Fat Distribution in Schizophrenia Patients: A Pilot Study Comparing First- and Second-Generation Antipsychotics.

BACKGROUND: Introduction of second-generation antipsychotics (SGAs) has reduced neurologic toxicity but are associated with increased weight gain and obesity. The objective of this pilot study is to compare the effects of first-generation antipsychotics (FGAs) and SGAs in patients with schizophrenia on body fat and presumed concomitant metabolic parameters. METHODS: Study compared schizophrenia nondiabetic men treated with FGAs (group 1, n = 5) and men treated with SGAs (group 2, n = 9). Each subject completed psychiatric and endocrine evaluation including severity of psychiatric symptoms, adverse effects, body weight, body composition, and measurements of glucose, insulin, adipokines, and inflammatory markers. Student t test was used for statistical analysis. RESULTS: Men treated with FGAs had a lower mean body mass index with a trend toward statistical significance (25.3 ± 1.4 vs 29.3 ± 1.7, P = 0.06). Treatment with FGAs was associated with lower waist/height ratio (0.55 ± 0.02 vs 0.62 ± 0.02, P = 0.036) and android fat mass index (0.62 ± 0.01 vs 0.96 ± 0.1, P = 0.03). Homeostasis Model Assessment for insulin resistance values were suggestive of significantly lower peripheral insulin resistance in men treated with FGAs (0.92 ± 0.15 vs 2.3 ± 0.34, P = 0.014). CONCLUSIONS: The results of this study are significant for decreased peripheral insulin resistance in men treated with SGAs in a setting of no significant age difference and only a trend toward higher body mass index, but consistent documentation of increased abdominal fat by 3 different methodologies. Future studies involving larger number of subjects are warranted to verify the present findings.

Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial.

IMPORTANCE: Less than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant. OBJECTIVE: To determine the relative effectiveness and safety of 3 common alternate treatments for MDD. DESIGN, SETTING, AND PARTICIPANTS: From December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks. INTERVENTIONS: Switch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase). MAIN OUTCOMES AND MEASURES: The primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects. RESULTS: Among 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain. CONCLUSIONS AND RELEVANCE: Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01421342.

Glucose ingestion acutely lowers pulsatile LH and basal testosterone secretion in men.

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/m(2). 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.

Analytical construct of reversible desensitization of pituitary-testicular signaling: illustrative application in aging.

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 (EC(50) 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 EC(50) (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.

Overnight ACTH-cortisol dose responsiveness: comparison with 24-h data, metyrapone administration and insulin-tolerance test in healthy adults.

OBJECTIVE: To estimate the dose dependence of endogenous ACTH stimulation of adrenal cortisol secretion overnight. DESIGN: Ten-minute sampling for ACTH and cortisol over 8 and 24 h (n = 17), after metyrapone administration (n = 6), during an insulin-tolerance test (n = 7). SUBJECTS: Healthy adults. MEASUREMENTS: ACTH dose-responsive estimates. RESULTS: Twenty-four hour ACTH-cortisol concentration pairs yielded an estimated EC(50) (one-half maximally stimulatory ACTH concentration) of 5·1 (2·2-9·5) pmol/l [median (range)]. This did not differ from EC(50) s based on 8- or 6-h data [5·9 (3·5-11) and 7·5 (3·7-41) pmol/l] in the same individuals. ACTH efficacy (maximally stimulatable cortisol secretion rate) was 8·4 (3·1-20), 11 (5·9-24) and 15 (5·9-22) nmol/l/min, when calculated over 24, 8 and 6 h, respectively (P = NS). Adrenal sensitivity (slope term) was also consistent across sampling durations, viz. 14 (1·3-95), 18 (1·3-64) and 20 (1·3-64) slope units. Compared with placebo, metyrapone reduced ACTH efficacy from 11 (6·2-62) to 2·8 (1·5-4·5) nmol/l/min for cortisol (n = 9, P < 0·001), while increasing ACTH efficacy for 11-desoxycortisol from 2·3 (0·9-2·9) to 99 (70-218) nmol/l/min (n = 6, P < 0·01), thus affirming face validity. Combined ACTH and cortisol responses to hypoglycaemia allowed an estimate of ACTH efficacy of 28 (22-81) nmol/l/min, compared with the control value of 8·7 (5·6-26), suggesting enhanced adrenal responsiveness. CONCLUSIONS: The results suggest that endogenous ACTH-adrenal drive can be approximated from overnight 8-h sampling of paired ACTH and cortisol concentrations. This strategy may have merit in clinical research in childhood, pregnancy, anxiety states and frail elderly individuals, when ACTH injections are not desired.

Computation of detour index of TUHC6[2p, q] nanotubes for any p and q.

The detour d(i, j) between vertices i and j of a graph is the number of edges of the longest path connecting these vertices. The matrix whose (i, j)-entry is the detour between vertices i and j is called the detour matrix. The half sum D of detours between all pairs of vertices (in a connected graph) is the detour index, i.e., D = (1/2) Sigma(j) Sigma(i) d(i, j). In this paper, we computed the detour index of TUHC6[2p, q] nanotubes for any p and q.

Clamping Cortisol and Testosterone Mitigates the Development of Insulin Resistance during Sleep Restriction in Men.

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.

Age and time-of-day differences in the hypothalamo-pituitary-testicular, and adrenal, response to total overnight sleep deprivation.

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.

Short Communication: Low Muscle Mass Is Associated with Osteoporosis in Older Adults Living with HIV.

Sarcopenia, age-related low muscle mass and function, is a well-established independent risk factor for bone fracture in the geriatric population but is understudied in older people living with HIV (PLWH). The objective of this cross-sectional study was to investigate in older PLWH the relationship between muscle mass and bone mineral density (BMD). Sedentary PLWH who were ≥50 years of age, receiving antiretroviral therapy, and enrolled in an exercise intervention trial were included. Established definitions for sarcopenia and osteopenia/osteoporosis were applied to muscle mass data and BMD collected by dual-energy X-ray absorptiometry before exercise training. Participants were 93% male and 33% Caucasian race with median age 61 years, and median CD4 lymphocytes 707 cells/µL. The majority (64%) were overweight and obese by body mass index. Appendicular skeletal muscle index (ASMI) correlated with BMD at the femoral neck (r = 0.49, p < .01), total hip (r = 0.54, p < .01), and lumbar spine (r = 0.48, p < .05). Low BMD at the femoral neck was present in 39% (26% osteopenia, 13% osteoporosis). ASMI was lower among those with low BMD compared with normal BMD (p = .02). Low muscle mass measured by ASMI is associated with low BMD in clinically stable older PLWH. Detailed body composition assessment may help guide lifestyle recommendations to prevent bone fractures in older PLWH.

Impact of Concurrent Posttraumatic Stress Disorder on Outcomes of Antipsychotic Augmentation for Major Depressive Disorder With a Prior Failed Treatment: VAST-D Randomized Clinical Trial.

OBJECTIVE: To determine whether concurrent posttraumatic stress disorder (PTSD) should affect whether to augment or switch medications when major depressive disorder (MDD) has not responded to a prior antidepressant trial. METHODS: Patients at 35 Veterans Health Administration medical centers from December 2012 to May 2015 with nonpsychotic MDD (N = 1,522) and a suboptimal response to adequate antidepressant treatment were randomly assigned to 3 "next step" treatments: switching to bupropion, augmenting the current antidepressant with bupropion, and augmenting with the antipsychotic aripiprazole. Blinded ratings with the 16-item Quick Inventory of Depressive Symptomatology-Clinician Rated (QIDS-C16) determined remission and response by 12 weeks and relapse after remission. Survival analyses compared treatment effects in patients with concurrent PTSD diagnosed with the Mini-International Neuropsychiatric Interview (n = 717, 47.1%) and those without PTSD (n = 805, 52.9%). RESULTS: Patients diagnosed with PTSD showed more severe depressive symptoms at baseline and were less likely to achieve either remission or response by 12 weeks. Augmentation with aripiprazole was associated with greater likelihood of achieving response (68.4%) than switching to bupropion (57.7%) in patients with PTSD (relative risk [RR] = 1.26; 95% CI, 1.01-1.59) as well as in patients without PTSD (RR = 1.29; 95% CI, 1.05-1.97) (78.9% response with aripiprazole augmentation vs 66.9% with switching to bupropion). Treatment comparisons with the group receiving augmentation with bupropion were not significant. There was no significant interaction between treatment group and PTSD on remission (P = .70), response (P = .98), or relapse (P = .15). CONCLUSIONS: Although PTSD was associated with poorer overall outcomes, the presence of concurrent PTSD among Veterans in this trial did not affect the comparative effectiveness of medications on response, remission, or relapse after initial remission. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01421342.

Sex defines the age dependence of endogenous ACTH-cortisol dose responsiveness.

Sex influences adrenal glucocorticoid responses to ACTH in experimental animals. Whether similar sex differences operate in humans is unknown. To test this notion, we estimated ACTH-cortisol dose-response properties analytically in 48 healthy adults (n = 22 women, n = 26 men), ages 18-77 yr, body mass index (BMI) 18-32 kg/m(2), previously studied at two medical centers. Plasma ACTH and cortisol concentrations were measured every 10 min for 24 h. The 145 sample pairs were used in each subject to estimate ACTH-cortisol drive via a logistic function. Statistical analyses revealed that 24-h cortisol secretion (>82% pulsatile) fell in men (r = -0.38, P = 0.028) and rose in women (r = +0.37, P = 0.045) with age (P = 0.01 sex effect). The mechanisms involved decreased ACTH efficacy with age in men (r = -0.35, P = 0.04), and increased ACTH efficacy with age in women (r = +0.42, P = 0.025) [P = 0.009 sex effect]. ACTH potency diminished with higher BMI in men (r = +0.38, P = 0.029) and in the cohort as a whole (r = 0.34, P = 0.0085). These outcomes demonstrate that sex, age, and BMI modulate selective properties of endogenous ACTH-cortisol drive in humans, thereby indicating the need to control these three major variables in experimental comparisons.

The aging male hypothalamic-pituitary-gonadal axis: pulsatility and feedback.

Aging results in insidious decremental changes in hypothalamic, pituitary and gonadal function. The foregoing three main anatomic loci of control are regulated by intermittent time-delayed signal exchange, principally via gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) and testosterone/estradiol (Te/E(2)). A mathematical framework is required to embody these dynamics. The present review highlights integrative adaptations in the aging male hypothalamic-pituitary-gonadal axis, as assessed by recent objective ensemble models of the axis as a whole.

Twenty-four hour continuous ghrelin infusion augments physiologically pulsatile, nycthemeral, and entropic (feedback-regulated) modes of growth hormone secretion.

BACKGROUND: Ghrelin is a 28-amino acid acylated peptide that potentiates GHRH stimulation and opposes somatostatin inhibition acutely. Whether prolonged ghrelin administration can sustain physiological patterns of GH secretion remains unknown. HYPOTHESIS: Continuous delivery of ghrelin will amplify physiological patterns of GH secretion over 24 h. SUBJECTS: Men and women ages 29-69 yr, body mass indices 23-52 kg/m2, were included in the study. LOCATION: The study was performed at an academic medical center. METHODS: Twenty-four hour continuous sc infusion of saline vs. ghrelin (1 microg/kg.h) with frequent sampling was examined. Deconvolution and entropy analyses were performed. OUTCOMES: IGF-I concentrations were determined. Basal, pulsatile, nycthemeral, and entropic measures of GH secretion were calculated. RESULTS: Ghrelin infusion compared with saline infusion for 24 h elevated (median) acylated ghrelin, GH, and IGF-I concentrations by 8.1-fold (P < 0.001),11-fold (P < 0.001), and 1.4-fold (P = 0.002). GH secretory-burst mass and frequency increased by 6.6-fold (P = 0.004) and 1.7-fold (P < 0.001), respectively, resulting in a 12-fold increase in pulsatile GH secretion (P < 0.001). Interpulse variability decreased significantly (P = 0.046), whereas GH secretory-burst shape and half-life did not change. The amplitude of the nycthemeral GH rhythm increased by 3.4-fold (P < 0.001), and GH patterns became more irregular (higher approximate entropy P < 0.001). Combining GHRH with ghrelin was not an additive in driving GH secretion. CONCLUSIONS: Continuous ghrelin infusion for 24 h elevates acylated ghrelin, GH and IGF-I concentrations, and stimulates pulsatile, nycthemeral, and entropic modes of GH secretion. The consistency of outcomes in a heterogeneous cohort of adults suggests potentially broad utility of this physiological secretagogue in hyposomatotropic states.

Computing the Szeged and PI indices of VC(5)C(7)[p,q] and HC(5)C(7)[p,q] nanotubes.

In this paper we give a GAP program for computing the Szeged and the PI indices of any graph. Also we compute the Szeged and PI indices of VC(5)C(7) [ p,q] and HC(5)C(7) [ p,q] nanotubes by this program.

Impact of opioid therapy on gonadal hormones: focus on buprenorphine.

Objective The USA is in the midst of an opioid crisis. Understanding the impact of opioids and commonly used treatments for opioid dependence is essential for clinicians and researchers in order to educate and treat the nation's growing population with opioid use disorders. As a relatively new treatment for opioid dependence, buprenorphine is gaining popularity to the extent of becoming not only a preferred approach to the maintenance of opiate addiction, but also an option for chronic pain management. The purpose of this report is to review the available evidence on the endocrine effects of buprenorphine, particularly as it relates to the hypothalamic-pituitary-gonadal (HPG) axis, which is controversial and not fully defined. Method We conducted a Pubmed search (2000-2017) for human studies in the English language for articles that were available as full length regarding buprenorphine, endocrinopathy, hypogonadism, bone density, opioids. Case reports were also reviewed, although prospective studies and randomized controlled trials received more weight. Results Opioid induced hypogonadism is well established. Most studies report that buprenorphine being a partial agonist/antagonist may not be impacting the pituitary trophic hormones as much. There are reports of sexual dysfunction in subjects maintained on buprenorphine, some without hormonal correlation. Thus with the understanding that pertinent clinical studies are limited in number, varied in methodology, mostly cross sectional, predominantly in men and small number of participants, more research in this area is warranted. Conclusion Based on a comprehensive review of the available literature, we conclude that despite its increasing popularity, buprenorphine has not been adequately studied in respect to its long-term effects on the hypothalamic-pituitary-adrenal (HPA) axis. There is a great need for longitudinal systematic trials to define the potential buprenorphine-induced endocrine consequences.

Putative somatostatin suppression potentiates adrenocorticotropin secretion driven by ghrelin and human corticotropin-releasing hormone.

CONTEXT: Ghrelin is a 28-amino-acid Ser(3)-octanoylated peptide, and CRH is a 41-amino-acid peptide, both of which stimulate ACTH secretion. In principle, actions of these agonists could be subject to inhibitory modulation by hypothalamic somatostatin (SS). OBJECTIVE: Our objective was to test the hypothesis that endogenous SS restrains ghrelin and CRH-stimulated ACTH secretion, thereby linking all three, ghrelin, CRH, and SS, with ACTH secretion. DESIGN AND SETTING: We conducted a randomized, double-blind, placebo-controlled, crossover interventional study at an academic medical center. PARTICIPANTS: Ten healthy postmenopausal women participated in the study. INTERVENTIONS: Interventions included iv injection of saline, ghrelin, human CRH, or both after an infusion of saline vs. l-arginine to putatively inhibit SS outflow (eight visits per subject). OUTCOME MEASURES: ACTH concentrations quantified by repetitive blood sampling and immunochemiluminometry. RESULTS: Infusion of ghrelin induced peak ACTH concentrations [median (range)] of 21 (17-28) compared with 16 (11-20) ng/liter after saline (P = 0.037). CRH and l-arginine infusion evoked ACTH peaks of 23 (14-48) and 31 (21-286) ng/liter, respectively (P = 0.037 and P = 0.005 vs. saline). l-Arginine enhanced stimulation by ghrelin by 1.43-fold (P = 0.028) and that by CRH by 1.91-fold (P = 0.005). Triple stimulation with ghrelin, CRH, and l-arginine potentiated the effect of combined ghrelin/CRH by 1.45-fold (P = 0.028). Downstream cortisol responses mimicked those of ACTH but were time delayed. CONCLUSIONS: The present outcomes indicate that the peptide ensemble comprising ghrelin, CRH, and SS (inferred by l-arginine infusion) can regulate ACTH and cortisol secretion in healthy adults.

Hypothalamo-pituitary-adrenal axis after a single epidural triamcinolone injection.

PURPOSE: To quantify adrenocorticotropin and cortisol secretion after epidural glucocorticoid injection. METHODS: Eight men (ages 25-63 year) were studied at baseline, 1, 4, and 12 weeks after triamcinolone (80 mg) injection epidurally. Adrenocorticotropin (pg/mL) and cortisol (µg/dL) were measured every 10 min for 4 h, and after Corticotropin-releasing hormone (CRH) (1 µg/kg) injection. RESULTS: Epidural triamcinolone markedly suppressed: (1) pre-CRH injection ACTH (from 18 ± 3.1 to 4.8 ± 0.4: P < 0.01) and cortisol (from 12.2 ± 1.6 to 1.6 ± 0.3: P < 0.0001) at week 1, with recovery at 4 weeks, and (2) CRH-stimulated 3-h summed ACTH (from 633 ± 116 to 129 ± 10 pg/mL, P < 0.0001), and 3-h summed cortisol at week 1 (from 385 ± 29 to 56 ± 22 µg/dL, P < 0.0001) and 4 weeks (284 ± 53; P < 0.01). Serum cortisol was <18 µg/dL in eight of eight men at 4 weeks, and six of eight men at week 12. Urinary-free cortisol (µg/24 h) remained low at week 12: baseline (60 ± 6.5); week 1 (9.0 ± 1.3, P < 0.01); week 4 (36 ± 8.6) and week 12 (38 ± 4.1). Urinary cortisol/cortisone ratios rose at week 4 only. Serum triamcinolone peaked at week 1 (16/16 samples), declining at week 4 (13/16 samples) and week 12 (6/16 samples). LIMITATIONS: Relatively small group. CONCLUSION: Epidural triamcinolone suppresses unstimulated and CRH-stimulated ACTH and cortisol secretion for 1-4 weeks but urinary free cortisol ≥12 weeks. Suppression of ACTH and cortisol after glucocorticoid treatment is thus complex.

Impact of age, sex and body mass index on cortisol secretion in 143 healthy adults.

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.

An ensemble model of the male gonadal axis: illustrative application in aging men.

Testosterone (Te) production declines in the aging male, albeit for unknown reasons. Plausible mechanisms include reduced secretion of GnRH, less feedforward by LH, and/or altered feedback by systemic Te. The present study tests all three postulates in a cohort of 10 young (20-35 yr old) and eight older (50-72 yr old) men. The experimental paradigm comprised graded blockade of the GnRH receptor to create four distinct strata of LH and Te pulsatility in each subject. A novel analytical formalism was developed to reconstruct implicit dose-response functions linking 1) virtual GnRH outflow positively to LH secretion, 2) LH pulses positively to Te secretion, and 3) Te concentrations negatively to the size and number of LH secretory bursts. Validation was by direct pituitary sampling in the horse and sheep. Statistical comparisons disclosed that age decreased the efficacy of each of 1) virtual GnRH outflow (P < 0.01), 2) LH drive of Te secretion (P < 0.01), and 3) total, bioavailable and free Te feedback on GnRH-driven LH secretion (P = 0.015). In contrast, age increased the potency of virtual GnRH feedforward (P = 0.013) and did not affect Te's inhibition of LH pulse frequency. Unexplained variance was less than 10%. Robustness was shown by resampling techniques. Accordingly, competitive silencing of one locus of control and ensemble-based analyses identified triple regulatory deficits in the aging male gonadal axis. The generality of the present integrative model suggests utility in parsing interlinked adaptations in other physiological networks.

Estradiol potentiates ghrelin-stimulated pulsatile growth hormone secretion in postmenopausal women.

CONTEXT: Ghrelin and an estrogen-rich milieu individually amplify pulsatile GH secretion by increasing the amount of hormone released per burst. However, how these distinct agonists interact in controlling pulsatile GH output is not known. OBJECTIVE: The objective of the study was to test the hypothesis that elevated estradiol (E(2)) concentrations potentiate hypothalamo-pituitary responses to a near-physiological ghrelin stimulus. DESIGN: This was a double-blind, placebo-controlled, prospectively randomized, parallel-cohort study. SETTING: The study was conducted at an academic medical center. SUBJECTS: Twenty-one postmenopausal women participated in the study. INTERVENTIONS: Eleven subjects received placebo (Pl) and 10 others E(2) transdermally in escalating doses over 3 wk to mimic late follicular-phase E(2) concentrations. Saline or a submaximally stimulatory amount of ghrelin (0.3 microg/kg) was infused iv on separate randomly ordered mornings fasting after 17-21 d of Pl or E(2) administration. OUTCOMES: Outcomes included serum concentrations of E(2), ghrelin, GH, IGF-I, IGF binding protein (IGFBP)-1 and IGFBP-3, and the estimated mass and waveform of stimulated GH secretory bursts. RESULTS: Administration of E(2) yielded late follicular-phase E(2) concentrations. Compared with Pl, E(2) did not alter ghrelin concentrations but reduced IGF-I and IGFBP-3 and elevated IGFBP-1 concentrations. Compared with saline, ghrelin infusion amplified pulsatile GH secretion by 7.1-fold (P < 0.01). The effect of E(2) alone was 2.0-fold placebo and that of combined ghrelin/E(2) 10.4-fold (P < 0.01). Ghrelin and E(2) accelerated initial GH release individually but nonadditively by more than 2-fold (P < 0.01). CONCLUSIONS: Estrogen augments ghrelin's near-physiological stimulation of pulsatile GH secretion and mimics ghrelin's acceleration of initial GH release. Thus, we hypothesize that estrogen and a GH secretagogue act via independent as well as convergent mechanisms.