Iranmanesh, Ali

Abstract Context Sleep loss in men increases cortisol and decreases testosterone, and sleep restriction by 3 to 4 hours/night induces insulin resistance. Objective We clamped cortisol and testosterone and determined the effect on insulin resistance. Methods This was a randomized double-blind, in-laboratory crossover study in which 34 healthy young men underwent 4 nights of sleep restriction of 4 hours/night under 2 treatment conditions in random order: dual hormone clamp (cortisol and testosterone fixed), or matching placebo (cortisol and testosterone not fixed). Fasting blood samples, and an additional 23 samples for a 3-hour oral glucose tolerance test (OGTT), were collected before and after sleep restriction under both treatment conditions. Cytokines and hormones were measured from the fasting samples. Overall insulin sensitivity was determined from the OGTT by combining complementary measures: homeostasis model assessment of insulin resistance of the fasting state; Matsuda index of the absorptive state; and minimal model of both fasting and absorptive states. Results Sleep restriction alone induced hyperinsulinemia, hyperglycemia, and overall insulin resistance (P < 0.001 for each). Clamping cortisol and testosterone alleviated the development of overall insulin resistance (P = 0.046) and hyperinsulinemia (P = 0.014) by 50%. Interleukin-6, high-sensitivity C-reactive protein, peptide YY, and ghrelin did not change, whereas tumor necrosis factor-α and leptin changed in directions that would have mitigated insulin resistance with sleep restriction alone. Conclusion Fixing cortisol-testosterone exposure mitigates the development of insulin resistance and hyperinsulinemia, but not hyperglycemia, from sustained sleep restriction in men. The interplay between cortisol and testosterone may be important as a mechanism by which sleep restriction impairs metabolic health.

Abstract While long term fasting is reported to augment the corticotropic function, effect of short term (overnight) fasting on ACTH-cortisol coordinated release pattern and potential effect(s) of nutrient intake is not fully defined. Eleven healthy men (age: 33-70 yrs, BMI 20.4-31.5 kg-m2) were studied after overnight fast on 4 separate days, involving oral ingestion of 300 ml of either water, dextrose, protein, or lipid solutions. Test meals were isocaloric (400 kcal). Sessions were 6.5 h long, starting at 0800-0900 hrs. Blood was collected at 10-min intervals for ACTH (pg per mL), and cortisol (µg per dL) measurements. Linear regression, cross-correlation, deconvolution, and ApEn were used for data analyses. ACTH and cortisol concentration time series during short-term fast (water day) were found not to be chronologically coupled per linear regression (r2= 0.0014, P=0.82), and cross-correlation (r= - 0.156, lag=150 min) statistics. Oral intake of the 3 macronutrients improved the temporal relationship between ACTH and cortisol concentrations, verified by linear regression (r2:P- dextrose 0.54:0.0001, protein 0.65: 0.0001, lipid 0.42:0.0001), and cross-correlation (r:lag in min- dextrose 0.8:10, protein 0.77:10, lipid 0.78:20). Oral ingestion of either macronutrient did not significantly alter mean ACTH and cortisol concentrations and their respective secretion pattern (total, pulsatile, basal) over the period of 6.5 hr. However compared to the control (water) session, dextrose ingestion evoked less frequent and larger ACTH secretory bursts, and more regular ACTH and cortisol secretory patterns. In this study, we have observed lack of concordance between ACTH and cortisol after overnight fasting, which is restored with oral intake of macronutrients. This effect appears to be uniform among the 3 macronutrients, except for less frequent and lager ACTH bursts and more regular ACTH and cortisol release events after dextrose intake. These findings and the specific role of nutrients being direct or via physiologic nutrient-induced hormonal adaptation warrants future investigation.

Abstract Introduction: In young men, sleep restriction decreases testosterone and increases afternoon cortisol, leading to anabolic-catabolic imbalance, insulin resistance and metabolic, neurocognitive, reproductive, and other adverse effects. Age-related differences in the hypothalamo-pituitary-testicular/adrenal response to sleep restriction could expose older individuals to greater or lesser risk, but this possibility has not been previously studied. Subjects and Methods: Thirty-five healthy young and older men aged 18-30y (n=17) and 60-80y (n=18), underwent blood sampling in the Mayo Clinic Center for Clinical and Translational Science every 10 minutes for 24 hours from 6PM-6PM under two conditions in random order spaced at least 3 weeks apart: awake (no sleep) or sleep (from 10PM to 6AM). Blood was assayed for LH, testosterone (T) and cortisol (F), and then analyzed by automated mathematical deconvolution and with cross approximate entropy statistics to determine hormone secretion and hormone synchrony, respectively. Statistical significance was construed by repeated measures ANOVA using a full factorial model that included age, sleep and the interaction. Results: Sleep deprivation had multiple effects on 24-hour (6PM-6PM) Te secretion with significant reductions in mean concentrations, basal, total and pulsatile secretion, and pulse frequency (each P<0.05), in the absence of detectable changes in LH. These effects were most apparent in older men and differed according to age for some parameters: pulsatile Te secretion (P=0.03) and T pulse frequency (P=0.02). Time-of-day analyses revealed that sleep restriction significantly reduced Te in the morning (6AM-9AM) and afternoon (3PM-6PM), reduced LH in the morning, and increased F in the afternoon, particularly in older men. Cross-approximate entropy statistics showed that sleep restriction enforced greater LH-Te and Te-LH joint synchrony in the morning (P<0.05 for each), but not in the afternoon. Conclusion: Sleep restriction decreases morning LH secretion, morning and afternoon Te secretion, and increases afternoon F secretion, especially in older men. This combination of findings could plausibly cause metabolic and reproductive ill-health when accumulated over decades of life, and may explain how chronic sleep loss contributes to metabolic and reproductive diseases that are more prevalent in older men. These preliminary data also suggest a time-of-day dependent uncoupling of the regulatory control of the testicular axis, and of cortisol secretion. Direct verification by interventions that manipulate hormones during the morning and late afternoon in appropriately matched cohorts of young and older men are now required.

Abstract Study Objectives In young men, sleep restriction decreases testosterone (Te) and increases afternoon cortisol (F), leading to anabolic–catabolic imbalance, insulin resistance, and other andrological health consequences. Age-related differences in the hypothalamo–pituitary–testicular/adrenal response to sleep restriction could expose older individuals to greater or lesser risk. We aimed to evaluate and compare the 24-h and time-of-day effect of sleep restriction on F, luteinizing hormone (LH), and Te in young and older men. Methods Thirty-five healthy men, aged 18–30 (n = 17) and 60–80 (n =18) years, underwent overnight sleep deprivation (complete nighttime wakefulness) or nighttime sleep (10 pm to 6 am) with concurrent 10-min blood sampling in a prospectively randomized crossover study. F, LH, and Te secretion were calculated by deconvolution analysis. Results Sleep deprivation had multiple effects on 24-h Te secretion with significant reductions in mean concentrations, basal, total and pulsatile secretion, and pulse frequency (each p < 0.05), in the absence of detectable changes in LH. These effects were most apparent in older men and differed according to age for some parameters: pulsatile Te secretion (p = 0.03) and Te pulse frequency (p = 0.02). Time-of-day analyses revealed that sleep restriction significantly reduced Te in the morning and afternoon, reduced LH in the morning in both age groups, and increased F in the afternoon in older men. Conclusions These data suggest a time-of-day dependent uncoupling of the regulatory control of the testicular axis and of F secretion. Future studies will need to directly verify these regulatory possibilities specifically and separately in young and older men. Clinical Trial Not applicable.

Context Studies on 24-h cortisol secretion are rare. The impact of sex, age and adiposity on cortisol levels, often restricted to one or a few samples, are well recognized, but conflicting. Objective To investigate cortisol dynamics in 143 healthy men and women, spanning 7 decades and with a 2-fold body mass index (BMI) range with different analytic tools. Setting Clinical Research Unit. Design Cortisol concentrations in 10-min samples collected for 24 h. Outcomes were mean levels, deconvolution parameters, approximate entropy (ApEn, regularity statistic) and 24-h rhythms. Results Total 24-h cortisol secretion rates estimated by deconvolution analysis were sex, age and BMI independent. Mean 24-h cortisol concentrations were lower in premenopausal women than those in men of comparable age (176 ± 8.2 vs 217 ± 9.4 nmol/L, P = 0.02), but not in subjects older than 50 years. This was due to lower daytime levels in women, albeit similar in the quiescent overnight period. Aging increased mean cortisol by 10 nmol/L per decade during the quiescent secretory phase and advanced the acrophase of the diurnal rhythm by 24 min/decade. However, total 24-h cortisol secretion rates estimated by deconvolution analysis were sex, age and BMI independent. ApEn of 24-h profiles was higher (more random) in premenopausal women than those in men (1.048 ± 0.025 vs 0.933 ± 0.023, P = 0.001), but not in subjects older than 50 years. ApEn peaked during the daytime. Conclusion Sex and age jointly determine the 24-h cortisol secretory profile. Sex effects are largely restricted to age <50 years, whereas age effects elevate concentrations in the late evening and early night and advance the timing of the peak diurnal rhythm.

Chronic hyperglycemia inhibits the male gonadal axis. The present analyses test the hypothesis that acute glucose ingestion also suppresses LH and testosterone (T) secretion and blunts the LH-T dose-response function. The design comprised a prospectively randomized crossover comparison of LH and T secretion after glucose vs. water ingestion in a Clinical Translational Research Center. The participants were healthy men ( n = 57) aged 19–78 yr with body mass index (BMI) of 20–39 kg/m2. The main outcome measurements were deconvolution and LH-T dose-response analyses of 10-min data. LH-T responses were regressed on glucose, insulin, leptin, adiponectin, age, BMI, and CT-estimated abdominal visceral fat. During the first 120 min after glucose ingestion, for each unit decrease in LH concentrations, T concentrations decreased by 86 (27–144) ng/dl ( r = 0.853, P < 0.001). Based upon deconvolution analysis, glucose compared with water ingestion reduced 1) basal (nonpulsatile; P < 0.001) and total ( P < 0.001) T secretion without affecting pulsatile T output and 2) pulsatile ( P = 0.043) but not basal LH secretion. By multivariate analysis, pulsatile LH secretion positively predicted basal T secretion after glucose ingestion ( r = 0.374, P = 0.0042). In addition, the glucose-induced fall in pulsatile LH secretion was exacerbated by higher fasting insulin concentrations ( P = 0.054) and attenuated by higher adiponectin levels ( P = 0.0037). There were no detectable changes in the analytically estimated LH-T dose-response curves ( P > 0.30). In conclusion, glucose ingestion suppresses pulsatile LH and basal T secretion acutely in healthy men. Suppression is influenced by age, glucose, adiponectin, and insulin concentrations.

Luteinizing hormone (LH) administered in pharmacological amounts downregulates Leydig cell steroidogenesis. Whether reversible downregulation of physiological gonadotropin drive operates in vivo is unknown. Most of the analytical models of dose-response functions that have been constructed are biased by the assumption that no downregulation exists. The present study employs a new analytical platform to quantify potential (but not required) pulsatile cycles of LH-testosterone (T) dose-response stimulation, desensitization, and recovery (pulse-by-pulse hysteresis) in 26 healthy men sampled every 10 min for 24 h. A sensitivity-downregulation hysteresis construct predicted marked hysteresis with a median time delay to LH dose-response inflection within individual T pulses of 23 min and with median T pulse onset and recovery LH sensitivities of 1.1 and 0.10 slope unit, respectively ( P < 0.001). A potency-downregulation model yielded median estimates of one-half maximally stimulatory LH concentrations (EC50 values) of 0.66 and 7.5 IU/l for onset and recovery, respectively ( P < 0.001). An efficacy-downregulation formulation of hysteresis forecasts median LH efficacies of 20 and 8.3 ng·dl−1·min−1 for onset and offset of T secretory burst, respectively ( P = 0.002). Segmentation of the LH-T data by age suggested greater sensitivity, higher EC50 (increased LH potency), and markedly (2.7-fold) attenuated LH efficacy in older individuals. Each of the three hysteresis models yielded a marked ( P < 0.005) reduction in estimated model residual error compared with no hysteresis. In summary, model-based analyses allowing for (but not requiring) reversible pituitary-gonadal effector-response downregulation are consistent with a hypothesis of recurrent, brief cycles of LH-dependent stimulation, desensitization, and recovery of pulsatile T secretion in vivo and an age-associated reduction of LH efficacy. Prospective studies would be required to prove this aging effect.

AbstractBackground: Aging is associated with a decline in incremental LH pulse amplitude, which could be due to decreased GnRH secretion or impaired GnRH action.Hypothesis: Inconsistent published studies of GnRH action in older men may be due to disparate sex-steroid milieus.Facility: This study was conducted at a clinical translational-research unit.Subjects: We studied 16 healthy men (8 young men and 8 older men).Methods: An overnight transdermal testosterone (T) clamp was implemented before randomly ordered injections of 0, 2.5, 10, 25, 250, and 750 ng GnRH on separate days (96 study sessions).Outcomes: LH responses were quantified by variable-waveform deconvolution analysis.Results: The T clamp maintained age-invariant mean concentrations of total, bioavailable, and free T, SHBG, LH, FSH, and prolactin. By two-way analysis of covariance, GnRH dose (P &lt; 0.001) but not age (0.15 ≤ P ≤ 0.83) determined mean, peak, incremental, and pulsatile LH responses. Statistical power (median) was 95, 98, 90, and 99% to detect a 30% or greater age contrast at P ≤ 0.05 in mean, peak, incremental, and pulsatile LH responses, and greater than 99% to detect a 30% or greater age contrast in bioavailable or total T concentrations. Higher GnRH doses (P &lt; 0.001) abbreviated LH secretory bursts in both age groups.Conclusion: In the face of eugonadal concentrations of total, bioavailable, and free T, young and older men exhibit remarkably similar LH responses to a 300-fold dose range of exogenous GnRH. Accordingly, previously reported disparate effects of age on GnRH action may reflect in part age-discrepant sex-steroid milieus.