Diurnal fluctuation of sleep propensity and hormonal secretion across the menstrual cycle.

BACKGROUND: The fact that most women experience sleep changes across the menstrual cycle is thought to be associated with changes in circadian rhythms; however, few studies have investigated this relationship. METHODS: We applied an ultrashort sleep-wake schedule to eight healthy women and studied diurnal fluctuations in sleep propensity, sleepiness, rectal temperature, and serum concentrations of melatonin, thyroid-stimulating hormone, and cortisol in the follicular and luteal phases. RESULTS: In the luteal phase, amplitude of core body temperature, total melatonin secretions, and amplitudes of TSH and cortisol rhythms were significantly decreased, whereas sleepiness and occurrence of slow-wave sleep during the daytime were significantly increased. Differences in the amount of daytime slow-wave sleep across the menstrual cycle were positively correlated with differences in the daily mean rectal temperature. CONCLUSIONS: The findings suggest that the amplitude of circadian oscillation may be dampened in the luteal phase. Increased daytime sleepiness in the luteal phase may be associated with increased daytime slow-wave sleep, due possibly to changes in thermoregulation in the luteal phase.     

Longitudinal sleep EEG, temperature, and activity measurements across the menstrual cycle in patients with premenstrual depression and in age-matched controls

After a 2-month evaluation period, eight women with moderate to severe premenstrual depression and eight age- and sex-matched controls underwent sleep electroencephalographic (EEG) and temperature recordings 2 nights a week over the course of one menstrual cycle. Overall, patients had more Stage 2 (%) sleep and less rapid eye movement (REM) sleep (% and minutes) than normal controls. Stage 3 sleep and number of intermittent awakenings varied with phases of the menstrual cycle. Temperature minima were earlier in patients compared with controls, but this difference was not statistically significant, and there was no significant effect of menstrual cycle phase on the timing of temperature minima. Wrist motor activity did not change during the menstrual cycle in patients or controls. Thus, in this sample of women with premenstrual depression, we did not find sleep EEG alterations similar to those reported in some patients with major depressive disorder. In light of the small number of subjects and the large individual variability, the absence of marked changes with the menstrual cycle may be a function of a Type II error.     

Changes in sleep–wake cycle during the period from late pregnancy to puerperium identified through the wrist actigraph and sleep logs

The purpose of this study was to understand the sleep-wake cycle during the period from late pregnancy to about 3 months of postpartum by evaluating the number of actigraphic activities in four women (one multipara and three primi gravidae), and to compare the results with the findings from sleep logs. An irregularity of the sleep-wake cycle with increased number of wakings at night was notable during about 1 month after delivery, compared to the late pregnancy period, and subsequently this number tended to decrease. These results were indicative of the association between the lactation cycle to neonates and the sleep-wake cycle.     

Menstrual factors in sleep

The changing endocrine profile in premenopausal women alters aspects of sleep and circadian rhythms. Subjectively women appear to feel a greater need for sleep and report poor and insufficient sleep more often than men. This greater sleep requirement may manifest with a higher amplitude of slow-wave sleep in the EEG in women. Healthy young women, with biphasic body temperature rhythms of ovulatory menstrual cycles, have more stage 2 sleep, higher spindle frequency activity and less rapid-eye movement (REM) sleep when progesterone predominates in the luteal phase. These sleep-EEG changes may largely be caused by neurosteroids acting on the brain. Sleep regulatory mechanisms, indicated by the onset to sleep, slow-wave sleep (SWS) and slow-wave activity, appear to be unaffected by menstrual phase in women with normal cycles. Women with premenstrual mood symptoms have more stage 2 sleep and seemingly less SWS and REM sleep, a blunted circadian rhythm of melatonin and an earlier minimum body temperature than asymptomatic women. Subjective repercussions include increased daytime sleepiness, lethargy and fatigue. Treatment strategies for menstrual-associated complaints include using oral contraceptives and sleep deprivation but the physiology and pharmacology of normal menstrual changes, the disorders and their treatment need to be better understood.     

Withdrawal from progesterone increases expression of alpha4, beta1, and delta GABA(A) receptor subunits in neurons in the periaqueductal gray matter in female Wistar rats

Premenstrual dysphoric disorder (PMDD) shows comorbidity with other psychiatric conditions such as panic disorder (PD). The symptoms of both conditions are exacerbated during the late luteal phase of the menstrual cycle, when progesterone levels fall sharply. The present study investigated the effect of withdrawal from progesterone (PWD) on expression of alpha4, beta1, and delta GABA(A) receptor subunits in neurons within the panic circuitry of the midbrain periaqueductal gray matter (PAG) in adult female Wistar rats. Immunostaining for alpha4, beta1, and delta GABA(A) receptor subunits was present in neurons throughout the PAG in vehicle-treated animals (VEH), in rats after 24 hours withdrawal from a progesterone dosing regime (PWD, 5 mg kg(-1) i.p. twice daily for 6 days), and in animals maintained on progesterone for 7 days (HP). Compared to HP and VEH animals, which did not differ significantly from each other, the number of immunostained neurons present in the PAG of PWD rats was significantly higher. The effect was most pronounced in the dorsolateral column of the PAG. The parallel changes in the three GABA(A) receptor subunits suggests that falling progesterone levels may be associated with expression of new receptors of the alpha4beta1delta subtype. This could lead to functional changes in GABAergic transmission within the PAG. We suggest that changes in GABA(A) receptor-mediated inhibitory tone in the PAG consequent to withdrawal from progesterone may contribute to the increased anxiety and susceptibility to panic seen during the late luteal phase of the menstrual cycle in PMDD and PD patients.     

Therapeutic progress of two sibling cases exhibiting sleep-wake rhythm disorder

In this study, two females, siblings who exhibited a non-24 h sleep-wake rhythm (non-24 h) at home were observed. However, they showed a delayed sleep phase syndrome (DSPS) immediately after admission to Kurume University Hospital. Melatonin (3 mg) was commenced following chronotherapy and this improved their sleep-wake rhythm. Polysomnography (PSG) showed decreased sleep latency and increased sleep stage. In these cases, the involvement of environmental factors was strongly suggested for the sleep-wake rhythm abnormalities as well as familial factors.     

Melatonin treatment for circadian rhythm sleep disorders

This study investigated the effects of melatonin administration on circadian rhythm sleep disorders, and aimed to clarify clinical characteristics of melatonin responders. The subjects were 46 patients with circadian rhythm sleep disorders: 30 Delayed Sleep Phase Syndrome (DSPS) and 16 non-24 h sleep-wake syndrome (non-24). Patients took 0.3-1.0 mg of melatonin 5, 3 and 1 h before habitual bedtime. Seventeen patients responded to melatonin (12 DSPS, five non-24). Comparison of clinical background between responders and non-responders revealed that the responders were characterized by short total sleep time and later onset age of clinical symptoms.     

Self-reported sleep across the menstrual cycle in young, healthy women

OBJECTIVE: To establish the association between subjective sleep and phase of the menstrual cycle in healthy, young, ovulating women. METHODS: Twenty-six women (mean age: 21 years) who did not suffer from any menstrual-associated disorders, and in whom we had detected ovulation, completed daily questionnaires about their sleep over 1 month. RESULTS: The women reported a lower sleep quality over the 3 premenstrual days and 4 days during menstruation, compared to the mid-follicular and early/mid luteal phases. Total sleep time, sleep onset latency, number and duration of awakenings, and morning vigilance were not affected by the menstrual cycle. CONCLUSION: The normal, ovulatory cycle is associated with changes in the perception of sleep quality but not sleep continuity in healthy, young women. The temporal relationship of sleep complaints with menstrual phase should be considered in the evaluation of sleep disorders, particularly insomnia, in women.     

Poor recovery sleep after sleep deprivation in delayed sleep phase syndrome

To clarify disturbances in sleep regulation in patients with delayed sleep phase syndrome (DSPS), we studied three patients with DSPS and seven healthy controls. Sleep propensity and melatonin rhythms after 24-h sleep deprivation were investigated under dim light condition by using the ultra-short sleep-wake schedule. The sleep propensity curves displayed clear differences between DSPS patients and the controls. During the subjective day when melatonin was not produced, recovery sleep after the sleep deprivation did not occur in DSPS patients, while recovery sleep occurred during the subjective day in controls. This suggests that DSPS may involve problems related to the homeostatic regulation of sleep after sleep deprivation.     

Clomipramine effectively reduces premenstrual irritability and dysphoria: a placebo-controlled trial.

Forty nondepressed women displaying severe premenstrual irritability and/or dysphoria and fulfilling the DSM-III-R criteria of late luteal phase dysphoric disorder were treated daily for 3 menstrual cycles with either the potent serotonin reuptake inhibitor clomipramine (25-75 mg; flexible dosage) (n = 20) or placebo (n = 20). In both treatment groups premenstrual irritability and dysphoria (as rated daily by the patients using a visual analogue scale) were significantly reduced as compared with the rating during 2 pretreatment reference cycles; however, in the placebo group this reduction was only about 40% whereas, in the clomipramine group, the symptom decrease was greater than 80%. At all 3 treatment cycles, patients on clomipramine displayed significantly lower symptom rating than controls. Also with respect to the rating of global improvement, the results obtained with clomipramine were considerably and significantly better than those obtained with placebo. It is concluded that low doses of clomipramine effectively reduce premenstrual irritability and dysphoria with a response rate close to 100%. The possible role of serotonin in the pathophysiology of the premenstrual syndrome is discussed.     

Long-term rectal temperature measurements in a patient with menstrual-associated sleep disorder

The international classification of sleep disorders has proposed menstrual-associated sleep disorder. However, few studies have investigated its pathophysiological mechanism. A 34-year-old woman complaining of insomnia in the late luteal phase underwent continuous rectal temperature measurements and simultaneous actigraphic monitoring for 146 days. The acrophase of rectal temperature rhythm was delayed in the luteal phase, compared with that in the follicular phase. Her bedtime and risetime did not differ across the menstrual cycle. These results suggest that her insomnia in the luteal phase may have been a consequence of desynchronization between her temperature rhythm and sleep phase in the luteal phase.     

Hippocampal structural changes across the menstrual cycle

Magnetic resonance imaging (MRI) in association with Jacobian-modulated voxel-based morphometry (VBM) was used to test for regional variation in gray matter over the menstrual cycle. T1-weighted anatomical images were acquired using a spoiled gradient recalled acquisition sequence in 21 women. Each subject was scanned twice: once during the postmenstrual late-follicular phase (Days 10-12 after onset of menses), and once during the premenstrual late-luteal phase (1-5 days before the onset of menses). Gray matter was relatively increased in the right anterior hippocampus and relatively decreased in the right dorsal basal ganglia (globus pallidus/putamen) in the postmenstrual phase. Verbal declarative memory was increased in the postmenstrual vs. premenstrual phase. This first report of human brain structural plasticity associated with the endogenous menstrual cycle extends well-established animal findings of hormone-mediated hippocampal plasticity to humans, and has implications for understanding alterations in cognition and behavior across the menstrual cycle.     

Acute psychiatric admission related to the menstrual cycle

A study of menstrual cycle phase on the day of acute admission to a psychiatric hospital for 121 women aged 20-39 showed an unequal distribution of admissions. More admissions than expected took place in the menstrual period, and correspondingly fewer intermenstrually. The difference was significant, and points to a certain degree of cyclicity in female psychiatric disturbance. This cyclicity was not significantly influenced by age, diagnosis, oral contraceptives or tendency for premenstrual symptoms. In the age group 20-39 one and a half times as many men as women are admitted to Danish psychiatric departments. Thus, in view of a common baseline, the most conspicuous feature is, that remarkably few women were admitted intermenstrually.     

Circadian rhythm sleep disorders in adolescents: clinical trials of combined treatments based on chronobiology

Delayed sleep phase syndrome (DSPS) and non-24-h sleep-wake rhythm are circadian rhythm sleep disorders that are common in adolescents. Most patients have difficulty adjusting to school life, poor class attendance or refuse to go to school. Since a treatment has not been established, the present paper is presented to propose a strategy for treating circadian rhythm sleep disorders in adolescents, based on our clinical studies. Twenty subjects (12 males and eight females, mean age 16.2+/-1.7 years) participated in the study. The onset of sleep disorder occurred between the ages of 11 and 17. The most common factors affecting the onset of disorders were changes in social environment. The subjects kept a sleep-log for the periods before and during treatments. The treatments were based on chronobiology: resetting the daily life schedule, chronotherapy, regulation of the lighting environment, methylcobalamin, and/or melatonin. Bright light exposure was successful in 10 patients, of whom four were treated with methylcobalamin. Melatonin treatment was successful in two patients (one with and one without chronotherapy). Thirteen of the 20 patients were successfully, treated with therapies based on chronobiology. After consideration of these results, a step-by-step procedure of combined treatments for the circadian rhythm sleep disorders is proposed.     

Peak visual gamma frequency is modified across the healthy menstrual cycle

Fluctuations in gonadal hormones over the course of the menstrual cycle are known to cause functional brain changes and are thought to modulate changes in the balance of cortical excitation and inhibition. Animal research has shown this occurs primarily via the major metabolite of progesterone, allopregnanolone, and its action as a positive allosteric modulator of the GABA_A receptor. Our study used EEG to record gamma oscillations induced in the visual cortex using stationary and moving gratings. Recordings took place during twenty females’ mid‐luteal phase when progesterone and estradiol are highest, and early follicular phase when progesterone and estradiol are lowest. Significantly higher (～5 Hz) gamma frequency was recorded during the luteal compared to the follicular phase for both stimuli types. Using dynamic causal modeling, these changes were linked to stronger self‐inhibition of superficial pyramidal cells in the luteal compared to the follicular phase. In addition, the connection from inhibitory interneurons to deep pyramidal cells was found to be stronger in the follicular compared to the luteal phase. These findings show that complex functional changes in synaptic microcircuitry occur across the menstrual cycle and that menstrual cycle phase should be taken into consideration when including female participants in research into gamma‐band oscillations.     

Napping predicts responsiveness to hypnotics in patients with primary circadian rhythm disorder

It is hypothesized that one of the primary abnormalities of primary circadian rhythm disorder (PCRD) is the strong link between any episode of sleep and circadian rhythm. To test this hypothesis, the relationship between napping and responsiveness to hypnotics was examined in 12 patients with PCRD. A significant association was found (P = 0.04, chi2 test). Patients with PCRD who napped were all responders to hypnotics. The results suggest a strong link between episodes of sleep and circadian rhythm in some patients with PCRD, and might also suggest the heterogeneity of PCRD. Napping in patients with PCRD may be a predictor for responsiveness to hypnotics. In addition, napping and responsiveness to hypnotics might have a clinical value to differentiate PCRD from secondary CRD.     

Reduced parasympathetic activity during sleep in the symptomatic phase of severe premenstrual syndrome

OBJECTIVE: Severe premenstrual syndrome (PMS) is a common distressing disorder in women that manifests during the premenstrual (late-luteal) phase of the ovulatory menstrual cycle. There is some evidence that altered autonomic function may be an important component of PMS, but few studies have used heart rate variability (HRV) as a sensitive marker of autonomic activity in severe PMS, and findings are conflicting. METHODS: We investigated HRV during sleep, a state that is relatively free of external disruptions, in 9 women with severe PMS and 12 controls. RESULTS: The normal-to-normal (NN) RR interval was shorter during the sleep period in women with PMS than in controls in both the follicular and the late-luteal phases of the menstrual cycle. The standard deviation of all NN intervals, a measure of total variability in the interbeat interval, was lower during the sleep period in the late-luteal phase than in the follicular phase in women with PMS. The square root of the mean of the sum of the squares of differences between adjacent NN intervals, a measure reflecting high-frequency (HF) activity, showed a similar pattern. HF power, a marker of parasympathetic activity, was lower during non-rapid eye movement (non-REM) and REM sleep in the late-luteal phase than in the follicular phase in women with severe PMS. Controls had a shorter NN interval, but similar HRV measures, in the late-luteal phase compared with the follicular phase. CONCLUSION: These results suggest that women with severe PMS have decreased parasympathetic activity during sleep in association with their premenstrual symptoms in the late-luteal phase compared with the follicular phase when they are symptom-free.     

Correlation between the circadian sleep propensity rhythm and hormonal rhythms under ultra-short sleep–wake cycle

The aim of this study was to clarify effects of hormonal and temperature rhythms on circadian fluctuations of sleep propensity. Ten healthy females underwent 24-h sleep deprivation and entered the circadian sleep propensity assessment setting under the ultra-short sleep-wake schedule. During the experiment, sleep propensity rhythm, rectal temperature, and 24-h serum hormone profiles (melatonin, cortisol and thyroid-stimulating hormone) were investigated. The circadian sleep propensity rhythms had two apparent peaks (afternoon and nocturnal peaks) and a trough (nocturnal sleep gate). The timings of the nocturnal sleep gate and the nocturnal peak were correlated exclusively with temperature and melatonin rhythms (P < 0.05), while that of the afternoon peak was significantly correlated with habitual wake time and melatonin rhythm. These results indicate that the circadian sleep propensity rhythm is influenced not only by the circadian pacemaker, but also by sleep habit.     

Variation of symptoms during the menstrual cycle in female patients with gastroparesis

Background Gastroparesis, a chronic gastric motility disorder with symptoms of nausea, vomiting, early satiety, postprandial fullness and bloating, predominantly affects women. Some studies suggest that gastric emptying may be slower in females especially during the luteal phase of the menstrual cycle when estrogen and progesterone levels are elevated. In females with irritable bowel syndrome, symptoms may worsen during the luteal phase. The aim of this study was to determine if symptoms of gastroparesis vary along the menstrual cycle and to determine the effect of oral contraceptive agents (OCPs) on symptoms. Methods Thirty‐nine premenopausal women were studied (10 gastroparesis patients not on OCPs, 10 gastroparesis on OCPs, nine healthy women not on OCPs and 10 healthy women on OCPs). The Gastroparesis Cardinal Symptom Index Daily Diary was used to assess daily symptoms (0 = none and 5 = very severe). Key Results Gastroparesis patients not on OCPs had significantly worse symptoms during the luteal phase compared to the follicular phase for nausea (2.25 ± 0.68 vs 1.58 ± 1.06; P < 0.001) and early satiety (2.80 ± 0.50 vs 1.70 ± 1.50; P < 0.001), but not for vomiting, bloating, abdominal pain, fullness, or loss of appetite. Gastroparesis patients on OCPs showed little day‐to‐day variation of symptoms. Vomiting was more severe in patients off OCPs (2.00 ± 0.80 vs 1.20 ± 0.83; P = 0.040). Healthy women exhibited little to no symptoms regardless of OCP use. Conclusions & Inferences Increased symptoms, particularly nausea and early satiety, occurred in the luteal phase of the menstrual cycle in female patients with gastroparesis. A variation in symptoms was not seen in gastroparesis female patients on hormonal contraception.