Can supplementation of tryptophan in parenteral nutrition increase melatonin and alleviate inflammatory response?

OBJECTIVE: Endogenous melatonin is produced from tryptophan which is an essential amino acid. Besides its role in the regulation of sleep patterns, melatonin has anti-inflammatory effects. In this case-control study, we aimed to compare tryptophan and melatonin levels and their relationship with the inflammatory response, specifically serum interleukin-1, interleukin-6, and c-reactive protein levels following major abdominal surgery in patients with food restriction and who receive parenteral nutritional therapy. METHODS: We enrolled 40 patients between the ages of 18 and 65 years in the study. We collected blood and urine samples 48 h before the operation and on postoperative days 1, 3, and 5. RESULTS AND CONCLUSION: The tryptophan levels in the experimental group were higher than in the control group but failed to reach any statistical difference. Melatonin levels were increased in both groups following the surgery compared with preoperative levels. The increase in the experimental group was statistically different 3 days after the surgery. The difference in the level of interleukin-1 between the control and the experimental groups was greatest on postoperative day 3. On postoperative day 3, the interleukin-6 level in the treatment group was slightly higher than in the control group. We did not find any difference in the levels of c-reactive protein between the groups. As a result, the levels of tryptophan and melatonin were increased in the parenteral nutrition group, irrespective of the postoperative inflammatory response.

Association between urine 6-sulfatoxy-melatonin level and intravesical Bacillus Calmette-Guerin treatment-induced sleep quality deterioration in patients with non-muscle invasive bladder cancer.

PURPOSE: The level of 6-sulfatoxy-melatonin (SaMT), a metabolite of melatonin, in first-void morning urine reflects blood melatonin levels from the previous night. We investigated the association between urine SaMT and sleep quality deterioration in patients with non-muscle invasive bladder cancer (NMIBC) treated with intravesical Bacillus Calmette-Guerin induction therapy (iBCG). METHODS: We enrolled 51 patients who received iBCG once weekly for 6 or 8 weeks. Patient-reported outcomes were assessed with questionnaires including the International Prostate Symptom Score (IPSS) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQC30). Questionnaires were completed before (baseline), during, at completion, and 1 and 3 months after iBCG. Melatonin and SaMT levels at baseline were measured in serum and first-void morning urine samples, respectively. RESULTS: Based on changes in the QLQC30 insomnia subscale, 28 (55%) patients experienced sleep quality deterioration (deterioration group). Urine SaMT values in the deterioration group were lower than those in the non-deterioration group (P = 0.0015; 7.5 vs 15.4 ng/mg creatinine, respectively). Nocturia scores in the non-deterioration group decreased over time, while those of the deterioration group remained high after completion of iBCG. A binary logistic regression analysis revealed that low urine SaMT levels (≤ 9.6 ng/mg creatinine), high IPSS nocturia scores at baseline, and high IPSS storage subscores at baseline were associated with BCG-induced sleep quality deterioration. CONCLUSIONS: This study confirmed the association among urine SaMT levels, nocturia, and sleep disturbance in patients with NMIBC who receive iBCG. We should be aware of treatment-induced impairments to aid in appropriate decision-making.

Urinary 6-sulfatoxymelatonin Levels and Prostate Cancer Risk among Men in the Multiethnic Cohort.

BACKGROUND: The circadian hormone melatonin has anticancer properties, and prior studies suggest a positive association between low melatonin and prostate cancer risk. The purpose of this study was to examine urinary melatonin levels and prostate cancer in a racially/ethnically diverse cohort. METHODS: We conducted a nested case-control study, including 1,263 prostate cancer cases and 2,346 controls, sampled from participants in the Multiethnic Cohort Study with prediagnostic urine samples assayed for 6-sulfatoxymelatonin, the primary melatonin metabolite. Conditional logistic regression was used to examine the association between melatonin levels and the development of prostate cancer outcomes (all incident cases, advanced, lethal, high-grade, and aggressive), overall and by race/ethnicity. RESULTS: Among 1,263 cases, 135 were advanced stage, 101 were lethal cases, and 282 were high-grade disease. Median melatonin levels were similar in controls [17.12 ng/mL; interquartile range (IQR), 19.78] and cases (17.93 ng/mL; IQR, 19.76), and we found no significant association between urinary melatonin levels and prostate cancer risk overall or in any clinical or racial subgroup. CONCLUSIONS: In this diverse cohort, there was no significant association between melatonin and any prostate cancer outcome, nor were there any differences by racial/ethnic group. IMPACT: These results do not support a strong association between melatonin levels and risk of prostate cancer.

Exploratory assessment of pineal gland volume, composition, and urinary 6-sulfatoxymelatonin levels on prostate cancer risk.

INTRODUCTION: Melatonin levels are partially driven by the parenchyma volume of the pineal gland. Low urinary levels of 6-sulfatoxymelatonin have been associated with increased risk of advanced prostate cancer, but the relationship between pineal gland volume and composition and prostate cancer risk has not been examined. MATERIALS AND METHODS: We utilized data from 864 men from the AGES-Reykjavik Study with complete pineal gland volumes and urinary 6-sulfatoxymelatonin measurements. Pineal parenchyma, calcification, and cyst volumes were calculated from brain magnetic resonance imaging. Levels of 6-sulfatoxymelatonin were assayed from prediagnostic urine samples. We calculated Pearson correlation coefficients between parenchyma volume and urinary 6-sulfatoxymelatonin levels. We used Cox proportional hazards regression to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) comparing prostate cancer risk across parenchyma volume tertiles and across categories factoring in parenchyma volume, gland composition, and urinary 6-sulfatoxymelatonin level. RESULTS: Parenchyma volume was moderately correlated with urinary 6-sulfatoxymelatonin level (r = .24; p < .01). There was no statistically significant association between parenchyma volume tertile and prostate cancer risk. Men with high parenchyma volume, pineal cysts and calcifications, and low urinary 6-sulfatoxymelatonin levels had almost twice the risk of total prostate cancer as men with low parenchyma volume, no pineal calcifications or cysts, and low urinary 6-sulfatoxymelatonin levels (HR: 1.98; 95% CI: 1.02, 3.84; p: .04). CONCLUSIONS: Although parenchyma volume is not associated with prostate cancer risk, pineal gland composition and other circadian dynamics may influence risk for prostate cancer. Additional studies are needed to examine the interplay of pineal gland volume, composition, and melatonin levels on prostate cancer risk.

Melatonin: From Pharmacokinetics to Clinical Use in Autism Spectrum Disorder.

The role of melatonin has been extensively investigated in pathophysiological conditions, including autism spectrum disorder (ASD). Reduced melatonin secretion has been reported in ASD and led to many clinical trials using immediate-release and prolonged-release oral formulations of melatonin. However, melatonin's effects in ASD and the choice of formulation type require further study. Therapeutic benefits of melatonin on sleep disorders in ASD were observed, notably on sleep latency and sleep quality. Importantly, melatonin may also have a role in improving autistic behavioral impairments. The objective of this article is to review factors influencing treatment response and possible side effects following melatonin administration. It appears that the effects of exposure to exogenous melatonin are dependent on age, sex, route and time of administration, formulation type, dose, and association with several substances (such as tobacco or contraceptive pills). In addition, no major melatonin-related adverse effect was described in typical development and ASD. In conclusion, melatonin represents currently a well-validated and tolerated treatment for sleep disorders in children and adolescents with ASD. A more thorough consideration of factors influencing melatonin pharmacokinetics could illuminate the best use of melatonin in this population. Future studies are required in ASD to explore further dose-effect relationships of melatonin on sleep problems and autistic behavioral impairments.

Associations between urinary 6-sulfatoxymelatonin excretion and diabetic vascular complications or arteriosclerosis in patients with type 2 diabetes.

AIMS/INTRODUCTION: There are limited reports on the association between melatonin levels and vascular complications in patients with type 2 diabetes. The aim of this study was to determine the association between urinary 6-sulfatoxymelatonin, which is a urinary metabolite of melatonin, and diabetic vascular complications or arteriosclerosis in patients with type 2 diabetes. MATERIALS AND METHODS: This retrospective study included patients (167 patients with type 2 diabetes and 27 patients without diabetes adjusted for age and sex) admitted to the hospital who underwent measurement of urinary 6-sulfatoxymelatonin. The urinary 6-sulfatoxymelatonin/creatinine ratio (6-SMT) was calculated. RESULTS: The natural logarithmically scaled 6-SMT level (Ln 6-SMT) was significantly lower in type 2 diabetes patients (1.9 ± 1.1) compared with patients without diabetes (2.8 ± 1.0, P < 0.001). Multivariate linear regression analysis identified duration of diabetes, smoking status, urinary albumin-to-creatinine ratio, retinopathy and coronary heart disease as factors that could influence Ln 6-SMT levels in type 2 diabetes patients (R2  = 0.232, P < 0.001). Ln 6-SMT was associated with decreased odds of diabetic retinopathy, even after adjustment for various confounding factors (odds ratio 0.559, 95% confidence interval 0.369-0.846, P = 0.006). Similarly, Ln 6-SMT was associated with decreased odds of coronary heart disease (odds ratio 0.442, P = 0.030). CONCLUSIONS: Our results showed the presence of low levels of Ln 6-SMT in type 2 diabetes patients relative to patients without diabetes. Furthermore, Ln 6-SMT is an independent risk factor of diabetic retinopathy and coronary heart diseases. These findings suggest that 6-SMT could be a useful biomarker for the prediction of micro- and macrovasculopathies in patients with type 2 diabetes.

Disrupted nocturnal melatonin in autism: Association with tumor necrosis factor and sleep disturbances.

Sleep disturbances, abnormal melatonin secretion, and increased inflammation are aspects of autism spectrum disorder (ASD) pathophysiology. The present study evaluated the daily urinary 6-sulfatoxymelatonin (aMT6s) excretion profile and the salivary levels of tumor necrosis factor (TNF) and interleukin-6 (IL-6) in 20 controls and 20 ASD participants, as well as correlating these measures with sleep disturbances. Although 60% of ASD participants showed a significant night-time rise in aMT6s excretion, this rise was significantly attenuated, compared to controls (P < .05). The remaining 40% of ASD individuals showed no significant increase in nocturnal aMT6s. ASD individuals showed higher nocturnal levels of saliva TNF, but not IL-6. Dysfunction in the initiation and maintenance of sleep, as indicated by the Sleep Disturbance Scale for Children, correlated with night-time aMT6s excretion (r = -.28, P < .05). Dysfunction in sleep breathing was inversely correlated with aMT6s (r = -.31, P < .05) and positively associated with TNF level (r = .42, P < .01). Overall such data indicate immune-pineal axis activation, with elevated TNF but not IL-6 levels associated with disrupted pineal melatonin release and sleep dysfunction in ASD. It is proposed that circadian dysregulation in ASD is intimately linked to heightened immune-inflammatory activity. Such two-way interactions of the immune-pineal axis may underpin many aspects of ASD pathophysiology, including sleep disturbances, as well as cognitive and behavioral alterations.

Urinary Melatonin in Relation to Breast Cancer Risk: Nested Case-Control Analysis in the DOM Study and Meta-analysis of Prospective Studies.

BACKGROUND: Exposure to higher levels of melatonin may be associated with lower breast cancer risk, but epidemiologic evidence has been limited. We examined the relationship in a case-control study nested within the Diagnostisch Onderzoek Mammacarcinoom (DOM) study and conducted a meta-analysis of prospective studies. METHODS: Concentrations of 6-sulfatoxymelatonin (aMT6s) in prediagnostic first morning urine voids were measured in 274 postmenopausal women diagnosed with breast cancer and 274 matched controls from the DOM study. Conditional logistic regression models were used to estimate multivariable adjusted ORs of breast cancer for thirds of aMT6s. Meta-analysis of this and previous prospective studies of urinary melatonin with breast cancer risk estimated the inverse-variance weighted averages of study-specific log RRs of breast cancer for the highest versus lowest levels of aMT6s. RESULTS: In the DOM study, the ORs of breast cancer for the middle and highest versus lowest thirds of aMT6s were 0.70 [95% confidence interval (CI), 0.45-1.09] and 0.72 (95% CI, 0.44-1.19), respectively. In the meta-analysis of the DOM study with six previous studies (2,296 cases), RR of breast cancer for the highest versus lowest levels of aMT6s was 0.87 (95% CI, 0.76-1.01). CONCLUSIONS: Results from the DOM study, together with the published prospective data, do not support a strong association of melatonin with breast cancer risk. IMPACT: This study adds to the relatively scarce prospective data on melatonin in relation to breast cancer risk. The totality of the prospective evidence does not clearly show an association between melatonin and breast cancer risk, but further data are needed to be able to exclude a modest association.

Loading-induced antitumor capability of murine and human urine.

While urine has been considered as a useful bio-fluid for health monitoring, its dynamic changes to physical activity are not well understood. We examined urine's possible antitumor capability in response to medium-level, loading-driven physical activity. Urine was collected from mice subjected to 5-minute skeletal loading and human individuals before and after 30-minute step aerobics. Six cancer cell lines (breast, prostate, and pancreas) and a mouse model of the mammary tumor were employed to evaluate the effect of urine. Compared to urine collected prior to loading, urine collected post-activity decreased the cellular viability, proliferation, migration, and invasion of tumor cells, as well as tumor weight in the mammary fat pad. Detection of urinary volatile organic compounds and ELISA assays showed that the loading-conditioned urine reduced cholesterol and elevated dopamine and melatonin. Immunohistochemical fluorescent images presented upregulation of the rate-limiting enzymes for the production of dopamine and melatonin in the brain. Molecular analysis revealed that the antitumor effect was linked to the reduction in molecular vinculin-linked molecular force as well as the downregulation of the Lrp5-CSF1-CD105 regulatory axis. Notably, the survival rate for the high expression levels of Lrp5, CSF1, and CD105 in tumor tissues was significantly lowered in the Cancer Genome Atlas database. Collectively, this study revealed that 5- or 10-minute loading-driven physical activity was sufficient to induce the striking antitumor effect by activating the neuronal signaling and repressing cholesterol synthesis. The result supported the dual role of loading-conditioned urine as a potential tumor suppressor and a source of diagnostic biomarkers.

Effects of Cataract Surgery on Melatonin Secretion in Adults 60 Years and Older: A Randomized Clinical Trial.

Importance: Cataract surgery, which increases perception of light, may increase melatonin secretion. Melatonin secretion has been associated with depression, diabetes, cognitive impairment, and breast cancer. To date, no evidence from a randomized clinical trial exists to support this cataract surgery hypothesis. Objective: To determine whether cataract surgery modifies the melatonin secretion at 3 months after cataract surgery in 169 adult patients. Design, Setting, and Participants: A parallel-group randomized clinical trial was conducted at a single referral center from July 1, 2014, to June 30, 2017. Data were analyzed from January 1, 2018, to March 31, 2019. Patients were aged 60 years or older, had no history of cataract surgery, and had cataracts with grade 2 or higher nuclear opacifications based on the Lens Opacities Classification System III. Analyses were based on intention to treat. Interventions: Patients were randomized 1:1:1:1 to receive cataract surgery using artificial clear intraocular lens (IOL) or yellow IOL. Group 1 received prompt surgery with clear IOL, group 2, prompt surgery with yellow IOL, group 3, delayed surgery with clear IOL, and group 4, delayed surgery with yellow IOL. The intervention group consisted of groups 1 and 2, and the control group consisted of groups 3 and 4. Main Outcomes and Measures: Urinary melatonin excretion in the intervention group was measured at 3 months after surgery, and urinary melatonin excretion in the control group was measured before delayed surgery. Results: Of the 169 randomized patients, 97 were men (57.4%). The mean (SD) age was 75.7 (6.7) years. Mean urinary melatonin excretion was calculated as standardized urinary concentration, the ratio of urinary concentration to urinary creatinine concentration (nanograms per milligram of creatinine), in the intervention group after cataract surgery. Mean urinary melatonin excretion was significantly higher than in the control group (adjusted mean difference of creatinine concentration, 0.159 log ng/mg, 95% CI, 0.045-0.273; P = .007) independent of baseline urinary melatonin excretion and potential confounders. Subgroup analysis comparing group 1 with group 3 revealed that concentration of urinary melatonin excretion in patients who received clear IOLs was higher than the control group by creatinine concentration 0.212 log ng/mg (95% CI of the difference, 0.058-0.365; P = .008). However, the difference between patients in group 2 and group 4 was not significant (adjusted mean difference for creatinine excretion, 0.083 log ng/mg, 95% CI, -0.087 to 0.253; P = .33). The difference of concentration of mean urinary melatonin excretion between patients in group 1 and those in group 2 was not significant (95% CI of the difference for creatinine concentration, -0.19 to 0.40 log ng/mg; P = .48). Conclusions and Relevance: The findings in this study support the hypothesis that cataract surgery increases melatonin secretion. The effect of clear IOLs vs yellow IOLs on these outcomes was not shown to be different. Trial Registration: UMIN-CTR Identifier: UMIN000014559.

Sleep parameters assessed by actigraphy in Fabry's disease patients: a proof-of-concept.

BACKGROUND: In a previous study developed by our group, we identified a phase inversion in 6-sulfatoxymelatonin - melatonin metabolite in urine - daily profile in Fabry's disease patients. Since melatonin is an endogenous marker, it could also be accompanied by behavioral changes in sleep-wake cycle, which impairs the overall patient's life quality. OBJECTIVE: In this study, we evaluated sleep-wake cycle in Fabry disease patients. We hypothesized that patients would have increased daytime naps, given our previous results for urinary 6-sulfatoxymelatonin. PATIENTS/METHODS: This was a cross-sectional and case-control study, performed between October 2016 and May 2017. Volunteers recorded activity and rest rhythm by actigraphy and answered Pittsburgh Sleep Quality Index (PSQI). From actigraphy data, we calculated sleep parameters: sleep latency, wake after sleep onset, sleep (WASO) efficiency, awakenings index (PSQI), and the amount and duration of daytime naps. We included 16 Fabry disease patients with biochemical and molecular diagnosis and 10 control individuals matched by age and gender. RESULTS: We did not observe significant differences for any of the parameters analyzed (p > 0.05). However, evaluating the magnitude of the effect, we found that patients dozed, on average, about 42 min longer (d = 0.9 - large effect size) than control group. CONCLUSIONS: This is a preliminary study, a proof-of-concept, and our results indicate that changes in melatonin secretion phase may have behavioral consequences in sleep-wake cycle, with longer duration of daytime naps.

Self-reported sleep disturbance in Crohn's disease is not confirmed by objective sleep measures.

Sleep disturbance and fatigue are commonly reported among patients with Crohn's disease (CD). In this prospective study, we aimed to define sleep quality in CD patients at various disease activity states and compare to healthy controls using objective and subjective measures. A prospective observational cohort study of CD patients seen at a tertiary academic inflammatory bowel diseases (IBD) clinic was compared to healthy volunteers. CD activity was assessed using the Harvey-Bradshaw Index (HBI). Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) and objectively over 1-week using actigraphy (motion-based) and morning urinary melatonin metabolite. 121 subjects (CD patients N = 61; controls N = 60) completed the study. 34 had active CD (HBI > 4). Sleep disturbance was more frequently reported by CD subjects than controls (PSQI: 57% vs. 35%, p = 0.02) and in patients with active CD versus in remission state (PSQI 75.8% vs. 33.3%, p < 0.01; ESS: 45.5% vs. 19%, p = 0.03). Sleep parameters as measured by actigraphy and urine melatonin metabolite did not vary by group. Crohn's patients report significantly more disturbed sleep than controls. However, poor sleep was not confirmed by objective measures of sleep quality. Excessive daytime sleepiness in CD patients may be driven by factors beyond objectively measured poor sleep.

Repercussions of melatonin on the risk of breast cancer: a systematic review and meta-analysis.

Breast Cancer is common in women, but its etiology is not yet fully understood. Several factors may contribute to its genesis, such as genetics, lifestyle, and the environment. Melatonin may be involved in the process of breast cancer. Therefore, the aim of this study is to evaluate the influence of the levels of melatonin on breast cancer through a systematic review and meta-analysis. We performed a systematic review according to PRISMA recommendations. The primary databases MEDLINE, Embase, and Cochrane were consulted. There was no restriction on the year of publication and language. Data of systematic reviews from April 2017 to September to 2017 were analyzed. The meta-analysis was conducted using RevMan 5.3 software provided by the Cochrane Collaboration. From a total of 570 articles, 9 manuscripts were included in this review. They analy onzed women with breast cancer and control patients, of which 10% and 90% were in the reproductive period and after menopause, respectively. The lowest level of melatonin was found in approximately 55% of studies with breast cancer in post-menopause. The metanalyses of the studies demonstrated low levels of melatonin in breast cancer patients (n=963) compared with control patients (n= 1332), with a mean difference between the studies of -3.54 (CI -6.01, -1.06). Another difference found was in the comparison between smoking patients, with an average difference between 1.80 [0.97-2.63]. Our data suggest that low levels of melatonin might be a risk factor for breast cancer.

Ethnic Differences in Nighttime Melatonin and Nighttime Blood Pressure: A Study in European Americans and African Americans.

BACKGROUND: Ethnic differences in nighttime blood pressure (BP) have long been documented with African Americans (AAs) having higher BP than European Americans (EAs). At present, lower nighttime melatonin, a key regulator of circadian rhythms, has been associated with higher nighttime BP levels in EAs. This study sought to test the hypothesis that AAs have lower nighttime melatonin secretion compared with EAs. We also determined if this ethnic difference in melatonin could partially explain the ethnic difference in nighttime BP. METHODS: A total of 150 young adults (71 AA; 46% females; mean age: 27.7 years) enrolled in the Georgia Stress and Heart study provided an overnight urine sample for the measurement of 6-sulfatoxymelatonin, a major metabolite of melatonin. Urine melatonin excretion (UME) was calculated as the ratio between 6-sulfatoxymelatonin concentration and creatinine concentration. Twenty-four-hour ambulatory BP was assessed and nighttime systolic BP (SBP) was used as a major index of BP regulation. RESULTS: After adjustment of age, sex, body mass index, and smoking, AAs had significantly lower UME (P = 0.002) and higher nighttime SBP than EAs (P = 0.036). Lower UME was significantly associated with higher nighttime SBP and this relationship did not depend on ethnicity. The ethnicity difference in nighttime SBP was significantly attenuated after adding UME into the model (P = 0.163). CONCLUSION: This study is the first to document the ethnic difference in nighttime melatonin excretion, demonstrating that AAs have lower melatonin secretion compared with EAs. Furthermore, the ethnic difference in nighttime melatonin can partially account for the established ethnic difference in nighttime SBP.

Repercussions of melatonin on the risk of breast cancer: a systematic review and meta-analysis

SUMMARY Breast Cancer is common in women, but its etiology is not yet fully understood. Several factors may contribute to its genesis, such as genetics, lifestyle, and the environment. Melatonin may be involved in the process of breast cancer. Therefore, the aim of this study is to evaluate the influence of the levels of melatonin on breast cancer through a systematic review and meta-analysis. We performed a systematic review according to PRISMA recommendations. The primary databases MEDLINE, Embase, and Cochrane were consulted. There was no restriction on the year of publication and language. Data of systematic reviews from April 2017 to September to 2017 were analyzed. The meta-analysis was conducted using RevMan 5.3 software provided by the Cochrane Collaboration. From a total of 570 articles, 9 manuscripts were included in this review. They analy onzed women with breast cancer and control patients, of which 10% and 90% were in the reproductive period and after menopause, respectively. The lowest level of melatonin was found in approximately 55% of studies with breast cancer in post-menopause. The metanalyses of the studies demonstrated low levels of melatonin in breast cancer patients (n=963) compared with control patients (n= 1332), with a mean difference between the studies of 8722;3.54 (CI8722;6.01,8722;1.06). Another difference found was in the comparison between smoking patients, with an average difference between 1.80 [0.97-2.63]. Our data suggest that low levels of melatonin might be a risk factor for breast cancer.

RESUMO O câncer de mama é comum em mulheres, mas sua etiologia ainda não é totalmente compreendida. Vários fatores podem contribuir para sua gênese, genética, estilo de vida e meio ambiente. A melatonina pode estar envolvida no processo de câncer de mama. Portanto, o objetivo deste estudo é avaliar a influência dos níveis de melatonina no câncer de mama por meio de uma revisão sistemática e meta-análise. Realizamos uma revisão sistemática de acordo com as recomendações do Prisma. Os principais bancos de dados, Medline, Embase e Cochrane, foram consultados. Não houve restrição quanto ao ano de publicação e idioma. Os dados de revisão sistemática obtidos de abril de 2017 a setembro a 2017 foram analisados. A meta-análise foi conduzida pelo programa RevMan 5.3 fornecido pela Cochrane Collaboration. De um total de 570 artigos, nove foram incluídos nesta revisão. As análises foram conduzidas em mulheres com câncer de mama e pacientes controle, dos quais 10% e 90% estavam no período reprodutivo e após a menopausa, respectivamente. O nível mais baixo de melatonina foi encontrado em aproximadamente 55% dos estudos com câncer de mama na pós-menopausa. As meta-análises de estudos demonstraram os baixos níveis de melatonina em doentes com câncer da mama (n=963), em comparação com os pacientes de controle (n=1.332), sendo a diferença de médias entre os estudos da 8722;3,54 (CI 8722;6,01, 8722;1,06). Outra diferença é demonstrada nas comparações entre pacientes fumantes, sendo a diferença da média entre 1,80 [0,97-2,63]. Nossos dados sugerem que baixos níveis de melatonina podem ser um fator de risco para câncer de mama.

Altered metabolic and hormonal responses in male rats exposed to acute bright light-at-night associated with global DNA hypo-methylation.

The association between light pollution and disruption of daily rhythms, metabolic and hormonal disorders, as well as cancer progression is well-recognized. These adverse effects could be due to nocturnal melatonin suppression. The signaling pathway by which light pollution affects metabolism and endocrine responses is unclear. We studied the effects of artificial light at night (ALAN1) on body mass, food and water intake, daily rhythms of body temperature, serum glucose and insulin in male rats. Daily rhythms of urine production and urinary 6-sulfatoxymelatonin (6-SMT2), as well as global DNA methylation in pancreas and liver tissues were also assessed. Mass gain was higher in ALAN rats compared with controls. Food intake, water consumption, glucose, insulin, and 6-SMT levels markedly lessened in response to ALAN. Conversely, urine production and body temperature were elevated in ALAN rats compared with controls. Significant 24-h rhythms were detected for all variables that were altered in mesor, amplitude, and acrophase occurrences under ALAN conditions. DNA hypo-methylation was detected in ALAN pancreatic tissue compared with controls, but not in hepatic tissue. Overall, ALAN affects metabolic and hormonal physiology in different levels in which flexible crosstalk between melatonin and both epigenetics and metabolic levels expressed as body temperature rhythm, is suggested to mediate the environmental exposure at the molecular level and subsequently physiology is altered. The flexibility of epigenetic modifications provides a potential therapeutic target for rectifying ALAN adverse effects by epigenetic markers such as melatonin and behavioral lifestyle interventions for confining ALAN exposures as much as possible.

Disruption of sleep, sleep-wake activity rhythm, and nocturnal melatonin production in breast cancer patients undergoing adjuvant chemotherapy: prospective cohort study.

OBJECTIVE: This prospective cohort study captured the patterns of sleep, sleep-wake activity rhythm, and first-morning urinary melatonin in breast cancer patients undergoing adjuvant chemotherapy. METHODS: Breast cancer patients undergoing adjuvant chemotherapy wore wrist actigraph for 168 h and collected first-morning void urine samples before treatment, during the first, and at the last cycle of chemotherapy. We converted actigraphy data into sleep duration, sleep efficiency, nighttime total wake time, percent rhythm, F-statistic, amplitude, mesor, and acrophase. We then assessed urinary 6-sulfatoxymelatonin (aMT6s) levels. RESULTS: This cohort contained 180 participants. Compared with the baseline, sleep efficiency during the first and last cycle decreased by 10.16% [95% confidence interval (95% CI): 5.85%, 14.47%] and 5.01% (95% CI: 0.50%, 9.53%), respectively. Similarly, percent rhythm decreased by 27.20% (95% CI: 19.95%, 34.45%) during the first cycle and 21.20% (95% CI: 13.52, 28.89) during the last cycle. Taking the baseline as the reference, aMT6s levels during the first and last cycle decreased by 11.27% (95% CI: 0.37%, 22.16%) and 14.74% (95% CI: 2.34, 27.11), respectively. CONCLUSION: The first administration of adjuvant chemotherapy is associated with sleep disturbance and sleep-wake activity rhythm disruption among breast cancer patients, while the disturbance and disruption during the last cycle are less severe; nevertheless, repeated administration of chemotherapy results in progressive impairment of nocturnal melatonin production.

Artificial Light at Night of Different Spectral Compositions Differentially Affects Tumor Growth in Mice: Interaction With Melatonin and Epigenetic Pathways.

Lighting technology is rapidly advancing toward shorter wavelength illuminations that offer energy-efficient properties. Along with this advantage, the increased use of such illuminations also poses some health challenges, particularly breast cancer progression. Here, we evaluated the effects of artificial light at night (ALAN) of 4 different spectral compositions (500-595 nm) at 350 Lux on melatonin suppression by measuring its urine metabolite 6-sulfatoxymelatonin, global DNA methylation, tumor growth, metastases formation, and urinary corticosterone levels in 4T1 breast cancer cell-inoculated female BALB/c mice. The results revealed an inverse dose-dependent relationship between wavelength and melatonin suppression. Short wavelength increased tumor growth, promoted lung metastases formation, and advanced DNA hypomethylation, while long wavelength lessened these effects. Melatonin treatment counteracted these effects and resulted in reduced cancer burden. The wavelength suppression threshold for melatonin-induced tumor growth was 500 nm. These results suggest that short wavelength increases cancer burden by inducing aberrant DNA methylation mediated by the suppression of melatonin. Additionally, melatonin suppression and global DNA methylation are suggested as promising biomarkers for early diagnosis and therapy of breast cancer. Finally, ALAN may manifest other physiological responses such as stress responses that may challenge the survival fitness of the animal under natural environments.

The effect of long-term melatonin supplementation on psychosomatic disorders in postmenopausal women.

Different psychosomatic disorders are observed in postmenopausal women. The decrease of estrogen production is believed to be the main cause of their severity. It is nowadays evident that the decreased melatonin release in women at this age who suffer from postmenopausal disorders might also contribute to the severity of the symptoms. The aim of the study was to evaluate the effect of melatonin supplementation on female hormones release and the alteration in climacteric symptoms. The study included 60 postmenopausal women, aged 51 - 64 years, who were randomly allotted into two equal groups. Group I was recommended placebo (2 x 1 tablet) and Group II - melatonin (3 mg in the morning and 5 mg at bedtime) for 12 months. Serum levels of 17ß-estradiol, follicle-stimulating hormone (FSH), melatonin and urinary 6-sulfatoxymelatonin (aMT6s) excretion as well as Kupperman Index (KI) and body mass index (BMI) were determined before the start and at 12 months after placebo or melatonin administration. In Group I only the value of KI slightly decreased (28.4 ± 2.9 versus 25.6 ± 3.8 points, P = 0,0619). In Group II - KI decreased from 29.1 ± 2.9 to 19.7 ± 3.1 points (P < 0.001) and BMI from 30.9 ± 2.9 to 28.1 ± 2.3 kg/m2 (P < 0.05). Melatonin supplementation failed to change significantly the serum concentration of female reproductive hormones 17ß-estradiol and FSH. We conclude that melatonin supplementation therapy exerts a positive effect on psychosomatic symptoms in postmenopausal women and can be recommended as the useful adjuvant therapeutic option in treatment of these disorders.

Association of urinary levels of 6-sulfatoxymelatonin (aMT6s) with prevalent and incident hypertension.

Laboratory studies indicate that melatonin has beneficial vascular effects. However, epidemiologic studies on the relationship between endogenous levels of melatonin and hypertension in humans are limited. We examined the association of quartile levels of 6-sulfatoxymelatonin (aMT6s) in first morning urines with prevalent and incident hypertension in 777 postmenopausal women who were originally part of a case-control study of breast cancer nested in the Women's Health Initiative Observational Study. A total of 321 prevalent and 172 incident cases of hypertension were studied. In cross-sectional analyses, higher quartile level of aMT6s was associated with lower odds of hypertension (Q4 versus Q1; odds ratio = 0.57; 95% confidence interval [CI]: 0.3-0.9), after adjustment for age, body mass index and other risk factors. We also examined the association between baseline aMT6s levels and risk of incident hypertension. Compared to women in the lowest quartile of urinary aMT6s, the multivariable-adjusted hazard ratios and 95% CIs of incident hypertension for women in the second, third and highest quartile were 1.16 (0.8-1.8), 0.96 (0.6-1.5) and 1.02 (0.6-1.6), respectively. The mean change in systolic and diastolic blood pressure over 3 years also did not vary by baseline quartile levels of aMT6s. Although we found no evidence of a prospective association between urinary levels of aMT6s and risk of incident hypertension in postmenopausal women, our cross-sectional results provide some possible evidence of a role for physiologic levels of melatonin in hypertension. Additional larger studies are warranted, preferably with a wider range of ages, both genders and multiple melatonin measurements.