Bret Zeldow

Effects of Testosterone Treatment in Older Men

BACKGROUND Serum testosterone concentrations decrease as men age, but benefits of raising testosterone levels in older men have not been established. METHODS We assigned 790 men 65 years of age or older with a serum testosterone concentration of less than 275 ng per deciliter and symptoms suggesting hypoandrogenism to receive either testosterone gel or placebo gel for 1 year. Each man participated in one or more of three trials--the Sexual Function Trial, the Physical Function Trial, and the Vitality Trial. The primary outcome of each of the individual trials was also evaluated in all participants. RESULTS Testosterone treatment increased serum testosterone levels to the mid-normal range for men 19 to 40 years of age. The increase in testosterone levels was associated with significantly increased sexual activity, as assessed by the Psychosexual Daily Questionnaire (P<0.001), as well as significantly increased sexual desire and erectile function. The percentage of men who had an increase of at least 50 m in the 6-minute walking distance did not differ significantly between the two study groups in the Physical Function Trial but did differ significantly when men in all three trials were included (20.5% of men who received testosterone vs. 12.6% of men who received placebo, P=0.003). Testosterone had no significant benefit with respect to vitality, as assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue scale, but men who received testosterone reported slightly better mood and lower severity of depressive symptoms than those who received placebo. The rates of adverse events were similar in the two groups. CONCLUSIONS In symptomatic men 65 years of age or older, raising testosterone concentrations for 1 year from moderately low to the mid-normal range for men 19 to 40 years of age had a moderate benefit with respect to sexual function and some benefit with respect to mood and depressive symptoms but no benefit with respect to vitality or walking distance. The number of participants was too few to draw conclusions about the risks of testosterone treatment. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00799617.).

Effect of Testosterone Treatment on Volumetric Bone Density and Strength in Older Men With Low Testosterone: A Controlled Clinical Trial

Importance As men age, they experience decreased serum testosterone concentrations, decreased bone mineral density (BMD), and increased risk of fracture. Objective To determine whether testosterone treatment of older men with low testosterone increases volumetric BMD (vBMD) and estimated bone strength. Design, Setting, and Participants Placebo-controlled, double-blind trial with treatment allocation by minimization at 9 US academic medical centers of men 65 years or older with 2 testosterone concentrations averaging less than 275 ng/L participating in the Testosterone Trials from December 2011 to June 2014. The analysis was a modified intent-to-treat comparison of treatment groups by multivariable linear regression adjusted for balancing factors as required by minimization. Interventions Testosterone gel, adjusted to maintain the testosterone level within the normal range for young men, or placebo gel for 1 year. Main Outcomes and Measures Spine and hip vBMD was determined by quantitative computed tomography at baseline and 12 months. Bone strength was estimated by finite element analysis of quantitative computed tomography data. Areal BMD was assessed by dual energy x-ray absorptiometry at baseline and 12 months. Results There were 211 participants (mean [SD] age, 72.3 [5.9] years; 86% white; mean [SD] body mass index, 31.2 [3.4]). Testosterone treatment was associated with significantly greater increases than placebo in mean spine trabecular vBMD (7.5%; 95% CI, 4.8% to 10.3% vs 0.8%; 95% CI, −1.9% to 3.4%; treatment effect, 6.8%; 95% CI, 4.8%-8.7%; P < .001), spine peripheral vBMD, hip trabecular and peripheral vBMD, and mean estimated strength of spine trabecular bone (10.8%; 95% CI, 7.4% to 14.3% vs 2.4%; 95% CI, −1.0% to 5.7%; treatment effect, 8.5%; 95% CI, 6.0%-10.9%; P < .001), spine peripheral bone, and hip trabecular and peripheral bone. The estimated strength increases were greater in trabecular than peripheral bone and greater in the spine than hip. Testosterone treatment increased spine areal BMD but less than vBMD. Conclusions and Relevance Testosterone treatment for 1 year of older men with low testosterone significantly increased vBMD and estimated bone strength, more in trabecular than peripheral bone and more in the spine than hip. A larger, longer trial could determine whether this treatment also reduces fracture risk. Trial Registration clinicaltrials.gov Identifier: NCT00799617

Association of Testosterone Levels With Anemia in Older Men: A Controlled Clinical Trial

Importance In one-third of older men with anemia, no recognized cause can be found. Objective To determine if testosterone treatment of men 65 years or older with unequivocally low testosterone levels and unexplained anemia would increase their hemoglobin concentration. Design, Setting, and Participants A double-blinded, placebo-controlled trial with treatment allocation by minimization using 788 men 65 years or older who have average testosterone levels of less than 275 ng/dL. Of 788 participants, 126 were anemic (hemoglobin ⩽12.7 g/dL), 62 of whom had no known cause. The trial was conducted in 12 academic medical centers in the United States from June 2010 to June 2014. Interventions Testosterone gel, the dose adjusted to maintain the testosterone levels normal for young men, or placebo gel for 12 months. Main Outcomes and Measures The percent of men with unexplained anemia whose hemoglobin levels increased by 1.0 g/dL or more in response to testosterone compared with placebo. The statistical analysis was intent-to-treat by a logistic mixed effects model adjusted for balancing factors. Results The men had a mean age of 74.8 years and body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) of 30.7; 84.9% were white. Testosterone treatment resulted in a greater percentage of men with unexplained anemia whose month 12 hemoglobin levels had increased by 1.0 g/dL or more over baseline (54%) than did placebo (15%) (adjusted OR, 31.5; 95% CI, 3.7-277.8; P = .002) and a greater percentage of men who at month 12 were no longer anemic (58.3%) compared with placebo (22.2%) (adjusted OR, 17.0; 95% CI, 2.8-104.0; P = .002). Testosterone treatment also resulted in a greater percentage of men with anemia of known cause whose month 12 hemoglobin levels had increased by 1.0 g/dL or more (52%) than did placebo (19%) (adjusted OR, 8.2; 95% CI, 2.1-31.9; P = .003). Testosterone treatment resulted in a hemoglobin concentration of more than 17.5 g/dL in 6 men who had not been anemic at baseline. Conclusions and Relevance Among older men with low testosterone levels, testosterone treatment significantly increased the hemoglobin levels of those with unexplained anemia as well as those with anemia from known causes. These increases may be of clinical value, as suggested by the magnitude of the changes and the correction of anemia in most men, but the overall health benefits remain to be established. Measurement of testosterone levels might be considered in men 65 years or older who have unexplained anemia and symptoms of low testosterone levels. Trial Registration clinicaltrials.gov Identifier: NCT00799617

Testosterone Treatment and Sexual Function in Older Men With Low Testosterone Levels.

CONTEXT The Testosterone Trials are a coordinated set of seven trials to determine the efficacy of T in symptomatic men ≥65 years old with unequivocally low T levels. Initial results of the Sexual Function Trial showed that T improved sexual activity, sexual desire, and erectile function. OBJECTIVE To assess the responsiveness of specific sexual activities to T treatment; to relate hormone changes to changes in sexual function; and to determine predictive baseline characteristics and T threshold for sexual outcomes. DESIGN A placebo-controlled trial. SETTING Twelve academic medical centers in the United States. PARTICIPANTS A total of 470 men ≥65 years of age with low libido, average T <275 ng/dL, and a partner willing to have sexual intercourse at least twice a month. METHODS Men were assigned to take T gel or placebo for 1 year. Sexual function was assessed by three questionnaires every 3 months: the Psychosexual Daily Questionnaire, the Derogatis Interview for Sexual Function, and the International Index of Erectile Function. RESULTS Compared with placebo, T administration significantly improved 10 of 12 measures of sexual activity. Incremental increases in total and free T and estradiol levels were associated with improvements in sexual activity and desire, but not erectile function. No threshold T level was observed for any outcome, and none of the 27 baseline characteristics predicted responsiveness to T. CONCLUSIONS In older men with low libido and low T levels, improvements in sexual desire and activity in response to T treatment were related to the magnitude of increases in T and estradiol levels, but there was no clear evidence of a threshold effect.

Language Impairment in Children Perinatally Infected with HIV Compared to Children Who Were HIV-Exposed and Uninfected

Objective: To investigate the risk for language impairment (LI) in children perinatally infected or exposed to HIV. Methods: We evaluated the prevalence of LI in 7- to 16-year-old children with perinatal HIV infection (HIV+) compared with HIV-exposed and uninfected children, using a comprehensive standardized language test (Clinical Evaluation of Language Functioning-Fourth Edition [CELF-4]). LI was classified as primary LI (Pri-LI) (monolingual English exposure and no cognitive or hearing impairment), concurrent LI (Con-LI) (cognitive or hearing impairment), or no LI. Associations of demographic, caregiver, HIV disease, and antiretroviral treatment factors with LI category were evaluated using univariate and multivariable logistic regression models. Results: Of the 468 children with language assessments, 184 (39%) had LI. No difference was observed by HIV infection status for overall LI or for Pri-LI or Con-LI; mean (SD) CELF-4 scores were 88.5 (18.4) for HIV+ versus 87.5 (17.9) for HIV-exposed and uninfected children. After adjustment, black children had higher odds of Pri-LI versus no LI (adjusted odds ratio [aOR] = 2.43, p = .03). Children who were black, Hispanic, had a caregiver with low education or low intelligence quotient, or a nonbiological parent as caregiver had higher odds of Con-LI versus no LI. Among HIV+ children, viral load >400 copies/mL (aOR = 3.04, p < .001), Centers for Disease Control and Prevention Class C (aOR = 2.19, p = .02), and antiretroviral treatment initiation <6 months of age (aOR = 2.12, p = .02) were associated with higher odds of Con-LI versus no LI. Conclusions: Children perinatally exposed to HIV are at high risk for LI, but such risk was not increased for youth with HIV. Risk factors differed for Pri-LI and Con-LI.

Evaluation of risk for late language emergence after in utero antiretroviral drug exposure in HIV-exposed uninfected infants.

Background: Combination antiretroviral (cARV) regimens are recommended for pregnant women with HIV to prevent perinatal HIV transmission. Safety is a concern for infants who were HIV-exposed but uninfected, particularly for neurodevelopmental problems, such as language delays. Methods: We studied late language emergence (LLE) in HIV-exposed but uninfected children enrolled in a US-based prospective cohort study. LLE was defined as a caregiver-reported score ⩽10th percentile in any of 4 domains of the MacArthur-Bates Communicative Development Inventory for 1-year olds and as ≥1 standard deviation below age-specific norms for the Ages and Stages Questionnaire for 2-year olds. Logistic regression models were used to evaluate associations of in utero cARV exposure with LLE, adjusting for infant, maternal and environmental characteristics. Results: 1129 language assessments were conducted among 792 1- and 2-year-old children (50% male, 62% black and 37% Hispanic). Overall, 86% had in utero exposure to cARV and 83% to protease inhibitors. LLE was identified in 26% of 1-year olds and 23% of 2-year olds, with higher rates among boys. In adjusted models, LLE was not associated with maternal cARV or ARV drug classes in either age group. Among cARV-exposed 1-year olds, increased odds of LLE was observed for those exposed to atazanavir (adjusted odds ratio = 1.83, 95% confidence interval: 1.10–3.04), particularly after the first trimester (adjusted odds ratio = 3.56, P = 0.001), compared with atazanavir-unexposed infants. No associations of individual ARV drugs with LLE were observed among 2-year olds. Conclusions: In utero cARV exposure showed little association with LLE, except for a higher risk of language delay observed in 1-year-old infants with atazanavir exposure.

Hearing Loss in Perinatally HIV-infected and HIV-exposed but Uninfected Children and Adolescents

Background: Little is known about hearing loss in children with HIV infection (HIV+). We examined the prevalence of hearing loss in perinatally HIV+ and HIV-exposed but uninfected (HEU) children, compared these with the percentage with hearing loss in the general population and evaluated possible risk factors for hearing loss in HIV+ and HEU children. Methods: Audiometric examinations were completed in children who met any prespecified criteria for possible hearing loss. The hearing examination consisted of a tympanogram in each ear and pure-tone air-conduction threshold testing from 500 through 4000 Hz. Hearing loss was defined as the pure-tone average over these frequencies ≥20 dB hearing level. The associations of demographic variables, parent/caregiver, HIV disease and HIV treatment with hearing loss were evaluated with univariate and multivariable logistic regression models. Results: Hearing testing was completed in 231 children (145 HIV+ and 86 HEU). Hearing loss occurred in 20.0% of HIV+ children and 10.5% of HEU children. After adjusting for caregiver education level, HIV infection was associated with increased odds of hearing loss (adjusted odds ratio = 2.13, 95% confidence interval: 0.95–4.76, P = 0.07). Among HIV+ children, those with a Centers for Disease Control and Prevention class C diagnosis had over twice the odds of hearing loss (adjusted odds ratio = 2.47, 95% confidence interval: 1.04–5.87, P = 0.04). The prevalence of hearing loss was higher in both HIV+ and HEU children compared with National Health and Nutrition Examination Survey III children. Conclusions: Hearing loss was more common in both HIV+ and HEU children than in children from a US population sample. More advanced HIV illness increased the risk of hearing loss in HIV+ children.

Discordance of cognitive and academic achievement outcomes in youth with perinatal HIV exposure.

Background: To evaluate achievement in youth with perinatally acquired HIV (PHIV) compared with HIV-exposed uninfected peers (HEU) and to examine differential effects of HIV on cognition-achievement concordance. Methods: Cognition and achievement were assessed using standardized measures. Intelligence quotient-derived predicted achievement scores were subtracted from observed achievement scores to calculate discrepancy values. Linear regression models were used to compare achievement discrepancies between PHIV and HEU, adjusting for demographic covariates. Results: Participants: 295 PHIV and 167 HEU youth; 71% black, 48% male, mean age 13.1 and 11.3 years, respectively. PHIV youth were relatively healthy (mean CD4%, 32%; viral load ⩽400 copies/mL, 72%). PHIV and HEU youth had cognitive and achievement scores significantly below population norm means (P < 0.001), but did not differ in cognition (mean full scale IQ = 86.7 vs. 89.4, respectively). In unadjusted models, HEU outperformed PHIV youth on total achievement (mean = 89.2 vs. 86.0, P = 0.04) and numerical operations (mean = 88.8 vs. 82.9, P < 0.001); no differences remained after adjustment. Mean observed-predicted achievement discrepancies reflected “underachievement”. History of encephalopathy predicted poorer achievement (P = 0.039) and greater underachievement, even after adjustment. PHIV showed greater underachievement than HEU for numerical operations (P < 0.001) and total achievement (P = 0.03), but these differences did not persist in adjusted models. Conclusions: Both PHIV and HEU youth demonstrated lower achievement than normative samples and underachieved relative to predicted achievement scores. Observed-predicted achievement discrepancies were associated with prior encephalopathy, older age and other non-HIV factors. PHIV youth with prior encephalopathy had significantly lower achievement and greater underachievement compared with PHIV without encephalopathy and HEU youth, even in adjusted models.

Biomarkers and neurodevelopment in perinatally HIV-infected or exposed youth: a structural equation model analysis

Objective:To examine the relationship between markers of vascular dysfunction and neurodevelopmental outcomes in perinatally HIV-infected (PHIV+) and perinatally HIV-exposed but uninfected (PHEU) youth. Design:Cross-sectional design within a prospective, 15-site US-based cohort study. Methods:Neurodevelopmental outcomes were evaluated in relation to nine selected vascular biomarkers in 342 youth (212 PHIV+, 130 PHEU). Serum levels were assessed for adiponectin, C-reactive protein (CRP), fibrinogen, interleukin-6 (IL-6), soluble vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-selectin), monocyte chemoattractant protein (sMCP-1), intercellular adhesion molecule-1 (sICAM-1), and P-selectin (sP-selectin). The Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) was administered at entry, yielding a Full-Scale IQ score, and four index scores. Factor analysis was conducted to reduce the biomarkers to fewer factors with related biological roles. Structural equation models (SEMs) were used to measure associations between resulting factors and WISC-IV scores. Results:Mean participant age was 11.4 years, 54% were female, 70% black. The nine biomarkers were clustered into three factor groups: F1 (fibrinogen, CRP, and IL-6); F2 (sICAM-1 and sVCAM-1); and F3 (MCP-1, sP-selectin, and sE-selectin). Adiponectin showed little correlation with any factor. SEMs revealed significant negative association of F1 with WISC-IV processing speed score in the total cohort. This effect remained significant after adjusting for HIV status and other potential confounders. A similar association was observed when restricted to PHIV+ participants in both unadjusted and adjusted SEMs. Conclusion:Aggregate measures of fibrinogen, CRP, and IL-6 may serve as a latent biomarker associated with relatively decreased processing speed in both PHIV+ and PHEU youth.

Cardiac biomarkers in HIV-exposed uninfected children.

Objectives:To evaluate associations of cardiac biomarkers with in-utero antiretroviral drug exposures and cardiac function/structure measured by echocardiograms in HIV-exposed but uninfected (HEU) children. Design and methods:We analyzed the association of three cardiac biomarkers (cardiac troponin T, cTnT; high sensitivity C-reactive protein, hsCRP; and N-terminal pro-brain natriuretic peptide, NT-proBNP) with prenatal antiretroviral drug exposures, maternal–child characteristics, and echocardiographic parameters. Results:Among 338 HEU children (mean age 4.3 years), 51% had at least one elevated cardiac biomarker. Maternal tobacco use was associated with elevated NT-proBNP [adjusted odds ratio (aOR) 2.28, P = 0.02]. Maternal alcohol and abacavir use were associated with elevated cTnT levels (aOR 3.56, P = 0.01 and aOR 2.33, P = 0.04, respectively). Among 94 children with paired echocardiogram-biomarker measurements, cTnT measurements were correlated with increased left-ventricular thickness-to-dimension ratio (r = 0.21, P = 0.04); and elevated cTnT was associated with higher mean left-ventricular end-diastolic (LVED) posterior wall thickness (P = 0.04). hsCRP measurements were negatively correlated with septal thickness (r = −0.22, P = 0.03) and elevated hsCRP was associated with lower mean left-ventricular contractility Z-scores (P = 0.04). NT-proBNP measurements were correlated with increased LVED dimension (r = 0.20, P = 0.05) and elevated NT-proBNP was associated with lower mean end-systolic septal thickness (P = 0.03). Conclusion:Our findings suggest that cardiac biomarkers may help identify HEU children who require further cardiac evaluation including echocardiography. Potential cardiac effects of prenatal abacavir exposure in this population need further investigation.