A systemic review and meta-analysis exploring the predictors of sperm retrieval in patients with non-obstructive azoospermia and chromosomal abnormalities.

To identify the most prevalent chromosomal abnormalities in patients with non-obstructive azoospermia (NOA), consolidate their surgical sperm retrieval (SSR) rates and determine the significant predictors of positive SSR in this patient population. A systematic review and meta-analysis were performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Fifty-three studies including 2965 patients were identified through searching the PubMed database. Klinefelter Syndrome (KS) was the most prevalent chromosomal abnormality reported in 2239 cases (75.5%). Azoospermia factor c (AZFc) microdeletions were the second most common (18.6%), but men with these deletions had higher SSR rates than patients with KS (41.95% with AZFc vs. 38.63% with KS). When examining predictors of SSR in KS patients, younger age was a significant predictor of positive SSR in patients undergoing microsurgical testicular sperm extraction (micro-TESE). Higher testosterone was a favourable predictor in those undergoing micro-TESE and conventional TESE. Lower luteinizing hormone (LH) and follicular stimulating hormone (FSH) values were significantly associated with positive SSR with testicular sperm aspiration (TESA). No parameter predicted SSR rates in patients with AZFc microdeletions. Overall, genetic abnormalities have significant implications on SSR success in patients with NOA.

Effects of sleep restriction on the human plasma metabolome.

This study examined the effects of recurrent sleep restriction on the plasma metabolome of adults with familial risk of type 2 diabetes. Eleven healthy adults (6M/5F; mean [SD] age: 26 [3]years; BMI 23.5 [2.3]kg/m(2)) with parental history of type 2 diabetes participated in a two-condition, two-period randomized crossover study at the Clinical Resource Center at an academic hospital. Each participant completed two 8-night inpatient sessions with restricted (5.5-h time-in-bed) vs. adequate (8.5-h time-in-bed) sleep opportunity while daily food intake and physical activity were carefully controlled. A combination of two UHPLC/MS/MS platforms and one GC/MS platform was used to measure 362 biochemicals in fasting plasma samples collected from study participants the morning after each 8-night sleep treatment. Relative concentrations of 12 amino acids and related metabolites were increased when sleep was curtailed. Sleep restriction also induced elevations in several fatty acid, bile acid, steroid hormone, and tricarboxylic acid cycle intermediates. In contrast, circulating levels of glucose, some monosaccharides, gluconate, and five-carbon sugar alcohols tended to decline when sleep was reduced. Recurrent sleep curtailment affected multiple pathways of intermediary metabolism in adults at risk for type 2 diabetes. An elevation in plasma amino acids and related biochemicals was the most pronounced metabolic signature seen in response to 8 nights of sleep restriction.

Differences in insulin secretion and sensitivity in short-sleep insomnia.

OBJECTIVE: Short-sleep insomnia is associated with increased risk of diabetes. The role of altered insulin secretion and action in this association is poorly understood. DESIGN: Observational study. SETTING: Academic clinical research center. PARTICIPANTS: Nondiabetic individuals with insomnia (mean [standard deviation] age 48 [9] y, body mass index 25.6 [3.9] kg/m(2)) with ≤ 6 h (short sleep, n = 14) and > 6 h of sleep (n = 14) during overnight laboratory polysomnography. MEASUREMENTS AND RESULTS: Standard oral glucose testing was used to assess glucose tolerance, beta-cell function (homeostasis model assessment [HOMA-B]; second-phase insulin secretion) and insulin resistance (HOMA-IR; insulin sensitivity index). There was no significant difference in hemoglobin A1C and fasting or 2-h blood glucose concentrations between sleep groups. Short-sleep insomnia sufferers had lower fasting and postchallenge serum insulin concentrations associated with lower estimates of fasting and glucose-stimulated insulin secretion, and increased insulin sensitivity. CONCLUSIONS: Individuals with short-sleep insomnia appear to have higher indices of systemic insulin sensitivity and secrete less insulin without changes in overall glucose tolerance.

Sleep restriction decreases the physical activity of adults at risk for type 2 diabetes.

STUDY OBJECTIVE: To test the hypothesis that recurrent sleep curtailment will result in decreased physical activity in adults at risk for type 2 diabetes. DESIGN: Two-condition 2-period randomized crossover study. SETTING: University General Clinical Research Center. PARTICIPANTS: Eighteen healthy patients with parental history of type 2 diabetes (9 females and 9 males, age 27 yr [standard deviation 3], body mass index 23.7 [2.3] kg/m²). INTERVENTIONS: Two week-long inpatient sessions with 8.5 or 5.5-hr nighttime sleep opportunity. Participants who exercised regularly (39%) could follow their usual exercise routines during both sessions. MEASUREMENTS AND RESULTS: Sleep and total body movement were measured by wrist actigraphy and waist accelerometry. Subjective mood and vigor was assessed using visual analog scales. The main outcome was the comparison of total activity counts between sleep conditions. Ancillary endpoints included changes in sedentary, light, and moderate plus vigorous activity, and their association with changes in mood and vigor. Daily sleep was reduced by 2.3 hr (P < 0.001) and total activity counts were 31% lower (P = 0.020) during the 5.5-hr time-in-bed condition. This was accompanied by a 24% reduction in moderate-plus-vigorous activity time (P = 0.005) and more sedentary behavior (+21 min/day; P = 0.020). The decrease in daily activity during the 5.5-hr time-in-bed condition was seen mostly in participants who exercised regularly (-39 versus -4% in exercisers versus nonexercisers; P = 0.027). Sleep loss-related declines in physical activity correlated strongly with declines in subjective vigor (R = 0.90; P < 0.001). CONCLUSIONS: Experimental sleep restriction results in decreased amount and intensity of physical activity in adults at risk for type 2 diabetes.

Effects of sleep restriction on glucose control and insulin secretion during diet-induced weight loss.

Insufficient sleep is associated with changes in glucose tolerance, insulin secretion, and insulin action. Despite widespread use of weight-loss diets for metabolic risk reduction, the effects of insufficient sleep on glucose regulation in overweight dieters are not known. To examine the consequences of recurrent sleep restriction on 24-h blood glucose control during diet-induced weight loss, 10 overweight and obese adults (3F/7M; mean (s.d.) age 41 (5) years; BMI 27.4 (2.0) kg/m(2)) completed two 14-day treatments with hypocaloric diet and 8.5- or 5.5-h nighttime sleep opportunity in random order 7 (3) months apart. Oral and intravenous glucose tolerance test (IVGTT) data, fasting lipids and free fatty acids (FFA), 24-h blood glucose, insulin, C-peptide, and counter-regulatory hormone measurements were collected after each treatment. Participants had comparable weight loss (1.0 (0.3) BMI units) during each treatment. Bedtime restriction reduced sleep by 131 (30) min/day. Recurrent sleep curtailment decreased 24-h serum insulin concentrations (i.e., enhanced 24-h insulin economy) without changes in oral glucose tolerance and 24-h glucose control. This was accompanied by a decline in fasting blood glucose, increased fasting FFA, which suppressed normally following glucose ingestion, and lower total and low-density lipoprotein cholesterol concentrations. Sleep-loss-related changes in counter-regulatory hormone secretion during the IVGTT limited the utility of the test in this study. In conclusion, sleep restriction enhanced 24-h insulin economy without compromising glucose homeostasis in overweight individuals placed on a balanced hypocaloric diet. The changes in fasting blood glucose, insulin, lipid and FFA concentrations in sleep-restricted dieters resembled the pattern of human metabolic adaptation to reduced carbohydrate availability.

Sleep and eating behavior in adults at risk for type 2 diabetes.

Insufficient quantity and quality of sleep may modulate eating behavior, everyday physical activity, overall energy balance, and individual risk of obesity and type 2 diabetes. We examined the association of habitual sleep quantity and quality with the self-reported pattern of eating behavior in 53 healthy urban adults with parental history of type 2 diabetes (30 F/23 M; mean (s.d.) age: 27 (4) years; BMI: 23.9 (2.3) kg/m(2)) while taking into consideration the amount of their everyday physical activity. Participants completed 13 (3) days of sleep and physical activity monitoring by wrist actigraphy and waist accelerometry while following their usual lifestyle at home. Overnight laboratory polysomnography was used to screen for sleep disorders. Subjective sleep quality was measured with the Pittsburgh Sleep Quality Index. Eating behavior was assessed using the original 51-item and the revised 18-item version of the Three-Factor Eating Questionnaire including measures of cognitive restraint, disinhibition, hunger, and uncontrolled and emotional eating. In multivariable regression analyses adjusted for age, BMI, gender, race/ethnicity, level of education, habitual sleep time measured by wrist actigraphy and physical activity measured by waist accelerometry, lower subjective sleep quality was associated with increased hunger, more disinhibited, uncontrolled and emotional eating, and higher cognitive restraint. There was no significant association between the amount of sleep measured by wrist actigraphy and any of these eating behavior factors. Our findings indicate that small decrements in self-reported sleep quality can be a sensitive indicator for the presence of potentially problematic eating patterns in healthy urban adults with familial risk for type 2 diabetes.

Reduced physical activity in adults at risk for type 2 diabetes who curtail their sleep.

Adults with parental history of type 2 diabetes have high metabolic morbidity, which is exacerbated by physical inactivity. Self-reported sleep <6 h/day is associated with increased incidence of obesity and diabetes, which may be mediated in part by sleep-loss-related reduction in physical activity. We examined the relationship between habitual sleep curtailment and physical activity in adults with parental history of type 2 diabetes. Forty-eight young urban adults with parental history of type 2 diabetes (27 F/21 M; mean (s.d.) age 26 (4) years; BMI 23.8 (2.5) kg/m(2)) each completed 13 (2) days of sleep and physical activity monitoring by wrist actigraphy and waist accelerometry while following their usual lifestyle at home. Laboratory polysomnography was used to screen for sleep disorders. The primary outcome of the study was the comparison of total daily activity counts between participants with habitual sleep <6 vs. ≥6 h/night. Secondary measures included daily time spent sedentary and in light, moderate, and vigorous physical activity. Short sleepers had no sleep abnormalities and showed signs of increased sleep pressure consistent with a behavioral pattern of habitual sleep curtailment. Compared to participants who slept ≥6 h/night, short sleepers had 27% fewer daily activity counts (P = 0.042), spent less time in moderate-plus-vigorous physical activity (-43 min/day; P = 0.010), and remained more sedentary (+69 min/day; P = 0.026). Our results indicate that young urban adults with parental history of type 2 diabetes who habitually curtail their sleep have less daily physical activity and more sedentary living, which may enhance their metabolic risk.

Changes in insulin secretion and action in adults with familial risk for type 2 diabetes who curtail their sleep.

OBJECTIVE: Experimental sleep deprivation is accompanied by changes in glucose regulation. However, the effects of chronic sleep insufficiency on insulin secretion and action in populations at high risk for type 2 diabetes are not known. This study examined the relationship between objectively documented habitual sleep curtailment and measures of insulin sensitivity, insulin secretion, and oral glucose tolerance in free-living adults with parental history of type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 47 healthy participants with parental history of type 2 diabetes (26 female/21 male, mean [SD] age 26 [4] years and BMI 23.8 [2.5] kg/m(2)) completed 13 (SD = 2) days of sleep and physical activity monitoring by wrist actigraphy and waist accelerometry while following their usual lifestyle at home. Laboratory polysomnography was used to screen for sleep disorders. Indices of diabetes risk based on oral glucose tolerance tests were compared between participants with habitual short sleep and those with usual sleep duration >6 h/day. RESULTS: Consistent with a behavioral pattern of habitual sleep curtailment, short sleepers obtained an average of 1.5 h less sleep per night and showed signs of increased sleep pressure. Participants who habitually curtailed their sleep had considerably higher indices of insulin resistance and increased insulin secretion but maintained normal glucose tolerance similar to that of subjects who slept more. CONCLUSIONS: Young lean adults with parental history of type 2 diabetes who habitually curtail their sleep have increased insulin resistance and compensatory hyperinsulinemia--a pattern that has been associated with higher risk of developing diabetes in such susceptible individuals.

Insufficient sleep undermines dietary efforts to reduce adiposity.

BACKGROUND: Sleep loss can modify energy intake and expenditure. OBJECTIVE: To determine whether sleep restriction attenuates the effect of a reduced-calorie diet on excess adiposity. DESIGN: Randomized, 2-period, 2-condition crossover study. SETTING: University clinical research center and sleep laboratory. PATIENTS: 10 overweight nonsmoking adults (3 women and 7 men) with a mean age of 41 years (SD, 5) and a mean body mass index of 27.4 kg/m² (SD, 2.0). INTERVENTION: 14 days of moderate caloric restriction with 8.5 or 5.5 hours of nighttime sleep opportunity. MEASUREMENTS: The primary measure was loss of fat and fat-free body mass. Secondary measures were changes in substrate utilization, energy expenditure, hunger, and 24-hour metabolic hormone concentrations. RESULTS: Sleep curtailment decreased the proportion of weight lost as fat by 55% (1.4 vs. 0.6 kg with 8.5 vs. 5.5 hours of sleep opportunity, respectively; P = 0.043) and increased the loss of fat-free body mass by 60% (1.5 vs. 2.4 kg; P = 0.002). This was accompanied by markers of enhanced neuroendocrine adaptation to caloric restriction, increased hunger, and a shift in relative substrate utilization toward oxidation of less fat. LIMITATION: The nature of the study limited its duration and sample size. CONCLUSION: The amount of human sleep contributes to the maintenance of fat-free body mass at times of decreased energy intake. Lack of sufficient sleep may compromise the efficacy of typical dietary interventions for weight loss and related metabolic risk reduction. PRIMARY FUNDING SOURCE: National Institutes of Health.

Changes in serum TSH and free T4 during human sleep restriction.

STUDY OBJECTIVES: To examine whether recurrent sleep restriction is accompanied by changes in measures of thyroid function. DESIGN: Two-period crossover intervention study. SETTING: University clinical research center and sleep laboratory. PARTICIPANTS: 11 healthy volunteers (5F/6M) with a mean (+/- SD) age of 39 +/- 5 y and BMI 26.5 +/- 1.5 kg/m2. INTERVENTION: Randomized exposure to 14 days of sedentary living with ad libitum food intake and 5.5- vs. 8.5-h overnight sleep opportunity. MEASUREMENTS AND RESULTS: Serum thyroid-stimulating hormone (TSH) and free thyroxine (T4) were measured at the end of each intervention. Partial sleep restriction was accompanied by a modest but statistically significant reduction in TSH and free T4, seen mainly in the female participants of the study. CONCLUSIONS: Compared to the well-known rise in TSH and thyroid hormone concentrations during acute sleep loss, tests obtained after 14 days of partial sleep restriction did not show a similar activation of the human thyroid axis.

Exposure to recurrent sleep restriction in the setting of high caloric intake and physical inactivity results in increased insulin resistance and reduced glucose tolerance.

CONTEXT: Epidemiological data indicate that reduced sleep duration is associated with increased incidence of type-2 diabetes. OBJECTIVE: The aim of the study was to test the hypothesis that, when part of a Western-like lifestyle, recurrent bedtime restriction may result in decreased glucose tolerance and reduced insulin secretion and action. DESIGN AND SETTING: We conducted a randomized crossover study at a university clinical research center and sleep research laboratory. PARTICIPANTS: Eleven healthy volunteers (five females and six males) with a mean (+/-sd) age of 39 +/- 5 yr and body mass index of 26.5 +/- 1.5 kg/m(2) participated in the study. INTERVENTION: The study included two 14-d periods of controlled exposure to sedentary living with ad libitum food intake and 5.5- or 8.5-h bedtimes. MAIN OUTCOME MEASURES: Oral and iv glucose challenges were used to obtain measures of glucose tolerance, glucose effectiveness, insulin secretion, and insulin sensitivity at the end of each intervention. Secondary measures included circulating concentrations of the glucose counter-regulatory hormones, cortisol, GH, epinephrine, and norepinephrine. RESULTS: Bedtime restriction reduced daily sleep by 122 +/- 25 min. Both study periods were associated with comparable weight gain; however, recurrent sleep restriction resulted in reduced oral glucose tolerance (2-h glucose value, 144 +/- 25 vs. 132 +/- 36 mg/dl; P < 0.01) and insulin sensitivity [3.3 +/- 1.1 vs. 4.0 +/- 1.6 (mU/liter)(-1) x min(-1); P < 0.03], and increased glucose effectiveness (0.023 +/- 0.005 vs. 0.020 +/- 0.005 min(-1); P < 0.04). Although 24-h cortisol and GH concentrations did not change, there was a modest increase in 24-h epinephrine and nighttime norepinephrine levels during the 5.5-h bedtime condition. CONCLUSIONS: Experimental bedtime restriction, designed to approximate the short sleep times experienced by many individuals in Westernized societies, may facilitate the development of insulin resistance and reduced glucose tolerance.

Sleep curtailment is accompanied by increased intake of calories from snacks.

BACKGROUND: Short sleep is associated with obesity and may alter the endocrine regulation of hunger and appetite. OBJECTIVE: We tested the hypothesis that the curtailment of human sleep could promote excessive energy intake. DESIGN: Eleven healthy volunteers [5 women, 6 men; mean +/- SD age: 39 +/- 5 y; mean +/- SD body mass index (in kg/m(2)): 26.5 +/- 1.5] completed in random order two 14-d stays in a sleep laboratory with ad libitum access to palatable food and 5.5-h or 8.5-h bedtimes. The primary endpoints were calories from meals and snacks consumed during each bedtime condition. Additional measures included total energy expenditure and 24-h profiles of serum leptin and ghrelin. RESULTS: Sleep was reduced by 122 +/- 25 min per night during the 5.5-h bedtime condition. Although meal intake remained similar (P = 0.51), sleep restriction was accompanied by increased consumption of calories from snacks (1087 +/- 541 compared with 866 +/- 365 kcal/d; P = 0.026), with higher carbohydrate content (65% compared with 61%; P = 0.04), particularly during the period from 1900 to 0700. These changes were not associated with a significant increase in energy expenditure (2526 +/- 537 and 2390 +/- 369 kcal/d during the 5.5-h and 8.5-h bedtime periods, respectively; P = 0.58), and we found no significant differences in serum leptin and ghrelin between the 2 sleep conditions. CONCLUSIONS: Recurrent bedtime restriction can modify the amount, composition, and distribution of human food intake, and sleeping short hours in an obesity-promoting environment may facilitate the excessive consumption of energy from snacks but not meals.

Impaired beta-cell compensation to dexamethasone-induced hyperglycemia in women with polycystic ovary syndrome.

Deterioration in glucose tolerance occurs rapidly in women with polycystic ovary syndrone (PCOS), suggesting that pancreatic beta-cell dysfunction may supervene early. To determine whether the compensatory insulin secretory response to an increase in insulin resistance induced by the glucocorticoid dexamethasone differs in women with PCOS and control subjects, we studied 10 PCOS and 6 control subjects with normal glucose tolerance. An oral glucose tolerance test (OGTT) and a graded glucose infusion protocol were performed at baseline and after subjects took 2.0 mg of dexamethasone orally. Basal (Phi(b)), static (Phi(s)), dynamic (Phi(d)), and global (Phi) indexes of beta-cell sensitivity to glucose were derived. Insulin sensitivity (S(i)) was calculated using the minimal model; a disposition index (DI) was calculated as the product of S(i) and Phi. PCOS and control subjects had nearly identical fasting and 2-h glucose levels at baseline. Phi(b) was higher, although not significantly so, in the PCOS subjects. The Phi(d), Phi(s), and Phi indexes were 28, 19, and 20% higher, respectively, in PCOS subjects. The DI was significantly lower in PCOS (30.01 +/- 5.33 vs. 59.24 +/- 7.59) at baseline. After dexamethasone, control subjects averaged a 9% increase (to 131 +/- 12 mg/dl) in 2-h glucose levels; women with PCOS had a significantly greater 26% increase to 155 +/- 6 mg/dl. The C-peptide-to-glucose ratios on OGTT increased by 44% in control subjects and by only 15% in PCOS subjects. The accelerated deterioration in glucose tolerance in PCOS may result, in part, from a relative attenuation in the response of the beta-cell to the demand placed on it by factors exacerbating insulin resistance.

Relationship of calpain-10 genotype to phenotypic features of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is associated with an increased risk of impaired glucose tolerance and type 2 diabetes. Recent evidence suggests that variation in the gene encoding the cysteine protease calpain-10 influences susceptibility to type 2 diabetes. The present study was undertaken to determine whether variation in this gene is associated with quantitative traits pertinent to the pathogenesis of PCOS and diabetes. We studied 212 women with PCOS (124 white of European ancestry, 57 African-American, 13 Hispanic, 13 Asian-American, and 5 Middle-Eastern). Each subject was genotyped for 3 DNA polymorphisms in the calpain-10 gene associated with type 2 diabetes (SNP-43, -19, and -63). The white and African-American subjects were examined for association of these polymorphisms with phenotypic features of PCOS and type 2 diabetes. There were not enough individuals in the other groups for similar genotype/phenotype analyses. Nineteen (9%) of the 212 women with PCOS were diabetic and were not included in the genotype/phenotype analyses. Twelve (63%) of these subjects were African-American. Phenotypic traits in nondiabetic white probands did not differ whether analyzed for each individual SNP (SNP-43, -19, -63) or haplotype combination. Nor was there association of SNP-43, -19, or -63 with any of the phenotypic features of type 2 diabetes or PCOS in nondiabetic African-Americans. However, nondiabetic African-Americans with the 112/121-haplotype combination had significantly higher insulin levels, in response to an oral glucose challenge, as reflected in the area under the insulin curve (257,021 +/- 95,384 vs. 136,240 +/- 11,468 pmol/min; P = 0.03), compared with those with other haplotypes. This finding was particularly notable because the 112/121 subjects were less obese. The difference between groups in area under the insulin response curve remained significant (P = 0.002 by analysis of covariance) after adjustment for body mass index. In addition to its association with insulin levels in African-Americans, the 112/121-haplotype combination was associated with an approximate 2-fold increase in risk of PCOS in both African-Americans and whites.