Impact of Sleep and Its Disturbances on Hypothalamo-Pituitary-Adrenal Axis Activity

The daily rhythm of cortisol secretion is relatively stable and primarily under the influence of the circadian clock. Nevertheless, several other factors affect hypothalamo-pituitary-adrenal (HPA) axis activity. Sleep has modest but clearly detectable modulatory effects on HPA axis activity. Sleep onset exerts an inhibitory effect on cortisol secretion while awakenings and sleep offset are accompanied by cortisol stimulation. During waking, an association between cortisol secretory bursts and indices of central arousal has also been detected. Abrupt shifts of the sleep period induce a profound disruption in the daily cortisol rhythm, while sleep deprivation and/or reduced sleep quality seem to result in a modest but functionally important activation of the axis. HPA hyperactivity is clearly associated with metabolic, cognitive and psychiatric disorders and could be involved in the well-documented associations between sleep disturbances and the risk of obesity, diabetes and cognitive dysfunction. Several clinical syndromes, such as insomnia, depression, Cushing's syndrome, sleep disordered breathing (SDB) display HPA hyperactivity, disturbed sleep, psychiatric and metabolic impairments. Further research to delineate the functional links between sleep and HPA axis activity is needed to fully understand the pathophysiology of these syndromes and to develop adequate strategies of prevention and treatment

Rai1 frees mice from the repression of active wake behaviors by light.

Besides its role in vision, light impacts physiology and behavior through circadian and direct (aka 'masking') mechanisms. In Smith-Magenis syndrome (SMS), the dysregulation of both sleep-wake behavior and melatonin production strongly suggests impaired non-visual light perception. We discovered that mice haploinsufficient for the SMS causal gene, Retinoic acid induced-1 (Rai1), were hypersensitive to light such that light eliminated alert and active-wake behaviors, while leaving time-spent-awake unaffected. Moreover, variables pertaining to circadian rhythm entrainment were activated more strongly by light. At the input level, the activation of rod/cone and suprachiasmatic nuclei (SCN) by light was paradoxically greatly reduced, while the downstream activation of the ventral-subparaventricular zone (vSPVZ) was increased. The vSPVZ integrates retinal and SCN input and, when activated, suppresses locomotor activity, consistent with the behavioral hypersensitivity to light we observed. Our results implicate Rai1 as a novel and central player in processing non-visual light information, from input to behavioral output

Is physiological glucocorticoid replacement important in children?

Cortisol has a distinct circadian rhythm with low concentrations at night, rising in the early hours of the morning, peaking on waking and declining over the day to low concentrations in the evening. Loss of this circadian rhythm, as seen in jetlag and shift work, is associated with fatigue in the short term and diabetes and obesity in the medium to long term. Patients with adrenal insufficiency on current glucocorticoid replacement with hydrocortisone have unphysiological cortisol concentrations being low on waking and high after each dose of hydrocortisone. Patients with adrenal insufficiency complain of fatigue, a poor quality of life and there is evidence of poor health outcomes including obesity potentially related to glucocorticoid replacement. New technologies are being developed that deliver more physiological glucocorticoid replacement including hydrocortisone by subcutaneous pump, Plenadren, a once-daily modified-release hydrocortisone and Chronocort, a delayed and sustained absorption hydrocortisone formulation that replicates the overnight profile of cortisol. In this review, we summarise the evidence regarding physiological glucocorticoid replacement with a focus on relevance to paediatrics

Longer sleep is associated with lower BMI and favorable metabolic profiles in UK adults: Findings from the National Diet and Nutrition Survey

Ever more evidence associates short sleep with increased risk of metabolic diseases such as obesity, which may be related to a predisposition to non-homeostatic eating. Few studies have concurrently determined associations between sleep duration and objective measures of metabolic health as well as sleep duration and diet, however. We therefore analyzed associations between sleep duration, diet and metabolic health markers in UK adults, assessing associations between sleep duration and 1) adiposity, 2) selected metabolic health markers and 3) diet, using National Diet and Nutrition Survey data. Adults (n = 1,615, age 19–65 years, 57.1% female) completed questions about sleep duration and 3 to 4 days of food diaries. Blood pressure and waist circumference were recorded. Fasting blood lipids, glucose, glycated haemoglobin (HbA1c), thyroid hormones, and high-sensitivity C-reactive protein (CRP) were measured in a subset of participants. We used regression analyses to explore associations between sleep duration and outcomes. After adjustment for age, ethnicity, sex, smoking, and socioeconomic status, sleep duration was negatively associated with body mass index (-0.46 kg/m2 per hour, 95% CI -0.69 to -0.24 kg/m2, p < 0.001) and waist circumference (-0.9 cm per hour, 95% CI -1.5 to -0.3cm, p = 0.004), and positively associated with high-density lipoprotein cholesterol (0.03 mmol/L per hour, 95% CI 0.00 to 0.05, p = 0.03). Sleep duration tended to be positively associated with free thyroxine levels and negatively associated with HbA1c and CRP (p = 0.09 to 0.10). Contrary to our hypothesis, sleep duration was not associated with any dietary measures (p ≥ 0.14). Together, our findings show that short-sleeping UK adults are more likely to have obesity, a disease with many comorbidities

Interactions between sleep, stress, and metabolism: From physiological to pathological conditions

AbstractPoor sleep quality due to sleep disorders and sleep loss is highly prevalent in the modern society. Underlying mechanisms show that stress is involved in the relationship between sleep and metabolism through hypothalamic–pituitary–adrenal (HPA) axis activation. Sleep deprivation and sleep disorders are associated with maladaptive changes in the HPA axis, leading to neuroendocrine dysregulation. Excess of glucocorticoids increase glucose and insulin and decrease adiponectin levels. Thus, this review provides overall view of the relationship between sleep, stress, and metabolism from basic physiology to pathological conditions, highlighting effective treatments for metabolic disturbances

Circadian Rhythm and Sleep Disruption: Causes, Metabolic Consequences and Countermeasures.

Circadian (∼ 24 hour) timing systems pervade all kingdoms of life, and temporally optimize behaviour and physiology in humans. Relatively recent changes to our environments, such as the introduction of artificial lighting, can disorganize the circadian system, from the level of the molecular clocks that regulate the timing of cellular activities to the level of synchronization between our daily cycles of behaviour and the solar day. Sleep/wake cycles are intertwined with the circadian system, and global trends indicate that these too are increasingly subject to disruption. A large proportion of the world's population is at increased risk of environmentally-driven circadian rhythm and sleep disruption, and a minority of individuals are also genetically predisposed to circadian misalignment and sleep disorders. The consequences of disruption to the circadian system and sleep are profound and include myriad metabolic ramifications, some of which may be compounded by adverse effects on dietary choices. If not addressed, the deleterious effects of such disruption will continue to cause widespread health problems; therefore, implementation of the numerous behavioural and pharmaceutical interventions that can help restore circadian system alignment and enhance sleep will be important

Sleep-disordered breathing-do we have to change gears in heart failure?

The majority of patients with heart failure have sleep-disordered breathing (SDB)-with central (rather than obstructive) sleep apnoea becoming the predominant form in those with more severe disease. Cyclical apnoeas and hypopnoeas are associated with sleep disturbance, hypoxaemia, haemodynamic changes, and sympathetic activation. Such patients have a worse prognosis than those without SDB. Mask-based therapies of positive airway pressure targeted at SDB can improve measures of sleep quality and partially normalise the sleep and respiratory physiology, but recent randomised trials of cardiovascular outcomes in central sleep apnoea have been neutral or suggested the possibility of harm, likely from increased sudden death. Further randomised outcome studies (with cardiovascular mortality and hospitalisation endpoints) are required to determine whether mask-based treatment for SDB is appropriate for patients with chronic systolic heart failure and obstructive sleep apnoea, for those with heart failure with preserved ejection fraction, and for those with decompensated heart failure. New therapies for sleep apnoea-such as implantable phrenic nerve stimulators-also require robust assessment. No longer can the surrogate endpoints of improvement in respiratory and sleep metrics be taken as adequate therapeutic outcome measures in patients with heart failure and sleep apnoea

Sex Differences in the Impact of Obstructive Sleep Apnea on Glucose Metabolism

Objectives: Obstructive sleep apnea (OSA) is more prevalent in men and is an independent risk factor for type 2 diabetes. We aimed to determine if there are sex differences in the impact of OSA on glucose metabolism in nondiabetic overweight and obese adults.Methods: One hundred and forty-five men and women (age 33.4 ± 0.6, BMI 37.2 ± 0.7, 70.3% blacks) from the community underwent in-laboratory polysomnography. Severity of OSA was assessed by the apnea-hypopnea index (AHI). Glucose tolerance was assessed using fasting glucose, 1-h glucose, 2-h glucose and the area under the curve (AUC) during the 2-h oral glucose tolerance test (OGTT). Fasting insulin resistance was assessed by HOMA-IR, and insulin sensitivity during the OGTT was assessed by the Matsuda Index. Pancreatic beta-cell function was assessed by fasting HOMA-%B and by AUCinsulin/glucose, insulinogenic index, and oral disposition index (DIoral) during the OGTT. All comparisons were adjusted for age, BMI, race and severity of OSA.Results: There were no significant demographic differences between men and women without OSA. Men and women with OSA were similar in age, BMI, and severity of OSA, but there were more black women with OSA. Compared to women with OSA, men with OSA had significantly higher fasting glucose, 1-h glucose levels, AUCglucose, and AUC for insulin secretion rate (AUCISR) but similar 2-h glucose levels. These differences persisted in adjusted analyses. Men with OSA secreted significantly more insulin than women with OSA in order to achieve similar glucose levels. Men with OSA had significantly worse beta cell function as measured by the DIoral than women with OSA. In contrast, there were no significant sex differences in measures of glucose tolerance and beta-cell function in participants without OSA.Conclusion: Men with OSA secreted more insulin compared to women with OSA in order to maintain glucose homeostasis. The adverse impact of OSA on beta-cell responsiveness was larger in men, which may result in an overall greater risk of type 2 diabetes compared to women

Stimulatory Effect of Morning Bright Light on Reproductive Hormones and Ovulation: Results of a Controlled Crossover Trial

OBJECTIVES: Studies have shown a shortening of the menstrual cycle following light exposure in women with abnormally long menstrual cycles or with winter depression, suggesting that artificial light can influence reproductive hormones and ovulation. The study was designed to investigate this possibility. DESIGN: Placebo-controlled, crossover, counterbalanced order. SETTING: Medical centres and participants' homes in Novosibirsk (55°N), Russia. PARTICIPANTS: Twenty-two women, aged 19–37 years, with baseline menstrual cycle length 28.1–37.8 d and no clinically evident endocrine abnormalities completed the study. The study lasted for two menstrual cycles separated by at least one off-protocol cycle. INTERVENTIONS: During one experimental cycle, bright light was administered at home for 1 wk with a light box emitting white light at 4,300 lux at 41 cm for 45 min shortly after awakening. During the other experimental cycle, dim light was <100 lux at 41 cm with a one-tube fluorescent source. OUTCOME MEASURES: Blood samples and ultrasound scans were obtained in the afternoon before and after the week of light exposure, on day ∼7 and 14 after menstruation onset. Further ultrasound scans after day 14 documented ovulation. Serum was assayed for thyroid-stimulating hormone (TSH), prolactin (PRL), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol (E2). RESULTS: Concentrations of PRL, LH, and FSH were significantly increased with bright versus dim light exposure, as was follicle size (ANOVA, intervention × day, p = 0.0043, 0.014, 0.049, and 0.042, respectively). The number of ovulatory cycles increased after exposure to bright compared to dim light (12 versus 6 cycles, Wilcoxon tied p = 0.034). CONCLUSIONS: Morning exposure to bright light in the follicular phase of the menstrual cycle stimulates the secretion of hypophyseal reproductive hormones, promotes ovary follicle growth, and increases ovulation rates in women with slightly lengthened menstrual cycles. This might be a promising method to overcome infertility

Sleep, circadian rhythm and body weight: parallel developments

Circadian alignment is crucial for body-weight management, and for metabolic health. In this context, circadian alignment consists of alignment of sleep, meal patterns and physical activity. During puberty a significant reduction in sleep duration occurs, and pubertal status is inversely associated with sleep duration. A consistent inverse association between habitual sleep duration and body-weight development occurs, independent of possible confounders. Research on misalignment reveals that circadian misalignment affects sleep-architecture and subsequently disturbs glucose-insulin metabolism, substrate oxidation, leptin- and ghrelin concentrations, appetite, food reward, hypothalamic-pituitary-adrenal-axis activity and gut-peptide concentrations enhancing positive energy balance and metabolic disturbance. Not only aligning meals and sleep in a circadian way is crucial, also regular physical activity during the day strongly promotes the stability and amplitude of circadian rhythm, and thus may serve as an instrument to restore poor circadian rhythms. Endogenicity may play a role in interaction of these environmental variables with a genetic predisposition. In conclusion, notwithstanding the separate favourable effects of sufficient daily physical activity, regular meal patterns, sufficient sleep duration and quality sleep on energy balance, the overall effect of the amplitude and stability of the circadian rhythm, perhaps including genetic predisposition, may integrate the separate effects in an additive way