Melatonin for Treatment of Sleep Disorders: Summary

N Buscemi, B Vandermeer, R Pandya, N Hooton, L Tjosvold, L Hartling, G Baker, S Vohra, and T Klassen.

Introduction: Sleep Disorders

Studies suggest that sleep disorders affect 50 to 70 million Americans, representing approximately 20 percent of the population.¹ A sleep disorder exists whenever a lower quality of sleep results in impaired functioning or excessive sleepiness.² Insomnia, literally "inability to sleep," has various etiologies and is the most common sleep disorder, affecting between 6 to 12 percent of the adult population.³ In addition to the adult population, difficulties initiating and maintaining sleep are very common in children, affecting about 15 to 25 percent of this population.¹

Melatonin

Melatonin (N‐acetyl‐5‐methoxytryptamine) is a neurohormone that is primarily produced by the pineal gland, located behind the third ventricle in the brain.⁴ In the synthesis of melatonin, tryptophan is hydroxylated to 5‐hydroxytryptophan, which in turn is decarboxylated to 5‐hydroxytryptamine (serotonin). Serotonin is converted to the melatonin precursor and metabolite Nacetylserotonin by the enzyme N‐acetyl transferase.⁵‐⁷N‐acetylserotonin is methylated via the enzyme hydroxyindole‐o‐methyltransferase to produce melatonin.⁸Approximately 90 percent of melatonin is cleared in a single passage through the liver. A small proportion of unmetabolized melatonin is also excreted in the urine.⁸ Commercially available melatonin may be isolated from the pineal glands of beef cattle⁹ or chemically synthesized.

Methods

In this report, we review the use of melatonin for the treatment of a number of categories of sleep disorders, including primary sleep disorders, secondary sleep disorders, and sleep restriction, in a number of different populations. Moreover, we review not only the safety and effectiveness of melatonin for the treatment of sleep disorders, but also the pharmacology of exogenous melatonin and the physiology of endogenous melatonin, to provide a comprehensive overview of the state of research in this area.

https://www.ncbi.nlm.nih.gov/books/NBK11941/

Meta-Analysis: Melatonin for the Treatment of Primary Sleep Disorders

Abstract:

Study Objectives:

To investigate the efficacy of melatonin compared to placebo in improving sleep parameters in patients with primary sleep disorders.

Design:

PubMed was searched for randomized, placebo-controlled trials examining the effects of melatonin for the treatment of primary sleep disorders. Primary outcomes examined were improvement in sleep latency, sleep quality and total sleep time. Meta-regression was performed to examine the influence of dose and duration of melatonin on reported efficacy.

Participants:

Adults and children diagnosed with primary sleep disorders.

Interventions:

Melatonin compared to placebo.

Results:

Nineteen studies involving 1683 subjects were included in this meta-analysis. Melatonin demonstrated significant efficacy in reducing sleep latency (weighted mean difference (WMD) = 7.06 minutes [95% CI 4.37 to 9.75], Z = 5.15, p<0.001) and increasing total sleep time (WMD = 8.25 minutes [95% CI 1.74 to 14.75], Z = 2.48, p = 0.013). Trials with longer duration and using higher doses of melatonin demonstrated greater effects on decreasing sleep latency and increasing total sleep time. Overall sleep quality was significantly improved in subjects taking melatonin (standardized mean difference = 0.22 [95% CI: 0.12 to 0.32], Z = 4.52, p<0.001) compared to placebo. No significant effects of trial duration and melatonin dose were observed on sleep quality.

Conclusion:

This meta-analysis demonstrates that melatonin decreases sleep onset latency, increases total sleep time and improves overall sleep quality. The effects of melatonin on sleep are modest but do not appear to dissipate with continued melatonin use. Although the absolute benefit of melatonin compared to placebo is smaller than other pharmacological treatments for insomnia, melatonin may have a role in the treatment of insomnia given its relatively benign side-effect profile compared to these agents.

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0063773

 

Circadian rhythm sleep disorders in the blind and their treatment with melatonin

Debra J.SkeneJosephineArendt

Abstract:

People who are blind, in addition to having to cope with partial or no sight, have an added handicap; the transmission of ocular light from the retina to their circadian clock is impaired. At its worse, for example in people with both eyes enucleated, this lesion results in desynchronisation of the biological clock (located in the hypothalamic suprachiasmatic nuclei) from the 24 h day/night environment. While in a desynchronised state, symptoms akin to jet lag are experienced (e.g., daytime sleepiness, poor night sleep, reduced alertness and performance during waking). This is a lifelong condition. Daily administration of exogenous melatonin is the current treatment of choice for this so-called “non-24 h sleep/wake disorder”. Melatonin has been shown to correct the underlying circadian rhythm abnormality as well as improve sleep and reduce daytime napping. The effectiveness of melatonin therapy depends upon its time of administration relative to the timing of the person’s circadian clock. If practicable, assessment of an individual’s circadian phase (by measurement of the endogenous melatonin rhythm in plasma, saliva or urine) is recommended prior to commencing treatment to optimise melatonin’s effectiveness.

https://www.sciencedirect.com/science/article/pii/S1389945706006861

Melatonin treatment for age-related insomnia.

Zhdanova IV¹, Wurtman RJ, Regan MM, Taylor JA, Shi JP, Leclair OU.

Abstract:

Older people typically exhibit poor sleep efficiency and reduced nocturnal plasma melatonin levels. The daytime administration of oral melatonin to younger people, in doses that raise their plasma melatonin levels to the nocturnal range, can accelerate sleep onset. We examined the ability of similar, physiological doses to restore nighttime melatonin levels and sleep efficiency in insomniac subjects over 50 yr old. In a double-blind, placebo-controlled study, subjects who slept normally (n = 15) or exhibited actigraphically confirmed decreases in sleep efficiency (n = 15) received, in randomized order, a placebo and three melatonin doses (0.1, 0.3, and 3.0 mg) orally 30 min before bedtime for a week. Treatments were separated by 1-wk washout periods. Sleep data were obtained by polysomnography on the last three nights of each treatment period. The physiologic melatonin dose (0.3 mg) restored sleep efficiency (P < 0.0001), acting principally in the midthird of the night; it also elevated plasma melatonin levels (P < 0.0008) to normal. The pharmacologic dose (3.0 mg), like the lowest dose (0.1 mg), also improved sleep; however, it induced hypothermia and caused plasma melatonin to remain elevated into the daylight hours. Although control subjects, like insomniacs, had low melatonin levels, their sleep was unaffected by any melatonin dose.

https://www.ncbi.nlm.nih.gov/pubmed/11600532

Prolonged-release melatonin improves sleep quality and morning alertness in insomnia patients aged 55 years and older and has no withdrawal effects.

Lemoine P¹, Nir T, Laudon M, Zisapel N.

Abstract:

Melatonin, secreted nocturnally by the pineal gland, is an endogenous sleep regulator. Impaired melatonin production and complaints on poor quality of sleep are common among the elderly. Non-restorative sleep (perceived poor quality of sleep) and subsequently poor daytime functioning are increasingly recognized as a leading syndrome in the diagnostic and therapeutic process of insomnia complaints. The effects of 3-weeks prolonged-release melatonin 2 mg (PR-melatonin) versus placebo treatment were assessed in a multi-center randomized placebo-controlled study in 170 primary insomnia outpatients aged > or =55 years. Improvements in quality of sleep (QOS) the night before and morning alertness (BFW) were assessed using the Leeds Sleep Evaluation Questionnaire and changes in sleep quality (QON) reported on five categorical unit scales. Rebound insomnia and withdrawal effects following discontinuation were also evaluated. PR-melatonin significantly improved QOS (-22.5 versus -16.5 mm, P = 0.047), QON (0.89 versus 0.46 units; P = 0.003) and BFW (-15.7 versus -6.8 mm; P = 0.002) compared with placebo. The improvements in QOS and BFW were strongly correlated (Rval = 0.77, P < 0.001) suggesting a beneficial treatment effect on the restorative value of sleep. These results were confirmed in a subgroup of patients with a greater symptom severity. There was no evidence of rebound insomnia or withdrawal effects following treatment discontinuation. The incidence of adverse events was low and most side-effects were judged to be of minor severity. PR-melatonin is the first drug shown to significantly improve quality of sleep and morning alertness in primary insomnia patients aged 55 years and older-suggesting more restorative sleep, and without withdrawal symptoms upon discontinuation.

https://www.ncbi.nlm.nih.gov/pubmed/18036082

  

Melatonin and insomnia.

Ellis CM¹, Lemmens G, Parkes JD.

Abstract:

The hypnotic action of melatonin 5 mg p.o. was explored in 15 subjects with psychophysiological insomnia in a double-blind controlled self-report questionnaire study. Melatonin or placebo was taken at 20.00 hours for a 1-week period in random order. Effects on sleep and wakefulness were monitored by visual analogue scale and structured interview. Bedtime, sleep onset time, estimated total sleep and wake time, as well as self-rated sleep quality, were not altered by melatonin, and estimates of next-day function did not change. The period of melatonin, treatment was retrospectively correctly identified by 8 of 15 subjects. Despite unchanged ratings of night sleep quality on the last night of each treatment, 7 of 15 subjects reported that sleep had subjectively improved to a minor extent in the week of active treatment. Side-effects attributed to melatonin included headache and an odd taste in the mouth. These data indicate that melatonin is probably of no clinical value in the management of psychophysiological insomnia.

https://www.ncbi.nlm.nih.gov/pubmed/8795804

  

Efficacy of prolonged release melatonin in insomnia patients aged 55-80 years: quality of sleep and next-day alertness outcomes.

Wade AG¹, Ford I, Crawford G, McMahon AD, Nir T, Laudon M, Zisapel N.

Abstract:

Objective:

Melatonin, the hormone produced nocturnally by the pineal gland, serves as a circadian time cue and sleep-anticipating signal in humans. With age, melatonin production declines and the prevalence of sleep disorders, particularly insomnia, increases. The efficacy and safety of a prolonged release melatonin formulation (PR-melatonin; Circadin* 2 mg) were examined in insomnia patients aged 55 years and older.

Design:

Randomised, double blind, placebo-controlled.

Setting:

Primary care.

Methodology:

From 1248 patients pre-screened and 523 attending visit 1, 354 males and females aged 55-80 years were admitted to the study, 177 to active medication and 177 to placebo. The study was conducted by primary care physicians in the West of Scotland and consisted of a 2-week, single blind, placebo run-in period followed by a 3-week double blind treatment period with PR-melatonin or placebo, one tablet per day at 2 hours before bedtime.

Main Outcome Measures:

Responder rate (concomitant improvement in sleep quality and morning alertness on Leeds Sleep Evaluation Questionnaire [LSEQ]), other LSEQ assessments, Pittsburgh Sleep Quality Index (PSQI) global score, other PSQI assessments, Quality of Night and Quality of Day derived from a diary, Clinical Global Improvement scale (CGI) score and quality of life (WHO-5 well being index).

Results:

Of the 354 patients entering the active phase of the study, 20 failed to complete visit 3 (eight PR-melatonin; 12 Placebo). The principal reasons for drop-out were patient decision and lost to follow-up. Significant differences in favour of PR-melatonin vs. placebo treatment were found in concomitant and clinically relevant improvements in quality of sleep and morning alertness, demonstrated by responder analysis (26% vs. 15%; p = 0.014) as well as on each of these parameters separately. A significant and clinically relevant shortening of sleep latency to the same extent as most frequently used sleep medications was also found (-24.3 vs.-12.9 minutes; p = 0.028). Quality of life also improved significantly (p = 0.034).

Conclusions:

PR-melatonin results in significant and clinically meaningful improvements in sleep quality, morning alertness, sleep onset latency and quality of life in primary insomnia patients aged 55 years and over.

https://www.ncbi.nlm.nih.gov/pubmed/17875243

 

Melatonin prolonged release: in the treatment of insomnia in patients aged ≥55 years.

Lyseng-Williamson KA¹.

Abstract:

Melatonin prolonged release (PR) 2 mg is approved for the treatment of primary insomnia characterized by poor sleep quality in patients aged ≥55 years in the EU and elsewhere. Patients may receive treatment with melatonin PR for up to 13 weeks. Production of endogenous nocturnal melatonin, which helps regulate circadian rhythm, may be decreased in older adults. Administration of melatonin PR 2 mg 1-2 h before bedtime mimics the natural secretion pattern of melatonin, thereby leading to improvements in the circadian regulation of the sleep-wake cycle. In older adults, melatonin PR 2 mg had no effect on psychomotor functions, memory recall or driving skills during the night or the next morning relative to placebo, and was associated with significantly less impairment on many of these tasks relative to zolpidem 10 mg alone or in combination with melatonin PR 2 mg. In 3-week and 6-month, randomized, double-blind clinical trials in patients with primary insomnia aged ≥55 years, melatonin PR 2 mg 1-2 h before bedtime was associated with significant improvements relative to placebo in many sleep and daytime parameters, including sleep quality and latency, morning alertness and health-related quality of life. Melatonin PR 2 mg was very well tolerated in clinical trials in older patients, with a tolerability profile that was similar to that of placebo. Short- or longer-term treatment with melatonin PR 2 mg was not associated with dependence, tolerance, rebound insomnia or withdrawal symptoms.

https://www.ncbi.nlm.nih.gov/pubmed/23044640

 

Melatonin secretion and excretion in patients with obstructive sleep apnea syndrome.

Wikner J¹, Svanborg E, Wetterberg L, Röjdmark S.

Abstract:

Melatonin (MT) secretion and excretion were investigated in patients with obstructive sleep apnea syndrome (OSAS). Nine men, mean age 55.1 years, mean body mass index 31.2, with a previously confirmed diagnosis of moderate to severe OSAS, were tested on two occasions: immediately before initiation of continuous positive airway pressure (CPAP) treatment and again after at least 4 weeks of continuous nocturnal use of CPAP. Serum MT concentrations were determined every second hour between 2000 and 0800 hours. Urine was collected between 2200 and 0700 hours for determination of urinary MT excretion. Sleep apnea recordings included ear oximetry, respiration and body movements, body position, and breathing sounds. Nine healthy male controls were tested on one occasion. We found that the MT secretion, as reflected by the area under the curve (AUC), among the OSAS patients did not differ from that found in healthy controls (MT AUC 1.68 vs. 1.92 nmol/l x h). Sleep apnea recordings were normalized during CPAP treatment. Moreover, the excessive daytime sleepiness disappeared in all patients. Neither MT secretion (MT AUC 1.68 vs. 1.56 nmol/l x h) nor urinary excretion of MT (0.122 vs. 0.108 nmol/9 h) changed significantly as a result of the CPAP treatment.

https://www.ncbi.nlm.nih.gov/pubmed/9456465

 

Phase-Dependent Treatment of Delayed Sleep Phase Syndrome with Melatonin

Kavita Mundey*1 ; Susan Benloucif*1,3; Krisztina Harsanyi1 ; Margarita L. Dubocovich2-4; Phyllis C. Zee1,3,4

Study Objective:

Delayed sleep phase syndrome (DSPS) is a circadianrhythm sleep disorder characterized by abnormally late sleep and wake times. Melatonin, taken in the evening, advances sleep and circadian phase in patients with DSPS. However, little is known about the most effective dose or time of administration. In the present study, we tested the effectiveness of melatonin to advance the timing of sleep and circadian phase in individuals with DSPS.

Design:

Following baseline assessment of sleep and circadian phase, subjects were randomly assigned to 1 of 3 treatment groups. The administration of melatonin (0.3 or 3.0 mg) or placebo was double-blinded.

Setting:

All procedures were conducted on an outpatient basis.

Participants:

Thirteen subjects with DSPS, recruited via flyers, advertisements, and referrals from the Sleep Clinic, completed this study.

Interventions:

Melatonin (0.3 or 3.0 mg) or placebo was administered between 1.5 and 6.5 hours prior to dim light melatonin onset for a 4-week period.

Measurements and Results:

Both doses of melatonin advanced the circadian phase of endogenous melatonin. The magnitude of phase advance in dim-light melatonin onset correlated strongly with the time of melatonin administration, with earlier times being more effective (r2 = 0.94, P < .0001). Similar, though weaker, relationships were obtained between the timing of melatonin administration and changes in sleep time.

Conclusions:

These results indicate that melatonin advances the circadian clock and sleep in patients with DSPS in a phase-dependent manner. This is the first study that reports a relationship between timing of melatonin administration and phase changes in patients with DSPS. Keywords: Circadian rhythms, melatonin, delayed sleep phase syndrome

Citation:

Mundey K; Benloucif S; Harsanyi K et al. Phase-dependent treatment of delayed sleep phase syndrome with melatonin. SLEEP 2005;28(10): 1271-1278.

http://jcsm.aasm.org/articles/020123.pdf

 

Melatonin Supplementation Improves Sleep in Children with Autism Spectrum Disorder

Study evaluates dose effectiveness of melatonin with sleep difficulties due to ASD

By Jessica Mitchell, ND

Reference:

Malow B, Adkins KW, McGrew SG, et al. Melatonin for sleep in children with autism: a controlled trial examining dose, tolerability, and outcomes. J Autism Dev Disor. 2012 Aug; 42(8):1729-37.

Design:

Open-label dose-escalation study. The first week consisted of structured sleep education, including establishment of regular bedtime and wake time. Parents were educated on use of actigraphy and began using the machine. The actigraphy readings were used to confirm the inclusion criteria of >30 min sleep onset.

After the first week, participants began a 2-week acclimation phase in which parents were asked to give the children inert liquid 30 min before bed that was flavored the same as the melatonin.

Children then began the dose escalation phase starting at 1 mg melatonin given 30 minutes before bedtime. Each dose was given for three weeks. When a satisfactory dose was established, that dose was maintained until the end of the 14-week trial. The doses were escalated from 1 mg to 3 mg, 6 mg, and finally 9 mg.

https://www.naturalmedicinejournal.com/journal/2013-07/melatonin-supplementation-improves-sleep-children-autism-spectrum-disorder

 

Melatonin Supplementation in Patients with Complete Tetraplegia and Poor Sleep

Jo Spong,¹ Gerard A. Kennedy,^1,2 Douglas J. Brown,³ Stuart M. Armstrong,^4,5 and David J. Berlowitz¹

People with complete tetraplegia have interrupted melatonin production and commonly report poor sleep. Whether the two are related is unclear. This pilot study investigated whether nightly supplementation of 3 mg melatonin would improve objective and subjective sleep in tetraplegia. Five participants with motor and sensory complete tetraplegia ingested 3 mg melatonin (capsule) two hours prior to usual sleep time for two weeks. Full portable sleep studies were conducted in participants’ homes on the night before commencing melatonin supplementation (baseline) and on the last night of the supplementation period. Endogenous melatonin levels were determined by assaying saliva samples collected the night of (just prior to sleep) and morning after (upon awakening) each sleep study. Prior to each sleep study measures of state sleepiness and sleep behaviour were collected. The results showed that 3 mg of melatonin increased salivary melatonin from near zero levels at baseline in all but one participant. A delay in time to Rapid Eye Movement sleep, and an increase in stage 2 sleep were observed along with improved subjective sleep experience with a reduction in time to fall asleep, improved quality of sleep and fewer awakenings during the night reported. Daytime sleepiness increased however. A randomised, placebo controlled trial with a larger sample is required to further explore and confirm these findings.

https://www.hindawi.com/journals/sd/2013/128197/

 

Lasting treatment effects in a postmarketing surveillance study of prolonged-release melatonin.

Int Clin Psychopharmacol.2015 Jan;30(1):36-42. doi: 10.1097/YIC.0000000000000046.

Hajak G¹, Lemme K, Zisapel N.

Abstract:

Surveillance studies are useful to evaluate how a new medicinal product performs in everyday treatment and how the patient who takes it feels and functions, thereby determining the benefit/risk ratio of the drug under real-life conditions. Prolonged-release melatonin (PRM; Circadin) was approved in Europe for the management of primary insomnia patients age 55 years or older suffering from poor quality of sleep. With traditional hypnotics (e.g. benzodiazepine-receptor agonists), there are concerns about rebound insomnia and/or withdrawal symptoms. We report data from a postmarketing surveillance study in Germany on the effects of 3 weeks of treatment with PRM on sleep in patients with insomnia during treatment and at early (1-2 days) and late (around 2 weeks) withdrawal. In total, 653 patients (597 evaluable) were recruited at 204 sites (mean age 62.7 years, 68% previously treated with hypnotics, 65% women). With PRM treatment, the mean sleep quality (on a scale of 1-5 on which 1 is very good and 5 is very bad) improved from 4.2 to 2.6 and morning alertness improved from 4.0 to 2.5. The improvements persisted over the post-treatment observation period. Rebound insomnia, defined as a one-point deterioration in sleep quality below baseline values, was found in 3.2% (early withdrawal) and 2.0% (late withdrawal). Most of the patients (77%) who used traditional hypnotics before PRM treatment had stopped using them and only 5.6% of naive patients started such drugs after PRM discontinuation. PRM was well tolerated during treatment and the most frequently reported adverse events were nausea (10 patients, 1.5%), dizziness, restlessness and headache (five patients each, <1%). There were no serious adverse events and no adverse events were reported after discontinuation. The persisting treatment effect and very low rebound rate suggest a beneficial role of sleep-wake cycle stabilization with PRM in the treatment of insomnia

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255979/

 

 

 

Sleepless in america: compounding with melatonin.

Int J Pharm Compd.2010 Jan-Feb;14(1):10.

Wynn T¹, Rawlings K.

Abstract:

Studies of Melatoninin the 1970s and 1980s revealed sedative and hypnotic properties of the compound, which have led to its use in treating sleep disorders. Commonly used for jet lag, melatoninis relatively inexpensive and associated with minimal side effects. Regulation of melatoninsecretion appears to be abnormal in children and adults in which pervasive development disorders have been observed. Alteration in melatoninrhythm may be responsible for sleep-onset and maintenance difficulties in autism. A recent review concluded that melatoninprimarily acts on the total length of time needed to fall asleep and on the total length of sleep. In addition, melatonin, which does not induce dependence or withdrawalsyndromes, may have advantages compared to commonly prescribed benzodiazepines. While there is an enormous amount of anecdotal information available, additional studies are necessary involving melatoninfor the treatment of sleep disorders. The condition of these well-controlled studies must be clearly defined, especially in regards to the melatoninformulation and pharmacology of the products used. Various areas remain unclear, such as how the effects of melatoninvary by age, gender, ethnicity, and comorbid conditions of the population, as well as formulation, timing, and duration of melatoninadministration. While the U.S. Food and Drug Administration does not strictly regulate herbs and supplements, based on available studies and clinical use, melatoninis generally regarded as safe in recommended doses when used in the short term. The safety of melatoninwhen used in the long term remains unclear.

https://www.ijpc.com/Abstracts/Abstract.cfm?ABS=3067

                                                                 

Melatonin for perceived sleep disturbances associated with benzodiazepine withdrawal among patients in methadone maintenance treatment: a double-blind randomized clinical trial.

Addiction.2007 Dec;102(12):1947-53. Epub 2007 Oct 4.

Peles E¹, Hetzroni T, Bar-Hamburger R, Adelson M, Schreiber S.

Abstract:

Aims:

To evaluate the effectiveness of melatoninin attenuating sleep difficulties during benzodiazepine(BDZ)withdrawal.

Design:

Double-blind cross-over control study.

Setting:

Methadone maintenance treatment clinic.

Participants:

Eighty patients enrolled at a community methadone maintenance clinic recruited to a BDZ withdrawalprogramme.

Intervention:

Melatonin(5 mg/day) or placebo: 6 weeks one arm, 1 week washout, 6 weeks other arm.

Measurements:

Urine BDZ; self-reported Pittsburgh Sleep Quality Index (PSQI) and the Center for Epidemiologic Studies Depression (CES-D) questionnaires administered at baseline, and at 6, 7 and 13 weeks.

Findings:

Sixty-one patients (77.5% in the 'melatoninfirst' condition and 75% in the 'placebo first' condition) completed 6 weeks of treatment, showing a similar BDZ discontinuation rate of 11/31 and 11/30, respectively. PSQI scores were significantly lower (indicating better sleep quality) in the 22 patients who discontinued BDZ (8.9 +/- 0.9) than in 39 with urine BDZ (11.2 +/- 0.7, P = 0.04). Sleep quality in patients who continued abusing BDZ improved more in the 'melatoninfirst' group than in the 'placebo first' group, with no differences in sleep quality improvement in patients who stopped BDZ. CONCLUSION Most improvement in sleep quality was attributed to BDZ discontinuation. Although melatonindid not enhance BDZ discontinuation, it improved sleep quality, especially in patients who did not stop BDZ.

https://www.medscape.com/medline/abstract/17916225

 

Rapid reversal of tolerance to benzodiazepine hypnotics by treatment with oral melatonin: a case report.

Eur Neuropsychopharmacol.1997 May;7(2):157-60.

Dagan Y¹, Zisapel N, Nof D, Laudon M, Atsmon J.

Abstract:

A 43 year old woman had suffered from insomnia for the past 11 years and was being treated with benzodiazepines. All attempts to stop benzodiazepinetreatment resulted in withdrawalsymptoms and a renewal of the insomnia. Treatment with 1 mg of controlled release melatoninenabled the patient to completely cease any benzodiazepineuse within two days, with an improvement in sleep quality and no side effects. Examination of urinary 6-sulphatoxymelatonin levels before the melatonintreatment indicated that the levels were very low and lacked the typical circadian rhythm of excretion. Reexamination of 6-sulphatoxymelatonin levels during melatonintreatment revealed the existence of a normal circadian rhythm of excretion. This case may suggest that some of the people suffering from insomnia and addicted to benzodiazepinesmay successfully undergo withdrawalfrom these drugs and improve their sleep by means of treatment with melatonin. The results of this single case study warrant further investigation of a larger population by means of a double-blind placebo-drug study.

https://www.researchgate.net/publication/14050023_Rapid_reversal_of_tolerance_to_benzodiazepine_hypnotics_by_treatment_with_oral_melatonin_A_case_report

 

Case series of perimenopausal women with insomnia treated with mirtazapine followed by prolonged-release melatoninadd-on and monotherapy.

Arch Womens Ment Health.2011 Jun;14(3):269-73. doi: 10.1007/s00737-011-0205-7. Epub 2011 Feb 12.

Dolev Z¹.

Abstract:

Objectives:

The sedating antidepressant mirtazapine is used off label for insomnia in perimenopausal women. Despite its apparent efficacy, mirtazapine causes significant increases in appetite and weight gain. Prolonged-release melatonin(PRM) is approved for primary insomnia in patients aged 55 years and older. A clinical experience with PRM add-on to mirtazapine in facilitating mirtazapine withdrawalwhile maintaining improved sleep quality and abrogating weight gain in perimenopausal women with insomnia is described.

Methods:

Eleven perimenopausal women (ages 45-52; FSH = 53 ± 8; normal BMI, 22.9 ± 0.6) with insomnia, who do not suffer from depression as assessed by the Hamilton scale, were treated with 15 mg mirtazapine (Remeron®) for 2-4 weeks. PRM, 2 mg (Circadin®), was then added on, and mirtazapine was tapered off for another 1-3 months. Prospective data on body weight and subjectively assessed sleep quality and well-being (assessed by the Pittsburgh Sleep Quality Index, PSQI, and Well-Being Index, WHO-5, respectively) were collected before, during, and at the end of the treatment.

Results:

Sleep quality ratings improved significantly (by 103% on average) during combined mirtazapine and PRM intake and 180% during subsequent intake of PRM alone or together with very low doses of mirtazapine (P < 0.05 for all). Well-being significantly improved by 83% during the treatment. Seven of 11 women demonstrated weight gain following mirtazapine intake, five of whom have started to reduce weight following mirtazapine withdrawaland PRM intake. No adverse events were reported.

Conclusion:

Application of mirtazapine followed by PRM add-on and monotherapy improves sleep in perimenopausal women while evading mirtazapine-induced weight gain. These results warrant further investigation of a larger population in controlled clinical trials.

https://www.researchgate.net/publication/49827430_Case_series_of_perimenopausal_women_with_insomnia_treated_with_mirtazapine_followed_by_prolonged-release_melatonin_add-on_and_monotherapy

 

Effect of melatonin administration on sleep, behavioral disorders and hypnotic drug discontinuation in the elderly: a randomized, double-blind, placebo-controlled study.

Aging Clin Exp Res.2009 Feb;21(1):38-42.

Garzón C¹, Guerrero JM, Aramburu O, Guzmán T.

Abstract:

Background and Aims:

The aim of the study was to evaluate the effect of melatonin administration on sleep and behavioral disorders in the elderly and the facilitation of the discontinuation of regular hypnotic drugs.

Methods:

This was a prospective, randomized, double-blind, placebo-controlled, crossover trial in a community-living population. Participants were 22 older adults (7 men, 15 women over 65) with a history of sleep disorder complaints. Fourteen of these subjects were receiving hypnotic drug therapy. Participants received 2 months of melatonin(5 mg/day) and 2 months of placebo. Sleep disorders were evaluated with the Northside Hospital Sleep Medicine Institute (NHSMI) test, discarding secondary insomnia and evaluating sleep quality. Behavioral disorders were evaluated with the Yesavage Geriatric Depression Scale (GDS) and Goldberg Anxiety Scale (GAS). Patients discontinuing hypnotic drugs were also recorded.

Results:

Melatonintreatment for two months significantly improved sleep quality scores measured by the NHSMI test (1.78+/-0.40) when compared with both basal (3.72+/-0.45; p=0.001) and placebo (3.44+/-0.56; p=0.025) groups. Depression measured by GDS and anxiety measured by GAS also improved significantly after melatoninadministration (p=0.043 and p=0.009, respectively). Nine out of 14 subjects receiving hypnotic drugs were able to discontinue this treatment during melatoninbut not placebo administration; one discontinued hypnotic drugs during both melatoninand placebo administration, and four were unable to discontinue hypnotic therapy.

Conclusions:

The results of this study suggest that melatonin administration significantly improves sleep and behavioral disorders in the elderly and facilitates discontinuation of therapy with conventional hypnotic drugs.

https://www.researchgate.net/publication/24023260_Effecf_of_melatonin_administration_on_sleep_behavioral_disorders_and_hypnotic_drug_discontinuation_in_the_elderly_A_randomized_double-blind_placebo-controlled_study

Melatonin as a mitochondria-targeted antioxidant: one of evolution’s best ideas

Authors: Russel J. ReiterSergio Rosales-Corral, Dun Xian Tan, Mei Jie Jou, Annia Galano, Bing Xu

Abstract:

Melatonin is an ancient antioxidant. After its initial development in bacteria, it has been retained throughout evolution such that it may be or may have been present in every species that have existed. Even though it has been maintained throughout evolution during the diversification of species, melatonin’s chemical structure has never changed; thus, the melatonin present in currently living humans is identical to that present in cyanobacteria that have existed on Earth for billions of years. Melatonin in the systemic circulation of mammals quickly disappears from the blood presumably due to its uptake by cells, particularly when they are under high oxidative stress conditions. The measurement of the subcellular distribution of melatonin has shown that the concentration of this indole in the mitochondria greatly exceeds that in the blood. Melatonin presumably enters mitochondria through oligopeptide transporters, PEPT1, and PEPT2. Thus, melatonin is specifically targeted to the mitochondria where it seems to function as an apex antioxidant. In addition to being taken up from the circulation, melatonin may be produced in the mitochondria as well. During evolution, mitochondria likely originated when melatonin-forming bacteria were engulfed as food by ancestral prokaryotes. Over time, engulfed bacteria evolved into mitochondria; this is known as the endosymbiotic theory of the origin of mitochondria. When they did so, the mitochondria retained the ability to synthesize melatonin. Thus, melatonin is not only taken up by mitochondria but these organelles, in addition to many other functions, also probably produce melatonin as well. Melatonin’s high concentrations and multiple actions as an antioxidant provide potent antioxidant protection to these organelles which are exposed to abundant free radicals.

https://link.springer.com/article/10.1007/s00018-017-2609-7

Melatonin Benefits for Women's Fertility

Long-term melatonin treatment delays ovarian aging.

J Pineal Res.2017 Mar;62(2). doi: 10.1111/jpi.12381. Epub 2017 Jan 23.

Tamura H1,Kawamoto M1,Sato S1,Tamura I1,Maekawa R1,Taketani T1,Aasada H1,Takaki E2,Nakai A2,Reiter RJ3,Sugino N1.

Abstract:

Ovarian aging is characterized by gradual declines in oocyte quantity and quality. Melatonin is considered an anti-aging agent due to its cytoprotective actions as an antioxidant. This study examined whether long-term melatonin treatment would delay ovarian aging in mice. Female ICR mice (10 weeks old) were given melatonin-containing water (100 μg/mL; melatonin) or water only until 43 weeks of age. Their oocytes were recovered from the oviduct, and in vitro fertilization was performed. The ovaries were used for a histological analysis of the number of follicles. The mRNA expression of the aging-related sirtuin genes (SIRT1, SIRT3) and the autophagy-related gene (LC3) and the telomere length of the ovarian chromosomes were analyzed. Transcriptome changes in the ovaries were also characterized using microarray. The number of ovulated oocytes decreased with age; however, it was greater in melatonin-treated mice than that from control animals. The decreased fertilization rate and blastocyst rate during aging also were higher in the melatonin-treated mice than in the controls, as were the numbers of primordial, primary, and antral follicles. The mRNA expression of SIRT1 and LC3 and telomere length were enhanced due to melatonin treatment. Seventy-eight genes that were downregulated during aging and upregulated by melatonin were identified by a microarray analysis. Forty of these 78 genes were ribosome-related genes, and a free radical scavenging network was identified. The present results indicate that melatonin delays ovarian aging by multiple mechanisms including antioxidant action, maintaining telomeres, stimulating SIRT expression and ribosome function, and by reducing autophagy.

https://onlinelibrary.wiley.com/doi/abs/10.1111/jpi.12381

 

Melatonin: shedding light on infertility?--A review of the recent literature.

J Ovarian Res.2014 Oct 21;7:98. doi: 10.1186/s13048-014-0098-y.

Fernando S1,2,Rombauts L3,4.

Abstract:

In recent years, the negative impact of oxidative stress on fertility has become widely recognised. Several studies have demonstrated its negative effect on the number and quality of retrieved oocytes and embryos following in-vitro fertilization (IVF). Melatonin, a pineal hormone that regulates circadian rhythms, has also been shown to exhibit unique oxygen scavenging abilities. Some studies have suggested a role for melatonin in gamete biology. Clinical studies also suggest that melatonin supplementation in IVF may lead to better pregnancy rates. Here we present a critical review and summary of the current literature and provide suggestions for future well designed clinical trials.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209073/

 

Does supplementation of in-vitro culture medium with melatonin improve IVF outcome in PCOS?

Reprod Biomed Online.2013 Jan;26(1):22-9. doi: 10.1016/j.rbmo.2012.10.007. Epub 2012 Oct 12.

Kim MK1,Park EA, Kim HJ, Choi WY, Cho JH, Lee WS, Cha KY, Kim YS, Lee DR, Yoon TK.

Abstract:

Human pre-ovulatory follicular fluid (FF) contains a higher concentration of melatonin than serum. The aim of this study was to evaluate the effect of melatonin supplementation of culture medium on the clinical outcomes of an in-vitro maturation (IVM) IVF-embryo transfer program for patients with polycystic ovarian syndrome (PCOS). Melatonin concentrations in the culture media of granulosa cells (GC) or cumulus-oocyte-complexes (COC) were measured and the clinical outcomes after using IVM media with or without melatonin were analyzed. In the culture media of GC or COC, melatonin concentrations gradually increased. When human chorionic gonadotrophin priming protocols were used, implantation rates in the melatonin-supplemented group were higher than those of the non-supplemented control group (P<0.05). Pregnancy rates were also higher, although not significantly. The findings suggest that the addition of melatonin to IVM media may improve the cytoplasmic maturation of human immature oocytes and subsequent clinical outcomes. It is speculated that follicular melatonin may be released from luteinizing GC during late folliculogenesis and that melatonin supplementation may be used to improve the clinical outcomes of IVM IVF-embryo transfer. Melatonin is primarily produced by the pineal gland and regulates a variety of important central and peripheral actions related to circadian rhythms and reproduction. Interestingly, human pre-ovulatory follicular fluid contains a higher concentration of melatonin than serum. However, in contrast to animal studies, the direct role of melatonin on oocyte maturation in the human system has not yet been investigated. So, the aim of the study was to evaluate the effect of melatonin supplementation of culture medium on the clinical outcome of an in-vitro maturation (IVM) IVF-embryo transfer program for PCOS patients. The melatonin concentrations in culture medium of granulosa cells (GC) or cumulus-oocyte-complexes (COC) were measured and the clinical outcomes of IVM IVF-embryo transfer using IVM medium alone or supplemented with melatonin were analyzed. In the culture media of GC or COC, the melatonin concentration gradually increased. With human chorionic gonadotrophin priming, the pregnancy and implantation rates in the melatonin-supplemented group were higher than those of the non-supplemented control (P<0.05). Our findings suggest that follicular melatonin is released from luteinizing GC during late folliculogenesis and plays a positive role in oocyte maturation. Therefore, addition of melatonin into IVM medium may improve cytoplasmic maturation of human immature oocytes and subsequent clinical outcomes.

https://www.ncbi.nlm.nih.gov/pubmed/23177415

 

Effect of Melatonin on the Outcome of Assisted Reproductive Technique Cycles in Women with Diminished Ovarian Reserve: A Double-Blinded Randomized Clinical Trial.

Iran J Med Sci.2017 Jan;42(1):73-78.

Jahromi BN1, Sadeghi S2, Alipour S3, Parsanezhad ME4, Alamdarloo SM2.

Abstract:

Diminished ovarian reserve (DOR) significantly decreases the success rate of the assisted reproductive technique (ART). In this study, we assessed the effect of melatonin on the ART outcomes in women with DOR. A double-blinded, randomized, clinical trial was performed on 80 women with DOR as a pilot study in Shiraz, between 2014 and 2015. DOR was defined as the presence of 2 of the following 3 criteria: 1) anti-Müllerian hormone ≤1, 2) follicle-stimulating hormone ≥10, and 3) bilateral antral follicle count ≤6. The women received 3 mg/d melatonin or a placebo since the fifth day of one cycle prior to gonadotropin stimulation and continued the treatment up to the time of ovum pickup. The ART outcomes were compared between the groups using SPSS software. Finally, there were 32 women in the case and 34 in the placebo groups. The mean age and basal ovarian reserve test were the same between the groups. The serum estradiol level on the triggering day was significantly higher in the case group (P=0.005). The mean number of MII oocytes was higher in the case group, but the difference did not reach statistical significance. Number of the patients who had mature MII oocytes (P=0.014), top-quality embryos with grade 1 (P=0.049), and embryos with grades 1 and 2 (P=0.014) was higher among the women who received melatonin. However, the other ART outcomes were not different between the groups. The serum estradiol level was higher and more women with DOR had good-quality oocytes and embryos after receiving melatonin; however, no other outcome was different between the case and control groups. Trial Registration Number: IRCT2014041417264N1

https://www.researchgate.net/publication/312594842_Effect_of_Melatonin_on_the_Outcome_of_Assisted_Reproductive_Technique_Cycles_in_Women_with_Diminished_Ovarian_Reserve_A_Double-Blinded_Randomized_Clinical_Trial

Melatonin levels in follicular fluid as markers for IVF outcomes and predicting ovarian reserve.

Reproduction.2017 Apr;153(4):443-451

Tong J1,2, Sheng S3, Sun Y1,2, Li H1,2,4, Li WP5,2, Zhang C5,2,6, Chen ZJ5,2,7,8,9,10.

Abstract:

Good-quality oocytes are critical for the success of in vitro fertilization (IVF), but, to date, there is no marker of ovarian reserve available that can accurately predict oocyte quality. Melatonin exerts its antioxidant actions as a strong radical scavenger that might affect oocyte quality directly as it is the most potent antioxidant in follicular fluid. To investigate the precise role of endogenous melatonin in IVF outcomes, we recruited 61 women undergoing treatment cycles of IVF or intracytoplasmic sperm injection (ICSI) procedures and classified them into three groups according to their response to ovarian stimulation. Follicular fluid was collected to assess melatonin levels using a direct RIA method. We found good correlations between melatonin levels in follicular fluid with age, anti-Müllerian hormone (AMH) and baseline follicle-stimulating hormone (bFSH), all of which have been used to predict ovarian reserve. Furthermore, as melatonin levels correlated to IVF outcomes, higher numbers of oocytes were collected from patients with higher melatonin levels and consequently the number of oocytes fertilized, zygotes cleaved, top quality embryos on D3, blastocysts obtained and embryos suitable for transplantation was higher. The blastocyst rate increased in concert with the melatonin levels across the gradient between the poor response group and the high response group. These results demonstrated that the melatonin levels in follicular fluid is associated with both the quantity and quality of oocytes and can predict IVF outcomes as well making them highly relevant biochemical markers of ovarian reserve.

Melatonin and the circadian system:

Contributions to successful female reproduction Russel J. Reiter, Ph.D., Hiroshi Tamura, M.D., Ph.D., Dun Xian Tan, M.D., Ph.D., and Xiao-Ying Xu, Ph.D. Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas

Objective:

To summarize the role of melatonin and circadian rhythms in determining optimal female reproductive physiology, especially at the peripheral level.

Design:

Databases were searched for the related English-language literature published up to March 1, 2014. Only papers in peerreviewed journals are cited. Setting: Not applicable.

Patient(s):

Not applicable. Intervention(s): Melatonin treatment, alterations of the normal light:dark cycle and light exposure at night.

Main Outcome Measure(s):

Melatonin levels in the blood and in the ovarian follicular fluid and melatonin synthesis, oxidative damage and circadian rhythm disturbances in peripheral reproductive organs.

Result(s):

The central circadian regulatory system is located in the suprachiasmatic nucleus (SCN). The output of this master clock is synchronized to 24 hours by the prevailing light-dark cycle. The SCN regulates rhythms in peripheral cells via the autonomic nervous system and it sends a neural message to the pineal gland where it controls the cyclic production of melatonin; after its release, the melatonin rhythm strengthens peripheral oscillators. Melatonin is also produced in the peripheral reproductive organs, including granulosa cells, the cumulus oophorus, and the oocyte. These cells, along with the blood, may contribute melatonin to the follicular fluid, which has melatonin levels higher than those in the blood. Melatonin is a powerful free radical scavenger and protects the oocyte from oxidative stress, especially at the time of ovulation. The cyclic levels of melatonin in the blood pass through the placenta and aid in the organization of the fetal SCN. In the absence of this synchronizing effect, the offspring may exhibit neurobehavioral deficits. Also, melatonin protects the developing fetus from oxidative stress. Melatonin produced in the placenta likewise may preserve the optimal function of this organ.

Conclusion(s):

Both stable circadian rhythms and cyclic melatonin availability are critical for optimal ovarian physiology and placental function. Because light exposure after darkness onset at night disrupts the master circadian clock and suppresses elevated nocturnal melatonin levels, light at night should be avoided. (Fertil Steril 2014;102:321–8. 2014 by American Society for Reproductive Medicine.)

Key Words:

Circadian rhythms, melatonin, oocyte, placenta, fetus

https://www.fertstert.org/article/S0015-0282(14)00547-0/pdf

 

Review Melatonin Scavenger Properties against Oxidative and Nitrosative Stress: Impact on Gamete Handling and In Vitro Embryo Production in Humans and Other Mammals

Pía Loren 1 , Raúl Sánchez 1,2, María-Elena Arias 1,2,3, Ricardo Felmer 1,4, Jennie Risopatrón 1,5 and Carolina Cheuquemán 1,*

Abstract:

Oxidative and nitrosative stress are common problems when handling gametes in vitro. In vitro development in mammalian embryos is highly affected by culture conditions, especially by reactive oxygen species (ROS) and reactive nitrogen species (RNS), because their absence or overproduction causes embryo arrest and changes in gene expression. Melatonin in gamete co-incubation during in vitro fertilization (IVF) has deleterious or positive effects, depending on the concentration used in the culture medium, demonstrating the delicate balance between antioxidant and pro-oxidant activity. Further research is needed to better understand the possible impact of melatonin on the different IVP steps in humans and other mammals, especially in seasonal breeds where this neuro-hormone system highly regulates its reproduction physiology.

https://pdfs.semanticscholar.org/a11e/dc2a37d83b5073a0b7a79d4981ec447382d2.pdf

 

Effects of night shift on plasma concentrations of melatonin, LH, FSH and prolactin, and menstrual irregularity.

Sangyo Igaku.1992 Nov;34(6):545-50.

Miyauchi F¹, Nanjo K, Otsuka K.

Abstract:

To examine the effect of night shift on the ovarian function, 122 teachers, 67 office workers, 377 nurses, 133 factory workers and 67 barmaids were surveyed. The incidence of irregular menstrual cycle was 13.1% in teachers, 14.9% in office workers, 24.9% in nurses, 36.8% in factory workers and 40.3% in barmaids. The incidence was significantly higher in women working at night than women working during the day. Plasma concentrations of melatonin, LH, FSH and prolactin were determined at 2200 h and 0200 h in 5 nurses working at night and in 6 nurses resting in their quarters. Plasma concentrations of melatonin and prolactin at 0200 h were significantly lower in nurses of the working group than others of the resting group, but plasma concentrations of LH and FSH did not differ between the two groups. These results indicate that night shift suppresses the ovarian function by affecting the circadian rhythm of melatonin and prolactin.

https://www.ncbi.nlm.nih.gov/pubmed/1460786

 

Oxidative stress impairs oocyte quality and melatonin protects oocytes from free radical damage and improves fertilization rate.

J Pineal Res.2008 Apr;44(3):280-7. doi: 10.1111/j.1600-079X.2007.00524.x.

Tamura H¹, Takasaki A, Miwa I, Taniguchi K, Maekawa R, Asada H, Taketani T, Matsuoka A, Yamagata Y, Shimamura K, Morioka H, Ishikawa H, Reiter RJ, Sugino N.

Abstract:

We investigated the relationship between oxidative stress and poor oocyte quality and whether the antioxidant melatonin improves oocyte quality. Follicular fluid was sampled at oocyte retrieval during in vitro fertilization and embryo transfer (IVF-ET). Intrafollicular concentrations of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in women with high rates of degenerate oocytes were significantly higher than those with low rates of degenerate oocytes. As there was a negative correlation between intrafollicular concentrations of 8-OHdG and melatonin, 18 patients undergoing IVF-ET were given melatonin (3 mg/day), vitamin E (600 mg/day) or both melatonin and vitamin E. Intrafollicular concentrations of 8-OHdG and hexanoyl-lysine adduct were significantly reduced by these antioxidant treatments. One hundred and fifteen patients who failed to become pregnant with a low fertilization rate (< or =50%) in the previous IVF-ET cycle were divided into two groups during the next IVF-ET procedure; 56 patients with melatonin treatment (3 mg/day) and 59 patients without melatonin treatment. The fertilization rate was improved by melatonin treatment compared to the previous IVF-ET cycle. However, the fertilization rate was not significantly changed without melatonin treatment. Oocytes recovered from preovulatory follicles in mice were incubated with H2O2 for 12 hr. The percentage of mature oocytes with a first polar body was significantly reduced by addition of H2O2 (300 microm). The inhibitory effect of H2O2 was significantly blocked by simultaneous addition of melatonin. In conclusion, oxidative stress causes toxic effects on oocyte maturation and melatonin protects oocytes from oxidative stress. Melatonin is likely to improve oocyte quality and fertilization rates.

https://www.ncbi.nlm.nih.gov/pubmed/18339123

 

Melatonin and the circadian system: contributions to successful female reproduction.

Fertil Steril.2014 Aug;102(2):321-8. doi: 10.1016/j.fertnstert.2014.06.014. Epub 2014 Jul 1.

Reiter RJ¹, Tamura H², Tan DX², Xu XY².

Abstract:

Objective:

To summarize the role of melatonin and circadian rhythms in determining optimal female reproductive physiology, especially at the peripheral level.

Design:

Databases were searched for the related english-language literature published up to march 1, 2014. Only papers in peer-reviewed journals are cited.

Setting:

Not applicable.

Patient(s):

Not applicable.

Intervention(s):

Melatonin treatment, alterations of the normal light/dark cycle and light exposure at night.

Main Outcome Measure(s):

Melatonin levels in the blood and in the ovarian follicular fluid and melatonin synthesis, oxidative damage and circadian rhythm disturbances in peripheral reproductive organs.

Result(s):

The central circadian regulatory system is located in the suprachiasmatic nucleus (scn). The output of this master clock is synchronized to 24 hours by the prevailing light-dark cycle. The scn regulates rhythms in peripheral cells via the autonomic nervous system and it sends a neural message to the pineal gland where it controls the cyclic production of melatonin; after its release, the melatonin rhythm strengthens peripheral oscillators. Melatonin is also produced in the peripheral reproductive organs, including granulosa cells, the cumulus oophorus, and the oocyte. These cells, along with the blood, may contribute melatonin to the follicular fluid, which has melatonin levels higher than those in the blood. Melatonin is a powerful free radical scavenger and protects the oocyte from oxidative stress, especially at the time of ovulation. The cyclic levels of melatonin in the blood pass through the placenta and aid in the organization of the fetal scn. In the absence of this synchronizing effect, the offspring may exhibit neurobehavioral deficits. Also, melatonin protects the developing fetus from oxidative stress. Melatonin produced in the placenta likewise may preserve the optimal function of this organ.

Conclusion(s):

Both stable circadian rhythms and cyclic melatonin availability are critical for optimal ovarian physiology and placental function. Because light exposure after darkness onset at night disrupts the master circadian clock and suppresses elevated nocturnal melatonin levels, light at night should be avoided.

https://www.fertstert.org/article/S0015-0282(14)00547-0/pdf

 

The role of melatonin as an antioxidant in the follicle.

J OvarianRes.2012 Jan 26;5:5. doi: 10.1186/1757-2215-5-5.

Tamura H¹, Takasaki A, Taketani T, Tanabe M, Kizuka F, Lee L, Tamura I, Maekawa R, Aasada H, Yamagata Y, Sugino N.

Abstract:

Melatonin (N-acetyl-5-methoxytryptamine) is secreted during the dark hours at night by pineal gland, and it regulates a variety of important central and peripheral actions related to circadian rhythms and reproduction. It has been believed that melatoninregulates ovarianfunction by the regulation of gonadotropin release in the hypothalamus-pituitary gland axis via its specific receptors. In addition to the receptor mediated action, the discovery of melatoninas a direct free radical scavenger has greatly broadened the understanding of melatonin's mechanisms which benefit reproductive physiology. Higher concentrations of melatoninhave been found in human pre-ovulatory follicular fluid compared to serum, and there is growing evidence of the direct effects of melatoninon ovarianfunction especially oocyte maturation and embryo development. Many scientists have focused on the direct role of melatonin on oocyte maturation and embryo development as an anti-oxidant to reduce oxidative stress induced by reactive oxygen species, which are produced during ovulation process. The beneficial effects of melatonin administration on oocyte maturation and embryo development have been confirmed by in vitro and in vivo experiments in animals. This review also discusses the first application of melaton into the clinical treatment of infertile women and confirms that melatonin administration reduces intra follicular oxidative damage and increase fertilization rates. This review summarizes our recent works and new findings related to the reported beneficial effects of melatoninon reproductive physiology in its roleas a reducer of oxidative stress, especially on oocyte maturation and embryo development.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3296634/

 

The efficacy of melatonin administration on oocyte quality.

Gynecol Endocrinol.2012 Feb;28(2):91-3. doi: 10.3109/09513590.2011.589925. Epub 2011 Jul 20.

Batıoğlu AS¹, Sahin U, Gürlek B, Oztürk N, Unsal E.

Abstract:

The aim of the study was to evaluate the efficacy of melatonin administration on oocyte quality in women underwent in vitro fertilization (IVF) cycles. Eighty-five women undergoing IVF cycles were randomized in two groups during IVF-embryo transfer (ET) procedure, 40 women with melatonin treatment (A) and 45 women without melatonin treatment (B). Primary endpoint was the number of morphologically mature oocytes retrieved (MII oocytes). Secondary endpoints were fertilization rate per number of mature oocytes, embryo quality and pregnancy rate. There were no differences between two groups according to age, and peak estradiol levels. The mean number of oocytes (15.33 vs. 14.27) and the mean number of mature oocytes did not differ between the two groups (12.63 vs. 10.94), whereas the percentage of mature oocytes (M2/oocytes retrieved) was significantly different in melatonin-treated group (p < 0.05). Fertilization rate (72.75 vs. 71.16) did not differ between the two groups. The mean number of class 1 embryos resulted higher in the group A (3.28 vs. 2.53) (p < 0.05). Clinical pregnancy rate was in tendency higher in the group treated with melatonin, although the differences did not reach statistical significance. Melatonin is likely to improve oocyte and embryo quality in women undergoing IVF or intracytoplasmic sperm insemination (ICSI).

https://www.researchgate.net/profile/Evrim_Unsal/publication/51503755_The_efficacy_of_melatonin_administration_on_oocyte_quality/links/553b24450cf245bdd7645f89.pdf?inViewer=true&disableCoverPage=true&origin=publication_detail

 

Oral melatonin supplementation improves oocyte and embryo quality in women undergoing in vitro fertilization-embryo transfer.

Gynecol Endocrinol.2014 May;30(5):359-62. doi: 10.3109/09513590.2013.879856. Epub 2014 Mar

Nishihara T¹, Hashimoto S, Ito K, Nakaoka Y, Matsumoto K, Hosoi Y, Morimoto Y.

Abstract:

The aim of this study was to evaluate the efficacy of oral melatonin supplementation on oocyte and embryo quality in patients in an assisted reproductive technologies program. All patients were treated for at least 2 weeks with melatonin (3 mg/day). To evaluate the cumulative effect of melatonin supplementation, we compared cycle outcomes between the first (no supplementation) and second cycles (melatonin supplementation) of patients who completed two treatment cycles. There were no significant differences in maturation rates (p = 0.50), blastocyst rates (p = 0.75), and the rate of good quality blastocysts (p = 0.59) between the first and second cycles. The fertilization rate of ICSI was higher in the second cycle than that in the first cycle (69.3 versus 77.5%). Being limited to patients with a low fertilization rate in the first cycle (<60%), the fertilization rate dramatically increased after melatonin treatment (35.1 versus 68.2%). The rate of good quality embryos also increased (48.0 versus 65.6%). An important finding in our study was that oral melatonin supplementation can have a beneficial effect on the improvement of fertilization and embryo quality and this may have occurred due to a reduction in oxidative damage.

https://www.researchgate.net/publication/260836615_Oral_melatonin_supplementation_improves_oocyte_and_embryo_quality_in_women_undergoing_in-vitro_fertilisation-embryo_transfer

 

Effect of the treatment with myo-inositol plus folic acid plus melatonin in comparison with a treatment with myo-inositol plus folic acid on oocyte quality and pregnancy outcome in IVF cycles. A perspective, clinical trial.

Eur Rev Med Pharmacol Sci.2010 Jun;14(6):555-61.

Rizzo P¹, Raffone E, Benedetto V.

Abstract:

Objective: The aim of the study was to evaluate the efficacy of a treatment with myo-inositol plus folic acid plus melatonin compared with myo-inositol plus folic acid alone on oocyte quality in women underwent in vitro fertilization (IVF) cycles.

Design: A prospective, clinical trial.

Materials and Methods: Starting on the day of GnRH administration, 65 women undergoing IVF cycles were randomized in two groups to receive myo-inositol plus folic acid plus melatonin (32 women, group A), and myo-inositol plus folic acid (33 women, group B), administered continuously. Primary endpoints were number of morphologically mature oocytes retrieved (MII oocytes), embryo quality, and pregnancy rate. Secondary endpoints were the total number of oocytes retrieved (immature and mature oocytes), fertilization rate per number of retrieved oocytes and embryo cleavage rate.

Results: The mean number of oocytes retrieved did not differ between the two groups (7.88 +/- 1.76 vs 7.67 +/- 1.88; P=0.65). Whereas the group cotreated with melatonin reported a significantly greater mean number of mature oocytes (6.56 +/- 1.64 vs 5.76 +/- 1.56; P=0.047) and a lower mean number of immature oocytes (1.31 +/- 0.74 vs. 1.91 +/- 0.68; P=0.001). The mean number of embyos of top-quality (class 1 and 2) resulted higher in the group A (1.69 +/- 0.64 vs 1.24 +/- 0.75; P=0.01). Fertilization rate did not differ between the two groups. A total of 22 pregnancies were obtained (13 in group A and 9 in group B; P=0.26). Clinical pregnancy rate and implantation rate were in tendency higher in the group cotreated with melatonin, although the differences did not reach statistical significance. Biochemical pregnancy rate and abortion rate were similar in both groups.

Conclusion: melatonin ameliorates the activity of myo-inositol and folic acid by improving oocyte quality and pregnancy outcome in women with low oocyte quality history.

https://www.researchgate.net/publication/45658578_Effect_of_the_treatment_with_myo-inositol_plus_folic_acid_plus_melatonin_in_comparison_with_a_treatment_with_myo-inositol_plus_folic_acid_on_oocyte_quality_and_pregnancy_outcome_in_IVF_cycles_A_prospe

 

Effect of myo-inositol and melatoninversus myo-inositol, in a randomized controlled trial, for improving in vitro fertilization of patients with polycystic ovarian syndrome.

Gynecol Endocrinol.2016;32(1):69-73. doi: 10.3109/09513590.2015.1101444. Epub 2015 Oct 28.

PacchiarottiA¹, Carlomagno G², Antonini G^1,3, PacchiarottiA^1,3.

Abstract:

Polycystic ovarian syndrome (PCOS) induces anovulation in women of reproductive age and is one of the pathological factors involved in the failure of in vitro fertilization (IVF). Indeed, PCOS women are characterized by poor quality oocytes. Therefore, a treatment for enhancing oocyte quality becomes crucial for these patients. Myo-Inositol and melatoninproved to be efficient predictors for positive IVF outcomes, correlating with high oocyte quality. We tested the synergistic effect of myo-inositol and melatoninin IVF protocols with PCOS patients in a randomized, controlled, double-blind trial. Five-hundred twenty-six PCOS women were divided into three groups: Controls (only folic acid: 400 mcg), Group A (Inofolic® plus, a daily dose of myo-inositol: 4000 mg, folic acid: 400 mcg, and melatonin: 3 mg), and Group B (Inofolic®, a daily dose of myo-inositol: 4000 mg, and folic acid: 400 mcg). The main outcome measures were oocyte and embryo quality, clinical pregnancy and implantation rates. The treatment lasted from the first day of the cycle until 14 days after embryo transfer. Myo-inositol and melatoninhave shown to enhance, synergistically, oocyte and embryo quality. In consideration of the beneficial effect observed in our trial and on the bases of previous studies, we decided to integrate routinely MI and M supplementation in the IVF protocols. The same treatment should be taken carefully in consideration in all procedures of this kind.

https://www.tandfonline.com/doi/abs/10.3109/09513590.2015.1101444?src=recsys&journalCode=igye20

Melatonin Benefits for Men's Fertility

Effect of follicular fluid oxidative stress parameters on intracytoplasmic sperm injection outcome.

Gynecol Endocrinol.2012 Jan;28(1):51-5. doi: 10.3109/09513590.2011.579652. Epub 2011 Jun 30.

Bedaiwy MA¹, Elnashar SA, Goldberg JM, Sharma R, Mascha EJ, Arrigain S, Agarwal A, Falcone T.

Abstract:

Objective: The purpose of this study was to evaluate the association between the follicular fluid (FF) reactive oxygen species (ROS) levels, total antioxidant capacity (TAC) and ROS-TAC score and pregnancy after intracytoplasmic sperm injection (ICSI).

Methods: A total of 138 consecutive women who had ICSI were included in this study. FF ROS and TAC were measured by enhanced chemiluminescence and colorimetric assay, respectively, and then the ROS-TAC score was calculated.

Results: Out of the 138 included patients, 42 (30%) achieved pregnancy after ICSI. Log ROS, TAC, and the ROS-TAC score were not significantly different across diagnoses. Pregnant cycles were associated with significantly lower ROS (P < 0.001), higher TAC (P < 0.001) and higher ROS-TAC scores (P < 0.001). After adjusting for age, there was a significant positive correlation between log ROS and the number of follicles on the day of HCG administration (correlation 0.20, 95% CI: 0.02, 0.39) as well as the number of oocytes retrieved (correlation 0.18, 0.001, 0.36) but not with TAC. Interestingly, in women with endometriosis, higher TAC levels and higher ROS-TAC scores were associated with a higher likelihood of finding normal oocytes (P = 0.005 and P = 0.002, respectively).

Conclusion: Higher FF TAC, higher FF ROS-TAC scores and lower FF ROS levels are associated with pregnancy after ICSI. Oxidative stress parameters may be markers of metabolic activity within the follicle.

https://www.researchgate.net/publication/51453296_Effect_of_follicular_fluid_oxidative_stress_parameters_on_intracytoplasmic_sperm_injection_outcome

 

Antioxidative potential of melatonin against mercury induced intoxication in spermatozoa in vitro.

Toxicol In Vitro.2008 Jun;22(4):935-42. doi: 10.1016/j.tiv.2008.01.014. Epub 2008 Feb

Rao MV¹, Gangadharan B.

Abstract:

Mercuryis one of the most investigated natural elements and potentialcontaminants in the environment. Antioxidants have long been known to reduce the free radical-inducedoxidative damage. Considering the antioxidant properties of melatonin, this study was aimed to evaluate the effect of melatoninon antioxidant system of rat epididymal sperm in vitro. Sperm samples were dispersed in RPS medium (pH 6.9) and incubated with mercuryin the form of mercuric chloride (MC) at three different concentrations (1 microM, 10 microM, 100 microM), melatonin(MLT) at a concentration (100 microM) and mercuric chloride+melatonin(100 microM each) for 3h at 32 degrees C. Sperm viability and motility were assessed every 30 min during the 3-h incubation period. An aliquot of sperm sample was homogenised, centrifuged and used for the assay of superoxide dismutase, glutathione peroxidase, glutathione reductase, TBARS assay to detect lipid peroxidation and hydrogen peroxide generation assay. Samples treated with mercuryshowed a dose-dependent decrease in motility while there was no significant decrease in sperm viability. In mercury-incubated sperm, the activity of superoxide dismutase, glutathione peroxidase and glutathione reductase decreased significantly while TBARS levels and H2O2 generation were increased in a dose-dependent manner. Co-incubation of sperm with mercuryand melatoninexhibited no significant changes in the levels of motility, viability and antioxidant indices as compared to untreated controls. The results suggest that graded doses of mercuryelicit depletion of antioxidant defense system in sperm without altering the viability and melatonintreatment was found to significantly inhibit oxidative damage caused by mercury.

https://www.sciencedirect.com/science/article/pii/S0887233308000325

 

Melatonin as a potential tool against oxidative damage and apoptosis in ejaculated human spermatozoa.

Fertil Steril.2010 Oct;94(5):1915-7. doi: 10.1016/j.fertnstert.2009.12.082. Epub 2010 Feb 12.

Espino J¹, Bejarano I, Ortiz A, Lozano GM, García JF, Pariente JA, Rodríguez AB.

Abstract:

It is assumed somatic cells can die in the apoptotic, the autophagic, or the necrotic way; however, the mechanisms of sperm death are not clear. Here, ejaculated human spermatozoawere evaluated for apoptosis and reactive oxygen species production in the absence or presence of melatonin, and we concluded that melatoninreverses sperm apoptosis due to its free radical scavenging actions.

https://www.sciencedirect.com/science/article/pii/S0015028209043416

 

High endogenous melatonin concentrations enhance sperm quality and short-term in vitro exposure to melatonin improves aspects of sperm motility.

J Pineal Res.2011 Mar;50(2):132-9. doi: 10.1111/j.1600-079X.2010.00822.x. Epub 2010 Oct 21.

Ortiz A¹, Espino J, Bejarano I, Lozano GM, Monllor F, García JF, Pariente JA, Rodríguez AB.

Abstract:

Although human seminal fluid contains melatoninand spermatozoareportedly possess membrane melatoninreceptors, there are no experimental studies that have ascertained the relationship between melatoninand male infertility. This study evaluated whether urinary 6-sulfatoxymelatonin and urinary total antioxidant capacity correlate with different seminal parameters including sperm concentration, motility and morphology. Also, the invitroeffects of melatoninon human sperm motility were investigated. Semen samples from 52 men who were counselled for infertility were obtained. Sperm concentration was determined using the haemocytometer method, motility kinematic parameters were assessed using a computer-aided semen analysis system, while morphology and vitality were evaluated after Diff-Quick and Eosin-Nigrosin vital staining, respectively. For the quantification of urinary 6-sulfatoxymelatonin, a commercial ELISA kit was used, and urinary total antioxidant capacity was evaluated by means of a colorimetric assay kit. For the in vitroeffects of melatonin, samples were incubated for 30min in the presence or absence of 1mm melatonin. Both urinary 6-sulfatoxymelatonin and total antioxidant capacity levels positively correlated with sperm concentration, motility and morphology, as well as negatively correlated with the number of round cells. Additionally, 30-min exposure of sperm to 1mm melatoninimproved the percentage of motile and progressively motile cells and decreased the number of static cells, thereby promoting the proportion of rapid cells. Therefore, melatoninimproves semen quality, which is important because melatoninsupplementation may be potentially used to obtain a successful assisted reproductive technique outcome.

https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-079X.2010.00822.x?globalMessage=0

 

The in vitro effects of melatonin on human sperm function and its scavenging activities on NO and ROS.

Andrologia.2010 Apr;42(2):112-6. doi: 10.1111/j.1439-0272.2009.00964.x.

du Plessis SS¹, Hagenaar K, Lampiao F.

Abstract:

Various systems of antioxidants exist endogenously in the body to help protect it againstfree radical damage by scavenging excessive ROS and RNS. Melatonin, a hormone secreted by the pineal gland, and responsible for controlling the circadian rhythm, is one such endogenous antioxidant. Melatoninhas been reported to be present in human seminal fluid, but its antioxidant activities in semen are rather contradictory. This study aimed at establishing the effects of melatonintreatment on human spermatozoa. Spermatozoawere incubated with 2 mm melatonin(120 min, 37 degrees C, 5% CO(2)) after which motility parameters were measured by computer aided motility analysis, while cell viability (PI), intracellular NO (DAF-2/DA) and ROS (DCFH-DA) were assessed using flow cytometry. In vitromelatonintreated samples (n = 12) showed a significantly higher percentage of motile, progressive motile and rapid cells, while simultaneously reducing the number of nonviable spermatozoawhen compared with the control. Endogenous NO was significantly decreased, but no effect was observed on ROS levels. From these results, it can be concluded that melatoninwas able to directly or indirectly scavenge NO, as indicated by the reduction in 4,5-diaminofluorescein-2/diacetate fluorescence. Future studies will indicate whether melatonintreatment during sperm preparation techniques could protect spermatozoafrom excessive NO production.

https://www.researchgate.net/publication/43130031_The_in_vitro_effects_of_melatonin_on_human_sperm_function_and_its_scavenging_activities_on_NO_and_ROS

 

Serum Levels of Melatonin and Oxidative Stress Markers and Correlation between Them in Infertile Men.

J Caring Sci.2013 Nov 30;2(4):287-94. doi: 10.5681/jcs.2013.034. eCollection 2013 Dec.

Soleimani Rad S¹, Abbasalizadeh S², Ghorbani Haghjo A³, Sadagheyani M², Montaseri A⁴, Soleimani Rad J⁴.

Abstract:

Introduction: Infertility is the problem of 15% of young couples in different societies. One of the factors that could affect fertility is oxidative stress. Therefore, the aim of the present study is to investigate the level of Melatonin, a free radical scavenger, and its correlation with oxidative biomarkers in infertile men.

Methods: For this purpose, fertile and infertile men in 2 groups, 30 people in each group, were studied. The fertile men were selected from husbands of patients admitted to Alzahra obstetric and gynecology hospital, according to WHO standards. The infertile men were selected from patients referred to infertility ward. Blood sampling from the participants carried out at a specific time, sera collected and the levels of malondialdehyde, total antioxidant capacity and Melatonin were detected in the sera. The data were analyzed using t-test and Sperman's correlation method.

Results: Melatonin level in the sera from fertile men were 522 (39.32) ng/L and in infertile men were 511.78 (34.6) ng/L. MDA level in fertile and infertile men were 2.26 (0.34) vs 2.99 (0.44) nmol/ml which was significantly different. The level of TAC in the sera from fertile men were significantly higher than in infertile men. The result obtained for correlation coefficient Spearman's test revealed a significant, strong and direct correlation between Melatonin and TAC and a significant and reverse correlation between melatonin and MDA.

Conclusion: It is concluded that melatonin could be involved in infertility. In other word, melatonin treatment and antioxidant-rich nutrition could help fertility by combating oxidative stress.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134149/

 

Melatonin alters the glycolytic profile of Sertoli cells: implications for male fertility.

Mol Hum Reprod.2014 Nov;20(11):1067-76. doi: 10.1093/molehr/gau080. Epub 2014 Sep 9.

Rocha CS1,Martins AD1,Rato L1,Silva BM1,Oliveira PF2,Alves MG2.

Abstract:

Melatonin co-operates with insulin in the regulation of glucose homeostasis. Within the testis, glucose metabolism in the somatic Sertoli cells (SCs) is pivotal for spermatogenesis. Since the effects of melatonin on male reproductive physiology remain largely unknown, we hypothesized that melatonin may affect spermatogenesis by modulating SC metabolism, interacting with insulin. To test our hypothesis, rat SCs were maintained in culture for 24 h in the presence of insulin, melatonin or both and metabolite production/consumption was determined by proton nuclear magnetic resonance ((1)H-NMR). Protein levels of glucose transporters (GLUT1 and GLUT3), phosphofructokinase 1, lactate dehydrogenase (LDH) and monocarboxylate transporter 4 were determined by western blot. LDH activity was also assessed. SCs treated with melatonin showed an increase in glucose consumption via modulation of GLUT1 levels, but decreased LDH protein expression and activity, which resulted in lower lactate production. Moreover, SCs exposed to melatonin produced and accumulated less acetate than insulin-exposed cells. The combined treatment (insulin plus melatonin) increased acetate production by SCs, but intracellular acetate content remained lower than in insulin exposed cells. Finally, the intracellular redox state, as reflected by intracellular lactate/alanine ratio, was maintained at control levels in SCs by melatonin exposure (i.e. melatonin, alone or with insulin, increased the lactate/alanine ratio versus cells treated with insulin). Furthermore, SCs exposed to insulin plus melatonin produced more lactate and maintained the protein levels of some glycolysis-related enzymes and transporters at control levels. These findings illustrate that melatonin regulates SCs metabolism, and thus may affect spermatogenesis. Since lactate produced by SCs provides nutritional support and has an anti-apoptotic effect in developing germ cells, melatonin supplementation may be an effective therapy for diabetic male individuals facing subfertility/infertility.

https://www.researchgate.net/publication/265515825_Melatonin_alters_the_glycolytic_profile_of_Sertoli_cells_Implications_for_male_fertility

 

Decreased melatonin levels and increased levels of advanced oxidation protein products in the seminal plasma are related to male infertility.

Reprod Fertil Dev.2016 Mar;28(4):507-15. doi: 10.1071/RD14165.

Kratz EM¹, Piwowar A², Zeman M³, Stebelová K³, Thalhammer T⁴.

Abstract:

Melatonin, an indolamine secreted by the pineal gland, is known as a powerful free-radical scavenger and wide-spectrum antioxidant. Therefore, the aim of this study was to correlate markers of oxidative protein damage (advanced oxidation protein products, AOPPs) and the total antioxidant capacity (TAC) with melatoninlevels in the seminal plasma of men with azoospermia (n=37), theratozoospermia (n=29) and fertile controls (normozoospermia, n=37). Melatoninconcentration was measured by radioimmunoassay. The levels of AOPP as well as TAC efficiency (determined by the ferric reducing antioxidant power, FRAP) were estimated by spectrophotometric methods. The concentration of melatoninand AOPP significantly differed in azoospermic (P<0.0001) and theratozoospermic (P<0.0001) patients versus fertile men, and correlated negatively (r=-0.33, P=0.0016). The TAC levels were significantly higher in azoospermia than in theratozoospermia (P=0.0022) and the control group (P=0.00016). In azoospermia, the AOPP concentration was also significantly higher than that observed in theratozoospermia (P=0.00029). Decreased levels ofmelatonintogether with elevated AOPP altered the oxidative-antioxidative balance in the ejaculate, thereby reducing fertility. Therefore, melatoninand AOPP levels may serve as additional diagnostic markers of semen quality andmalereproductive potential.

https://www.researchgate.net/publication/265610827_Decreased_melatonin_levels_and_increased_levels_of_advanced_oxidation_protein_products_in_the_seminal_plasma_are_related_to_male_infertility

 

Seasons in the sun: the impact on IVF results one month later

Frank Vandekerckhove (UGent) , Hannelore Van der Veken, Kelly Tilleman (UGent) , Ilse De Croo (UGent) , Etienne Van den Abbeel (UGent) , Jan Gerris (UGent) and Petra De Sutter (UGent)

(2016) FACTS VIEWS AND VISION IN OBGYN. 8(2). p.75-83

Abstract:

Background: Several retrospective studies have evaluated seasonal variations in the outcome of IVF treatment. Some also included weather conditions, mostly temperature and hours of daylight. The results were conflicting.

Methods: In a retrospective study we analyzed all fresh cycles (N = 9865) that were started between January 1, 2007 and December 31, 2012. Because some patients were included more than once, correction for duplicate patients was performed. We focused on individual variables provided as monthly results by our national meteorological institute. We evaluated if weather conditions determined by temperature, rain and sunshine at the start of ovarian stimulation had an effect on the outcome of IVF in terms of number of mature and fertilized oocytes, pregnancy and live birth rates. We shifted the results in IVF outcome to the weather results of one month earlier, as we supposed that the selection of good quality oocytes might start in the weeks before ovarian stimulation is initiated.

Results: There was a clear trend towards better results when the “early” weather conditions (one month before the treatment cycle) were good. There was a statistically significant correlation between the number of rainy days (Pearson Correlation -0.326; p < 0.01) and the rain flow (Pearson Correlation -0.262; p < 0.05) on the one hand and the live birth rate per cycle on the other. The live birth rate per cycle was statistically different between cohorts of patients that were stratified into quartiles of sunshine hours (p < 0.01) and of number of rainy days (p < 0.05) during the month before the start of ovarian stimulation.

Conclusions: Weather conditions during the month before IVF treatment have an impact on live birth rate.

https://biblio.ugent.be/publication/8126430

Melatonin for women in pregnancy for neuroprotection of the fetus.

Cochrane Database Syst Rev.2016 Mar 29;3:CD010527. doi: 10.1002/14651858.CD010527.pub2.

Wilkinson D1,Shepherd E, Wallace EM.

Abstract:

Background: Melatonin is an antioxidant with anti-inflammatory and anti-apoptotic effects. Animal studies have supported a fetal neuroprotective role for melatonin when administered maternally. It is important to assess whether melatonin, given to the mother, can reduce the risk of neurosensory disabilities (including cerebral palsy) and death, associated with fetal brain injury, for the preterm or term compromised fetus.

Objectives: To assess the effects of melatonin when used for neuroprotection of the fetus.

Search Methods: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2016).

Selection Criteria: We planned to include randomized controlled trials and quasi-randomized controlled trials comparing melatonin given to women in pregnancy (regardless of the route, timing, dose and duration of administration) for fetal neuroprotection with placebo, no treatment, or with an alternative agent aimed at providing fetal neuroprotection. We also planned to include comparisons of different regimens for administration of melatonin.

Data Collection and Analysis: Two review authors planned to independently assess trial eligibility, trial quality and extract the data.

Author's Conclusions: As we did not identify any randomized trials for inclusion in this review, we are unable to comment on implications for practice at this stage. Although evidence from animals studies has supported a fetal neuroprotective role for melatonin when administered to the mother during pregnancy, no trials assessing melatonin for fetal neuroprotection in pregnant women have been completed to date. However, there is currently one ongoing randomized controlled trial (with an estimated enrollment target of 60 pregnant women) which examines the dose of melatonin, administered to women at risk of imminent very preterm birth (less than 28 weeks' gestation) required to reduce brain damage in the white matter of the babies that were born very preterm. Further high-quality research is needed and research efforts should directed towards trials comparing melatonin with either no intervention (no treatment or placebo), or with alternative agents aimed at providing fetal neuroprotection (such as magnesium sulphate for the very preterm infant). Such trials should evaluate maternal and infant short- and longer-term outcomes (including neurosensory disabilities such as cerebral palsy), and consider the costs of care.

http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010527.pub2/full

 

Melatonin in Pregnancy: Effects on Brain Development and CNS Programming Disorders.

Curr Pharm Des.2016;22(8):978-86.

Sagrillo-Fagundes L, Assunção Salustiano EM, Yen PW, Soliman A, Vaillancourt C1.

Abstract:

Melatonin is an important neuroprotective factor and its receptors are expressed in the fetal brain. During normal pregnancy, maternal melatonin level increases progressively until term and is highly transferred to the fetus, with an important role in brain formation and differentiation. Maternal melatonin provides the first circadian signal to the fetus. This indolamine is also produced de novo and plays a protective role in the human placenta. In pregnancy disorders, both maternal and placental melatonin levels are decreased. Alteration in maternal melatonin level has been associated with disrupted brain programming with long-term effects. Melatonin has strong antioxidant protective effects directly and indirectly via the activation of its receptors. The fetal brain is highly susceptible to oxygenation variation and oxidative stress that can lead to neuronal development disruption. Based on that, several approaches have been tested as a treatment in case of pregnancy disorders and melatonin, through its neuroprotective effect, has been recently accepted against fetal brain injury. This review provides an overview about the protective effects of melatonin during pregnancy and on fetal brain development.

https://www.researchgate.net/publication/286978168_Melatonin_in_Pregnancy_Effects_on_Brain_Development_and_CNS_Programming_Disorders

 

The regulations and role of circadian clock and melatonin in uterine receptivity and pregnancy-An immunological perspective.

Am J Reprod Immunol.2017 Jun 6. doi: 10.1111/aji.12715. [Epub ahead of print]

Man GCW1,2,Zhang T3,Chen X2,Wang J2,Wu F2,Liu Y2,Wang CC2,4,5,Cheong Y6,Li TC2.

Abstract:

During normal pregnancy, the mechanism by which the fetus escapes immunological rejection by the maternal womb remains elusive. Given the biological complexities, the immunological mechanism is unlikely to be simply an allograft response in acceptance or rejection of the early pregnancy. Circadian clock responsible for the mammalian circadian rhythm is an endogenously generated rhythm associated with almost all physiological processes including reproduction. There is now growing evidence to suggest that the circadian clocks are intricately linked to the immune system and pregnancy. When perturbed, the role of immune cells can be affected on maintaining the enriched vascular system needed for placentation. This alteration can be triggered by the irregular production of maternal and placental melatonin. Hence, the role of circadian rhythm modulators such as melatonin offers intriguing opportunities for therapy. In this review, we evaluate the complex interaction between the circadian clock and melatonin within the immune system and their roles in the circadian regulation and maintenance of normal pregnancy.

https://eprints.soton.ac.uk/410625/

 

Developmental Programming of Adult Disease: Reprogramming by Melatonin?

Int J Mol Sci.2017 Feb 16;18(2). pii: E426. doi: 10.3390/ijms18020426.

Tain YL1,2,Huang LT3,4,Hsu CN5,6.

Abstract:

Adult-onset chronic non-communicable diseases (NCDs) can originate from early life through so-called the "developmental origins of health and disease" (DOHaD) or "developmental programming". The DOHaD concept offers the "reprogramming" strategy to shift the treatment from adulthood to early life, before clinical disease is apparent. Melatonin, an endogenous indoleamine produced by the pineal gland, has pleiotropic bioactivities those are beneficial in a variety of human diseases. Emerging evidence support that melatonin is closely inter-related to other proposed mechanisms contributing to the developmental programming of a variety of chronic NCDs. Recent animal studies have begun to unravel the multifunctional roles of melatonin in many experimental models of developmental programming. Even though some progress has been made in research on melatonin as a reprogramming strategy to prevent DOHaD-related NCDs, future human studies should aim at filling the translational gap between animal models and clinical trials. Here, we review several key themes on the reprogramming effects of melatonin in DOHaD research. We have particularly focused on the following areas: mechanisms of developmental programming; the interrelationship between melatonin and mechanisms underlying developmental programming; pathophysiological roles of melatonin in pregnancy and fetal development; and insight provided by animal models to support melatonin as a reprogramming therapy. Rates of NCDs are increasing faster than anticipated all over the world. Hence, there is an urgent need to understand reprogramming mechanisms of melatonin and to translate experimental research into clinical practice for halting a growing list of DOHaD-related NCDs.

https://www.ncbi.nlm.nih.gov/pubmed/28212315

 

Gestational Chronodisruption Impairs Circadian Physiology in Rat Male Offspring, Increasing the Risk of Chronic Disease.

Endocrinology.2016 Dec;157(12):4654-4668. Epub 2016 Nov 1.

Mendez N1,Halabi D1,Spichiger C1,Salazar ER1,Vergara K1,Alonso-Vasquez P1,Carmona P1,Sarmiento JM1,Richter HG1,Seron-Ferre M1,Torres-Farfan C1.

Abstract:

Chronic exposure to light at night, as in shift work, alters biological clocks (chronodisruption), negatively impacting pregnancy outcome in humans. Actually the interaction of maternal and fetal circadian systems could be a key factor determining a fitting health in adults. We propose that chronic photoperiod shift (CPS) during pregnancy alter maternal circadian rhythms and impair circadian physiology in the adult offspring, increasing health risks. Pregnant rats were exposed to normal photoperiod (12 h light, 12 h dark) or to CPS until 85% of gestation. The effects of gestational CPS were evaluated on the mother and adult offspring. In the mother we measured rhythms of heart rate, body temperature, and activity through gestation and daily rhythms of plasma variables (melatonin, corticosterone, aldosterone, and markers of renal function) at 18 days of gestation. In adult offspring, we measured rhythms of the clock gene expression in the suprachiasmatic nucleus (SCN), locomotor activity, body temperature, heart rate, blood pressure, plasma variables, glucose tolerance, and corticosterone response to ACTH. CPS altered all maternal circadian rhythms, lengthened gestation, and increased newborn weight. The adult CPS offspring presented normal rhythms of clock gene expression in the SCN, locomotor activity, and body temperature. However, the daily rhythm of plasma melatonin was absent, and corticosterone, aldosterone, renal markers, blood pressure, and heart rate rhythms were altered. Moreover, CPS offspring presented decreased glucose tolerance and an abnormal corticosterone response to ACTH. Altogether these data show that gestational CPS induced long-term effects on the offspring circadian system, wherein a normal SCN coexists with altered endocrine, cardiovascular, and metabolic function.

https://www.researchgate.net/publication/309617765_Gestational_Chronodisruption_Impairs_Circadian_Physiology_in_Rat_Male_Offspring_Increasing_the_Risk_of_Chronic_Disease

 

Potential Utility of Melatonin in Preeclampsia, Intrauterine Fetal Growth Retardation, and Perinatal Asphyxia.

Reprod Sci.2016 Aug;23(8):970-7. doi: 10.1177/1933719115612132. Epub 2015 Nov 12. 

Marseglia L1,D'Angelo G2,Manti S2,Reiter RJ3,Gitto E2.

Abstract:

Aim: Reactive oxygen species play an important role in the pathogenesis of several diseases during gestation and the perinatal period. During pregnancy, increased oxygen demand augments the rate of production of free radicals. Oxidative stress is involved in pregnancy disorders including preeclampsia and intrauterine fetal growth retardation (IUGR). Moreover, increased levels of oxidative stress and reduced antioxidative capacities may contribute to the pathogenesis of perinatal asphyxia. Melatonin, an efficient antioxidant agent, diffuses through biological membranes easily and exerts pleiotropic actions on every cell and appears to be essential for successful gestation. This narrative review summarizes current knowledge concerning the role of melatonin in reducing complications during human pregnancy and in the perinatal period.

Results: Melatonin levels are altered in women with abnormally functioning placentae during preeclampsia and IUGR. Short-term melatonin therapy is highly effective and safe in reducing complications during pregnancy and in the perinatal period. Because melatonin has been shown to be safe for both mother and fetus, it could be an attractive therapy in pregnancy and is considered a promising neuroprotective agent in perinatal asphyxia.

Conclusion: We believe that the use of melatonin treatment during the late fetal and early neonatal period might result in a wide range of health benefits, improved quality of life, and may help limit complications during the critical periods prior to, and shortly after, delivery.

https://scholars.uthscsa.edu/en/publications/potential-utility-of-melatonin-in-preeclampsia-intrauterine-fetal

The effect of melatonin on early postoperative cognitive decline in elderly patients undergoing hip arthroplasty: A randomized controlled trial.

J Clin Anesth.2017 Jun;39:77-81.

Fan Y¹, Yuan L², Ji M³,Yang J³, Gao D⁴.

Abstract:

Study Objective:

The purpose of the present study was to investigate whether exogenous melatonin supplementation could ameliorate early postoperative cognitive decline (POCD) in aged patients undergoing hip arthroplasty with spinal anesthesia.

Design:

Prospective cohort study.

Setting:

Department of Anesthesiology, Jinling Hospital, Nanjing University, Nanjing, China.

Patients:

One hundred and thirty-nine patients with ASA I-III, older than 65yr of age (mean age: 74.5±5.5; gender: male 53 and female 86), scheduled for hip arthroplasty were included in the present study.

Interventions:

Patients were randomized to receive 1mg oral melatonin or placebo daily 1h before bedtime one day before surgery and for another 5 consecutive days postoperatively.

Measurements:

The subject assessment, including Mini-Mental State Examination (MMSE) score, subjective sleep quality, general well-being, postoperative fatigue, and visual analogue scale for pain were evaluated pre-operatively and at days 1, 3, 5, and 7 after surgery.

Main Results:

The MMSE score in the control group decreased significantly after surgery when compared with its own preoperative value or the melatonin group at days 1, 3, and 5. However, the MMSE score in the melatonin group remained unchanged during the 7days of monitoring. In addition, significant postoperative impairments of subjective sleep quality, general well-being, and fatigue were found in the control group when compared with the melatonin group.

Conclusion:

Peroperative melatonin supplementation might improve early POCD, suggesting restoration of normal circadian function with good sleep quality may be one of the key factors in preventing or treating POCD.

http://www.jcafulltextonline.com/article/S0952-8180(16)30752-8/abstract

 

Melatonin and Dependency

Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia or bipolar disorder: A randomised, placebo-controlled, blinded trial.

World J Biol Psychiatry. 2015 Jun 18:1-11. [Epub ahead of print]

Baandrup L1, Lindschou J, Winkel P, Gluud C, Glenthoj BY.

Abstract:

Objectives:

We assessed if prolonged-release melatonin can facilitate withdrawal of long-term benzodiazepine usage in patients with schizophrenia or bipolar disorder.

Methods:

Randomised, placebo-controlled, blinded, parallel superiority trial of 24 weeks duration. Participants were randomised to prolonged-release melatonin 2 mg daily versus matching placebo and were continuously guided to gradually reduce their usual benzodiazepine dosage. The primary outcome was mean benzodiazepine daily dosage at 24 weeks. Secondary outcomes included pattern of benzodiazepine dosage over time, benzodiazepine cessation proportion, and benzodiazepine withdrawal symptoms.

Results:

In total, 86 patients (21-74 years) were enrolled: 42 were randomised to melatonin versus 44 to placebo. We found no significant effect of melatonin on mean benzodiazepine dosage at 24 weeks (melatonin group 8.01 mg versus placebo group 5.72 mg diazepam equivalents; difference between means -2.29; 95% CI -5.78 to 1.21; P = 0.20). Benzodiazepine cessation proportion was 38.1% (16/42) in the melatonin group versus 47.7% (21/44) in the placebo group (OR 0.64; 95% CI 0.26 to 1.56; P = 0.32). Prolonged-release melatonin had no effect on benzodiazepine withdrawal symptoms.

Conclusion:

Benzodiazepine dosage was comparably low between the groups after 24 weeks of guided gradual dose reduction. In this context, prolonged-release melatonin did not seem to further facilitate benzodiazepine discontinuation

CAVE: in this study the placebo effect was extremely high!

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3213077/

 

Contribution of prolonged-release melatonin and anti-benzodiazepine campaigns to the reduction of benzodiazepine and Z-drugs consumption in nine European countries.

Eur J Clin Pharmacol. 2013 Apr;69(4):1-10. doi: 10.1007/s00228-012-1424-1. Epub 2012 Nov 1.

Clay E¹, Falissard B, Moore N, Toumi M.

Abstract:

Background:

Benzodiazepines(BZD) and benzodiazepinereceptor agonists (zolpidem, zaleplon, zopiclone, altogether Z-drugs) are most commonly prescribed for the treatment of insomnia. However, long-term use of BZD/Z-drugs is associated with major adverse events including, but not limited to, falls and fractures, domestic and traffic accidents, confusion, cognitive impairment, Alzheimer's disease and cancer. The prolonged use of these drugs is thought to be related to severe withdrawalsymptoms and potential dependency. The chronic and extensive use of BZD/Z drugs has become a public health issue and has led to multiple campaigns to reduce both prescription and consumption of BZD/Z-drugs. Prolonged-release (PR) melatoninis the first of a new class of melatoninreceptor agonist drugs that has demonstrated clinically relevant efficacy on improving quality of sleep and morning alertness, with a good safety profile.

Objective:

This study aimed to analyze and evaluate the impact of anti-BZD/Z-drugs campaigns and the availability of alternative pharmacotherapy (PR-melatonin) on the consumption of BZD and Z-drugs in several European countries.

Methods:

Annual sales data from nine European countries were extracted from the IMS sales database and analyzed to determine whether trends in use of these treatment options were attributed to campaigns and/or availability and affordability of safer alternatives on the market.

Results:

Campaigns aiming to reduce the use of BZD/Z-drugs failed when they were not associated with the availability and market uptake of PR-melatonin. The reimbursement of PR-melatoninsupports better penetration rates and a higher reduction in sales for BZD/Z-drugs.

https://core.ac.uk/display/81164344

Hypogonadism and its treatment following ischaemic stroke in men with type 2 diabetes mellitus

Abstract:

Premature mortality in Russia is a major socio-economic problem, especially from acute cerebrovascular diseases which constitute 21.4% of the total mortality and is a considerable contributor to chronic disability. Risk of vascular catastrophe is higher in males than females, thought, in part, due to anti-atherosclerotic effects of oestrogens in females whilst an associated age-related deficiency of testosterone is observed in men. Clinical symptoms such as high blood pressure, changes in lipid profile, insulin resistance, obesity, and blood coagulation factors often accompany declining testosterone in males and reduced total testosterone is considered a cardiovascular risk factor. In the present study, the prevalence of hypogonadism in men who had suffered ischaemic stroke was evaluated along with the efficacy of testosterone undecanoate injections (TU) in patients with testosterone deficiency and type-2 diabetes (T2DM) in the acute phase of hemispheric ischaemic stroke. Hypogonadism was present in 66.3% of patients with ischaemic stroke, 50% with T2DM, and 26.3% without T2DM, respectively. TU treatment, at both the 2 and 5-year observation points, demonstrated significant improvements in biochemical, physical, and mental parameters. This supports that testosterone deficiency is a contributing factor in ischaemic events and that long-term testosterone therapy could play an important role in patient recovery.

https://www.tandfonline.com/doi/10.1080/13685538.2018.1487932

Inversion of melatonin circadian rhythm in chronic alcoholic patients during withdrawal: preliminary study on seven patients.

Alcohol Alcohol.2009 Jan-Feb;44(1):42-5. doi: 10.1093/alcalc/agn091. Epub 2008 Nov 22.

Danel T¹, Cottencin O, Tisserand L, Touitou Y.

Abstract:

Aims:

The inversion of melatonin circadian rhythm secretion in some alcoholics during both intake and acute withdrawal has been widely reported. In the same way, what happens to this inversion when these patients are in long-term withdrawal is not known. To document this abnormality in alcoholics after withdrawal we investigated melatonin secretion observed during chronic alcoholization and after withdrawal.

Methods:

We measured the urinary 6-sulfatoxymelatonin (6SM) (6SM/creatinine ratio), main metabolite of the hormone, in two fractions, one diurnal and the other nocturnal, in seven alcohol-dependent patients presenting with this abnormality during alcoholization at two times: in acute withdrawal phase (under benzodiazepines) and 15 days after beginning of withdrawal (free of any psychotropic treatment).

Results:

Our results show that this reversed rhythm of melatonin secretion as seen by the diurnal excretion of 6SM (6SM/creatinine ratio) persists during acute withdrawal in more than half of the patients and is still present 15 days after withdrawal in three patients.

Conclusion:

It is remarkable that the inversion of the melatoninrhythms gets corrected in four out of seven patients afterwithdrawal. But, the circadian disorganization of melatoninsecretion in three patients could underline a desynchronization in some alcoholic patients and may indicate more widespread circadian temporal structure disturbances in these patients.

Note: Melatonin secretion rhythm is still disorganized within 3 of 7 patients and Melatonin might help these patients to get their normal rhythm

https://www.researchgate.net/publication/23492995_Inversion_of_Melatonin_Circadian_Rhythm_in_Chronic_Alcoholic_Patients_during_Withdrawal_Preliminary_Study_on_Seven_Patients

 

The Effects of Melatonin in Patients with Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial.

Adv Biomed Res.2017 Apr 17;6:40.

Pakravan H1, Ahmadian M2, Fani A3, Aghaee D3, Brumanad S4, Pakzad B1.

Abstract:

Background:

This study was designed to evaluate the effect of melatonin on nonalcoholic fatty liver disease (NAFLD) in compared to placebo.

Materials and Methods:

A total of 100 patients with histopathological diagnosis NAFLD in two groups of case and control received oral melatonin or placebo thrice daily for 3 months. Collected data were weight, waist, systolic blood pressure (SBP), diastolic blood pressure (DBP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), high sensitive C-reactive protein (hsCRP), fatty liver grade, and side effects which were measured at baseline and after treatment period using standard clinical chemistry techniques.

Results:

Before treatment the mean of weight, waist, SBP, DBP, ALT, AST, and hsCRP between cases and controls were similar (P > 0.5). After treatment, only the differences in the mean of hsCRP in cases was significantly lower than controls (P = 0.003). In case group, all variables after treatment were significantly decreased compare to baseline (P > 0.5) and only AST after treatment was similar to before treatment (P > 0.5). The mean of a decrease in the level of weight, waist, SBP, and ALT were not statistically significant between groups (P > 0.5). In the case group in compare to control group the level of DBP, AST, and hsCRP significantly more decreased. After treatment fatty, liver grade was statistically improved in more cases than controls (P = 0.001). Side effects were similar between the two groups.

Conclusion:

Melatonin significantly decreases liver enzymes, so the use of melatonin in patients with NAFLD can be effective.

http://www.advbiores.net/article.asp?issn=2277-9175;year=2017;volume=6;issue=1;spage=40;epage=40;aulast=Pakravan