Diminished Melatonin Secretion Research Articles

Association between Melatonin Secretion and Nocturia in Elderly Individuals: a Cross-Sectional Study of the HEIJO-KYO Cohort

Nocturnal voids are regulated by circadian biological rhythms, including decreased urine production and increased bladder storage capacity at night. A previous experimental study suggested that exogenous melatonin decreases urine production and increases bladder capacity in rats. However, little is known about whether melatonin secretion, which is considerably lower than exogenous melatonin, is associated with nocturia in humans. We evaluated the association between melatonin secretion and nocturia. In this cross-sectional study we examined 861 community based elderly individuals with a mean age of 72.1 years. We measured nocturnal void frequency and overnight urinary 6-sulfatoxymelatonin excretion as an index of melatonin secretion. Nocturia was defined as 2 or more nocturnal voids. Univariate comparisons between the 261 and 600 study participants with and without nocturia, respectively, showed marginal to significant associations of nocturia with age, gender, body mass index, estimated glomerular filtration rate, calcium channel blockers, benign prostatic hyperplasia, total voided urine volume, urinary 6-sulfatoxymelatonin, duration in bed, day length, and daytime and nighttime physical activity. The multivariate logistic regression model adjusted for the former confounding factors revealed that higher urinary 6-sulfatoxymelatonin was significantly associated with a lower nocturia OR (adjusted OR 0.73, 95% CI 0.56-0.96, p=0.023). After adjustment for age, gender and duration in bed the mean volume of a single voided urine significantly increased with tertiles of increasing urinary 6-sulfatoxymelatonin (p for trend=0.022). Melatonin secretion is significantly and inversely associated with nocturia in a general elderly population.

Melatonin and diabetes: from pathophysiology to the treatment perspectives

Pineal hormone melatonin synchronizes insulin secretion and glucose homeostasis with solar periods. Misalliance between melatonin-mediated circadian rhythms and insulin secretion characterizes diabetes mellitus type 1 (T1DM) and type 2 (T2DM). Insulin deficiency in T1DM is accompanied by increased melatonin production. Conversely, T2DM is characterized by diminished melatonin secretion. In genome-wide association studies the variants of melatonin receptor MT2 gene (rs1387153 and rs10830963) were associated with fasting glucose, beta-cell function and T2DM. In experimental models of diabetes melatonin enhanced beta-cell proliferation and neogenesis, improved insulin resistance and alleviated oxidative stress in retina and kidneys. However, further investigation is required to assess the therapeutic value of melatonin in diabetic patients.

Age‐related Changes in the Circadian and Homeostatic Regulation of Human Sleep

The reduction of electroencephalographic (EEG) slow‐wave activity (SWA) (EEG power density between 0.75–4.5 Hz) and spindle frequency activity, together with an increase in involuntary awakenings during sleep, represent the hallmarks of human sleep alterations with age. It has been assumed that this decrease in non‐rapid eye movement (NREM) sleep consolidation reflects an age‐related attenuation of the sleep homeostatic drive. To test this hypothesis, we measured sleep EEG characteristics (i.e., SWA, sleep spindles) in healthy older volunteers in response to high (sleep deprivation protocol) and low sleep pressure (nap protocol) conditions. Despite the fact that the older volunteers had impaired sleep consolidation and reduced SWA levels, their relative SWA response to both high and low sleep pressure conditions was similar to that of younger persons. Only in frontal brain regions did we find an age‐related diminished SWA response to high sleep pressure. On the other hand, we have clear evidence that the circadian regulation of sleep during the 40 h nap protocol was changed such that the circadian arousal signal in the evening was weaker in the older study participants. More sleep occurred during the wake maintenance zone, and subjective sleepiness ratings in the late afternoon and evening were higher than in younger participants. In addition, we found a diminished melatonin secretion and a reduced circadian modulation of REM sleep and spindle frequency—the latter was phase‐advanced relative to the circadian melatonin profile. Therefore, we favor the hypothesis that age‐related changes in sleep are due to weaker circadian regulation of sleep and wakefulness. Our data suggest that manipulations of the circadian timing system, rather than the sleep homeostat, may offer a potential strategy to alleviate age‐related decrements in sleep and daytime alertness levels.

Age-related attenuation of the evening circadian arousal signal in humans

The human circadian pacemaker maintains timing and consolidation of sleep–wake behavior by opposing the build-up of homeostatic sleep pressure during the wake episode, particularly in the evening during the ‘wake maintenance zone’. We tested whether age-related changes in sleep are a consequence of a weaker circadian arousal signal in the evening. Circadian rhythms and spectral components of the sleep EEG were investigated in 17 young (20–31 year) and 15 older (57–74 year) volunteers under constant posture conditions during a 40-h nap protocol (75/150 min sleep/wake schedule). Quantitative evidence for a weaker circadian arousal signal in aging arose from significantly more sleep occurring during the wake maintenance zone and higher subjective sleepiness ratings in the late afternoon and evening in the older group. In addition, we found a diminished melatonin secretion and a reduced circadian modulation of REM sleep together with less pronounced day–night differences in the lower alpha and spindle range of sleep EEG activity in the older group. Thus, our data indicate that age-related changes in sleep propensity are clearly related to a reduced circadian signal opposing the homeostatic drive for sleep.

Magnetic fields and the melatonin hypothesis: a study of workers chronically exposed to 50-Hz magnetic fields.

Because epidemiological studies report clinical disorders (mainly neurobehavioral alterations and/or cancer) that may be related to diminished melatonin secretion or to changes in its circadian rhythm in subjects living or working in environments exposed to magnetic fields, research on the effects of these fields in humans is particularly important. In this study, we examine the circadian rhythm of melatonin in 15 men exposed chronically and daily for a period of 1-20 yr, in the workplace and at home, to a 50-Hz magnetic field in search of any cumulative effect from those chronic conditions of exposure. The weekly geometric mean of individual exposures ranged from 0.1 to 2.6 microT. The results are compared with those for 15 unexposed men who served as controls (individual exposures ranged from 0.004 to 0.092 microT). Blood samples were taken hourly from 2000 to 0800. Nighttime urine was also collected and analyzed. This work shows that subjects exposed over a long period (up to 20 yr) and on a daily basis to magnetic fields experienced no changes in their plasma melatonin level, their urinary 6-sulfatoxymelatonin level, or the circadian rhythm of melatonin. Our data strongly suggest that magnetic fields do not have cumulative effects on melatonin secretion in humans and thus clearly rebut the "melatonin hypothesis" that a decrease in plasma melatonin concentration (or a disruption in its secretion) explains the occurrence of clinical disorders or cancers possibly related to magnetic fields.

Diminished Melatonin Secretion in the Elderly Caused by Insufficient Environmental Illumination

Diminished Melatonin Secretion in the Elderly Caused by Insufficient Environmental Illumination

Diminished melatonin secretion in the elderly caused by insufficient environmental illumination.

The pineal hormone melatonin has some circadian regulatory effects and is assumed to have a close relation with sleep initiation and maintenance. Many previous reports have described age-related decreases in melatonin levels, especially in elderly insomniacs (EIs), which may act as causal or exacerbating factors in sleep disturbances in the elderly. Ten elderly residents with psychophysiological insomnia (mean age, 74.2 yr), 10 healthy residents of the same home [elderly control (EC) group; mean age, 72.7 yr], and 10 healthy young control subjects (mean age, 20.9 yr) living at home participated in this study. The elderly persons, especially the EIs, were exposed to significantly less environmental light and simultaneously suffered from significantly diminished nocturnal melatonin secretion. Supplementary exposure to 4 h (1000 to 1200 h, 1400 to 1600 h) of midday bright light in the EI group significantly increased melatonin secretion to levels similar to those in the young control group without circadian phase-shifting. There was a tendency for the magnitude of the increase in nocturnal melatonin secretion stimulated by bright light to parallel amelioration of sleep disturbances in these subjects. The present findings suggest that we need to pay attention to elderly individuals who suffer under conditions of poor environmental light resulting in disorganized circadian rhythms, including the sleep-wake cycle.

Mood-Dependent Fluctuations in the Severity of Tardive Dyskinesia and Psoriasis Vulgaris in a Patient with Schizoaffective Disorder: Possible Role of Melatonin

There is evidence that patients with affective disorders are at high risk for developing Tardive dyskinesia (TD). In addition, in patients with bipolar illness, depressive episodes have been associated with exacerbation of the TD, while manic episodes were accompanied by attenuation of TD. Since depression is associated with diminished melatonin secretion, the high incidence of TD in patients with history of depression may be linked to diminished secretory activity of the pineal melatonin. We report a 28-year old female patient with schizoaffective disorder associated with psoriasis vulgaris in whom periodic exacerbation of depressive moods and suicidal thoughts were accompanied by worsening of the TD as well as the psoriatic lesions. Spontaneous improvements of mood were associated with disappearance of the involuntary movements and regression of the psoriatic lesions. Since melatonin secretion is diminished in patients with depression and in patients with psoriasis vulgaris, this report may add further support to the hypothesis that the development of TD may be associated with diminished secretory activity of pineal melatonin. The mechanisms by which diminished melatonin secretion may facilitate the emergence of TD are discussed. In addition, the possibility that light therapy, as has been successfully used in the management of seasonal affective disorders, may be useful in the management and perhaps prophylaxis of TD is discussed.

The Relationship of Pineal Calcification to Subtypes of Tardive Dyskinesia in Bipolar Patients

Recent studies have suggested that bipolar patients may be at high risk for developing tardive dyskinesia (TD) if exposed to chronic neuroleptic therapy. It has been suggested that reduced melatonin secretion may favor the development of TD in bipolar and schizoaffective patients. Since pinealectomized rats have been reported to develop increased incidence and severity of abnormal chewing movements, and as depression is associated with reduced melatonin secretion, the increased risk of TD in bipolar patients may be associated with diminished melatonin secretion. Evidence suggestive of an inverse correlation between pineal calcification and reduced melatonin secretion, led me to study the relationship between pineal calcification on CT scan and the severity of axial (truncal) and limb and orofacial dyskinesias in bipolar patients with TD. The incidence of pathologically enlarged pineal calcifications (i.e., greater than 1 cm in diameter) in the bipolar patients was 25 times greater than the reported incidence in the literature among nonpsychiatric patients. In addition, there was a significant difference in scores of axial dyskinesias between patients with pineal calcification of less than 1 cm in diameter compared to those with pineal calcification of greater than 1 cm in diameter (F = 3.24; p = .04, one-way ANOVA). There was no significant association between scores of limb and orofacial dyskinesias and pineal calcification. These findings suggest a meaningful association between the presence of enlarged pineal calcification, and axial dyskinesias in bipolar patients. Further studies using direct plasma melatonin measurements are required to more precisely define the association between TD and melatonin secretion in bipolar patients.

Melanocyte-Stimulating Hormone and Persistent Tardive Dyskinesia: A Hypothesis

An increased incidence of abnormal perioral movements has recently been reported in drug-naive pinealectomized rats with further accentuation of these movements following administration of haloperidol. Analysis of the temporal course of the development of the perioral dyskinetic movements revealed that the onset of these movements occurred within 4 days postoperatively and peaked at 3 weeks to plateau over the following 4-6 weeks. Increased pituitary Melanocyte-stimulating hormone (MSH) content has been reported in pinealectomized rats. Elevation of MSH content in the pinealectomized rats occurred within 3 days of surgery and was followed by normalization within 4 weeks. These findings suggest that compensatory mechanisms involving hypothalamic-pituitary MSH release must have been activated to induce normalization of pituitary MSH levels. Moreover, reduction of pituitary MSH levels may have coincided with attenuation in the severity of the perioral dyskinetic movements. It is possible that the development of tardive dyskinesia (TD) may in part be associated with increased brain and plasma MSH levels and that impaired hypothalamic-pituitary regulatory mechanisms of MSH release may be associated with persistent TD. The pineal gland may be implicated in this process as diminished melatonin secretion may be associated with disinhibition of MSH release. Thus, the above hypothesis complements and extends the recently presented "melatonin hypothesis" and suggests that research of pineal-hypothalamic interactions may be crucial to the further understanding of TD.

Possible Role of Pineal Melatonin in the Mechanisms of Aging

The pineal gland has captured man's attention as early in recorded history as the Greeks when philosophers considered it the "seat of the soul". Descartes, in the Middle Ages, furthered this concept naming it "esprits animaux" or, in current language, the psychic and somatic activating principle. These notions about the pineal gland were initially purely speculative and unsupported by scientific facts. However, with the development of a sound knowledge base concerning the pineal gland over the past twenty years, evidence has accumulated to suggest a pivotal role for the pineal in the 'fine tuning' and integrating of various neural and endocrine functions. The secretion of pineal melatonin has been shown to decline progressively with age. Recent hypotheses of aging have suggested that cumulative neuronal insults associated with free radical production may be associated with the process of aging. There is evidence to suggest that melatonin may protect against the age processes in part by attenuating the effects of free radical-induced neuronal damage. Other studies derived mainly from observations on pinealectomized rats also suggest that diminished melatonin secretion may be associated with acceleration of the aging process. Thus, pineal melatonin may be a natural anti-aging hormone.

Pineal Melatonin in Schizophrenia: A Review and Hypothesis

It has long been suggested that abnormal functions of the pineal gland may be implicated in the pathophysiology of schizophrenia. We present evidence proposing that diminished melatonin secretion may be associated with the pathophysiology of a subgroup of schizophrenic patients characterized by cerebral atrophy and ventricular enlargement, negative symptoms, impaired cognitive and psychosexual development, onset at pubescence, poor response to neuroleptic medication, and possible increased risk of extrapyramidal symptoms. This view holds that a subnormal plasma melatonin level may be a marker of a subgroup of schizophrenia and may also denote a specific genetic susceptibility.