Effects of Insufficient Sleep on Pituitary-Adrenocortical Response to CRH Stimulation in Healthy Men.

Study Objectives: Severe sleep restriction results in elevated evening cortisol levels. We examined whether this relative hypercortisolism is associated with alterations in the pituitary-adrenocortical response to evening corticotropin-releasing hormone (CRH) stimulation. Methods: Eleven subjects participated in 2 sessions (2 nights of 10 hours vs. 4 hours in bed) in randomized order. Sleep was polygraphically recorded. After the second night of each session, blood was sampled at 20-minute intervals from 09:00 to 24:00 for adrenocorticotropic hormone (ACTH) and cortisol measurements, and perceived stress was assessed hourly. Ovine CRH was injected at 18:00 (1 µg/kg body weight). Results: Prior to CRH injection, baseline ACTH, but not cortisol, levels were elevated after sleep restriction. Relative to the well-rested condition, sleep restriction resulted in a 27% decrease in overall ACTH response to CRH (estimated by the incremental area under the curve from 18:00 to 24:00; p = .002) while the cortisol response was decreased by 21% (p = .083). Further, the magnitude of these decreases was correlated with the individual amount of sleep loss (ACTH: rSp = -0.65, p = .032; cortisol: rSp = -0.71, p = .015). The acute post-CRH increment of cortisol was reduced (p = .002) without changes in ACTH reactivity, suggesting decreased adrenal sensitivity. The rate of decline from peak post-injection levels was reduced for cortisol (p = .032), but not for ACTH. Scores of perceived stress were unaffected by CRH injection and were low and similar under both sleep conditions. Conclusions: Sleep restriction is associated with a reduction of the overall ACTH and cortisol responses to evening CRH stimulation, and a reduced reactivity and slower recovery of the cortisol response.

Effects of a 3-week dehydroepiandrosterone administration on sleep, sex steroids and multiple 24-h hormonal profiles in postmenopausal women: a pilot study.

OBJECTIVE: Dehydroepiandrosterone (DHEA) administration is widely evocated as a 'fountain of youth', but previous studies have provided inconsistent results. We aimed to investigate in healthy postmenopausal women the effects of a 3-week oral DHEA administration on individual steroid levels, multiple 24-h hormonal profiles and sleep architecture. DESIGN: Seven healthy nonobese postmenopausal women, off hormone replacement therapy for ≥2 months, were investigated in a randomized, crossover, double-blind, placebo-controlled study. For 3 weeks, subjects took daily at 2300 h a capsule of either 50 mg DHEA or placebo. Sleep was polygraphically recorded during the last two nights, and blood samples were drawn at 15-min intervals during the last 24 h. RESULTS: Under DHEA, testosterone and estradiol levels were increased in all individuals. Individual increments were highly variable, not related to each other, and were not related to placebo values. However, the testosterone to estradiol ratio was markedly increased under DHEA. DHEA administration had little, if any, effect on thyroid function, GH secretion, prolactin, ACTH and cortisol profiles. DHEA effects on sleep appeared to be mediated by its conversion to androgens and oestrogens: sleep quality was enhanced by increments in testosterone and dampened by increments in estradiol levels. CONCLUSION: As DHEA-induced elevations in testosterone and estradiol levels varied widely between individuals and were largely unpredictable, DHEA administration might not be the most appropriate approach to compensate for the reduction observed in androgen and oestrogen production in postmenopausal women. DHEA supplementation may result either in sleep stimulation or in inhibition, depending on the ratio between DHEA-induced increments in testosterone vs estradiol.

Progesterone prevents sleep disturbances and modulates GH, TSH, and melatonin secretion in postmenopausal women.

CONTEXT: A number of neuroactive progesterone metabolites produce sedative-like effects. However, the effects of progesterone administration on sleep are not well characterized. OBJECTIVE: To investigate the effects of a 3-wk progesterone administration on sleep architecture and multiple hormonal profiles. SUBJECTS: Eight healthy postmenopausal women, 48-74 yr old, without sleep complaints or vasomotor symptoms. None was on hormone replacement therapy. They did not take any medication for ≥ 2 months. DESIGN: Randomized, double-blind, placebo-controlled study. For 3 wk, subjects took daily at 2300 h a capsule of either 300 mg of progesterone or placebo. Sleep was polygraphically recorded during the last two nights, and blood samples were obtained at 15-min intervals for 24 h. RESULTS: During the first night (no blood sampling), sleep was similar in both conditions. Under placebo, blood sampling procedure was associated with marked sleep disturbances, which were considerably reduced under progesterone treatment: mean duration of wake after sleep onset was 53% lower, slow-wave sleep duration almost 50% higher, and total slow-wave activity (reflecting duration and intensity of deep sleep) almost 45% higher under progesterone than under placebo (P ≤ 0.05). Nocturnal GH secretion was increased, and evening and nocturnal TSH levels were decreased under progesterone (P ≤ 0.05). CONCLUSIONS: Progesterone had no effect on undisturbed sleep but restored normal sleep when sleep was disturbed (while currently available hypnotics tend to inhibit deep sleep), acting as a "physiologic" regulator rather than as a hypnotic drug. Use of progesterone might provide novel therapeutic strategies for the treatment of sleep disturbances, in particular in aging where sleep is fragmented and of lower quality.

A potential role of endogenous progesterone in modulation of GH, prolactin and thyrotrophin secretion during normal menstrual cycle.

OBJECTIVE: Previous studies investigating the fluctuations of endocrine secretion across the menstrual cycle yielded inconsistent results. Our objective was to evaluate during the menstrual cycle the potential role of endogenous oestradiol and progesterone in the regulation of hormones primarily controlled by the circadian clock and/or the sleep-wake cycle. SUBJECTS AND DESIGN: Ten normally cycling young lean women were investigated once during follicular and once during luteal phase. Sleep was polygraphically recorded, and blood samples were obtained at 20-min intervals for 24 h. RESULTS: Sleep variables and diurnal melatonin and cortisol profiles (hormones primarily controlled by the circadian clock) were similar in both conditions. The TSH evening rise (a circadian marker) was similar in both conditions, but the sleep-related nocturnal TSH decrease occurred earlier during the luteal phase (P = 0.03) and tended to correlate positively with progesterone levels (r(s) = -0.64, P < 0.06). Daytime GH secretion and afternoon/evening PRL secretion (hormones primarily controlled by the sleep-wake homeostasis) were increased in the luteal phase compared with those of the follicular phase (GH: P = 0.04; PRL: P = 0.01). The increase in 24-h GH secretion was associated with higher progesterone levels (r(s) = 0.78, P = 0.02). In luteal phase, the evening PRL rise was associated with higher progesterone (r(s) = 0.70, P = 0.04) and oestradiol (r(s) = 0.72, P = 0.03) levels. CONCLUSION: The present data indicate that in normally cycling young women, daytime GH and PRL secretions are increased in luteal phase. These data also suggest that endogenous progesterone could play a modulation role on pituitary hormone secretion, stimulating GH and PRL release and enhancing the inhibitory action of sleep on TSH secretion.

Phase-shifts of 24-h rhythms of hormonal release and body temperature following early evening administration of the melatonin agonist agomelatine in healthy older men.

OBJECTIVE: Older adults are less responsive to the phase-shifting effects of light than younger subjects and may have difficulties adapting to abrupt time shifts. This study aims to determine whether the potent melatonin agonist agomelatine (S-20098) is capable of phase-shifting overt circadian rhythms in older adults. SUBJECTS AND DESIGN: Eight healthy elderly men participated in a double-blind, two-period, cross-over study of 15 days of daily administration of either agomelatine (50 mg) or placebo at 1830 h. MEASUREMENTS: At the end of each treatment period, the 24-h profiles of body temperature and of the plasma levels of GH, PRL, cortisol and TSH were collected and sleep was monitored polygraphically. RESULTS: Phase-advances, averaging nearly 2 h, were observed for the temperature profile and for the variables characterizing the temporal organization of cortisol secretion following agomelatine administration. A similar trend was observed for the circadian rise of plasma TSH. There was no effect of agomelatine on any of the sleep variables. Agomelatine stimulated GH secretion during the wake period and was associated with a transient elevation of PRL levels. CONCLUSIONS: Melatonin agonists such as agomelatine may be useful to phase-shift at least some overt circadian rhythms in older adults.

Sex differences in nocturnal growth hormone and prolactin secretion in healthy older adults: relationships with sleep EEG variables.

STUDY OBJECTIVES: To examine sex differences in nocturnal growth hormone and prolactin release in older adults. DESIGN: Sleep was polygraphically recorded for 2 consecutive nights, and blood was sampled at frequent intervals during the last 24 hours. SETTING: The University of Chicago Clinical Research Center. PARTICIPANTS: Two groups of healthy nonobese older subjects: 10 men (59 +/- 2 years, mean +/- SEM), and 10 postmenopausal women (63 +/- 2 years). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: A spectral analysis of the electroencephalogram was performed in the delta and alpha bands. When delta activity was normalized for the activity in rapid eye movement sleep, women had lower delta activity than men. Growth hormone secretion was estimated by deconvolution. The prolactin profile was quantified by a best-fit curve. In both sexes, growth hormone was released both before and after sleep onset. In men, there was no relationship between presleep growth hormone release and subsequent sleep quality and postsleep growth hormone release correlated with delta activity. In women, presleep growth hormone release appeared to inhibit both postsleep growth hormone release and sleep consolidation. Prolactin release was related to rapid eye movement sleep and was lower in men than in women. Women with poor sleep maintenance had a lower prolactin acrophase. CONCLUSIONS: Major sex differences in the nocturnal profiles of growth hormone and prolactin and their relationship to sleep electroencephalogram variables are present in healthy older adults. Our analyses suggest that lower sleep-onset release of growth hormone in women as compared with men could be related to lower levels of delta activity. Improvements in the homeostatic control of sleep could have hormonal benefits in older adults.

Leptin levels are dependent on sleep duration: relationships with sympathovagal balance, carbohydrate regulation, cortisol, and thyrotropin.

Sleep plays an important role in energy homeostasis. The present study tests the hypothesis that circulating levels of leptin, a hormone that signals energy balance to the brain, are influenced by sleep duration. We also analyzed associations between leptin and sympathovagal balance, cortisol, TSH, glucose, and insulin under different bedtime conditions. Twenty-four-hour hormonal and glucose profiles were sampled at frequent intervals, and sympathovagal balance was estimated from heart rate variability in 11 subjects studied after 6 d of 4-h bedtimes (mean +/- sem of sleep duration during last 2 d: 3 h and 49 +/- 2 min) and after 6 d of 12-h bedtimes (sleep: 9 h and 03 +/- 15 min). A study with 8-h bedtimes was performed 1 yr later (sleep: 6 h and 52 +/- 10 min). Caloric intake and activity levels were carefully controlled in all studies. Mean levels, maximal levels, and rhythm amplitude of leptin were decreased (-19%, -26%, and -20%, respectively) during sleep restriction compared with sleep extension. The decrease in leptin levels was concomitant with an elevation of sympathovagal balance. The effects of sleep duration on leptin were quantitatively associated with alterations of the cortisol and TSH profiles and were accompanied by an elevation of postbreakfast homeostasis model assessment values. Measures of perceived stress were not increased during sleep restriction. During the study with 8-h bedtimes, hormonal and metabolic parameters were intermediate between those observed with 4-h and 12-h bedtimes. In conclusion, sleep modulates a major component of the neuroendocrine control of appetite.

Exercise elicits phase shifts and acute alterations of melatonin that vary with circadian phase.

To examine the immediate phase-shifting effects of high-intensity exercise of a practical duration (1 h) on human circadian phase, five groups of healthy men 20-30 yr of age participated in studies involving no exercise or exposure to morning, afternoon, evening, or nocturnal exercise. Except during scheduled sleep/dark and exercise periods, subjects remained under modified constant routine conditions allowing a sleep period and including constant posture, knowledge of clock time, and exposure to dim light intensities averaging (+/-SD) 42 +/- 19 lx. The nocturnal onset of plasma melatonin secretion was used as a marker of circadian phase. A phase response curve was used to summarize the phase-shifting effects of exercise as a function of the timing of exercise. A significant effect of time of day on circadian phase shifts was observed (P < 0.004). Over the interval from the melatonin onset before exercise to the first onset after exercise, circadian phase was significantly advanced in the evening exercise group by 30 +/- 15 min (SE) compared with the phase delays observed in the no-exercise group (-25 +/- 14 min, P < 0.05). Phase shifts in response to evening exercise exposure were attenuated on the second day after exercise exposure and no longer significantly different from phase shifts observed in the absence of exercise. Unanticipated transient elevations of melatonin levels were observed in response to nocturnal exercise and in some evening exercise subjects. Taken together with the results from previous studies in humans and diurnal rodents, the current results suggest that 1) a longer duration of exercise exposure and/or repeated daily exposure to exercise may be necessary for reliable phase-shifting of the human circadian system and that 2) early evening exercise of high intensity may induce phase advances relevant for nonphotic entrainment of the human circadian system.