Jagadish Ulloor

Adverse events associated with testosterone administration.

BACKGROUND Testosterone supplementation has been shown to increase muscle mass and strength in healthy older men. The safety and efficacy of testosterone treatment in older men who have limitations in mobility have not been studied. METHODS Community-dwelling men, 65 years of age or older, with limitations in mobility and a total serum testosterone level of 100 to 350 ng per deciliter (3.5 to 12.1 nmol per liter) or a free serum testosterone level of less than 50 pg per milliliter (173 pmol per liter) were randomly assigned to receive placebo gel or testosterone gel, to be applied daily for 6 months. Adverse events were categorized with the use of the Medical Dictionary for Regulatory Activities classification. The data and safety monitoring board recommended that the trial be discontinued early because there was a significantly higher rate of adverse cardiovascular events in the testosterone group than in the placebo group. RESULTS A total of 209 men (mean age, 74 years) were enrolled at the time the trial was terminated. At baseline, there was a high prevalence of hypertension, diabetes, hyperlipidemia, and obesity among the participants. During the course of the study, the testosterone group had higher rates of cardiac, respiratory, and dermatologic events than did the placebo group. A total of 23 subjects in the testosterone group, as compared with 5 in the placebo group, had cardiovascular-related adverse events. The relative risk of a cardiovascular-related adverse event remained constant throughout the 6-month treatment period. As compared with the placebo group, the testosterone group had significantly greater improvements in leg-press and chest-press strength and in stair climbing while carrying a load. CONCLUSIONS In this population of older men with limitations in mobility and a high prevalence of chronic disease, the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events. The small size of the trial and the unique population prevent broader inferences from being made about the safety of testosterone therapy. (ClinicalTrials.gov number, NCT00240981.)

Reference Ranges for Testosterone in Men Generated Using Liquid Chromatography Tandem Mass Spectrometry in a Community-Based Sample of Healthy Nonobese Young Men in the Framingham Heart Study and Applied to Three Geographically Distinct Cohorts

CONTEXT Reference ranges are essential for partitioning testosterone levels into low or normal and making the diagnosis of androgen deficiency. We established reference ranges for total testosterone (TT) and free testosterone (FT) in a community-based sample of men. METHODS TT was measured using liquid chromatography tandem mass spectrometry in nonobese healthy men, 19-40 yr old, in the Framingham Heart Study Generation 3; FT was calculated. Values below the 2.5th percentile of reference sample were deemed low. We determined the association of low TT and FT with physical dysfunction, sexual symptoms [European Male Aging Study (EMAS) only], and diabetes mellitus in three cohorts: Framingham Heart Study generations 2 and 3, EMAS, and the Osteoporotic Fractures in Men Study. RESULTS In a reference sample of 456 men, mean (sd), median (quartile), and 2.5th percentile values were 723.8 (221.1), 698.7 (296.5), and 348.3 ng/dl for TT and 141. 8 (45.0), 134.0 (60.0), and 70.0 pg/ml for FT, respectively. In all three samples, men with low TT and FT were more likely to have slow walking speed, difficulty climbing stairs, or frailty and diabetes than those with normal levels. In EMAS, men with low TT and FT were more likely to report sexual symptoms than men with normal levels. Men with low TT and FT were more likely to have at least one of the following: sexual symptoms (EMAS only), physical dysfunction, or diabetes. CONCLUSION Reference ranges generated in a community-based sample of men provide a rational basis for categorizing testosterone levels as low or normal. Men with low TT or FT by these criteria had higher prevalence of physical dysfunction, sexual dysfunction, and diabetes. These reference limits should be validated prospectively in relation to incident outcomes and in randomized trials.

Testosterone and Growth Hormone Improve Body Composition and Muscle Performance in Older Men

CONTEXT Impairments in the pituitary-gonadal axis with aging are associated with loss of muscle mass and function and accumulation of upper body fat. OBJECTIVES We tested the hypothesis that physiological supplementation with testosterone and GH together improves body composition and muscle performance in older men. DESIGN, SETTING, AND PARTICIPANTS One hundred twenty-two community-dwelling men 70.8 +/- 4.2 yr of age with body mass index of 27.4 +/- 3.4 kg/m2, testosterone of 550 ng/dl or less, and IGF-I in lower adult tertile (< or =167 ng/dl) were randomized to receive transdermal testosterone (5 or 10 g/d) during a Leydig cell clamp plus GH (0, 3, or 5 microg/kg . d) for 16 wk. MAIN OUTCOME MEASURES Body composition by dual-energy x-ray absorptiometry, muscle performance, and safety tests were conducted. RESULTS Total lean body mass increased (1.0 +/- 1.7 to 3.0 +/- 2.2 kg) as did appendicular lean tissue (0.4 +/- 1.4 to 1.5 +/- 1.3 kg), whereas total fat mass decreased by 0.4 +/- 0.9 to 2.3 +/- 1.7 kg as did trunk fat (0.5 +/- 0.9 to 1.5 +/- 1.0 kg) across the six treatment groups and by dose levels for each parameter (P < or = 0.0004 for linear trend). Composite maximum voluntary strength of upper and lower body muscles increased by 14 +/- 34 to 35 +/- 31% (P < 0.003 in the three highest dose groups) that correlated with changes in appendicular lean mass. Aerobic endurance increased in all six groups (average 96 +/- 137 sec longer). Systolic and diastolic blood pressure increased similarly in each group with mean increases of 12 +/- 14 and 8 +/- 8 mm Hg, respectively. Other predictable adverse events were modest and reversible. CONCLUSIONS Supplemental testosterone produced significant gains in total and appendicular lean mass, muscle strength, and aerobic endurance with significant reductions in whole-body and trunk fat. Outcomes appeared to be further enhanced with GH supplementation.

Activation of Phasic Pontine-Wave Generator Prevents Rapid Eye Movement Sleep Deprivation-Induced Learning Impairment in the Rat: A Mechanism for Sleep-Dependent Plasticity

Animal and human studies of sleep and learning have demonstrated that training on various tasks increases subsequent rapid eye movement (REM) sleep and phasic pontine-wave (P-wave) activity, followed by improvement in performance on the learned task. It is well documented that REM sleep deprivation after learning trials blocks the expected improvement in performance on subsequent retesting. Our aim was to test whether experimentally induced P-wave generator activation could eliminate the learning impairment produced by post-training REM sleep deprivation. Rats were trained on a two-way active avoidance-learning task. Immediately thereafter, two groups of those rats received a control vehicle (100 nl saline) microinjection and one group received a carbachol (50 ng in 100 nl saline) microinjection into the P-wave generator. The carbachol-injected group and one of the two control saline microinjected groups were selectively deprived of REM sleep during a 6 hr polygraphic recording session. All rats were then tested on the avoidance-learning task. The rats that received both the control saline injection and REM sleep deprivation showed learning deficits compared with the control saline-injected rats that were allowed to sleep normally. In contrast, the rats that received the carbachol microinjection and REM sleep deprivation demonstrated normal learning. These results demonstrate, for the first time, that carbachol-induced activation of the P-wave generator prevents the memory-impairing effects of post-training REM sleep deprivation. This evidence supports our hypothesis that the activation of the P-wave generator during REM sleep deprivation enhances a physiological process of memory, which occurs naturally during post-training REM sleep.

Testosterone Suppresses Hepcidin in Men: A Potential Mechanism for Testosterone-Induced Erythrocytosis

CONTEXT The mechanisms by which testosterone increases hemoglobin and hematocrit are unknown. OBJECTIVE The aim was to test the hypothesis that testosterone-induced increase in hematocrit is associated with suppression of the iron regulatory peptide hepcidin. PARTICIPANTS Healthy younger men (ages 19-35 yr; n = 53) and older men (ages 59-75 yr; n = 56) were studied. METHODS Weekly doses of testosterone enanthate (25, 50, 125, 300, and 600 mg) were administered over 20 wk, whereas endogenous testosterone was suppressed by monthly GnRH agonist administration. Blood and serum parameters from each individual were measured at wk 0, 1, 2, 4, 8, and 20. Longitudinal analyses were performed to examine the relationship between hepcidin, hemoglobin, hematocrit, and testosterone while controlling for potential confounders. RESULTS High levels of testosterone markedly suppressed serum hepcidin within 1 wk. Hepcidin suppression in response to testosterone administration was dose-dependent in older men and more pronounced than in young men, and this corresponded to a greater rise in hemoglobin in older men. Serum hepcidin levels at 4 and 8 wk were predictive of change in hematocrit from baseline to peak levels. CONCLUSION Testosterone administration is associated with suppression of serum hepcidin. Greater increases in hematocrit in older men during testosterone therapy are related to greater suppression of hepcidin.

Influence of Ginger Rhizome (Zingiber officinale Rosc) on Survival, Glutathione and Lipid Peroxidation in Mice after Whole-Body Exposure to Gamma Radiation

Abstract Jagetia, G. C., Baliga, M. S., Venkatesh, P. and Ulloor, J. N. Influence of Ginger Rhizome (Zingiber officinale Rosc) on Survival, Glutathione and Lipid Peroxidation in Mice after Whole-Body Exposure to Gamma Radiation. Radiat. Res. 160, 584–592 (2003). The radioprotective effect of the hydroalcoholic extract of ginger rhizome, Zingiber officinale (ZOE), was studied. Mice were given 10 mg/kg ZOE intraperitoneally once daily for five consecutive days before exposure to 6–12 Gy of γ radiation and were monitored daily up to 30 days postirradiation for the development of symptoms of radiation sickness and mortality. Pretreatment of mice with ZOE reduced the severity of radiation sickness and the mortality at all doses. The ZOE treatment protected mice from GI syndrome as well as bone marrow syndrome. The dose reduction factor for ZOE was found to be 1.15. The optimum protective dose of 10 mg/kg ZOE was 150 of the LD50 (500 mg/kg). Irradiation of the animals resulted in a dose-dependent elevation in the lipid peroxidation and depletion of GSH on day 31 postirradiation; both effects were lessened by pretreatment with ZOE. ZOE also had a dose-dependent antimicrobial activity against Pseudomonas aeruginosa, Salmonella typhimurium, Escherichia coli and Candida albicans.

Genetic Determinants of Serum Testosterone Concentrations in Men

Testosterone concentrations in men are associated with cardiovascular morbidity, osteoporosis, and mortality and are affected by age, smoking, and obesity. Because of serum testosterones high heritability, we performed a meta-analysis of genome-wide association data in 8,938 men from seven cohorts and followed up the genome-wide significant findings in one in silico (n = 871) and two de novo replication cohorts (n = 4,620) to identify genetic loci significantly associated with serum testosterone concentration in men. All these loci were also associated with low serum testosterone concentration defined as <300 ng/dl. Two single-nucleotide polymorphisms at the sex hormone-binding globulin (SHBG) locus (17p13-p12) were identified as independently associated with serum testosterone concentration (rs12150660, p = 1.2×10−41 and rs6258, p = 2.3×10−22). Subjects with ≥3 risk alleles of these variants had 6.5-fold higher risk of having low serum testosterone than subjects with no risk allele. The rs5934505 polymorphism near FAM9B on the X chromosome was also associated with testosterone concentrations (p = 5.6×10−16). The rs6258 polymorphism in exon 4 of SHBG affected SHBGs affinity for binding testosterone and the measured free testosterone fraction (p<0.01). Genetic variants in the SHBG locus and on the X chromosome are associated with a substantial variation in testosterone concentrations and increased risk of low testosterone. rs6258 is the first reported SHBG polymorphism, which affects testosterone binding to SHBG and the free testosterone fraction and could therefore influence the calculation of free testosterone using law-of-mass-action equation.

Effect of Testosterone Replacement on Response to Sildenafil Citrate in Men With Erectile Dysfunction: A Parallel, Randomized Trial

BACKGROUND Erectile dysfunction and low testosterone levels frequently occur together. OBJECTIVE To determine whether addition of testosterone to sildenafil therapy improves erectile response in men with erectile dysfunction and low testosterone levels. DESIGN Randomized, double-blind, parallel, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00512707) SETTING Outpatient academic research center. PARTICIPANTS Men aged 40 to 70 years with scores of 25 or less for the erectile function domain (EFD) of the International Index of Erectile Function, total testosterone levels less than 11.45 nmol/L (<330 ng/dL), or free testosterone levels less than 173.35 pmol/L (<50 pg/mL). INTERVENTION Sildenafil dose was optimized, and 140 participants were then randomly assigned to 14 weeks of daily transdermal gel that contained 10-g testosterone for 70 participants and placebo for the remaining 70 participants. All participants were included in the primary analysis, although 10 in the testosterone group and 12 in the placebo group did not complete the study. RESULTS At baseline, the 2 groups had similar EFD scores. Administration of sildenafil alone was associated with a substantial increase in EFD score (mean, 7.7 [95% CI, 6.5 to 8.8]), but change in EFD score after randomization did not differ between the groups (difference, 2.2 [CI, -0.8 to 5.1]; P = 0.150). The findings were similar for other domains of sexual function in younger men, more obese men, and men with lower baseline testosterone levels or an inadequate response to sildenafil alone. Frequency of adverse events was similar for testosterone and placebo groups. LIMITATION Whether testosterone could improve erectile function without sildenafil was not studied. CONCLUSION Sildenafil plus testosterone was not superior to sildenafil plus placebo in improving erectile function in men with erectile dysfunction and low testosterone levels. PRIMARY FUNDING SOURCE National Institute of Child Health and Human Development.

Free Testosterone Levels Are Associated with Mobility Limitation and Physical Performance in Community-Dwelling Men: The Framingham Offspring Study

CONTEXT Mobility limitation is associated with increased morbidity and mortality. The relationship between circulating testosterone and mobility limitation and physical performance is incompletely understood. OBJECTIVE Our objective was to examine cross-sectional and prospective relations between baseline sex hormones and mobility limitations and physical performance in community-dwelling older men. DESIGN, SETTING, AND PARTICIPANTS We conducted cross-sectional and longitudinal analyses of 1445 men (mean age 61.0 +/- 9.5 yr) who attended Framingham Offspring Study examinations 7 and 8 (mean 6.6 yr apart). Total testosterone (TT) was measured by liquid chromatography tandem mass spectrometry at examination 7. Cross-sectional and longitudinal analyses of mobility limitation and physical performance were performed with continuous (per SD) and dichotomized [low TT and free testosterone (FT) and high SHBG vs. normal] hormone levels. MAIN OUTCOME MEASURES Self-reported mobility limitation, subjective health, usual walking speed, and grip strength were assessed at examinations 7 and 8. Short physical performance battery was performed at examination 7. RESULTS Higher continuous FT was positively associated with short physical performance battery score (beta = 0.13; P = 0.008), usual walking speed (beta = 0.02; P = 0.048), and lower risk of poor subjective health [odds ratio (OR) = 0.72; P = 0.01]. In prospective analysis, 1 SD increase in baseline FT was associated with lower risk of developing mobility limitation (OR = 0.78; 95% confidence interval = 0.62-0.97) and progression of mobility limitation (OR = 0.75; 95% confidence interval = 0.60-0.93). Men with low baseline FT had 57% higher odds of reporting incident mobility limitation (P = 0.03) and 68% higher odds of worsening of mobility limitation (P = 0.007). CONCLUSIONS Lower levels of baseline FT are associated with a greater risk of incident or worsening mobility limitation in community-dwelling older men. Whether this risk can be reduced with testosterone therapy needs to be determined by randomized trials.

Effect of testosterone supplementation with and without a dual 5α-reductase inhibitor on fat-free mass in men with suppressed testosterone production: a randomized controlled trial.

CONTEXT Steroid 5α-reductase inhibitors are used to treat benign prostatic hyperplasia and androgenic alopecia, but the role of 5α-dihydrotestosterone (DHT) in mediating testosterones effects on muscle, sexual function, erythropoiesis, and other androgen-dependent processes remains poorly understood. OBJECTIVE To determine whether testosterones effects on muscle mass, strength, sexual function, hematocrit level, prostate volume, sebum production, and lipid levels are attenuated when its conversion to DHT is blocked by dutasteride (an inhibitor of 5α-reductase type 1 and 2). DESIGN, SETTING, AND PATIENTS The 5α-Reductase Trial was a randomized controlled trial of healthy men aged 18 to 50 years comparing placebo plus testosterone enthanate with dutasteride plus testosterone enanthate from May 2005 through June 2010. INTERVENTIONS Eight treatment groups received 50, 125, 300, or 600 mg/wk of testosterone enanthate for 20 weeks plus placebo (4 groups) or 2.5 mg/d of dutasteride (4 groups). MAIN OUTCOME MEASURES The primary outcome was change in fat-free mass; secondary outcomes: changes in fat mass, muscle strength, sexual function, prostate volume, sebum production, and hematocrit and lipid levels. RESULTS A total of 139 men were randomized; 102 completed the 20-week intervention. Men assigned to dutasteride were similar at baseline to those assigned to placebo. The mean fat-free mass gained by the dutasteride groups was 0.6 kg (95% CI, -0.1 to 1.2 kg) when receiving 50 mg/wk of testosterone enanthate, 2.6 kg (95% CI, 0.9 to 4.3 kg) for 125 mg/wk, 5.8 kg (95% CI, 4.8 to 6.9 kg) for 300 mg/wk, and 7.1 kg (95% CI, 6.0 to 8.2 kg) for 600 mg/wk. The mean fat-free mass gained by the placebo groups was 0.8 kg (95% CI, -0.1 to 1.7 kg) when receiving 50 mg/wk of testosterone enanthate, 3.5 kg (95% CI, 2.1 to 4.8 kg) for 125 mg/wk, 5.7 kg (95% CI, 4.8 to 6.5 kg) for 300 mg/wk, and 8.1 kg (95% CI, 6.7 to 9.5 kg) for 600 mg/wk. The dose-adjusted differences between the dutasteride and placebo groups for fat-free mass were not significant (P = .18). Changes in fat mass, muscle strength, sexual function, prostate volume, sebum production, and hematocrit and lipid levels did not differ between groups. CONCLUSION Changes in fat-free mass in response to graded testosterone doses did not differ in men in whom DHT was suppressed by dutasteride from those treated with placebo, indicating that conversion of testosterone to DHT is not essential for mediating its anabolic effects on muscle. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00493987.