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In this subtrial involving middle-aged and older men with hypogonadism, testosterone treatment did not result in a lower incidence of clinical fracture than placebo. Fracture incidence was numerically higher with testosterone.

Abstract Context A novel formulation of oral testosterone (T) undecanoate (TU) was evaluated in a phase 3 clinical trial. Objective Determine efficacy, short-term safety, and alignment of new oral TU formulation with current US approval standards for T replacement therapy. Design Randomized, active-controlled, open-label study. Setting and Patients Academic and private clinical practice sites; enrolled patients were clinically hypogonadal men 18 to 65 years old. Methods Patients were randomized 3:1 to oral TU, as prescribed (JATENZO®; n = 166) or a topical T product once daily (Axiron®; n = 56) for 3 to 4 months. Dose titration was based on average T levels (Cavg) calculated from serial pharmacokinetic (PK) samples. T was assayed by liquid chromatography–mass spectrometry/mass spectrometry. Patients had 2 dose adjustment opportunities prior to final PK visit. Safety was assessed by standard clinical measures, including ambulatory blood pressure (BP). Results 87% of patients in both groups achieved mean T Cavg in the eugonadal range. Sodium fluoride-ethylenediamine tetra-acetate plasma T Cavg (mean ± standard deviation) for the oral TU group was 403 ± 128 ng/dL (~14 ± 4 nmol/L); serum T equivalent, ~489 ± 155 ng/dL (17 ± 5 nmol/L); and topical T, 391 ± 140 ng/dL (~14 ± 5 nmol/L). Modeling/simulation of T PK data demonstrated that dose titration based on a single blood sample 4 to 6 h after oral TU dose yielded efficacy (93%) equivalent to Cavg-based titration (87%). Safety profiles were similar in both groups, but oral TU was associated with a mean increase in systolic BP of 3 to 5 mm Hg. Conclusion A new oral TU formulation effectively restored T to mid-eugonadal levels in hypogonadal patients.

Context:Findings of studies of testosterone’s effects on muscle strength and physical function in older men have been inconsistent; its effects on muscle power and fatigability have not been studied.Objective:To determine the effects of testosterone administration for 3 years in older men on muscle strength, power, fatigability, and physical function.Design, Setting, and Participants:This was a double-blind, placebo-controlled, randomized trial of healthy men ≥60 years old with total testosterone levels of 100 to 400 ng/dL or free testosterone levels <50 pg/mL.Interventions:Random assignment to 7.5 g of 1% testosterone or placebo gel daily for 3 years.Outcome Measures:Loaded and unloaded stair-climbing power, muscle strength, power, and fatigability in leg press and chest press exercises, and lean mass at baseline, 6, 18, and 36 months.Results:The groups were similar at baseline. Testosterone administration for 3 years was associated with significantly greater performance in unloaded and loaded stair-climbing power than placebo (mean estimated between-group difference, 10.7 W [95% confidence interval (CI), −4.0 to 25.5], P = 0.026; and 22.4 W [95% CI, 4.6 to 40.3], P = 0.027), respectively. Changes in chest-press strength (estimated mean difference, 16.3 N; 95% CI, 5.5 to 27.1; P < 0.001) and power (mean difference 22.5 W; 95% CI, 7.5 to 37.5; P < 0.001), and leg-press power were significantly greater in men randomized to testosterone than in those randomized to placebo. Lean body mass significantly increased more in the testosterone group.Conclusion:Compared with placebo, testosterone replacement in older men for 3 years was associated with modest but significantly greater improvements in stair-climbing power, muscle mass, and power. Clinical meaningfulness of these treatment effects and their impact on disability in older adults with functional limitations remains to be studied.Testosterone replacement in older men for 3 years was associated with modest but significantly greater improvements in muscle power and physical function compared with placebo.

Abstract Context The effect of testosterone on depressive symptoms in men with hypogonadism remains incompletely understood. Objective We assessed the effects of testosterone-replacement therapy (TRT) in improving depressive symptoms in hypogonadal men with and without depressive symptoms enrolled in the TRAVERSE cardiovascular safety trial. Methods A randomized, placebo-controlled, double-blind study was conducted at 316 trial sites. Participants included men, aged 45 to 80 years, with 2 fasting testosterone levels less than 300 ng/dL, 1 or more hypogonadal symptoms, cardiovascular disease (CVD), or increased risk of CVD. We evaluated 3 subgroups of participants: (1) men with rigorously defined, late-life-onset, low-grade persistent depressive disorder (LG-PDD, previously “dysthymia”); (2) all men with significant depressive symptoms (Patient Health Questionnaire-9 Score >4); and (3) all randomly assigned men. Intervention included 1.62% transdermal testosterone or placebo gel. Outcome measures included the proportions of participants (1) meeting criteria for LG-PDD or (2) with significant depressive symptoms; and changes in depressive symptoms, energy, sleep quality, and cognition in testosterone-treated vs placebo-treated men in the 3 subgroups. Results Of 5204 randomly assigned participants, 2643 (50.8%) had significant depressive symptoms, but only 49 (1.5%) met rigorous criteria for LG-PDD. Among those with LG-PDD, there was no significant difference in any outcome measure between the TRT and placebo groups, possibly reflecting low statistical power. In men with significant depressive symptoms (n = 2643) and in all randomly assigned participants (n = 5204), TRT was associated with modest but significantly greater improvements in mood and energy but not cognition or sleep quality. Conclusion Depressive symptoms are common in middle-aged and older men with hypogonadism but LG-PDD is uncommon. TRT is associated with small improvements in mood and energy in hypogonadal men with and without significant depressive symptoms.

Severe gonadal steroid deficiency induces bone loss in adult men; however, the specific roles of androgen and estrogen deficiency in hypogonadal bone loss are unclear. Additionally, the threshold levels of testosterone and estradiol that initiate bone loss are uncertain. One hundred ninety-eight healthy men, ages 20-50, received goserelin acetate, which suppresses endogenous gonadal steroid production, and were randomized to treatment with 0, 1.25, 2.5, 5, or 10 grams of testosterone gel daily for 16 weeks. An additional cohort of 202 men was randomized to receive these treatments plus anastrozole, which suppresses conversion of androgens to estrogens. Thirty-seven men served as controls and received placebos for goserelin and testosterone. Changes in bone turnover markers, bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA), and BMD by quantitative computed tomography (QCT) were assessed in all men. Bone microarchitecture was assessed in 100 men. As testosterone dosage decreased, the percent change in C-telopeptide increased. These increases were considerably greater when aromatization of testosterone to estradiol was also suppressed, suggesting effects of both testosterone and estradiol deficiency. Decreases in DXA BMD were observed when aromatization was suppressed but were modest in most groups. QCT spine BMD fell substantially in all testosterone-dose groups in which aromatization was also suppressed, and this decline was independent of testosterone dose. Estradiol deficiency disrupted cortical microarchitecture at peripheral sites. Estradiol levels above 10 pg/ml and testosterone levels above 200 ng/dl were generally sufficient to prevent increases in bone resorption and decreases in BMD in men. Estrogens primarily regulate bone homeostasis in adult men, and testosterone and estradiol levels must decline substantially to impact the skeleton. ClinicalTrials.gov, NCT00114114. AbbVie Inc., AstraZeneca Pharmaceuticals LP, NIH.

Abstract Objective To determine the effect of testosterone vs placebo treatment on health-related quality of life (HR-QOL) and psychosocial function in men without pathologic hypogonadism in the context of a lifestyle intervention. Design, Setting, Participants Secondary analysis of a 2-year randomized controlled testosterone therapy trial for prevention or reversal of newly diagnosed type 2 diabetes, enrolling men ≥ 50 years at high risk for type 2 diabetes from 6 Australian centers. Interventions Injectable testosterone undecanoate or matching placebo on the background of a community-based lifestyle program. Main Outcomes Self-reported measures of HR-QOL/psychosocial function. Results Of 1007 participants randomized into the Testosterone for Type 2 Diabetes Mellitus (T4DM) trial, 648 (64%) had complete data available for all HR-QOL/psychosocial function assessments at baseline and 2 years. Over 24 months, while most measures were not different between treatment arms, testosterone treatment, compared with placebo, improved subjective social status and sense of coherence. Baseline HR-QOL/psychosocial function measures did not predict the effect of testosterone treatment on glycemic outcomes, primary endpoints of T4DM. Irrespective of treatment allocation, larger decreases in body weight were associated with improved mental quality of life, mastery, and subjective social status. Men with better baseline physical function, greater sense of coherence, and fewer depressive symptoms experienced greater associated decreases in body weight, with similar effects on waist circumference. Conclusion In this diabetes prevention trial, weight loss induced by a lifestyle intervention improved HR-QOL and psychosocial function in more domains than testosterone treatment. The magnitude of weight and waist circumference reduction were predicted by baseline physical function, depressive symptomology, and sense of coherence.

•In the TRAVERSE trial, testosterone replacement therapy in hypogonadal men increased circulating neutrophil and monocyte counts and decreased lymphocyte and platelet counts.•As reported previously, testosterone replacement therapy in the TRAVERSE Trial was associated with a higher incidence of pulmonary embolism than placebo treatment. Here we show that changes from baseline in neutrophil and monocyte counts in testosterone-treated men were positively associated with occurrence of VTE.•Men with higher baseline and on-treatment neutrophil and monocyte counts were at higher risk of MACE.•Neutrophil and monocyte counts should be considered in the evaluation of VTE risk prior to starting TRT in men with hypogonadism. In epidemiological studies, higher leukocyte and platelet counts are associated with increased risk of cardiovascular events. Effects of testosterone replacement therapy (TRT) on leukocyte subsets and platelets in men with hypogonadism and association of circulating leukocyte subtypes and platelets during TRT with cardiovascular events remain unknown. In the TRAVERSE Trial, 5,204 men, 45-80 years with hypogonadism and preexisting or increased risk of cardiovascular disease (CVD) were randomized to transdermal testosterone or placebo gel daily for up to 5 years. We determined the effect of TRT on neutrophils, monocytes, lymphocytes and platelets and association of changes in leukocyte subtypes and platelets with risk of major adverse cardiovascular (MACE) and venous thromboembolism (VTE) events. TRT was associated with significantly greater increase in neutrophils and monocytes, and greater decrease in lymphocytes and platelets than placebo. Changes in neutrophil (odds ratio for 1 SD increase in cell count (OR) 1.32 [1.01, 1.73]) and monocyte (OR 1.39 [1.08, 1.79]) counts were associated with increased risk of VTE, accounting for TRT. Neutrophil and monocyte counts at baseline and on-treatment were also associated with increased risk of MACE, adjusting for treatment (baseline: neutrophils OR 1.18 [1.06,1.31], monocytes OR 1.16 [1.05,1.29]; on-treatment neutrophils: OR 1.25 [1.12, 1.40]; monocytes: OR 1.18 [1.06,1.31]). TRT increased circulating neutrophils and monocytes and decreased lymphocytes and platelets in men with hypogonadism. Changes in monocyte and neutrophil counts were associated with increased risk of VTE. Neutrophil and monocyte counts should be considered when evaluating VTE risk in hypogonadal men treated with TRT. URL:https://clinicaltrials.gov/study/NCT03518034. Unique identifier: NCT03518034. The study was initially registered on March 5, 2018, and the first participant was enrolled on May 23, 2018.

In this double-blind, placebo-controlled, 52-week trial among postmenopausal women not receiving estrogen therapy, treatment with a patch delivering 300 μg of testosterone per day resulted in a significant although modest increase in the 4-week frequency of satisfying sexual episodes (1.4 more episodes per month), but the women were also subject to more adverse events, including androgenic side effects. In postmenopausal women not receiving estrogen therapy, treatment with a patch delivering 300 '1;g of testosterone per day resulted in a significant although modest increase in the 4-week frequency of satisfying sexual episodes. The literature suggests that the prevalence of sexual problems among women ranges from 9 to 43%. 1 – 4 Among these women, hypoactive sexual desire disorder is a commonly reported, symptom-driven condition characterized by a decrease or absence of interest in sexual activity, causing distress. 5 Decreased libido is common after natural menopause 6 , 7 and bilateral oophorectomy. 8 – 10 Several studies have shown the efficacy and short-term safety of a transdermal patch delivering 300 μg of testosterone per day for the treatment of hypoactive sexual desire disorder in women who have undergone either surgically induced or natural menopause and who use concomitant estrogen. 11 – . . .

The social heuristic hypothesis posits that human cooperation is an intuitive response that is expressed especially under conditions of time-constraint. Conversely, it proposes that for individuals given an opportunity for reflection, cooperation is more likely to be curtailed by an optimizing process calibrated to maximize individual benefit in a given situation. Notably, the steroid hormone testosterone has also been implicated in intuitive decision-making, including both prosocial and anti-social behaviors, with effects strongest in men with particular dispositional characteristics. This raises the possibility that increased testosterone may augment the effects predicted by the social heuristic hypothesis, particularly among men higher in specific dispositional characteristics (dominance, impulsivity, independent self-construal: high risk for testosterone-induced antisocial behavior). Here, in a testosterone administration study with a relatively large sample of men (N = 400), we test this possibility in a double-blind, placebo-controlled paradigm, with men randomly assigned to play a one-shot public goods game either under time-pressure (forced intuition) or with a time delay (forced reflection). Results revealed that within the placebo group, time-pressure (versus forced delay) increased cooperation among low risk men, but decreased cooperation among high risk men. Testosterone further moderated this pattern by abolishing the time-pressure effect in low risk men and—in high risk men—reversing the effect by selectively reducing offers (compared to placebo) under forced delay. This is the first evidence that testosterone and personality can interact with time-pressure and delay to predict human cooperation.

Little is known about the neurobiological pathways through which testosterone promotes aggression or about the people in whom this effect is observed. Using a psychopharmacogenetic approach, we found that testosterone increases aggression in men (N = 308) with select personality profiles and that these effects are further enhanced among those with fewer cytosine-adenine-guanine (CAG) repeats in exon 1 of the androgen receptor (AR) gene, a polymorphism associated with increased AR efficiency. Testosterone’s effects were rapid (~30 min after administration) and mediated, in part, by subjective reward associated with aggression. Testosterone thus appears to promote human aggression through an AR-related mechanism and to have stronger effects in men with the select personality profiles because it more strongly upregulates the subjective pleasure they derive from aggression. Given other evidence that testosterone regulates reward through dopaminergic pathways, and that the sensitivity of such pathways is enhanced among individuals with the personality profiles we identified, our findings may also implicate dopaminergic processes in testosterone’s heterogeneous effects on aggression.