Circadian profiles of progesterone, gonadotropins, cortisol and corticotropin in cycling and postmenopausal women.

Little is known about the regulation of temporal variations of progesterone over the 24-hr span in young cycling women as well as in postmenopausal women. The purpose of the present study was to investigate the relationships between diurnal variations of progesterone and diurnal variations of hormones of the gonadotropic and corticotropic axes, and to provide further information on the source of progesterone secretion under physiological conditions. Twenty-four-hour hormonal profiles were explored under well-controlled laboratory conditions in 10 healthy women (21-36 yr old) with normal ovulatory cycles during early-mid follicular and late luteal phases, and in 8 healthy postmenopausal women (48-74 yr old). In young cycling women, significant positive relationships were found between progesterone and follicle-stimulating hormone (FSH) - but not luteinizing hormone (LH) - profiles during late luteal phase. Conversely, during follicular phase, significant positive relationships were evidenced between progesterone and cortisol profiles, but not between progesterone and FSH or LH. In postmenopausal women, strong positive correlations were found between progesterone and corticotropin (ACTH) or cortisol profiles. The present results indicate that during late luteal phase, temporal progesterone profiles are associated with FSH rather than with LH profiles. They also provide evidence that adrenal cortex is a major - or possibly the only - source of progesterone production during the follicular phase of the normal ovulatory cycle, and probably the only source after menopause.

The important role of sleep in metabolism.

Both reduction in total sleep duration with slow-wave sleep (SWS) largely preserved and alterations of sleep quality (especially marked reduction of SWS) with preservation of total sleep duration are associated with insulin resistance without compensatory increase in insulin secretion, resulting in impaired glucose tolerance and increased risk of type 2 diabetes. When performed under rigorously controlled conditions of energy intake and physical activity, sleep restriction is also associated with a decrease in circulating levels of leptin (an anorexigenic hormone) and an increase in circulating levels of ghrelin (an orexigenic hormone), hunger and appetite. Furthermore, sleep restriction is also associated with a stimulation of brain regions sensitive to food stimuli, indicating that sleep loss may lead to obesity through the selection of high-calorie food. There is also evidence that sleep restriction could provide a permissive environment for the activation of genes that promote obesity. Indeed, the heritability of body mass index is increased in short sleepers. Thus, chronic sleep curtailment, which is on the rise in modern society, including in children, is likely to contribute to the current epidemics of type 2 diabetes and obesity.

Sleep and hormonal changes in aging.

Age-related sleep and endocrinometabolic alterations frequently interact with each other. For many hormones, sleep curtailment in young healthy subjects results in alterations strikingly similar to those observed in healthy old subjects not submitted to sleep restriction. Thus, recurrent sleep restriction, which is currently experienced by a substantial and rapidly growing proportion of children and young adults, might contribute to accelerate the senescence of endocrine and metabolic function. The mechanisms of sleep-hormonal interactions, and therefore the endocrinometabolic consequences of age-related sleep alterations, which markedly differ from one hormone to another, are reviewed in this article.

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.

Impact of GH replacement therapy on sleep in adult patients with GH deficiency of pituitary origin.

OBJECTIVES: We previously reported that adult patients with GH deficiency (GHD) due to a confirmed or likely pituitary defect, compared with healthy controls individually matched for age, gender, and BMI, have more slow-wave sleep (SWS) and higher delta activity (a marker of SWS intensity). Here, we examined the impact of recombinant human GH (rhGH) therapy, compared with placebo, on objective sleep quality in a subset of patients from the same cohort. DESIGN: Single-blind, randomized, crossover design study. METHODS: Fourteen patients with untreated GHD of confirmed or likely pituitary origin, aged 22-74 years, participated in the study. Patients with associated hormonal deficiencies were on appropriate replacement therapy. Polygraphic sleep recordings, with bedtimes individually tailored to habitual sleep times, were performed after 4 months on rhGH or placebo. RESULTS: Valid data were obtained in 13 patients. At the end of the rhGH treatment period, patients had a shorter sleep period time than at the end of the placebo period (479±11 vs 431±19 min respectively; P=0.005), primarily due to an earlier wake-up time, and a decrease in the intensity of SWS (delta activity) (559±125 vs 794±219 µV(2) respectively; P=0.048). CONCLUSIONS: Four months of rhGH replacement therapy partly reversed sleep disturbances previously observed in untreated patients. The decrease in delta activity associated with rhGH treatment adds further evidence to the hypothesis that the excess of high-intensity SWS observed in untreated pituitary GHD patients is likely to result from overactivity of the hypothalamic GHRH system due to the lack of negative feedback inhibition by GH.

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.

Sleep disturbances, daytime sleepiness, and quality of life in adults with growth hormone deficiency.

CONTEXT: Low energy and fatigue are frequent complaints in subjects with GH deficiency (GHD). Because interrelations between sleep and GH regulation are well documented, these complaints could partly reflect alterations of sleep quality. OBJECTIVE: The objective of the study was to determine objective and subjective sleep quality and daytime sleepiness in adult GHD patients. SUBJECTS: Thirty patients, aged 19-74 yr, with untreated GHD (primary pituitary defects confirmed or likely in 26 patients, hypothalamic origin in four patients), and 30 healthy controls individually matched for gender, age, and body mass index participated in the study. Patients with associated pituitary deficiencies (n = 28) were on hormonal replacement therapy. METHODS: Polygraphic sleep recordings, assessment of Pittsburgh Sleep Quality Index, and Quality of Life Assessment for GHD in Adults were measured. RESULTS: Irrespective of etiology, GHD patients had a Pittsburgh Sleep Quality Index score above the clinical cutoff for poor sleep and lower Quality of Life Assessment for GHD in Adults scores than controls, with tiredness being the most affected domain. Patients with pituitary GHD spent more time in slow-wave sleep (SWS) and had a higher intensity of SWS than their controls. Among these patients, older individuals obtained less total sleep than controls, and their late sleep was more fragmented. Contrasting with pituitary GHD, the four patients with hypothalamic GHD had lower intensity of SWS than their controls. CONCLUSIONS: GHD is associated with sleep disorders that may be caused by specific hormonal alterations as well as with poor subjective sleep quality and daytime sleepiness. Disturbed sleep is likely to be partly responsible for increased tiredness, a major component of quality of life in GHD.

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.

Sex hormone binding globulin decrease as a potential pathogenetic factor for hirsutism in adolescent girls.

We investigated 252 non-obese female subjects aged 13-39 years to evaluate if an exaggerated descent of sex hormone binding globulin (SHBG) levels during adolescence can play a role in the development of hirsutism. Body hair was assessed according to Ferriman and Gallwey (FG), with a stringent criterion of normality of < or = 4. In 13-14 years girls, SHBG and free testosterone (FT) levels were similar in "hirsute" girls (FG > 4) and controls (FG < or = 4, regular menstrual cycles, no acne). In 15-18 years girls, SHBG values were lower in "hirsute" girls, FT levels were similar in both groups, FG correlated inversely with SHBG. In 19-39 yr women, FT levels were higher in "hirsute" subjects, SHBG values were similar in both groups, FG correlated positively with FT. Lowest SHBG values were observed at 15-18 years, but the slope of the decrease from 13-14 years values was greater in the "hirsute" group. FT values increased progressively with age, but the increase was greater in the "hirsute" group. Those results suggest an important role of SHBG decrease in adolescence vs. a more accentuated testosterone increase in adults, as factors conditioning the development of hirsutism in these two different periods of life.

Sex hormone binding globulin decrease as potential pathogenetic factor for hirsutism in adolescent girls / Disminución de la globulina transportadora de hormonas sexuales como factor patogénico de hirsutismo en la adolescencia

We investigated 252 non-obese female subjects aged 13-39 years to evaluate if an exaggerated descent of sex hormone binding globulin (SHBG) levels during adolescence can play a role in the development of hirsutism. Body hair was assessed according to Ferriman and Gallwey (FG), with a stringent criterion of normality of < 4. In 13-14 years girls, SHBG and free testosterone (FT) levels were similar in "hirsute" girls (FG > 4) and controls (FG < 4, regular menstrual cycles, no acne). In 15-18 years girls, SHBG values were lower in "hirsute" girls, FT levels were similar in both groups, FG correlated inversely with SHBG. In 19-39 yr women, FT levels were higher in "hirsute" subjects, SHBG values were similar in both groups, FG correlated positively with FT. Lowest SHBG values were observed at 15-18 years, but the slope of the decrease from 1314 years values was greater in the "hirsute" group. FT values increased progressively with age, but the increase was greater in the "hirsute" group. Those results suggest an important role of SHBG decrease in adolescence vs. a more accentuated testosterone increase in adults, as factors conditioning the development of hirsutism in these two different periods of life.

Se investigaron 252 mujeres con peso normal, de 13 a 39 años de edad, para evaluar si un descenso exagerado en los niveles de la globulina transportadora de hormonas sexuales ("sex hormone binding globulin"; SHBG) puede tener un rol en el desarrollo de hirsutismo. Este signo fue evaluado con la escala de Ferriman y Gallwey (FG), empleando un criterio riguroso de normalidad < 4. En niñas de 13-14 años, tanto SHBG como la testosterona libre ("free testosterone"; FT) fueron similares en niñas "hirsutas" (FG > 4) y controles (FG < 4, ciclos menstruales regulares, sin acné). En adolescentes de 15-18 años, los valores de SHBG fueron menores en las "hirsutas", los niveles de FT fueron similares en ambos grupos y el índice de FG correlacionó inversamente con SHBG. En las mujeres de 19-39 años, los niveles de FT fueron mayores en las "hirsutas", los valores de SHBG fueron similares en ambos grupos y FG correlacionó positivamente con FT. Los valores más bajos de SHBG se observaron entre 15 y 18 años, pero la pendiente de disminución a partir de los valores de 13-14 años fue mayor en el grupo de "hirsutas". Los valores de FT se incrementaron progresivamente con la edad, pero el aumento fue mayor en el grupo de "hirsutas". Estos resultados sugieren un rol importante del descenso de SHBG en la adolescencia vs. un incremento más acentuado de los niveles de testosterona en las adultas, como factores que condicionan el desarrollo del hirsutismo en esos dos diferentes periodos de la vida.

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.

Metabolic and endocrine effects of sleep deprivation.

Sleep deprivation has multiple effects on endocrine and metabolic function. In particular, sleep restriction is accompanied by increased cortisol levels in the afternoon and early evening and a shorter quiescent period compared with extended sleep periods. Those alterations could facilitate central and peripheral disturbances that are associated with glucocorticoid excess, such as memory deficits, and are similar to those observed in aging. Thus, chronic sleep loss could contribute to acceleration of the aging process. Sleep restriction is also associated with an impairment of carbohydrate tolerance, similar to that observed in individuals with clinically significant impaired glucose tolerance. Thus, chronic sleep deprivation may increase the risk for diabetes. Finally, sleep plays an important role in energy balance. Partial sleep deprivation was found to be associated with a decrease in plasma levels of leptin and a concomitant increase in plasma levels of ghrelin; subjective ratings of hunger and appetite also increased (the appetite for protein-rich foods was not significantly affected). Moreover, a remarkable correlation was found between the increase in hunger and the increase in the ghrelin:leptin ratio. Thus, the neuroendocrine regulation of appetite and food intake appears to be influenced by sleep duration, and sleep restriction may favor the development of obesity.

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.

Reciprocal interactions between the GH axis and sleep.

For more than 30 years, growth hormone (GH) has been observed to be preferentially secreted during deep, slow-wave sleep (SWS). However, the mechanisms that underlie this robust relationship that links anabolic processes in the body with behavioral rest and decreased cerebral metabolism remain to be elucidated. Current evidence indicates that GH secretion during the beginning of sleep appears to be primarily regulated by GH-releasing hormone (GHRH) stimulation occurring during a period of relative somatostatin withdrawal, which also is associated with elevated levels of circulating ghrelin. Apparently, two populations of GHRH neurons need to be simultaneously active to stimulate, in a coordinated fashion, SWS and pituitary GH release. Pharmacological interventions that are capable of increasing the duration and/or the intensity of SWS such as oral administration of gamma-hydroxybutyrate (GHB), also increase the rate of GH release. Because the normal negative feedback exerted by GH on central GHRH is inoperative in patients with GH deficiency, it is possible that the decreased energy levels and fatigue often reported by GH-deficient adults partly reflect an alteration in sleep-wake regulation. Preliminary data from a sleep study of adults with GH deficiency using wrist actigraphy for 6 nights at home and polysomnography in the laboratory indeed show decreased total sleep time and increased sleep fragmentation in GH-deficient patients as compared with normal controls.

Immediate effects of an 8-h advance shift of the rest-activity cycle on 24-h profiles of cortisol.

To investigate the adaptation of plasma cortisol profiles to an abrupt phase advance of the rest-activity cycle, eight normal young subjects were submitted in a sleep laboratory to an 8-h advance shift of their sleep-wake and dark-light cycles. The shift was achieved by advancing bedtimes from 2300-0700 to 1500-2300. Blood samples were obtained at 20-min intervals for 68 consecutive hours. The shift resulted within 6-9 h in a 3- to 4-h advance of timings of the nadir of the cortisol profile and of the end of the quiescent period but had no immediate effect on the timing of cortisol acrophase. The quiescent period of cortisol secretion was shortened and fragmented. Thus a major advance shift achieved without enforcing sleep deprivation results in a rapid partial adaptation of the temporal profiles of cortisol but also in a marked disruption of the cortisol quiescent period. Sleep onset was consistently followed by a decrease in cortisol concentrations. Conversely, both sleep-wake and dark-light transitions were consistently associated with cortisol secretory pulses.