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1.  Impact of growth hormone replacement therapy on sleep in adult patients with growth hormone deficiency of pituitary origin 
We previously reported that adult patients with GH deficiency (GHD) due to a confirmed or likely pituitary defect, as compared to 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 to placebo, on objective sleep quality in a subset of patients from the same cohort.
Single-blind randomized cross-over design study.
Fourteen patients with untreated GHD of confirmed or likely pituitary origin, aged 22–74 yr, 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.
Valid data were obtained in 13 patients. At the end of 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 μV2, respectively; p=0.048).
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.
PMCID: PMC3832204  PMID: 23447518
growth hormone; sleep; slow-wave activity; hormonal replacement
2.  Sleep Disturbances and Their Relationship to Glucose Tolerance in Pregnancy 
Diabetes Care  2011;34(11):2454-2457.
To explore relationships among sleep disturbances, glucose tolerance, and pregnancy outcomes.
Four validated sleep questionnaires were administered to 169 pregnant women at the time of 50-g oral glucose tolerance testing (OGTT) during the second trimester. Pregnancy outcomes were analyzed in 108 women with normal glucose tolerance (NGT).
Of the participants, 41% had excessive daytime sleepiness (Epworth Sleepiness Scale [ESS] >8); 64% had poor sleep quality; 25% snored frequently; 29% had increased risk of sleep-disordered breathing (SDB); 52% experienced short sleep (SS); 19% had both increased SDB risk and SS (SDB/SS); and 14% had daytime dysfunction. Reported sleep duration inversely correlated with glucose values from 50-g OGTT (r = −0.21, P < 0.01). Each hour of reduced sleep time was associated with a 4% increase in glucose levels. Increased likelihood of gestational diabetes mellitus (GDM) was found in subjects with increased SDB risk (odds ratio 3.0 [95% CI 1.2–7.4]), SS (2.4 [1.0–5.9]), SDB/SS (3.4 [1.3–8.7]), and frequent snoring (3.4 [1.3–8.8], after adjustment for BMI). Among NGT subjects, preterm delivery was more frequent in those with increased ESS (P = 0.02), poor sleep quality (P = 0.02), and SS (P = 0.03). Neonatal intensive care unit admissions were associated with increased ESS (P = 0.03), SDB/SS (P = 0.03), and daytime dysfunction (P < 0.01) in mothers.
Pregnant women experience significant sleep disturbances that are associated with increased risk of GDM and unfavorable pregnancy outcomes. Pregnant women with increased SDB risk, frequent snoring, and sleep duration of <7 h/night have increased risk of developing GDM.
PMCID: PMC3198297  PMID: 21926292
3.  Cross-Sectional Associations Between Measures of Sleep and Markers of Glucose Metabolism Among Subjects With and Without Diabetes 
Diabetes Care  2011;34(5):1171-1176.
To examine whether sleep duration and quality are associated with fasting glucose, fasting insulin, or estimated insulin resistance in a community-based sample of early middle-aged adults.
This was an ancillary study to the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Habitual sleep duration and fragmentation were estimated from 6 days of wrist actigraphy collected in 2003–2005. Insomnia was defined as self-reported difficulty falling asleep or waking up in the night three or more times per week plus average sleep efficiency of <80% based on actigraphy. Fasting blood samples to measure glucose and insulin were collected after the sleep measures during the CARDIA clinical examination in 2005–2006. Insulin resistance was estimated using the homeostatic model assessment (HOMA) method. Analyses were cross-sectional and stratified by the presence of diabetes.
There was no association between sleep measures and fasting glucose, insulin, or HOMA in the 115 subjects without diabetes. Among the 40 subjects with diabetes, after adjustment for covariates, 10% higher sleep fragmentation was associated with a 9% higher fasting glucose level, a 30% higher fasting insulin level, and a 43% higher HOMA level. Insomnia was associated with a 23% higher fasting glucose level, a 48% higher fasting insulin level, and an 82% higher HOMA level.
The observed association between poor sleep quality and higher glucose, insulin, and estimated insulin resistance among subjects with diabetes warrants further examination of the effect of sleep disturbances on glucose control in type 2 diabetes.
PMCID: PMC3114508  PMID: 21411507
4.  Role of Sleep and Sleep Loss in Hormonal Release and Metabolism 
Endocrine development  2009;17:11-21.
Compared to a few decades ago, adults, as well as children, sleep less. Sleeping as little as possible is often seen as an admirable behavior in contemporary society. However, sleep plays a major role in neuroendocrine function and glucose metabolism. Evidence that the curtailment of sleep duration may have adverse health effects has emerged in the past 10 years. Accumulating evidence from both epidemiologic studies and well-controlled laboratory studies indicates that chronic partial sleep loss may increase the risk of obesity and weight gain. The present chapter reviews epidemiologic studies in adults and children and laboratory studies in young adults indicating that sleep restriction results in metabolic and endocrine alterations, including decreased glucose tolerance, decreased insulin sensitivity, increased evening concentrations of cortisol, increased levels of ghrelin, decreased levels of leptin and increased hunger and appetite. Altogether, the evidence points to a possible role of decreased sleep duration in the current epidemic of obesity. Bedtime extension in short sleepers should be explored as a novel behavioral intervention that may prevent weight gain or facilitate weight loss. Avoiding sleep deprivation may help to prevent the development of obesity, particularly in children.
PMCID: PMC3065172  PMID: 19955752
5.  Impact of Untreated Obstructive Sleep Apnea on Glucose Control in Type 2 Diabetes 
Rationale: Obstructive sleep apnea (OSA), a treatable sleep disorder that is associated with alterations in glucose metabolism in individuals without diabetes, is a highly prevalent comorbidity of type 2 diabetes. However, it is not known whether the severity of OSA is a predictor of glycemic control in patients with diabetes.
Objectives: To determine the impact of OSA on hemoglobin A1c (HbA1c), the major clinical indicator of glycemic control, in patients with type 2 diabetes.
Methods: We performed polysomnography studies and measured HbA1c in 60 consecutive patients with diabetes recruited from outpatient clinics between February 2007 and August 2009.
Measurements and Main Results: A total of 77% of patients with diabetes had OSA (apnea–hypopnea index [AHI] ≥5). Increasing OSA severity was associated with poorer glucose control, after controlling for age, sex, race, body mass index, number of diabetes medications, level of exercise, years of diabetes and total sleep time. Compared with patients without OSA, the adjusted mean HbA1c was increased by 1.49% (P = 0.0028) in patients with mild OSA, 1.93% (P = 0.0033) in patients with moderate OSA, and 3.69% (P < 0.0001) in patients with severe OSA (P < 0.0001 for linear trend). Measures of OSA severity, including total AHI (P = 0.004), rapid eye movement AHI (P = 0.005), and the oxygen desaturation index during total and rapid eye movement sleep (P = 0.005 and P = 0.008, respectively) were positively correlated with increasing HbA1c levels.
Conclusions: In patients with type 2 diabetes, increasing severity of OSA is associated with poorer glucose control, independent of adiposity and other confounders, with effect sizes comparable to those of widely used hypoglycemic drugs.
PMCID: PMC2830401  PMID: 20019340
sleep disordered breathing; glycemic control; diabetes
6.  Association between sleep and blood pressure in mid life: The CARDIA Sleep Study 
Archives of internal medicine  2009;169(11):1055-1061.
Epidemiologic studies have reported an association between self-reported short sleep duration and high blood pressure. Our objective was to examine both cross-sectional and longitudinal associations between objectively-measured sleep and blood pressure.
This is an ancillary study to the Coronary Artery Risk Development in Young Adults (CARDIA) cohort study. Blood pressure was measured in 2000-2001 and 2005-2006. Sleep was measured using wrist actigraphy for 3 consecutive days twice between 2003 and 2005. Sleep duration and sleep maintenance (a component of sleep quality) were calculated. Analyses included 578 African-Americans and whites aged 33 to 45 years at baseline. Outcome measures were systolic and diastolic blood pressure, 5-year change in blood pressure and incident hypertension.
After excluding those taking anti-hypertensive medications and adjusting for age, race and sex, shorter sleep duration and lower sleep maintenance significantly predicted higher systolic and diastolic blood pressure cross-sectionally and more adverse changes in systolic and diastolic blood pressure over five years (all p<.05). Short sleep duration also significantly predicted increased odds of incident hypertension (OR 1.37, 95% CI: 1.05, 1.78). Adjustment for 16 additional covariates, including snoring and daytime sleepiness, slightly attenuated the associations between sleep and blood pressure. Sleep duration appeared to mediate the difference between African Americans and Whites in diastolic blood pressure change over time (p=.02).
Reduced sleep duration and consolidation predicted higher blood pressure levels and adverse changes in blood pressure, suggesting the need for studies of whether interventions to optimize sleep may reduce blood pressure.
PMCID: PMC2944774  PMID: 19506175
7.  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.
PMCID: PMC2902103  PMID: 20628523
8.  Polycystic Ovary Syndrome and Obstructive Sleep Apnea 
Sleep medicine clinics  2008;3(1):37-46.
Polycystic ovary syndrome (PCOS), the most common endocrine disorder of pre-menopausal women, is characterized by chronic hyperandrogenism, oligoanovulation, obesity and insulin resistance. Importantly, PCOS women are at increased risk for glucose intolerance, type 2 diabetes and cardiovascular disorders. Recent reports indicate an unexpectedly high prevalence of obstructive sleep apnea (OSA) in PCOS. Alterations in sex steroids (i.e. high androgen and low estrogen levels) and increased visceral adiposity in PCOS could potentially contribute to the increased prevalence of OSA in this disorder. There is some evidence to suggest that there may be strong associations between the presence and severity of OSA and the metabolic disturbances that characterize PCOS. Causal mechanisms in the link between PCOS and OSA remain to be elucidated. Clinicians who manage PCOS patients should be aware of the high prevalence of OSA in these patients and systematically evaluate these women for sleep disturbances.
PMCID: PMC2390828  PMID: 19255602
PCOS; visceral adiposity; obesity; insulin resistance; OSA
9.  Sleep and the epidemic of obesity in children and adults 
European Journal of Endocrinology  2008;159(S1):S59-S66.
Sleep is an important modulator of neuroendocrine function and glucose metabolism in children as well as in adults. In recent years, sleep curtailment has become a hallmark of modern society with both children and adults having shorter bedtimes than a few decades ago. This trend for shorter sleep duration has developed over the same time period as the dramatic increase in the prevalence of obesity. There is rapidly accumulating evidence from both laboratory and epidemiological studies to indicate that chronic partial sleep loss may increase the risk of obesity and weight gain. The present article reviews laboratory evidence indicating that sleep curtailment in young adults results in a constellation of metabolic and endocrine alterations, including decreased glucose tolerance, decreased insulin sensitivity, elevated sympathovagal balance, increased evening concentrations of cortisol, increased levels of ghrelin, decreased levels of leptin, and increased hunger and appetite. We also review cross-sectional epidemiological studies associating short sleep with increased body mass index and prospective epidemiological studies that have shown an increased risk of weight gain and obesity in children and young adults who are short sleepers. Altogether, the evidence points to a possible role of decreased sleep duration in the current epidemic of obesity.
PMCID: PMC2755992  PMID: 18719052
10.  The Metabolic Consequences of Sleep Deprivation 
Sleep medicine reviews  2007;11(3):163-178.
The prevalence of diabetes and obesity is increasing at an alarming rate worldwide, and the causes of this pandemic are not fully understood. Chronic sleep curtailment is a behavior that has developed over the past 2-3 decades. Laboratory and epidemiological studies suggest that sleep loss may play a role in the increased prevalence of diabetes and/or obesity. Current data suggest the relationship between sleep restriction, weight gain and diabetes risk may involve at least three pathways: 1. alterations in glucose metabolism; 2. upregulation of appetite; 3. decreased energy expenditure. The present article reviews the current evidence in support of these three mechanisms that might link short sleep and increased obesity and diabetes risk.
PMCID: PMC1991337  PMID: 17442599
Sleep Deprivation; Diabetes; Obesity; Glucose Tolerance; Energy Expenditure; Epidemiology; leptin; ghrelin; appetite; orexins

Results 1-10 (10)