Blood Melatonin Concentrations Research Articles

Overcoming poor ovarian response in assisted reproductive technology programs in patients of late reproductive age

Objective: to increase the effectiveness of in vitro fertilization in patients of late reproductive age by optimizing prepregnancy preparation for the IVF program.Materials and methods: The study included 67 patients of late reproductive age with a history of unsuccessful IVF attempts, divided into two groups at the second stage of the study, depending on the volume of prepregnancy preparation: group 1 (33 patients), group 2 (34 patients). The control group (50 patients) were healthy women of reproductive age. Immunohistochemical examination of the endometrium and microbiological examination of the uterine cavity, hormonal status of peripheral blood, study of the concentration of melatonin in peripheral blood and follicular fluid, antioxidant status of follicular fluid, expression of leukemia inhibitory factor (LIF) in the cervical secretion were performed.Results: in patients with age-related dysregulation of the hypothalamic-pituitary-ovarian axis and impaired fertile function, a systemic and local (in follicles) decrease in melatonin levels was revealed. The studied effects of melatonin suggested that its use in patients of late reproductive age with reduced follicular reserve and a "poor" response to ovarian stimulation may increase the effectiveness of in vitro fertilization (IVF).Conclusions: The inclusion in the pre-gravidar preparation of a complex of water-soluble polypeptide fractions of the epiphysis, stimulating the production of endogenous melatonin, made it possible to increase the effectiveness of IVF in patients by an average of 3.1 times according to the criterion of "clinical pregnancy" and 4.1 times according to the criterion of "live birth".

Sleep disorders and changes in melatonin concentrations in pregnant women with preeclampsia

Melatonin plays a significant role in the development of normal pregnancy, in particular, it contributes to the successful implantation of the fertilized egg, affects the act of childbirth, is actively produced by the trophoblast and placenta, reduces oxidative stress, in particular, with preeclampsia. In addition, melatonin is one of the essential hormones in the protection of the endothelium and stem cells from the oxidant stress. Objective – to study the mechanisms of development, terms of manifestation, and types of sleep disorders, as well as changes in the concentrations of melatonin in the blood of pregnant women with preeclampsia. Material and methods. 50 pregnant women at a mean age of 29.1±3.4 years who had preeclampsia in the 3rd pregnancy trimester were examined (experimental group). All women in the research group had a gestation term of 30-32 weeks of pregnancy. The control group consisted of 33 women with a mean age of 31.2±6.6 years who had an uncomplicated pregnancy. The presence of sleep disorders was established using a questionnaire: pregnant women were asked about the term of pregnancy in which complaints of sleep disorders appeared, the nature of sleep disorders, the frequency of episodes of sleep disorders (how many times a week such a condition was noted), etc. The concentration of melatonin in the venous blood of the examined pregnant women was also determined, for which IBL melatonin ELISA diagnostic kits manufactured by IBL, Germany were used. Blood was taken at 9:00 a.m., on an empty stomach, and all patients were analyzed at the same time of a day. Results and their discussion. The study showed that sleep disorders in pregnant women with pre-eclampsia, which complicates the pregnancy in the 3rd trimester, occurred earlier, compared to women with an uncomplicated course of pregnancy: pregnant women with pre-eclampsia were more likely to notice worsening of sleep, starting from 22-30 weeks of pregnancy (in 26.0 % of cases), while in pregnant women with a physiological course of gestation, similar complaints appeared mainly after 30 weeks. In the third trimester of pregnancy women with preeclampsia were more likely to wake up 2 or more times per night (in 68.0 % of cases) compared to controls (in 23.3 % of cases, p < 0.001) and 3 or more times per night per week (in 54.0 % of cases, in controls – in 16.7 % of cases, p < 0.001), which may be a consequence of a disorder of the function of the pineal gland. Women with preeclampsia were more likely (56.0 % vs. 13.3 % in the control group, p < 0.01) to use gadgets (electronic devices, mainly smartphones) for more than 2 hours after 9:00 p.m., which also negatively affects the function of the pineal gland. In pregnant women whose pregnancy was complicated by preeclampsia in the 3rd trimester, a significant (1.78-fold) decrease in the level of melatonin in venous blood taken at 9 a.m. was observed, compared to women with an uncomplicated pregnancy (p = 0.029). Conclusions. Sleep disorders in pregnant women with preeclampsia occur earlier and are more expressed compared to women with an uncomplicated course of pregnancy. The appearance of complaints of insomnia in the second trimester of pregnancy, in our opinion, can be considered a diagnostic sign of pineal gland dysfunction in preeclampsia. A decrease in the level of melatonin in pregnant women with preeclampsia, established against the background of minimal daily activity of the pineal gland (at 9 a.m.), indicates a decrease in the melatonin-producing function of the placenta which might have an impact on the condition of stem cells of fetus and placenta.

Effects of SNPs in AANAT and ASMT Genes on Milk and Peripheral Blood Melatonin Concentrations in Holstein Cows (Bos taurus).

Aralkylamine N-acetyltransferase (AANAT) and acetylserotonin O-methyltransferase (ASMT), the two rate-limiting enzymes for melatonin synthesis, regulate melatonin production in mammals. Through analysis of the milk melatonin level and dairy herd improvement (DHI) index, it was found that the melatonin concentration in milk was significantly negatively correlated with the 305 day milk yield (305M) and peak milk yield (PeakM) (p < 0.05), while it was significantly positively correlated with the serum melatonin concentration (p < 0.05). The full-length of AANAT and ASMT were sequenced and genotyped in 122 cows. Three SNPs in AANAT and four SNPs in ASMT were significantly related to MT levels in the milk and serum (p < 0.05). The SNPs in AANAT were temporarily denoted as N-SNP1 (g.55290169 T>C), N-SNP2 (g.55289357 T>C), and N-SNP3 (g.55289409 C>T). The SNPs in ASMT were temporarily denoted as M-SNP1 (g.158407305 G>A), M-SNP2 (g.158407477 A>G), M-SNP3 (g.158407874 G>A), and M-SNP4 (g.158415342 T>C). The M-SNP1, M-SNP2, and M-SNP3 conformed to the Hardy−Weinberg equilibrium (p > 0.05), while other SNPs deviated from the Hardy−Weinberg equilibrium (p < 0.05). The potential association of MT production and each SNP was statistically analyzed using the method of linkage disequilibrium (LD). The results showed that N-SNP2 and N-SNP3 had some degree of LD (D′ = 0.27), but M-SNP1 and M-SNP2 had a strong LD (D′ = 0.98). Thus, the DHI index could serve as a prediction of the milk MT level. The SNPs in AANAT and ASMT could be used as potential molecular markers for screening cows to produce high melatonin milk.

Anhedonia as target symptom in personalized therapy of patients with mood disorders and alcohol use disorder comorbidity

To estimate the efficacy of antidepressants in the treatment of anhedonia in mood disorders (MD) comorbid with alcohol use disorder (AUD), considering melatonin concentration in the patient's blood serum. Seventy patients, aged 18-65 years old, with MD, including patients with- (group F3+F10, n=36) or without comorbid AUD (group F3, n=34), were examined. Control group consisted of 26 healthy volunteers. Clinical-dynamic evaluation was carried out using SIGH-SAD and SHAPS-C. Melatonin concentration was measured with MAGPIX analyzer (Luminex, USA). The statistical analysis was carried out using the SPSS (V. 23.0) standard package. In the case of MD/AUD comorbidity anhedonia symptom does not respond well to psychopharmacotherapy during four weeks (p=0.192, Wilcoxon test) whereas anhedonia in «pure» MD does (p=0.007, Wilcoxon test). At the same time, only patients with «pure» MD have a statistically significant decrease in melatonin concentration in blood serum compared with the control group (p=0.025, p=0.031, Mann-Whitney test), on the contrary, in the case of MD/AUD comorbidity, a relative increase in melatonin concentration (p>0.05 Mann-Whitney test) was demonstrated. The relatively low response of anhedonia symptom in the case of MD/AUD comorbidity compared with the «pure» MD, makes perspective using antidepressants with prodophaminergic mechanism of action in this cohort of patients. Furthermore, in MD/AUD comorbidity, contrary to «pure» MD, a relative increase in melatonin concentration in blood serum was detected, therefore it could be a limitation to prescribing antidepressants directly or indirectly modulating melatoninergic system.

Circadian Rhythm and Concentration of Melatonin in Breast Cancer Patients.

Melatonin is a biomarker of the central circadian clock and its chronobiotic actions entraining circadian rhythms to the light-dark cycle are well known. Reduction in melatonin levels and altered circadian rhythms have been associated with a high risk of breast cancer. Melatonin has also been shown to display anti-proliferative effects on breast cancer growth and proliferation. Evaluation of melatonin circadian rhythm alterations in patients bearing breast cancer may have interesting prognostic and therapeutic applications. To review studies evaluating the circadian rhythm of melatonin in breast cancer patients. The effects of surgery and chemotherapy on melatonin secretion were also reviewed. Electronic databases, including PubMed/MEDLINE and Scopus, were searched from their inception to May 2020, using the keywords "Melatonin", "Circadian rhythm" and "Breast cancer". Patients with breast cancer maintain a circadian rhythm of melatonin secretion with relatively high levels during the night and low levels during the day, however, a reduction in nocturnal melatonin peak and decreased amplitude of melatonin circadian rhythms in these patients have also been reported. Melatonin levels can influence estrogen receptor concentrations in hormone-dependent estrogen- positive breast cancer. Chemotherapy alters melatonin levels and breast surgery tends to alter melatonin secretion at first-day post-operation. Melatonin levels correlate with clinical and psychological symptoms of breast cancer, such as sleep quality and depression severity. Circadian rhythm and the concentration of melatonin in the blood are altered in patients with breast cancers, and it can modify not only the sleep-wake cycle and, thus, patients' quality of life but due to melatonin's antioxidant effects, the effect of therapies can be modulated. Due to the heterogonous protocols used to assess melatonin and variable environmental factors during sampling, further studies need to control, such variables in order to tailor clinical trials based on melatonin rhythm adjustment and/or supplementation in breast cancer patients.

Melatonin concentration in peripheral blood and melatonin receptors (MT1 and MT2) in the testis and epididymis of male roe deer during active spermatogenesis

Melatonin regulates male reproductive function in seasonal and non-seasonal breeder mammals. The presence of melatonin membrane receptors (MT1 and MT2) in the testis and epididymis has been demonstrated in several species. Wild roe deer are a short-day breeding species characterised by a short rutting season lasting from mid-July to mid-August. The aim of this study was to determine the concentration of melatonin in the peripheral blood and the presence of MT1 and MT2 receptors in the testis and epididymis in male roe deer during the pre-rut (May), rut (July/August) and post-rut (September) periods. The melatonin concentration was higher in May (522.50 ± 54.20 pg/mL) compared to July/August (258.50 ± 36.82 pg/mL; P < 0.05). During September, the melatonin concentration was higher (393.50 ± 36.77 pg/mL) than in July/August (P < 0.05) but lower than in May (P < 0.05). Immunohistochemical analysis showed the presence of MT1 and MT2 receptors in Leydig cells, Sertoli cells and germ cells in the testis, in addition to the epithelial cells of the epididymis caput, corpus and cauda. MT1 and MT2 receptor expression in the testis and epididymis, assessed by Western blot, was higher in May and July/August (when spermatogenic and steroidogenic activity restarts and reaches its peak, respectively) compared to September (when spermatogenic and steroidogenic activity decreases). This could indicate a stimulatory effect of melatonin on testicular (i.e., steroidogenesis and spermatogenesis) and epididymal (i.e., spermatozoa maturation) function in male roe deer through the MT1 and MT2 receptors. Our results form the basis for further studies into the detailed mechanism of action of melatonin through MT1 and MT2 receptors for optimal reproductive activity in male roe deer and other mammals.

Melatonin Levels Decrease in the Umbilical Cord in Case of Intrauterine Growth Restriction.

Intrauterine growth restriction (IUGR) is a common reason for perinatal morbidity and mortality. Also, it is often complicated with fetal distress. Melatonin is widely known as an anti-oxidant agent, and it might decrease the damage of tissues caused by hypoxia. It is also known that levels of pro- and anti-inflammatory cytokines are changed during pregnancy. Placental growth factor (PlGF) is responsible for the angiogenesis in the placenta. We aimed to investigate whether the level of melatonin, cytokines, and PlGF in umbilical blood after birth is different in the case of IUGR compared to normal fetuses. Fourteen women whose pregnancies were complicated with IUGR were included in the study group. The presence of IUGR was confirmed by ultrasound fetometry in the third pregnancy trimester, 30-36 weeks of gestation. All patients delivered their children vaginally after 37 weeks of pregnancy. The cases of severe fetal distress that required a caesarian section, obstetrical forceps, or vacuum extraction of the fetus were excluded from the study. We found that the concentrations of cytokines did not differ significantly between the groups. Also, no significant difference in the daytime of delivery was found between the groups. The concentrations of melatonin and PlGF in the umbilical blood at labor were significantly lowered in the case of IUGR compared to normal pregnancies. This fact, as we consider, is caused by altered production of melatonin and PlGF by the placenta. Therefore, the protective action of these two factors for the fetus at labor is decreased in IUGR.

Pharmacodynamic evaluation of the effects of oral melatonin on expression of the T-cell cytokines interleukin-2 and interferon gamma in the dog.

To determine the effects of exogenous melatonin administration on activated whole blood expression of the T-cell cytokines interleukin-2 (IL-2) and interferon gamma (INF-γ) in dogs. Ten healthy dogs. Heparinized whole blood was collected from 10 dogs for analysis of cytokine expression before administration of melatonin (baseline). Each dog was then administered melatonin at a dosage of approximately 1mg/kg, PO, q 12hr for 14days. On day 14, whole blood was again collected from each dog at the time points of trough (0hr) and 6hr postmelatonin administration to evaluate the effects of melatonin on cytokine expression. At all evaluated time points, analysis of activated whole blood expression of mRNA coding for both IL-2 and IFN-γ was performed using quantitative reverse transcription polymerase chain reaction to determine whether a difference existed for any time point. Blood melatonin concentrations were also measured at comparable time points. A statistical difference in the expression of either cytokine was not appreciated at any time point, despite attainment of expected blood concentrations of the drug. Results indicate that melatonin therapy does not significantly affect IL-2 or IFN-γ expression in healthy dogs. While melatonin is thought to have an effect on the immune system in dogs, it does not appear this effect is through altering T-cell IL-2 or IFN-γ expression. Further studies investigating the effects of melatonin on the immune system of dogs are warranted.

Urinary 6-sulfatoxymelatonin level and breast cancer risk: systematic review and meta-analysis

6-Sulfatoxymelatonin (aMT6s) is the main metabolite of melatonin in urine, and is a reliable surrogate biomarker reflecting the blood melatonin concentration. This meta-analysis assessed the association between urinary aMT6s level and BC incidence. The electronic databases PubMed, EMBASE, Cochrane Library, and Web of Science were searched. Risk ratios (RRs) were adopted to estimate the relative BC incidence. A total of 7 prospective case-control publications were included, and 6 of them were distinct studies. Pooled analysis of data from the 6 studies involving 1824 women with incident BC and 3954 matched control participants with no overlapping of subjects among studies indicated no significant association between the highest levels of urinary aMT6s and the incidence of BC (RR = 0.97, 95% CI, 0.88–1.08, P = 0.56). Negative associations were observed in postmenopausal women (RR = 0.88, 95% CI, 0.75–1.02, P = 0.10), estrogen receptor positive BC (RR = 0.83, 95% CI, 0.64–1.07, P = 0.15), and studies using 12-hour overnight urine (RR = 0.81, 95% CI, 0.61–1.07, P = 0.13), all with borderline significances. Lag time or invasive degree did not interfere with the results. There was no evident publication bias detected by the Egger’s test and the funnel plot. Conclusively, the current evidence did not support a significant association between urinary aMT6s level and BC risk.

Relationship of nocturnal concentrations of melatonin, gamma-aminobutyric acid and total antioxidants in peripheral blood with insomnia after stroke: study protocol for a prospective non-randomized controlled trial.

Melatonin and gamma-aminobutyric acid (GABA) have been shown to regulate sleep. The nocturnal concentrations of melatonin, GABA and total antioxidants may relate to insomnia in stroke patients. In this prospective single-center non-randomized controlled clinical trial performed in the China Rehabilitation Research Center, we analyzed the relationship of nocturnal concentrations of melatonin, GABA and total antioxidants with insomnia after stroke. Patients during rehabilitation of stroke were recruited and assigned to the insomnia group or non-insomnia group. Simultaneously, persons without stroke or insomnia served as normal controls. Each group contained 25 cases. The primary outcome was nocturnal concentrations of melatonin, GABA and total antioxidants in peripheral blood. The secondary outcomes were Pittsburgh Sleep Quality Index, Insomnia Severity Index, Epworth Sleepiness Scale, Fatigue Severity Scale, Morningness-Eveningness Questionnaire (Chinese version), and National Institute of Health Stroke Scale. The relationship of nocturnal concentrations of melatonin, GABA and total antioxidants with insomnia after stroke was analyzed and showed that they were lower in the insomnia group than in the non-insomnia group. The severity of stroke was higher in the insomnia group than in the non-insomnia group. Correlation analysis demonstrated that the nocturnal concentrations of melatonin and GABA were associated with insomnia after stroke. This trial was registered at ClinicalTrials.gov, identifier: NCT03202121.

Are the proposed benefits of melatonin-rich foods too hard to swallow?

ABSTRACT Melatonin has been proposed as a potent anti-oxidant, and its presence in many plants and foods has been suggested to be beneficial for health. Indeed, the concentrations of melatonin in blood and the melatonin metabolite 6 sulphatoxymelatonin in urine have been found to increase significantly after ingestion of melatonin-rich foods. In this review, the studies have been critically evaluated in light of the reported plant melatonin concentrations and our knowledge of pharmacokinetics of orally administered pure melatonin. In the case of studies involving measurement of plasma melatonin following ingestion of beer or fruits, the reported increase in melatonin is not consistent with the amount of melatonin ingested. Similarly, the amount of melatonin metabolite excreted following ingestion of melatonin-rich foods greatly exceeded the amount of melatonin ingested. It is concluded that studies reporting the appearance of melatonin in blood and its metabolites in urine following ingestion of melatonin-rich foods are flawed. While there may be health benefits for certain foods, it is difficult to accept that these are due to their low melatonin content.

Melatonin: an ancient molecule that makes oxygen metabolically tolerable.

Melatonin is remarkably functionally diverse with actions as a free radical scavenger and antioxidant, circadian rhythm regulator, anti-inflammatory and immunoregulating molecule, and as an oncostatic agent. We hypothesize that the initial and primary function of melatonin in photosynthetic cyanobacteria, which appeared on Earth 3.5-3.2 billion years ago, was as an antioxidant. The evolution of melatonin as an antioxidant by this organism was necessary as photosynthesis is associated with the generation of toxic-free radicals. The other secondary functions of melatonin came about much later in evolution. We also surmise that mitochondria and chloroplasts may be primary sites of melatonin synthesis in all eukaryotic cells that possess these organelles. This prediction is made on the basis that mitochondria and chloroplasts of eukaryotes developed from purple nonsulfur bacteria (which also produce melatonin) and cyanobacteria when they were engulfed by early eukaryotes. Thus, we speculate that the melatonin-synthesizing actions of the engulfed bacteria were retained when these organelles became mitochondria and chloroplasts, respectively. That mitochondria are likely sites of melatonin formation is supported by the observation that this organelle contains high levels of melatonin that are not impacted by blood melatonin concentrations. Melatonin has a remarkable array of means by which it thwarts oxidative damage. It, as well as its metabolites, is differentially effective in scavenging a variety of reactive oxygen and reactive nitrogen species. Moreover, melatonin and its metabolites modulate a large number of antioxidative and pro-oxidative enzymes, leading to a reduction in oxidative damage. The actions of melatonin on radical metabolizing/producing enzymes may be mediated by the Keap1-Nrf2-ARE pathway. Beyond its direct free radical scavenging and indirect antioxidant effects, melatonin has a variety of physiological and metabolic advantages that may enhance its ability to limit oxidative stress.

Effects of exercise with or without light exposure on sleep quality and hormone reponses.

[Purpose]The objectives of the present study were to determine the effect of sun exposure and aerobic exercise on quality of sleep and investigate sleep-related hormonal responses in college-aged males.[Methods]In this study, the cross-over design was utilized. The subjects (N = 10) without any physical problems or sleep disorders participated in the experimental performed 4 protocols in only sun exposure (for 30 minutes, EG1) protocol, only aerobic exercise (walking and jogging for 30 minutes, EG2) protocol, aerobic exercise with sun exposure (EG3) protocol, and control (no exercise and no sun exposure, EG4) protocol. Each protocol was 5 times per week with one-week break (wash-out period) between protocols to prevent the effects of the previous protocol. Total test period was should be 7 weeks (one week of protocol and one week of break). Before and after each aerobic exercise session, the subjects completed stretching to warm up for 5 to 10 minutes. Surveys consisting of (bedtime, wake-up time, sleep onset latency, and (Pittsburgh Sleep Quality Index (PSQI) were obtained before the test and after each protocol. After each protocol, the following sleep-related hormonal responses were measured: blood concentrations of melatonin, cortisol, epinephrine, and norepinephrine. One-way ANOVA was used to determine differences between protocols. Statistical significance was set at p < 0.05.[Results]Bedtime of EG4 was significantly later than that of the EG1 or EG3. Wake-up time in the EG4 was significantly later than that of the EG1 or the EG3. Sleep onset latency in the EG4 was longer than that of the EG3. The quality of sleep in the EG4 was lower than that of the EG3. Sleep cycle in the EG4 was significantly shorter than that of the EG1. Blood melatonin concentrations of the EG3 was significantly higher than that of the EG4. There were no significant differences in blood concentrations of cortisol, epinephrine, or norepinephrine among protocols, with the order from the lowest to the highest values of EG1 < EG2 < EG3 < EG4.[Conclusion]The present data found that EG1 and EG3 showed positive sleep-related hormonal responses, sleep habits, and quality of sleep, indicating that sun exposure or exercise with sun exposure may improve the physical status and quality of life.

Night milking adds value to cow's milk

Melatonin is synthesized in greater concentration at night, and it plays an important role in sleep regulation. This study aimed to evaluate the melatonin concentration in milk collected by milking during the night and evaluates its effect, with or without tryptophan supplementation, in the sleep quality of adult Wistar rats. A difference (P < 0.05) was observed between the milking times, where the milk obtained at 02:00 presented a higher melatonin concentration (39.43 pg mL(-1) ) than that acquired at 15:00 (4.03 pg mL(-1) ). A biological assay was also performed on 32 male adult Wistar rats distributed among four groups (n = 8): those receiving an AIN-93M diet (control group) and three test groups [diets containing milk from milking at 02:00 (M2h ), milking at 15:00 (M15h ), and milking at 02:00 plus tryptophan supplementation (M2h T)] for 28 days. It was observed that the control group did not differ (P > 0.05) from the M15h group in terms of the levels of blood melatonin and urinary sulfatoxymelatonin, but differed from groups M2h and M2h T, whereas group M2h T presented higher blood melatonin and urinary sulfatoxymelatonin concentrations. Combining the techniques of night milking with tryptophan supplementation resulted in production of milk that improves sleep quality in rats.

Daily rhythm of blood melatonin concentrations in sheep of different ages

The aim of the study was to investigate the daily pattern of melatonin during short photoperiods in sheep of different age. Thirty Sarda sheep kept under natural light conditions and divided into three equal groups were used: Group 1 (12–18 months); Group 2 (3–4 years); Group 3 (8–9 years). Blood samples were collected every 2 h for 22 h, starting at 21 December (12:00 h) until 22 December (10:00 h) for plasma melatonin radioimmunoassay determination. Statistical significant effect of time of day and age on melatonin concentration was registered. Mesor and amplitude values were statistically lower in Group 3 than in Groups 1 and 2. This study provides the first characterization of the relationship between age and daily pattern of melatonin in sheep, highlighting a decrease in melatonin production in the older animals.

Melatonin reduces body weight gain and increases nocturnal activity in male Wistar rats

AimThis study evaluated the effect of the administration of melatonin, the chief secretory product of the pineal gland, on the body weight in male Wistar rats. Main methodsThe animals were housed for 4months in cages equipped to log horizontal activity within a thermostatically-controlled chamber, under a 12h/12h light/dark photoperiod (lights on at 08:00h). After acclimatization, the animals were divided into two groups: (1) control animals, and (2) melatonin-treated animals. Melatonin was administered in tap water (20μg/ml), and fresh drinking fluid was changed twice weekly. Rats were fed a standard diet ad libitum. Key findingsFood and water intake, body weight, the amplitude of the activity/rest rhythm (motor activity), and blood melatonin and glucose concentrations were measured. The administration of melatonin did not influence either food or water intake or glucose levels relative to those found in the control animals. However, melatonin administration reduced body weight gain and increased nocturnal locomotor activity. The peak concentration of melatonin was found at night coinciding with the increase in nocturnal activity. SignificanceThe results show that exogenous melatonin reduces body weight gain without having marked effects on metabolism. This may be due in part to the increased nocturnal activity shown by the animals treated with the indoleamine.

The foetal pig pineal gland is richly innervated by nerve fibres containing catecholamine-synthesizing enzymes, neuropeptide Y (NPY) and C-terminal flanking peptide of NPY, but it does not secrete melatonin.

Innervation of the mammalian pineal gland during prenatal development is poorly recognized. Therefore, immunofluorescence studies of the pineals of 70- and 90-day-old foetuses of the domestic pig were performed using antibodies against tyrosine hydroxylase (TH), dopamine-β-hydroxylase (DβH), neuropeptide Y (NPY) and C-terminal flanking peptide of NPY (CPON). The investigated glands were supplied by numerous nerve fibres containing TH and DβH. The density of these fibres was higher in the distal and middle parts of the gland than in the proximal one. NPY and CPON were identified in the majority of DβH-positive fibres as well as in a small population of DβH-negative fibres localized mainly in the proximal part of the pineal. The immunoreactive fibres were more numerous in 90-day-old foetuses than in 70-day-old ones. The effect of norepinephrine on melatonin secretion by the foetal pineals in the short-term organ culture was studied to determine the role of DβH-positive fibres during prenatal life. For the same purpose melatonin was measured in the blood in the umbilical cords and in the jugular vein of the mother. The pineals of both groups of foetuses did not secrete melatonin in the organ culture, independently of the presence or absence of norepinephrine in the medium. Melatonin concentrations in the blood in the umbilical cords of foetuses from the same litter and in the jugular vein of their mother were similar. The presence of adrenergic nerve fibres in the pig pineal during gestation does not seem to be associated with the control of melatonin secretion.

A Mathematical Model of the Circadian Phase-Shifting Effects of Exogenous Melatonin

Melatonin is endogenously produced and released in humans during nighttime darkness and is suppressed by ocular light exposure. Exogenous melatonin is used to induce circadian phase shifts and sleep. The circadian phase-shifting ability of a stimulus (e.g., melatonin or light) relative to its timing may be displayed as a phase response curve (PRC). Published PRCs to exogenous melatonin show a transition from phase advances to delays approximately 1 h after dim light melatonin onset. A previously developed mathematical model simulates endogenous production and clearance of melatonin as a function of circadian phase, light-induced suppression, and resetting of circadian phase by light. We extend this model to include the pharmacokinetics of oral exogenous melatonin and phase-shifting effects via melatonin receptors in the suprachiasmatic nucleus of the mammalian hypothalamus. Model parameters are fit using 2 data sets: (1) blood melatonin concentration following a 0.3- or 5.0-mg dose, and (2) a PRC to a 3.0-mg dose of melatonin. After fitting to the 3.0-mg PRC, the model correctly predicts that, by comparison, the 0.5-mg PRC is slightly decreased in amplitude and shifted to a later circadian phase. This model also reproduces blood concentration profiles of various melatonin preparations that differ only in absorption rate and percentage degradation by first-pass hepatic metabolism. This model can simulate experimental protocols using oral melatonin, with potential application to guide dose size and timing to optimally shift and entrain circadian rhythms.

Melatonin concentration in umbilical cord blood depends on mode of delivery

Background and aimsMelatonin (MT) is rapidly transferred from the maternal to fetal circulation in humans. There is little knowledge about factors which influence the MT concentration (MTc) in the umbilical cord (UC) blood during delivery. The aim of our study was to evaluate the MT status in the UC blood according to the time and mode of delivery. Subjects and methodsBlood samples from umbilical artery (UA) and vein (UV) were collected from spontaneous vaginal deliveries (SVD, n=122) and cesarean section deliveries (CSD, n=188). MTc was measured using a commercially available radioimmunoassay. ResultsThe MTc was not significantly different between UA and UV blood both at daytime and at nighttime (p=0.216 and p=0.440, respectively). Both in UA and in UV, the MTc was significantly higher at nighttime than at daytime (p<0.0001). Compared with the CSD group, MTc in the SVD group was significantly higher both at night- and daytime (p<0.05). MTc both in UA and in UV was found to be not significantly different between patients with and without risk factors for stress including pregnancy complications (e.g., preeclampsia) and intrapartum complications (e.g., emergency section, pathological doppler, and pathological cardiotocography) (p>0.05). ConclusionOur study revealed for the first time that MTc both in UA and in UV depends on modus of labor. In agreement with other studies, we found a clear circadian MT rhythm in the UC blood of neonates. The results of our study may suggest to a physiological role of MT at the onset of labor.

Melatonin in Epilepsy and Febrile Seizures

A study on melatonin rhythm in children with generalized idiopathic epilepsy and simple fever is presented in this article. A population of 40 children was divided into 4 groups, namely, epilepsy, febrile seizure, and 2 control groups. Salivary melatonin was measured by means of radioimmunoassay. Friedman 2-way analysis of variance (ANOVA) and Wilcoxon tests were employed to assess the existence of melatonin rhythm. Comparison across groups was performed by means of ANOVA and Mann-Whitney tests. Higher melatonin levels were found at night, with a peak at 04:00 h in all groups. Significant diurnal rhythm was also detected for these levels. No significant overall differences between case and control groups were found for melatonin levels, though patients showed lower peak melatonin values than controls at 04:00 h with a significant difference in the febrile seizure group (10.70 vs 19.5 pg/mL respectively; P<.04). Our data support the presence of diurnal rhythm in blood melatonin concentrations in children with epileptic and febrile seizures. Comparison between case and control groups showed lower peak concentrations in the febrile seizure group with respect to healthy controls.