrow (BM) cells in DNA synthesis has been studied by sampling BM from the sternum or the iliac crests every 4 hours during one 24-hour period in 16 healthy male volunteers. Three of the subjects underwent the sampling procedure twice, resulting in 19 24-hour profiles. The percentage of cells in DNA synthesis measured by flow cytometry demonstrated a large variation along the circadian time scale for each 24-hour profile, with a range of variation from 29% to 339% from lowest to highest value. Seventeen profiles (89.5%) had the highest DNA synthesis during waking hours between 08:00 hours and 20:00 hours, and the lowest percentage of cells in DNA synthesis between 00:00 hours and 04:00 hours. The mean value of the lowest DNA synthesis for each 19 24-hour period was 8.7% +/- 0.6%, while the mean value of the highest DNA synthesis was 17.6% +/- 0.6%, ie, a twofold difference. There was no difference in DNA synthesis between winter and summer. A significantly higher DNA synthesis was demonstrated for samples obtained from sternum as compared with the iliac crests, but the same circadian pattern was demonstrated for both localizations. By taking circadian stage-dependent variations in DNA synthesis into account it may be possible to reduce BM sensitivity to cytotoxic chemotherapy, to increase the effect of hematopoietic growth factors as well as increase the fraction of proliferating cells with careful selection of time of day for harvesting BM cells for auto- or allografting.     

Hypoxic depression of melatonin secretion after simulated long duration flights in man

Fatigue is often reported after long duration flights. Mild hypobaric hypoxia caused by pressurization may be involved in this effect through disruption of circadian rhythms, independent of the number of time zones crossed. In this controlled crossover study we assessed the effects of two levels of hypoxia equivalent to 8000 and 12,000 ft on the rhythm of plasma melatonin concentrations, a marker of circadian rhythmicity. Sixteen healthy young male volunteers (23-39 years) were exposed in a hypobaric chamber for 8 hr (08:00-16:00 hours) to 8000 ft, followed 4 wk later by 12,000 ft. Plasma melatonin was assayed over two 24-hr cycles (control and hypoxic exposure) every 2 hr in all subjects. We found a significant decrease in the nocturnal melatonin peak after hypoxic exposure at both altitudes, and we found that this effect was age dependent for the 12,000-ft exposure: the decrease was only seen in the younger subjects (23-28 years). Analysis of heart rate variability allowed us to demonstrate that the older and less trained subjects (29-39 yr) in our study exhibited a far greater increase in sympathetic tone than the younger subjects during the 12,000-ft exposure. These results show that hypoxic depression of melatonin secretion may be influenced by individual factors such as age, physical fitness and sympathetic reactivity to hypoxia. Our findings suggest that hypoxia may by itself contribute at least in part to postflight fatigue after long duration flights, and to the clinical disorders of jet lag in transmeridian flights through its effects on the circadian system.     

Neuroendocrine, immunohistochemical, and ultrastructural study of pineal region tumors

Abstract: Thirteen patients with tumors in the pineal region were submitted to pre- and post-operative blood sampling (08:00, 14:00, 20:00, and 02:00 hr) for three or four consecutive days. A single cerebrospinal fluid (CSF) sample was collected at surgery, and melatonin levels determined. In all patients, serum and CSF beta subunit of human chorionic gonadotrophin (βHCG), carcino embryonic antigen (CEA), and alpha-fetoprotein (AFP) levels were measured. Histology revealed four pineocytomas, one pineoblastoma, four germinomas, one immature teratoma, one pilocytic astrocytoma, one lymphoma, and one meningioma. Serum and CSF levels of serological biomarkers were normal, except for one of the germinoma cases. In most patients, alteration either in the circadian rhythm or in the melatonin concentration was observed before surgery. In benign neoplasms the circadian rhythm was conserved. In pineoblastoma, lymphoma, and three out of four germinomas, melatonin concentrations were undetectable. In one case of germinoma, melatonin levels were high, with the circadian rhythm being abolished. According to conventional histology, all germinomas were similar. Therefore, in a rare case of pineal germinoma with high melatonin levels, the tissue was subjected to an in depth investigation (immunohistochemical and ultrastructural) in order to determine the pathology and the possible differences from the other typical germinomas. Results were compared to those provided from other pineal neoplasms. Electron microscopy examination detected the presence of clusters of intermediate filaments and numerous electrondense granules only in the case of a germinoma producing melatonin.     

Ontogeny of Circadian Rhythmicity for Melatonin, Serotonin, and N-Acetylserotonin in Humans

The serum concentration of melatonin, serotonin, and N-acetylserotonin were measured by RIA procedures in 28 infants aged 1 week to 9 months. Blood specimens were obtained at 12:00 hr and 24:00 hr. A day-night difference in serum serotonin was present immediately after birth. A significant (P less than 0.001) decrease in serum serotonin concentrations at 12:00 hr and 24:00 hr was observed from the first month of age to the third to ninth month of age. A significant (P less than 0.05) difference in day-night N-acetylserotonin concentration is first seen at age 1-3 months. Serum melatonin concentrations, though detectable, did not show any day-night difference at birth. Melatonin concentrations progressively increased up to the third month of age, and a significant (P less than 0.01) day-night difference appeared thereafter. The results indicate that in humans the circadian organization for serotonin already exists at birth, and the circadian melatonin rhythm develops after birth.