Peter Y. Liu

Pathophysiology of hypercortisolism in depression

Objective:  The mechanisms mediating hypercortisolemia in depression remain controversial. Adopting the biomarker strategy, we studied adrenocorticotropin (ACTH) and cortisol dynamics in hypercortisolemic and non‐hypercortisolemic depressed in‐patients, and in normal volunteers.

Rate, extent, and modifiers of spermatogenic recovery after hormonal male contraception: an integrated analysis

BACKGROUND Hormonal methods for safe, reliable, and reversible contraception based on the suppression of spermatogenesis could soon become available. We have investigated the rate, extent, and predictors of reversibility of hormonal male contraception. METHODS We undertook an integrated multivariate time-to-event analysis of data from individual participants in 30 studies published in 1990-2005, in which sperm output was monitored every month until recovery. The primary outcome was the time for the sperm concentration to recover to a threshold of 20 million per mL, an indicator of fertility. We undertook univariate and multivariate analyses, using Kaplan-Meier and Coxs methods. FINDINGS 1549 healthy eugonadal men who were white (n=965), Asian (almost all Chinese men; n=535), or of other origins (n=49) and aged 18-51 years underwent 1283.5 man-years of treatment and 705 man-years of post-treatment recovery. These data represented about 90% of all published data from individuals using androgen or androgen-progestagen regimens. The median times for sperm to recover to thresholds of 20, 10, and 3 million per mL were 3.4 months (95% CI 3.2-3.5), 3.0 months (2.9-3.1), and 2.5 months (2.4-2.7), respectively. Multivariate Coxs analysis showed higher rates of recovery with older age, Asian origin, shorter treatment duration, shorter-acting testosterone preparations, higher sperm concentrations at baseline, faster suppression of spermatogenesis, and lower blood concentrations of luteinising hormone at baseline. The typical probability of recovery to 20 million per mL was 67% (61-72) within 6 months, 90% (85-93) within 12 months, 96% (92-98) within 16 months, and 100% within 24 months. INTERPRETATION Hormonal male contraceptive regimens show full reversibility within a predictable time course. Various covariables affect the rate but not the extent of recovery, although their effect sizes are minor. These data are crucial for the further safe and practical development of such regimens.

Induction of spermatogenesis and fertility during gonadotropin treatment of gonadotropin-deficient infertile men: predictors of fertility outcome.

BACKGROUND The induction of spermatogenesis and fertility with gonadotropin therapy in gonadotropin-deficient men varies in rate and extent. Understanding the predictors of response would inform clinical practice but requires multivariate analyses in sufficiently large clinical cohorts that are suitably detailed and frequently assessed. DESIGN, SETTING, AND PARTICIPANTS A total of 75 men, with 72 desiring fertility, was treated at two academic andrology centers for a total of 116 courses of therapy from 1981-2008. OUTCOMES Semen analysis and testicular examination were performed every 3 months. RESULTS A total of 38 men became fathers, including five through assisted reproduction. The median time to achieve first sperm was 7.1 months [95% confidence interval (CI) 6.3-10.1]) and for conception was 28.2 months (95% CI 21.6-38.5). The median sperm concentration at conception for unassisted pregnancies was 8.0 m/ml (95% CI 0.2-59.5). Multivariate correlated time-to-event analyses show that larger testis volume, previous treatment with gonadotropins, and no previous androgen use each independently predicts faster induction of spermatogenesis and unassisted pregnancy. CONCLUSIONS Larger testis volume is a useful prognostic indicator of response. The association of slower responses after prior androgen therapy suggests that faster pregnancy rates might be achieved by substituting gonadotropin for androgen therapy for pubertal induction, although a prospective randomized trial will be required to prove this.

Cardiometabolic changes after continuous positive airway pressure for obstructive sleep apnoea: a randomised sham-controlled study

Rationale and objectives Impaired insulin sensitivity (ISx), increased visceral abdominal fat (VAF) and liver fat are all central components of the metabolic syndrome and characteristics of men with obstructive sleep apnoea (OSA). The reversibility of these observed changes with continuous positive airway pressure (CPAP) treatment in men with OSA has not been systematically studied in a randomised sham-controlled fashion. Methods 65 men without diabetes who were CPAP naïve and had moderate to severe OSA (age=49±12 years, apnoea hypopnoea index (AHI)=39.9±17.7 events/h, body mass index=31.3±5.2 kg/m2) were randomised to receive either real (n=34) or sham (n=31) CPAP for 12 weeks. At 12 weeks, all subjects received real CPAP for an additional 12 weeks. Measurements and main results Main outcomes were the change at week 12 from baseline in VAF, ISx and liver fat. Other metabolic outcomes were changes in the disposition index, total fat, and blood leptin and adiponectin concentrations. The AHI was lower on CPAP compared with sham by 33 events/h (95% CI−43.9 to −22.2, p<0.0001) after 12 weeks. There were no between-group differences at 12 weeks in VAF (−13.0 cm3, −42.4 to 16.2, p=0.37), ISx (−0.13 (min−1)(μU/ml))−1, −0.40 to 0.14, p=0.33), liver fat (−0.5 cm3, −3.8 to 2.7, p=0.74) or any other cardiometabolic parameter. At 24 weeks, ISx (3.2×104 (min−1)(μU/ml))−1, 0.9×104 to 6.0×104, p=0.009), but not VAF (−1.4 cm3, −19.2 to 16.4, p=0.87) or liver fat (−0.2 Hounsfield units, −2.4 to 2.0, p=0.83) were improved compared with baseline in the whole study group. Conclusion Reducing visceral adiposity in men with OSA cannot be achieved with CPAP alone and is likely to require weight-loss interventions. Longer-term effects of CPAP on other cardiometabolic markers such as ISx require further investigation to fully examine time dependencies. Trial Registration Number ACTRN12608000301369.

Impact of Five Nights of Sleep Restriction on Glucose Metabolism, Leptin and Testosterone in Young Adult Men

Background Sleep restriction is associated with development of metabolic ill-health, and hormonal mechanisms may underlie these effects. The aim of this study was to determine the impact of short term sleep restriction on male health, particularly glucose metabolism, by examining adrenocorticotropic hormone (ACTH), cortisol, glucose, insulin, triglycerides, leptin, testosterone, and sex hormone binding globulin (SHBG). Methodology/Principal Findings N = 14 healthy men (aged 27.4±3.8, BMI 23.5±2.9) underwent a laboratory-based sleep restriction protocol consisting of 2 baseline nights of 10 h time in bed (TIB) (B1, B2; 22:00–08:00), followed by 5 nights of 4 h TIB (SR1–SR5; 04:00–08:00) and a recovery night of 10 h TIB (R1; 22:00–08:00). Subjects were allowed to move freely inside the laboratory; no strenuous activity was permitted during the study. Food intake was controlled, with subjects consuming an average 2000 kcal/day. Blood was sampled through an indwelling catheter on B1 and SR5, at 09:00 (fasting) and then every 2 hours from 10:00–20:00. On SR5 relative to B1, glucose (F 1,168 = 25.3, p<0.001) and insulin (F 1,168 = 12.2, p<0.001) were increased, triglycerides (F 1,168 = 7.5, p = 0.007) fell and there was no significant change in fasting homeostatic model assessment (HOMA) determined insulin resistance (F 1,168 = 1.3, p = 0.18). Also, cortisol (F 1,168 = 10.2, p = 0.002) and leptin (F 1,168 = 10.7, p = 0.001) increased, sex hormone binding globulin (F 1,167 = 12.1, p<0.001) fell and there were no significant changes in ACTH (F 1,168 = 0.3, p = 0.59) or total testosterone (F 1,168 = 2.8, p = 0.089). Conclusions/Significance Sleep restriction impaired glucose, but improved lipid metabolism. This was associated with an increase in afternoon cortisol, without significant changes in ACTH, suggesting enhanced adrenal reactivity. Increased cortisol and reduced sex hormone binding globulin (SHBG) are both consistent with development of insulin resistance, although hepatic insulin resistance calculated from fasting HOMA did not change significantly. Short term sleep curtailment leads to changes in glucose metabolism and adrenal reactivity, which when experienced repeatedly may increase the risk for type 2 diabetes.

Continuous Positive Airway Pressure Reduces Postprandial Lipidemia in Obstructive Sleep Apnea A Randomized, Placebo-Controlled Crossover Trial

RATIONALE Dyslipidemia is common in Obstructive Sleep Apnea (OSA). Postprandial lipidemia (PPL) is a strong marker of cardiovascular risk. Evidence that OSA treatment improves PPL is lacking. OBJECTIVES To investigate the effect of continuous positive airway pressure (CPAP) treatment on postprandial lipidemia (PPL) in patients with obstructive sleep apnea (OSA) in the upper moderate or severe range. METHODS In this randomized, placebo-controlled crossover trial, we compared the effects of 2 months each of therapeutic and placebo CPAP on PPL. MEASUREMENTS AND MAIN RESULTS PPL was determined from the area under the 24-hour triglyceride concentration curve (TAG-AUC(24)) using seven blood samples drawn across both the wake and sleep periods. Secondary outcomes were the difference in other 24-hour lipid profiles. Thirty-eight eligible patients were randomly assigned to a treatment order and 29 patients completed the trial. CPAP reduced PPL compared with placebo with a mean TAG-AUC(24) difference of -357 mmol/L/d (95% confidence interval [CI], -687.3 to -26.8; P = 0.035). During both the CPAP and placebo studies, TAG levels peaked during both wakefulness (2:00 p.m.) and sleep (3:00 a.m.). Both peaks were lower during CPAP than placebo: 2:00 p.m., -0.49 mmol/L (95% CI, -0.74 to -0.24; P < 0.0005) and 3:00 a.m., -0.40 mmol/L (95% CI, -0.65 to -0.15; P = 0.002). Moreover, mean 24-hour total cholesterol was -0.19 mmol/L lower on CPAP (95% CI, -0.27 to -0.11; P < 0.00001). CONCLUSIONS This randomized trial demonstrated that treatment of severe OSA with CPAP improves postprandial TAG and total cholesterol levels. These effects may reduce the risk for cardiovascular events. The results imply that the association between OSA and cardiovascular disease may, in part, be caused by direct effects on dyslipidemia. Clinical trial registered with the Australian and New Zealand Clinical Trials Registry at www.anzctr.org.au (ACTRN 12605000066684).

Sensitivity and specificity of pulse detection using a new deconvolution method

Quantifying pulsatile secretion from serial hormone concentration measurements (deconvolution analysis) requires automated, objective, and accurate detection of pulse times to ensure valid estimation of secretion and elimination parameters. Lack of validated pulse identification constitutes a major deficiency in the deconvolution field, because individual pulse size and number reflect regulated processes that are critical for the function and response of secretory glands. To evaluate deconvolution pulse detection accuracy, four empirical models of true-positive markers of pituitary (LH) pulses were used. 1) Sprague-Dawley rats had recordings of hypothalamic arcuate nucleus multiunit electrical activity, 2) ovariectomized ewes underwent sampling of hypothalamo-pituitary gonadotropin-releasing hormone (GnRH pulses), 3) healthy young men were infused with trains of biosynthetic LH pulses after GnRH receptor blockade, and 4) computer simulations of pulsatile LH profiles were constructed. Outcomes comprised sensitivity, specificity, and receiver-operating characteristic curves. Sensitivity and specificity were 0.93 and 0.97, respectively, for combined empirical data in the rat, sheep, and human (n = 156 pulses) and 0.94 and 0.92, respectively, for computer simulations (n = 1,632 pulses). For simulated data, pulse-set selection by the Akaike information criterion yielded slightly higher sensitivity than by the Bayesian information criterion, and the reverse was true for specificity. False-positive errors occurred primarily at low-pulse amplitude, and false-negative errors occurred principally with close pulse proximity. Random variability (noise), sparse sampling, and rapid pulse frequency reduced pulse detection sensitivity more than specificity. We conclude that an objective automated pulse detection deconvolution procedure has high sensitivity and specificity, thus offering a platform for quantitative neuroendocrine analyses.

Body compositional and cardiometabolic effects of testosterone therapy in obese men with severe obstructive sleep apnea: a randomized placebo-controlled trial.

Camilla M Hoyos, Brendon J Yee, Craig L Phillips, Elizabeth A Machan, Ronald R Grunstein and Peter Y Liu Endocrine and Cardiometabolic Research Group and Sleep and Circadian Research Group, NHMRC Centre for Integrated Research and Understanding of Sleep (CIRUS), Woolcock Institute of Medical Research, University of Sydney, Glebe, Australia, Royal Prince Alfred Hospital, Sydney, Australia, Royal North Shore Hospital, Sydney, Australia and Division of Endocrinology, Department of Medicine, David Geffen School of Medicine at UCLA, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, 1000 W Carson Street, Torrance, California 90502, USA

Prospective Study of Effect of Androgens on Serum Inflammatory Markers in Men

Objective—Because male sex is an independent risk factor for the severity of atherosclerosis, it is possible that androgens may be proatherogenic. There is evidence that sex hormones, particularly estrogens, regulate (or modulate) inflammation, a process integral to atherogenesis. Because levels of serum inflammatory markers predict cardiovascular outcomes, we prospectively assessed the effects of androgen therapy on these markers in older men. Methods and Results—Levels of high-sensitivity C-reactive protein (CRP), soluble intracellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured from sera collected at baseline and at the end of 2 randomized double-blind placebo-controlled trials evaluating the effects of 3 months of androgen treatment with either dihydrotestosterone (DHT) or recombinant human chorionic gonadotropin (rhCG) in healthy men aged >60 years with partial androgen deficiency (serum testosterone levels <15 nmol/L). For the DHT study (70 mg transdermally daily), 33 men completed 3 months of treatment (16 men were treated with DHT, and there were 17 controls). For the rhCG (250 &mgr;g twice weekly) study, 20 men were treated with rhCG, and there were 20 controls. In both studies, groups were well matched for age and vascular risk factors. Androgen levels (DHT and testosterone) were consistently maintained at eugonadal levels throughout the trials, with estradiol markedly increased by rhCG but not DHT. Baseline CRP levels were 0.74 to 1.49 mg/L, sVCAM-1 levels were 847 to 950 ng/mL, and sICAM-1 levels were 256 to 292 ng/mL in all groups. Neither DHT nor rhCG resulted in significant changes in CRP, sVCAM-1, or sICAM-1 compared with placebo (P >0.3 in both studies). Conclusions—Exogenous androgen therapy with or without increased estradiol levels does not alter serum inflammatory markers in older men; this finding is in contrast to the effects of estrogens on inflammatory markers that have been found in postmenopausal women. These data provide a measure of reassurance concerning potential adverse cardiovascular effects of androgen therapy in older men.

Effects of 8 weeks of continuous positive airway pressure on abdominal adiposity in obstructive sleep apnoea

The aim of the present study was to investigate the effect of continuous positive airway pressure (CPAP) treatment on regional adipose tissue distribution in patients with moderate or severe obstructive sleep apnoea. Patients received both therapeutic and sham CPAP in a random order for 2 months each with an intervening 1-month washout. Abdominal subcutaneous, visceral and liver fat were quantified using magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). Liver enzymes and plasma glucose were also determined. Measurements were obtained at baseline and at the end of both treatment arms. 38 eligible patients were randomly assigned to a treatment order, with 27 patients having complete MRI/MRS data. No significant difference was observed in subcutaneous (-28.6 cm3; p=0.49) or visceral (-16.8 cm3; p=0.59) adipose tissue, intrahepatic lipid (-0.2%; p=0.21), or fasting glucose measurements (-0.1 mmol·L−1; p=0.46) between treatment modalities. Alkaline phosphatase decreased (-3.1 U·L−1; p=0.02) while on therapeutic CPAP compared with sham CPAP but other liver enzymes, including aspartate aminotransferase (0.3 U·L−1; p=0.82), alanine aminotransferase (1.34 U·L−1; p=0.59) and &ggr;-glutamyltransferase (-2.3 U·L−1; p=0.33), remained unchanged. In this first randomised, sham-controlled trial, there was no change in adipose tissue distribution after 8 weeks of therapeutic CPAP compared with 8 weeks of sham CPAP. Longer duration of CPAP use may be necessary to demonstrate a difference.