Increase In Melatonin Levels Research Articles

The impact of skin-to-skin contact upon stress in preterm infants in a neonatal intensive care unit

IntroductionNeonatal stress significantly affects the early adaptation, maturation and long-term development of preterm infants.The objective of the studyTo investigate the effect of skin-to-skin contact (SSC) on stress level in preterm infants.Materials and methodsThe research was a prospective study. Stress indicators (cortisol, melatonin) were measured before the SSC began (pre-intervention level) and after this intervention (post-intervention).ResultsThe study included 150 preterm infants in the NICU with gestational age (GA) ≤36 weeks. Pre-intervention salivary cortisol level was higher in extremely and very preterm neonates compared to moderate and late preterm newborns (p = 0.028), in children with low Apgar scores (p = 0.041), in those who were on mechanical ventilation (p = 0.005), and suffered neonatal sepsis (p = 0.005). Pre-intervention melatonin level was lower in children with low Apgar scores (p = 0.032). Salivary cortisol levels were significantly decreased after SSC in preterm infants [pre-intervention: 0.294 (0.111; 0.854) μg/dL vs. post-intervention: 0.127 (0.070; 0.229) μg/dL, p < 0.001], and urinary melatonin levels were significantly increased after SSC [pre-intervention: 4.01 (2.48; 6.34) ng/mL vs. post-intervention: 5.48 (3.39; 9.17) ng/mL, p < 0.001]. A greater reduction in cortisol levels after skin-to-skin contact was revealed in infants with a lower gestational age (p = 0.022), in boys compared to girls (p = 0.012), in infants with respiratory distress syndrome (p = 0.048), in those who had mechanical ventilation compared to non-ventilated neonates (p = 0.008), and in infants with seizures (p = 0.036). The melatonin levels increased more intensively in infants with low Apgar scores (p = 0.002), and in those with late-onset sepsis (p = 0.006).ConclusionThe reduction in cortisol levels and the increase in melatonin levels provided strong evidence that SSC ameliorated the NICU-related stress in preterm infants. We found higher indicators of stress and more dramatic responses to SSC in reducing indicators of stress in infants with lower GA than in infants with higher GA, indicating that SSC may be even more important for lower GA infants. The infants who need SSC the most should not be denied the care they need to reduce the stress they experience from being born too soon and continuing their gestational development in the stressful environment of the NICU.

The inhalation effect of Osmanthus fragrans var. Aurantiacus on physiological parameters in chronically stressed rats

This study evaluated the effects of inhaling Osmanthus fragrans var. aurantiacus (OFA) extracts in Sprague-Dawley (SD) rats experiencing chronic stress. Rats were exposed to restraint stress or circadian disruption and were inhaled either distilled water or OFA extracts. Electronic nose (E-nose) analysis identified 35 volatile aromatic compounds (VACs) in OFA extracts. Chronic stress led to a decrease in body weight initially, serotonin concentration, and the weights of the liver, kidneys, and fat pads. Additionally, circadian disruption increased melatonin levels and decreased cholesterol concentrations. Inhalation of OFA increased dietary intake during the early phase and restored the tissue weights that have changed by chronic stress. Furthermore, it led to an increase in melatonin levels and changes in cholesterol levels. Taken together, our results indicate that OFA inhalation improves physiological changes caused by chronic stress through regulating dietary intake, restoring tissue weights, and modulating hormone and cholesterol levels.

Effects of slow-wave sleep fragmentation and rapid eye movement sleep fragmentation on melatonin secretion

To compare the effect of stage 3 fragmentation and the paradoxical phase of night sleep on melatonin (MT) secretion, and to evaluate the effects of changes in autonomic balance and activation reactions that occur in the orthodox and paradoxical phases of sleep. Fifteen healthy men participated in three sessions: with stage 3 fragmentation, with fragmentation of paradoxical sleep, and in a control experiment in which sleep was not disturbed. In each experiment, 7 saliva samples were collected in the evening, at night and in the morning and the MT content was determined. Heart rate variability was analyzed using an electrocardiogram and autonomic balance was assessed. Sleep fragmentation was accompanied by activation reactions and reduced the duration of stage 3 and paradoxical phase sleep by 50% and 51% in the corresponding sessions. Fragmentation of paradoxical sleep also led to an increase in the duration of night wakefulness. Sleep disturbances caused an increase in MT secretion in the second half of the night and in the morning, especially pronounced in sessions with fragmentation of paradoxical sleep, in which upon awakening MT was 1.8 times higher than in the control. Stage 3 fragmentation was accompanied by increased sympathetic activation, while fragmentation of paradoxical sleep did not cause autonomic shifts. The subjects were divided into 2 clusters: with high and low MT in night and morning saliva samples. In all sessions, subjects with high MT had 1.7-2 times longer duration of night wakefulness; in sessions with fragmentation, they had significantly more activations in the paradoxical phase of sleep. Night sleep disturbances cause an increase in MT secretion, especially pronounced during the fragmentation of the paradoxical phase. An increase in MT levels does not depend on changes in autonomic balance and is apparently associated with activation of the serotonergic system, which accompanies disturbances in the depth and continuity of sleep.

Melatonin for the regulation of sleep and other biological rhythms

Melatonin, as the hormone of the circadian system, plays a major role in regulating physiological functions and facilitating adaptation to environmental changes. Here we provide brief overview of circadian physiology, as related to the use of melatonin as hormone replacement therapy for older individuals with reduced melatonin secretion and melatonin treatment for patients with chronic insomnia or circadian desynchronization. Emphasizing the importance of minimal effective doses, we discuss the use of both immediate and delayed-release formulations, stress the significance of regular administration timing, and advise against exposure to bright light during increase in melatonin levels. Our discussion underscores that the medical guidance is essential for utilizing melatonin-containing preparations in the therapy of chronic insomnia.

Changes in the Secretion of Melatonin and Selected Adipokines during the Progression of Parkinson’s Disease—Preliminary Studies

Parkinson's disease (PD) is one of the most common neurodegenerative diseases affecting elderly people. Considering the gap in the literature on melatonin and adipokine levels in PD patients at various stages of the disease, we conducted a study to investigate the levels of selected parameters in PD patients at the disease's early (ES) and advanced (AS) stages. Melatonin, leptin, adiponectin, and resistin concentrations were measured in the blood serum of 20 PD patients without dyskinesia (ES), 24 PD patients with dyskinesia (AS), and 20 healthy volunteers as a control group (CG). The data were analyzed using ANOVA. Melatonin was significantly lower in ES (p < 0.05) and higher in AS patients (p < 0.05) compared to CG. The level of leptin was increased both in ES (p < 0.001) and AS (p < 0.001) versus CG, while resistin was increased only in patients with dyskinesia (p < 0.05). Higher melatonin (p < 0.001) and resistin (p < 0.05) and lower leptin (p < 0.05) levels were found in AS versus ES. The main findings of the study include the changes in inflammatory markers' levels during PD and a surprising increase in melatonin level in dyskinesia patients. Further research is necessary, which will be aimed at modulating the secretion of melatonin and adipokines as a treatment target for PD.

Melatonin in the saliva of adolescent girls with polycystic ovary syndrome

Background. The formation of polycystic ovary syndrome (PCOS) and the manifestation of its clinical manifestations often begin in adolescence. In recent years, one of the new and modern areas in the study of reproductive dysfunction is the problem of melatonin on the gonadotropic function of the pituitary gland (ovariogenesis). The purpose of the study was to determine the level of melatonin in the saliva of adolescent girls with PCOS. Materials and methods. A single-center prospective simple randomized study was conducted with 23 patients aged 14–18 years (inclusive) with PCOS. The control group consisted of 25 girls of the same age without gynecological status violations. Determination of melatonin levels in saliva was performed by high performance liquid chromatography with tandem mass spectrometry (HPLC-MS). Before salivation during the day and throughout the saliva collection period, patients excluded caffeine, alcohol, and exercise, did not smoke for one hour before collection, did not brush their teeth, did not floss, rinsed their mouths, and did not chew gum. Results. There were no significant differences in the age of the girls in the main group and the comparison group (16.70±0.11 years in the main group and 16.90±0.14 years in the comparison group, p&gt;0.05). The most common symptoms of PCOS in girls were: hypomenstrual syndrome (86.9%), dermopathy (82.6%) and hirsutism (60.8%). Girls with PCOS had significantly higher melatonin levels in saliva (03:00) (28.89 [18.17; 46.53] pg/ml) compared to girls in the comparison group (12.07 [11.56; 16.27] pg/ml, p&lt;0.01). A probable difference in melatonin levels in saliva depending on age has not been established. Conclusions. The results of the study indicate a violation of hormonal balance in polycystic ovary syndrome, in particular an increase in melatonin levels, which indicates the need to determine it in the process of diagnosis and treatment.

Effects of exercise on sleep, melatonin level, and behavioral functioning in children with autism.

This study examined the impact of physical exercise on sleep and behavioral functioning in children (aged 8-12 years) with autism spectrum disorders. It also investigated whether exercise would alter endogenous melatonin level among the population. Participants were divided into two groups: exercise group (12-week, 30-min morning jogging intervention) and a control group (i.e. did not receive any physical exercise intervention during the study period). Significant improvements on sleep and behavioral functioning were found in the exercise group, but not in the control group Moreover, a significant increase in melatonin level was also shown in the exercise group. Findings of this study reconfirmed the sleep and behavioral benefits of exercise in children with autism spectrum disorder. Melatonin-mediated mechanism should be further explored to develop an effective treatment intervention.

The effect of plasma melatonin levels in the treatment of lifelong premature ejaculation with selective serotonin reuptake inhibitors

The aim of our study was to compare melatonin levels of patients with lifelong premature ejaculation (LPE) (n:60) with healthy controls (n:30) and to investigate the changes of melatonin levels in the treatment with dapoxetine and sertraline. Age, body mass index, duration of marriage, weekly intercourse number, International Index of Erectile Function scores, Intravaginal Ejaculation Latency Time (IELT) and melatonin levels were recorded. LPE patients were divided into two treatment groups. The first group was included 30 patients, who received 60mg dapoxetine for six weeks, twice a week, an hour before intercourse. The second group received 50mg of sertraline daily, for six weeks. IELT and melatonin measures were repeated after the treatment. IELT (dapoxetine group: 41.22±21.3s, sertraline group: 48±23.11s, control group: 195.54±84.14s; p<.001) and melatonin levels (dapoxetine group: 5.75±2.04pg/mL, sertraline group: 5.49±2.88pg/mL, control group: 13.4±12.09pg/mL; p<.001) of both LPE groups were significantly lower than control group. Following the six-week sertraline (before: 48±23.11s, after: 101.01±59.55s; p<.001) and dapoxetine (before: 41.22±21.3s, after: 97.39±44.1s; p<.001) treatments, IELT increased. The melatonin levels increased in the sertraline group (before: 5.49±2.88pg/mL, after: 10.6±7.37pg/mL; p<.001). Our results indicate that melatonin levels of LPE patients are lower than levels of healthy volunteers. Furthermore, we found a significant increase in melatonin levels following sertraline treatment.

Rhythmic expression of the melatonergic biosynthetic pathway and its differential modulation in vitro by LPS and IL10 in bone marrow and spleen

Daily oscillation of the immune system follows the central biological clock outputs control such as melatonin produced by the pineal gland. Despite the literature showing that melatonin is also synthesized by macrophages and T lymphocytes, no information is available regarding the temporal profile of the melatonergic system of immune cells and organs in steady-state. Here, the expression of the enzymes arylalkylamine-N-acetyltransferase (AA-NAT), its phosphorylated form (P-AA-NAT) and acetylserotonin-O-methyltransferase (ASMT) were evaluated in phagocytes and T cells of the bone marrow (BM) and spleen. We also determined how the melatonergic system of these cells is modulated by LPS and the cytokine IL-10. The expression of the melatonergic enzymes showed daily rhythms in BM and spleen cells. Melatonin rhythm in the BM, but not in the spleen, follows P-AA-NAT daily variation. In BM cells, LPS and IL10 induced an increase in melatonin levels associated with the increased expressions of P-AA-NAT and ASMT. In spleen cells, LPS induced an increase in the expression of P-AA-NAT but not of melatonin. Conversely, IL10 induced a significant increase in melatonin production associated with increased AA-NAT/P-AA-NAT expressions. In conclusion, BM and spleen cells present different profiles of circadian production of local melatonin and responses to immune signals.

Determination of Melatonin Deprivation Impact on Sepsis With Acute Phase Reactants

BackgroundThe aim of the present study is to determine the association of melatonin hormone level on CRP, Total Antioxidant Status, Leukocyte, Procalcitonin, and Malondialdehyde, all acute phase reactants in the dark and light cycle of rats with sepsis model. Materials and methodsIn this study, 54 rats were divided into three groups. Whereas the first and third groups had a 12 h dark-light cycle, the second group was exposed to light for 24 h at 21°C-22°C for 10 d without any water and food restrictions. In the second and third groups, sepsis model was formed by cecal ligation and puncture (CLP) method at the end of 10th day, and blood samples were taken at the end of the 10th day. C-reactive protein, Malondialdehyde, Procalcitonin in the blood samples were analyzed by ELISA, and the levels of Total Antioxidant Status and leukocyte were determined by colorimetric method in the subsequent 12 and 24 h. ResultsCRP values increased in the second group rats, which were kept continuously under light and had undergone CLP, from 288.8 mg/L to 584.0 mg/L at the end of the 12 h and the end of the 24 h, approximately, two times. In rats, which were kept under 12 h of light, 12 h of darkness, and applied CLP (group 3), these values increased from 416.9 to 619.1; an increase of 1.5 times. When assessed for MDA, it was determined that the differences between Group 2 and Group 3 were more prominent between 0 h and 12 h. While the MDA values in group 2 increased from 16.53 nmol/mL at the 12 h to 17.66 nmol/mL at the 24 h. However, MDA values did not yield statistically significant changes in the third group. Changes in the in PCT values were similar to the MDA values obtained. Increase coefficient of the PCT values between 0 h and 12 h in the second group 2 was 1.26; however, in the third group, it was negligible. ConclusionsAn increase in the oxidative stress was observed in the rats that underwent CLP and melatonin deprivation via continuous 24 h light exposure for 10 d. Accordingly, deprivation of light is considered to be effective in sepsis treatment due to the increase in melatonin levels in intensive care unit patients.

Association of Intraocular Cataract Lens Replacement With Circadian Rhythms, Cognitive Function, and Sleep in Older Adults

Cataract is associated with a progressive decline in light transmission due to the clouding and yellowing of the natural crystalline lens. While the downstream effects of aging lenses include long-term disruption of circadian rhythms, cognitive function, and sleep regulation, it remains unknown whether there is an association of intraocular cataract lens (IOLs) replacement with circadian rhythms, cognition, and sleep. To test whether IOL replacement (blue blocking [BB] or ultraviolet [UV] only blocking) in older patients with previous cataract is associated with the beneficial light effects on the circadian system, cognition, and sleep regulation. Cross-sectional study at the Centre for Chronobiology, University of Basel in Switzerland from February 2012 to April 2014, analyzed between June 2012 and September 2018. Sixteen healthy older controls and 13 patients with previous cataract and IOL replacement participated without medication and no medical and sleep comorbidities. Three and a half hours of prior light control (dim-dark adaptation), followed by 2 hours of evening blue-enriched (6500 K) or non-blue-enriched light exposure (3000 K and 2500 K), 30 minutes in dim post-light exposure, 8 hours of sleep opportunity, and 2 hours of morning dim light following sleep. Salivary melatonin, cognitive tests, and sleep structure and electroencephalographic activity to test the association of IOLs with markers of circadian rhythmicity, cognitive performance, and sleep regulation, respectively. The participants included 16 healthy older controls with a mean (standard error of the mean [SEM]) of 63.6 (5.6) years; 8 women and 13 patients with previous cataract (mean [SEM] age, 69.9 [5.2] years; 10 women); 5 patients had UV IOLs and 8 had BB IOLs. Patients with previous cataract and IOLs had an attenuated increase in melatonin levels during light exposure (mean [SEM] increase in the BB group: 23.3% [2.6%] and in the UV lens group: 19.1% [2.1%]) than controls (mean [SEM] increase, 48.8% [5.2%]) (difference between means, 27.7; 95% CI, 15.4%-41.7%; P < .001). Cognitive function, indexed by sustained attention performance, was improved in patients with UV lens (mean [SEM], 276.9 [11.1] milliseconds) compared with patients with BB lens (mean [SEM], 348.3 [17.8] milliseconds) (difference between means, 71.4; 95% CI, 29.5%-113.1%; P = .002) during light exposure and in the morning after sleep. Patients with UV lens had increased slow-wave sleep (mean [SEM] increase, 13% [3.4%]) compared with controls (mean [SEM] increase, 5.2% [0.8%]) (percentage of total sleep time; difference between means, 7.9; 95% CI, 2.4%-13.4%; P = .02) and frontal non-rapid eye movement slow-wave activity (0.75-4.5 Hz) during the first sleep cycle (mean [SEM], 79.9 [13.6] μV2/Hz) compared with patients with BB lens (mean [SEM], 53.2 [10.7] μV2/Hz) (difference between means, 26.7; 95% CI, 9.2-48.9; P = .03). These in-laboratory empirical findings suggest that optimizing the spectral lens transmission in patients with previous cataract may minimize the adverse age-related effects on circadian rhythms, cognition, and sleep.

Urinary levels of 6-sulphatoxymelatonin and their associations with sleep disorders and behavioural impairments in children with autism spectrum disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental condition associated with sleep disturbances that may result from abnormalities in melatonin production. The correlations of melatonin levels with the severity of sleep disorder and/or severity of ASD were reported. To evaluate urinary levels of the melatonin metabolite, 6-sulphatoxymelatonin (aMT6s), in children with ASD, and their associations with sleep abnormalities and behavioural impairments. Study involved 77 children with ASD and 84 controls aged 2.5‒15.5 years. Sleep disorders were assessed by Children's Sleep Habits Questionnaire. Morning and afternoon levels of aMT6s were determined by radioimmunoassay method. Urinary creatinine levels were assessed by an enzymatic method. The urinary aMT6s/creatinine values indicate that the night-time melatonin levels are significantly lower in ASD than in controls, but there are no significant differences in the daytime levels. In the ASD group, on average, a 6.8-fold difference between night-time and daytime values of urinary aMT6s/creatinine was found, whereas for the controls a 12.5-fold difference was observed, indicating a lower night-time increase in melatonin levels. In ASD group, the difference in night-time-daytime aMT6s/creatinine value correlated with some types of sleep problems, but not with the severity of ASD. The results indicate that in ASD there are differences in the patterns of melatonin secretion that may be associated with sleep impairment (Tab. 4, Fig. 2, Ref. 28).

Changes On Neuroendocrine Parameters (cortisol, Melatonin) And Anxiety Levels After A School-based Exercising And Nutrition Counseling Intervention In School-aged Obese Adolescents From Monterrey méXico.

BACKGROUND: Recent studies point to high prevalences of obesity in adolescent populations worldwide. Its implications derive in various disorders, among which are inflammatory processes, as well as disorders related to sleep-wake, both processes involved in stress situations. There are two neuroendocrine parameters (cortisol and melatonin) two hormones associated with the same sleep-wake process that lead to a certain level of anxiety in obese subjects. Both cortisol and anxiety have been evidenced in various investigations as obesogenic factors. For its part, the practice of physical exercise has been indicated as a factor associated with the increase in melatonin levels, which has anti-inflammatory and recovery functions. PURPOSE: To assess the changes in the levels of neuroendocrine parameters (cortisol, melatonin) and anxiety after an intervention of nutritional counseling and exercise in school age obese adolescents of Monterrey Mexico METHODS: Experimental study with a sample of 51 adolescents (13 ± 2) randomly assigned in three work groups had participation during 4 months. The control group (CG) did not receive any treatment; experimental group 1 (EG1) participated in a health program composed of 4 weekly sessions of 60 minutes of physical activity; Experimental group 2 (EG2) 4 weekly sessions of 60 minutes of physical activity sessions of nutritional guidance and 2 weekly sessions of light therapy of 45 minutes. The values of cortisol and melatonin were taken in saliva and for anxiety the questionnaire of state anxiety (STAI) was used. RESULTS: After comparing initial and final values, the results showed significative changes into EG2 increasing melatonin (p > 0.001). Salivary cortisol showed significant decreases into EG1 (p = 0.004) and also into EG2 (p =0.006). Anxiety state showed a significant increase into CG (p<0.001), and significant decreases into EG1 (p< 0.005) and into EG2 (p< 0.001) CONCLUSIONS: The School-based Exercising And Nutrition Counseling shows favorable effects in the reduction of cortisol levels y ansiedad, both factors associated with inflammation. The use of light therapy seems to help into the recovery processes increasing secretion of melatonin and recovery after exercise. we suggest analize sleep variables for further studies

The relationship between the levels of melatonin and testosterone in male rats of different ages with ulcer of the stomach

Seasonality and dependence of age and sex is an important question in the development of ulcer of the stomach. Melatonin has an important place among the hormones that are involved in the formation of ulcer of the gastric mucosa.Aim. In order to establish the relationship between the levels of melatonin and testosterone in ulcerative lesions of the stomach in male rats of different ages their level in the blood serum was studied by enzyme immunoassay ELISA.Methods and results. It was found that against the background of gastric ulceration a significant increase in melatonin levels and decrease in serum testosterone occur, most expressed in rats aged 9 months.Conclusion. The obtained results indicate the presence of the relationship between melatonin and testosterone levels in both normal and pathological conditions.

Melatonin biosynthesis requires N-acetylserotonin methyltransferase activity of caffeic acid O-methyltransferase in rice.

Caffeic acid O-methyltransferase (COMT) methylates N-acetylserotonin into melatonin; that is, it has N-acetylserotonin O-methyltransferase (ASMT) activity. The ASMT activity of COMT was first detected in Arabidopsis thaliana COMT (AtCOMT). To confirm the involvement of COMT on melatonin synthesis in other plant species, the ASMT activity of a COMT from rice (Oryza sativa) (OsCOMT) was evaluated. Purified recombinant OsCOMT protein from Escherichia coli was used to validate the high ASMT activity of OsCOMT, similar to that of AtCOMT. The K m and V max values for the ASMT activity of OsCOMT were 243 µM and 2400 pmol min(-1) mg protein(-1), which were similar to those of AtCOMT. Similar to AtCOMT, OsCOMT was localized in the cytoplasm. In vitro ASMT activity was significantly inhibited by either caffeic acid or quercetin in a dose-dependent manner. Analogously, in vivo production of melatonin was significantly inhibited by quercetin in 4-week-old detached rice leaves. Lastly, the transgenic rice plants overexpressing rice COMT showed an increase in melatonin levels whereas transgenic rice plants suppressing the rice COMT had a significant decrease on melatonin levels, suggestive of the direct role of COMT in melatonin biosynthesis in plants.

Experimental and clinical aspects of melatonin and clock genes in diabetes.

The pineal hormone melatonin influences insulin secretion, as well as glucagon and somatostatin secretion, both invivo and invitro. These effects are mediated by two specific, high-affinity, seven transmembrane, pertussis toxin-sensitive, Gi-protein-coupled melatonin receptors, MT1 and MT2. Both isoforms are expressed in the β-cells, α-cells as well as δ-cells of the pancreatic islets of Langerhans and are involved in the modulation of insulin secretion, leading to inhibition of the adenylate cyclase-dependent cyclic adenosine monophosphate as well as cyclic guanosine monophosphate formation in pancreatic β-cells by inhibiting the soluble guanylate cyclase, probably via MT2 receptors. In this way, melatonin also likely inhibits insulin secretion, whereas using the inositol triphosphate pathway after previous blocking of Gi-proteins by pertussis toxin, melatonin increases insulin secretion. Desynchrony of receptor signaling may lead to the development of type 2 diabetes. This notion has recently been supported by genomewide association studies pinpointing variances of the MT2 receptor as a risk factor for this rapidly spreading metabolic disturbance. As melatonin is secreted in a clearly diurnal fashion, it is safe to assume that it also has a diurnal impact on the blood-glucose-regulating function of the islet. Observations of the circadian expression of clock genes (Clock, Bmal1, Per1,2,3, and Cry1,2) in pancreatic islets, as well as in INS1 rat insulinoma cells, may indicate that circadian rhythms are generated in the β-cells themselves. The circadian secretion of insulin from pancreatic islets is clock-driven. Disruption of circadian rhythms and clock function leads to metabolic disturbances, for example, type 2 diabetes. The study of melatonin-insulin interactions in diabetic rat models has revealed an inverse relationship between these two hormones. Both type 2 diabetic rats and patients exhibit decreased melatonin levels and slightly increased insulin levels, whereas type 1 diabetic rats show extremely reduced levels or the absence of insulin, but statistically significant increases in melatonin levels. Briefly, an increase in melatonin levels leads to a decrease in stimulated insulin secretion and vice versa. Melatonin levels in blood plasma, as well as the activity of the key enzyme of melatonin synthesis, AA-NAT (arylalkylamine-N-acetyltransferase) in pineal, are lower in type 2 diabetic rats compared to controls. In contrast, melatonin and pineal AA-NAT mRNA are increased and insulin receptor mRNA is decreased in type 1 diabetic rats, which also indicates a close relationship between insulin and melatonin. As an explanation, it was hypothesized that catecholamines, which reduce insulin levels and stimulate melatonin synthesis, control insulin-melatonin interactions. This conviction stems from the observation that catecholamines are increased in type 1 but are diminished in type 2 diabetes. In this context, another important line of inquiry involves the fact that melatonin protects β-cells against functional overcharge and, consequently, hinders the development of type 2 diabetes.

How Does Energy Intake Influence the Levels of Certain Steroids?

The influence of steroid hormones on food intake is well described. However, there are only a few studies on the effect of food intake on steroid levels. The study involved eight non-smoker women (average age 29.48±2.99 years; average BMI 21.3±1.3 kg/m2); they did not use any kind of medication affecting steroidogenesis. We analysed the influence of four various stimuli on the levels of steroid hormones and melatonin. During their follicular phase of menstrual cycle, each woman had an oral glucose tolerance test (OGTT), intravenous glucose tolerance test (IVGTT), a standard breakfast and psyllium (a non-caloric fibre). Cortisol declined during each test, which is a physiological decline in the morning hours. In all tests (except of the application of the non-caloric fibre, psyllium), however, this decline was modified. After the standard breakfast there was an increase in cortisol at 40th minute. The OGTT and IVGTT tests led to a plateau in cortisol levels. Testosterone levels and those of other steroid hormones showed no relationships to tested stimulations. Oral and intravenous glucose have influenced physiological decline of melatonin levels. During the IVGTT test, melatonin levels started to increase at 20th minute, reaching a maximum at 40th minute. The OGTT test led to a delayed increase in melatonin levels, compared to IVGTT. Despite the fact that we performed the tests in the morning hours, when steroid hormone levels physiologically start to change due to their diurnal rhythm, we still found that food intake influences some of the hormone levels.

Is it time to consider patients suffering from endometriosis-related infertility as “novel candidates” for targeted peri-conceptional D-chiro inositol supplementation? Hypothesis, rationale and some considerations

Dear Editor, We read with great pleasure the interesting data reported by Piomboni et al. concerning several advantages patients affected by polycystic ovarian syndrome (PCOS) and undergoing controlled ovarian hyperstimulation (COH) with pre-treatment supplementation by D-chiro inositol and/or metformin treatment. [1] The demonstrat D-chiro inositol supplementation and metformin treatment were both shown to significantly improve the follicular fluid (FF) milieu by decreasing the oxidative damage (measured as free-SH groups levels) on FF proteins and, as a consequence, significantly increase the number of good quality MII oocytes. Although for many years it was known that the oxidative stress could have a negative effects on FF environment, recent evidence has suggested that good quality oocytes require a correct balance in FF pro-oxidative and anti-oxidative factors, [2] since an excess in pro-oxidative status is associated with poor quality oocytes, low fertilization and implantation rates while a deficit may be responsible for follicular atresia. [3, 4] Interestingly, several studies reported that women suffering from endometriosis frequently experience infertility and poor IVF outcomes (poor qualitative and quantitative ovarian response, low implantation rate), particularly when they have an imbalance in thiol-redox and oxidative status. [5–8] It is known that, frequently, abnormalities in oxidative status balance may reflect alterations in glucose and lipid metabolism. Similarly to PCOS patients, several studies noticed that patients suffering from endometriosis have abnormalities in both glucose and lipid metabolism. For example, McKinnon et al. found that in endometriotic lesions GLUT4 (glucose transporter-4) protein expression was enhanced, probably due to increase glucose availability in the growing lesions. [8] In contrast, Melo et al. report that patients affected by endometriosis frequently show “unfavourable” lipid profile (increase in low-density and reduction in high-density lipoprotein), potentially favouring the oxidative stress (via lipid peroxidation) typically increased in this cohort of women. [9–11] D-chiro inositol is a “dietary supplement” of Inositol, an essential component of the phospholipids that make up cellular membranes, detectable in every cell of the body. The available formulations for oral administration show good bioavailability, safe pharmacologic profiles and beneficial effects in improving spontaneous fertility (or success rate of ARTs) also after short-term treatment, particularly in patients affected by PCOS and anovulation. [11] Basically, oral formulations of D-chiro inositol appear to significantly reduce oxidative status as a result of its antioxidant properties that in turn lead to improvements in glucose metabolism (insulin-sensitizing effect mainly fulfilled by D-chiro inositol phosphoglycan via glycogen synthase activity) and a reduction in circulating levels of LDL and triglycerides in addition to BMI reduction. [12] The properties of D-chiro inositol in reducing the “unbalanced” oxidative status of PCOS patients without significant adverse effects prompts speculation as to whether patients suffering from endometriosis in association with hypo/infertility should be considered as “novel candidates” who may potentially benefit from this supplementation in a pre-conception period (or pre-treatment period when referred to ARTs). Our proposal warrants further investigation. Much effort is being made to improve the fertility of patients suffering from endometriosis, and more and more therapeutic strategies are targeted to oxidative stress reduction. [11, 12] In fact, several Authors [13] recently showed that pre-treatment administration of ultra-long GnRH agonist (1.8 mg s.c. every 28 days for three courses) was effective in balancing intra follicular oxidative stress (checked by 8-hydroxy-2-deoxyguanosine reduction and increase in melatonin levels) and in improving ARTs outcomes of women affected by endometriosis. Others [14] have proposed the use of statins for endometriosis targeted treatment. Despite the beneficial effects, potential adverse effects should not be underestimated. In the future both scientists and clinicians must join forces in seeking novel approaches to improve fertility in patients suffering from endometriosis reducing their “over” oxidative status. It is our opinion that the time has arrived to shift attention towards potential efficacy and safety of D-chiro inositol supplementation to balance the oxidative status of patients suffering from endometriosis, evaluating by appropriate studies the real cost-efficacy of peri-conceptional D-chiro inositol supplementation in this potential “novel candidate” cohort of patients.

Ambulatory monitoring in humans: a new method to objectively assess circadian phase as compared with dim light melatonin onset (DLMO)

Introduction It is important to develop a system able to detect the endogenous circadian phase easily, since current techniques imply either expensive hormonal quantification or uncomfortable monitorization of central temperature by rectal probes. Materials and methods In this work, a new ambulatory circadian monitoring system (ACM) was validated. To this, activity and position, wrist temperature rhythm as well as light exposure pattern were recorded for 10 days in 13 healthy subjects, thanks to an actimeter on the arm, a temperature sensor on the ventral side of the wrist and a pendant luxometer. DLMO was determined in saliva, and it was used as “the gold standard” to evaluate the accuracy of ACM to assess the circadian phase. Besides, subjects completed a sleep log and Horne-Ostberg morningness–eveningness, Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale questionnaires to evaluate diurnal preference and its influence in sleep quality. Results The peripheral wrist temperature increase in the evening (and its new indexes WTOnset or WTOn and WT increase onset or WTiO) anticipated that of melatonin; while the decrease in motor activity, position and the composite variable TAP (including wrist temperature, activity and position), and the increase in sleep probability occurred after the increase in melatonin levels. The score of morningness–eveningness and sleep quality questionnaires showed high correlations with DLMO, confirming that the later the DLMO occurs higher eveningness and worse sleep quality are reported. Conclusion This ambulatory method allows accurately detecting the circadian phase while subjects maintain their normal life style. The proposed new phase markers based on wrist temperature rhythm (named WTOn and WTiO) would be appropriate in Clinics when it is important to know the subject circadian phase, like in cancer chronotherapy or light therapy. Acknowledgements Study supported by Instituto de Salud Carlos III, RETICEF (RD12/0043/0011), MINECO (BFU 2010-21945-C02-01and IPT-2011-0833-900000) with FEDER cofounding to JAM, and a research fellowship to MA Bonmati-Carrion (FPU2009-1051). We also thank Stockgrand Ltd. (UK) for the melatonin assay reagents. DJ Skene is a Royal Society Wolfson Research Merit Award holder.

Melatonin and Pancreatic Islets: Interrelationships between Melatonin, Insulin and Glucagon

The pineal hormone melatonin exerts its influence in the periphery through activation of two specific trans-membrane receptors: MT1 and MT2. Both isoforms are expressed in the islet of Langerhans and are involved in the modulation of insulin secretion from β-cells and in glucagon secretion from α-cells. De-synchrony of receptor signaling may lead to the development of type 2 diabetes. This notion has recently been supported by genome-wide association studies identifying particularly the MT2 as a risk factor for this rapidly spreading metabolic disturbance. Since melatonin is secreted in a clearly diurnal fashion, it is safe to assume that it also has a diurnal impact on the blood-glucose-regulating function of the islet. This factor has hitherto been underestimated; the disruption of diurnal signaling within the islet may be one of the most important mechanisms leading to metabolic disturbances. The study of melatonin–insulin interactions in diabetic rat models has revealed an inverse relationship: an increase in melatonin levels leads to a down-regulation of insulin secretion and vice versa. Elucidation of the possible inverse interrelationship in man may open new avenues in the therapy of diabetes.