Zhuoying Li

Effects of Testosterone Supplementation for 3-Years on Muscle Performance and Physical Function in Older Men.

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.

Effects of long-term testosterone administration on cognition in older men with low or low-to-normal testosterone concentrations: a prespecified secondary analysis of data from the randomised, double-blind, placebo-controlled TEAAM trial

BACKGROUND The effects of testosterone on cognitive function in older men are incompletely understood. We aimed to establish the effects of long-term testosterone administration on multiple domains of cognitive function in older men with low or low-to-normal testosterone concentrations. METHODS We did the randomised, double-blind, placebo-controlled, parallel-group TEAAM trial at three medical centres in Boston, Phoenix, and Los Angeles, USA. Men aged 60 years and older with low or low-to-normal testosterone concentrations (3·47-13·9 nmol/L, or free testosterone <173 pmol/L) were randomly assigned (1:1), via computer-generated randomisation, to receive either 7·5 g of 1% testosterone gel or placebo gel daily for 3 years. Randomisation was stratified by age (60-75 years vs >75 years) and study site. The testosterone dose was adjusted to achieve concentrations of 17·3-31·2 nmol/L. Participants and all study personnel were masked to treatment allocation. Multiple domains of cognitive function were assessed as prespecified secondary outcomes by use of standardised tests at baseline and months 6, 18, and 36. We did analyses by intention to treat (in men who had baseline assessments of cognitive function) and per protocol (restricted to participants who completed the study drug and had both baseline and 36 month assessments of cognitive function). The TEAAM trial is registered with ClinicalTrials.gov, number NCT00287586. FINDINGS Between Sept 1, 2004, and Feb 12, 2009, we randomly assigned 308 participants to receive either testosterone (n=156) or placebo (n=152). 280 men had baseline cognitive assessments (n=140 per group). Mean follow-up time was 29·0 months (SD 11·5) in the testosterone group and 31·1 months (9·5) in the placebo group. The last participant completed the study on May 11, 2012. In the testosterone group, mean concentrations of serum total testosterone increased from 10·6 nmol/L (SD 2·2) to 19·7 nmol/L (9·2) and free testosterone concentrations increased from 222 pmol/L (62) to 364 pmol/L (222). In the placebo group, mean concentrations of serum total testosterone were 10·7 nmol/L (SD 2·3) at baseline and 11·1 nmol/L (3·2) post-intervention and free testosterone concentrations were 210 pmol/L (61) and 172 pmol/L (49), respectively. We recorded no between-group differences in changes in visuospatial ability (mean difference: Complex Figure Test -0·51, 95% CI -2·0 to 1·0), phonemic or category verbal fluency (phonemic fluency test 0·90, -1·3 to 3·1; categorical fluency test 1·1, -0·3 to 2·6), verbal memory (paragraph recall test 0·29, -1·2 to 1·8), manual dexterity (Grooved Pegboard Test 4·2, -1·3 to 9·7), and attention or executive function (Stroop Interference Test -2·6, -7·4 to 2·3) after adjustment for age, education, and baseline cognitive function. In both the intention-to-treat and per-protocol (n=86 per group) populations, changes in cognitive function scores were not related significantly to changes in total or free testosterone, or oestradiol concentrations. INTERPRETATION Testosterone administration for 36 months in older men with low or low-to-normal testosterone concentrations did not improve cognitive function. Future long-term trials are needed to investigate the efficacy of testosterone replacement in patients with impaired cognition, such as people with Alzheimers disease. FUNDING AbbVie Pharmaceuticals, Aurora Foundation, Boston Claude D Pepper Older Americans Independence Center, and Boston Universitys Clinical and Translational Science Institute.

Long-Term Testosterone Administration on Insulin Sensitivity in Older Men With Low or Low-Normal Testosterone Levels.

Background Serum testosterone levels and insulin sensitivity both decrease with age. Severe testosterone deficiency is associated with the development of insulin resistance. However, the effects of long-term testosterone administration on insulin sensitivity in older men with low or low-normal testosterone levels remain unknown. Methods The Testosterone Effects on Atherosclerosis in Aging Men Trial was a placebo-controlled, randomized, double-blind trial. The participants were 308 community-dwelling men, ≥60 years old, with total testosterone 100 to 400 ng/dL or free testosterone <50 pg/mL. A subset of 134 nondiabetic men (mean age, 66.7 ± 5.1 years) underwent an octreotide insulin suppression test at baseline and at 3 and 36 months after randomization to measure insulin sensitivity. Insulin sensitivity was estimated as the steady-state plasma glucose (SSPG) concentration at equilibrium during octreotide and insulin administration. Secondary outcomes included total lean mass (TLM) and total fat mass (TFM) by dual energy x-ray absorptiometry. Results There was a significant (P = 0.003) increase in SSPG in the placebo group, whereas no change was seen in testosterone-treated subjects from baseline to 36 months; however, the between-group differences in change in SSPG over 3 years were not statistically significant (+15.3 ± 6.9 mg/dL in the placebo group vs +6.2 ± 6.4 mg/dL in the testosterone group; mixed-model effect, P = 0.17). Changes in SSPG with testosterone treatment were not associated with changes in serum total or free testosterone concentrations. Changes in TFM but not TLM were associated with increases in SSPG. Stratification by age or baseline total testosterone level did not show significant intervention effects. Conclusion Testosterone administration for 36 months in older men with low or low-normal testosterone levels did not improve insulin sensitivity.

Effect of Protein Intake on Lean Body Mass in Functionally Limited Older Men: A Randomized Clinical Trial

Importance The Institute of Medicine set the recommended dietary allowance (RDA) for protein at 0.8 g/kg/d for the entire adult population. It remains controversial whether protein intake greater than the RDA is needed to maintain protein anabolism in older adults. Objective To investigate whether increasing protein intake to 1.3 g/kg/d in older adults with physical function limitations and usual protein intake within the RDA improves lean body mass (LBM), muscle performance, physical function, fatigue, and well-being and augments LBM response to a muscle anabolic drug. Design, Setting, and Participants This randomized clinical trial with a 2 × 2 factorial design was conducted in a research center. A modified intent-to-treat analytic strategy was used. Participants were 92 functionally limited men 65 years or older with usual protein intake less thanor equal to 0.83 g/kg/d within the RDA. The first participant was randomized on September 21, 2011, and the last participant completed the study on January 19, 2017. Interventions Participants were randomized for 6 months to controlled diets with 0.8 g/kg/d of protein plus placebo, 1.3 g/kg/d of protein plus placebo, 0.8 g/kg/d of protein plus testosterone enanthate (100 mg weekly), or 1.3 g/kg/d of protein plus testosterone. Prespecified energy and protein contents were provided through custom-prepared meals and supplements. Main Outcomes and Measures The primary outcome was change in LBM. Secondary outcomes were muscle strength, power, physical function, health-related quality of life, fatigue, affect balance, and well-being. Results Among 92 men (mean [SD] age, 73.0 [5.8] years), the 4 study groups did not differ in baseline characteristics. Changes from baseline in LBM (0.31 kg; 95% CI, −0.46 to 1.08 kg; P = .43) and appendicular (0.04 kg; 95% CI, −0.48 to 0.55 kg; P = .89) and trunk (0.24 kg; 95% CI, −0.17 to 0.66 kg; P = .24) lean mass, as well as muscle strength and power, walking speed and stair-climbing power, health-related quality of life, fatigue, and well-being, did not differ between men assigned to 0.8 vs 1.3 g/kg/d of protein regardless of whether they received testosterone or placebo. Fat mass decreased in participants given higher protein but did not change in those given the RDA: between-group differences were significant (difference, −1.12 kg; 95% CI, −2.04 to −0.21; P = .02). Conclusions and Relevance Protein intake exceeding the RDA did not increase LBM, muscle performance, physical function, or well-being measures or augment anabolic response to testosterone in older men with physical function limitations whose usual protein intakes were within the RDA. The RDA for protein is sufficient to maintain LBM, and protein intake exceeding the RDA does not promote LBM accretion or augment anabolic response to testosterone. Trial Registration clinicaltrials.gov Identifier: NCT01275365

Effects of Testosterone Replacement on Electrocardiographic Parameters in Men: Findings from Two Randomized Trials.

Context Endogenous testosterone levels have been negatively associated with QTc interval in small case series; the effects of testosterone therapy on electrocardiographic parameters have not been evaluated in randomized trials. Objective To evaluate the effects of testosterone replacement on corrected QT interval (QTcF) in two randomized controlled trials. Participants Men with pre- and postrandomization electrocardiograms (ECGs) from the Testosterone and Pain (TAP) and the Testosterone Effects on Atherosclerosis in Aging Men (TEAAM) Trials. Interventions Participants were randomized to either placebo or testosterone gel for 14 weeks (TAP) or 36 months (TEAAM). ECGs were performed at baseline and at the end of interventions in both trials; in the TEAAM trial ECGs were also obtained at 12 and 24 months. Outcomes Difference in change in the QTcF between testosterone and placebo groups was assessed in each trial. Association of changes in testosterone levels with changes in QTcF was analyzed in men assigned to the testosterone group of each trial. Results Mean total testosterone levels increased in the testosterone group of both trials. In the TAP trial, there was a nonsignificant reduction in mean QTcF in the testosterone group compared with placebo (effect size = -4.72 ms; P = 0.228) and the changes in QTcF were negatively associated to changes in circulating testosterone (P = 0.036). In the TEAAM trial, testosterone attenuated the age-related increase in QTcF seen in the placebo group (effect size= -6.30 ms; P < 0.001). Conclusion Testosterone replacement attenuated the age-related increase in QTcF duration in men. The clinical implications of these findings require further investigation.

Muscles of the trunk and pelvis are responsive to testosterone administration: data from testosterone dose-response study in young healthy men

Testosterone dose‐dependently increases appendicular muscle mass. However, the effects of testosterone administration on the core muscles of the trunk and the pelvis have not been evaluated. The present study evaluated the effects of testosterone administration on truncal and pelvic muscles in a dose–response trial. Participants were young healthy men aged 18–50 years participating in the 5α‐Reductase (5aR) Trial. All participants received monthly injections of 7.5 mg leuprolide acetate to suppress endogenous testosterone production and weekly injections of 50, 125, 300, or 600 mg of testosterone enanthate and were randomized to receive either 2.5 mg dutasteride (5aR inhibitor) or placebo daily for 20 weeks. Muscles of the trunk and the pelvis were measured at baseline and the end of treatment using 1.5‐Tesla magnetic resonance imaging. The dose effect of testosterone on changes in the psoas major muscle area was the primary outcome; secondary outcomes included changes in paraspinal, abdominal, pelvic floor, ischiocavernosus, and obturator internus muscles. The association between changes in testosterone levels and muscle area was also assessed. Testosterone dose‐dependently increased areas of all truncal and pelvic muscles. The estimated change (95% confidence interval) of muscle area increase per 100 mg of testosterone enanthate dosage increase was 0.622 cm2 (0.394, 0.850) for psoas; 1.789 cm2 (1.317, 2.261) for paraspinal muscles, 2.530 cm2 (1.627, 3.434) for total abdominal muscles, 0.455 cm2 (0.233, 0.678) for obturator internus, and 0.082 cm2 (0.003, 0.045) for ischiocavernosus; the increase in these volumes was significantly associated with the changes in on‐treatment total and free serum testosterone concentrations. In conclusion, core muscles of the trunk and pelvis are responsive to testosterone administration. Future trials should evaluate the potential role of testosterone administration in frail men who are predisposed to falls and men with pelvic floor dysfunction.

Testosterone does not affect agrin cleavage in mobility-limited older men despite improvement in physical function

In a subset of men, sarcopenia and physical dysfunction occur due to destabilization of the neuromuscular junction (NMJ), which is manifested by elevated serum concentrations of C‐terminal agrin fragment (CAF). Testosterone administration improves physical function in some studies; however, its effects on serum circulating CAF concentrations remain unknown. Here we evaluate the effects of testosterone administration on circulating CAF levels in mobility‐limited men with low testosterone aged 65 or older participating in the Testosterone in Older Men with Mobility Limitations (TOM) Trial. We analyzed the difference in change in serum CAF levels between testosterone and placebo groups, as well as its association with muscle strength and physical function. Association of change in serum CAF levels with serum total (TT) and free testosterone (FT) was also evaluated. Men randomized to testosterone experienced significant improvement in muscle strength and physical function (assessed by loaded stair‐climbing power). However; testosterone administration was not associated with a reduction in serum CAF levels (effect size = −50.3 pm; 95% CI = −162.1 to 61.5 pm; p = 0.374); there was no association between changes in CAF levels with changes in TT (p = 0.670) or FT (p = 0.747). There was no association between changes in serum CAF levels with improvement in either muscle strength or stair‐climbing power. In conclusion, testosterone treatment in mobility‐limited older men with low to low‐normal testosterone levels did not reduce serum CAF levels. Additionally, testosterone‐induced improvements in muscle strength and physical function were not associated with changes in serum CAF concentrations. These findings suggest that improvement in physical function with testosterone replacement in older men with mobility limitations and elevated CAF levels is mediated by mechanisms other than stabilization of the NMJ.

Long-Term Testosterone Supplementation in Older Men Attenuates Age-Related Decline in Aerobic Capacity

Context Testosterone increases skeletal muscle mass and strength, but long-term effects of testosterone supplementation on aerobic capacity, or peak oxygen uptake (V̇O2peak), in healthy older men with low testosterone have not been evaluated. Objective To determine the effects of testosterone supplementation on V̇O2peak during incremental cycle ergometry. Design A double-blind, randomized, placebo-controlled, parallel-group trial (Testosterones Effects on Atherosclerosis Progression in Aging Men). Setting Exercise physiology laboratory. Participants Healthy men aged ≥ 60 years with total testosterone levels of 100 to 400 ng/dL (3.5 to 13.9 nmol/L) or free testosterone levels < 50 pg/mL (174 pmol/L). Interventions Randomization to 1% transdermal testosterone gel adjusted to achieve serum levels of 500 to 950 ng/dL or placebo applied daily for 3 years. Main Outcome Measures Change in V̇O2peak. Results Mean (±SD) baseline V̇O2peak was 24.2 ± 5.2 and 23.6 ± 5.6 mL/kg/min for testosterone and placebo, respectively. V̇O2peak did not change in men treated with testosterone but fell significantly in men receiving placebo (average 3-year decrease, 0.88 mL/kg/min; 95% CI, -1.39 to 0.38 mL/kg/min; P = 0.035); the difference in change in V̇O2peak between groups was significant (average 3-year difference, 0.91 mL/kg/min; 95% CI, 0.010 to 0.122 mL/kg/min; P = 0.008). The 1-g/dL mean increase in hemoglobin (P < 0.001) was significantly associated with changes in V̇O2peak in testosterone-treated men. Conclusion The mean 3-year change in V̇O2peak was significantly smaller in men treated with testosterone than in men receiving placebo and was associated with increases in hemoglobin. The difference in V̇O2peak change between groups may indicate attenuation of its expected age-related decline; the clinical meaningfulness of the modest treatment effect remains to be determined.

Metabolic Changes in Androgen Deprived Non-Diabetic Men with Prostate Cancer are not mediated by Cytokines or aP2.

Context Androgen deprivation therapy (ADT) remains the cornerstone of management of prostate cancer (PCa). Previous studies have shown that men undergoing ADT develop insulin resistance and diabetes, but the mechanisms behind ADT-induced metabolic abnormalities remain unclear. Objective To evaluate the role of inflammatory cytokines and adipocyte protein-2 (aP2) in ADT-induced metabolic dysfunction. Participants and Interventions This 6-month prospective cohort study enrolled nondiabetic men with PCa about to undergo ADT (ADT group) and a control group of nondiabetic men who had previously undergone prostatectomy for localized PCa and were in remission (non-ADT group); all participants had normal testosterone at study entry. Fasting blood samples were collected at baseline and at 6, 12, and 24 weeks after initiation of ADT and at the same intervals in the non-ADT group. Glucose, insulin, lipids, inflammatory cytokines, and C-reactive protein were measured. We also measured serum aP2, an adipocyte-secreted protein that promotes hepatic glucose production. Homeostatic model assessment of insulin resistance (HOMA-IR) was calculated. Results Seventy-three participants formed the analytical sample (33 ADT, 40 non-ADT). HOMA-IR increased in the ADT group (estimated change = 0.25; P = 0.05), but was unchanged in the non-ADT group (0.11; P = 0.342). Serum concentrations of inflammatory cytokines or aP2 did not change significantly. There was a treatment-associated increase in total (16 mg/dL; P < 0.001), high-density lipoprotein (8 mg/dL; P < 0.001), and low-density lipoprotein (7 mg/dL; P = 0.02) cholesterol. Conclusion ADT-induced metabolic abnormalities were not associated with changes in circulating inflammatory cytokines or aP2 levels.

Oral glucose load and mixed meal feeding lowers testosterone levels in healthy eugonadal men

PurposePrecise evaluation of serum testosterone levels is important in making an accurate diagnosis of androgen deficiency. Recent practice guidelines on male androgen deficiency recommend that testosterone be measured in the morning while fasting. Although there is ample evidence regarding morning measurement of testosterone, studies that evaluated the effect of glucose load or meals were limited by inclusion of hypogonadal or diabetic men, and measurement of testosterone was not performed using mass spectrometry.MethodsSixty men (23–97 years) without pre-diabetes or diabetes who had normal total testosterone (TT) levels underwent either an oral glucose tolerance test (OGTT) or a mixed meal tolerance test (MMTT) after an overnight fast. Serum samples were collected before and at regular intervals for 2 h (OGTT cohort) or 3 h (MMTT cohort). TT was measured by LC-MS/MS. LH and prolactin were also measured.ResultsTT decreased after a glucose load (mean drop at nadir = 100 ng/dL) and after a mixed meal (drop at nadir = 123 ng/dL). Approximately 11% of men undergoing OGTT and 56% undergoing MMTT experienced a transient decrease in TT below 300 ng/dL, the lower normal limit. Testosterone started declining 20 min into the tests, with average maximum decline at 60 min. Most men still had TT lower than baseline at 120 min. This effect was independent of changes in LH or prolactin.ConclusionA glucose load or a mixed meal transiently, but significantly, lowers TT levels in healthy, non-diabetic eugonadal men. These findings support the recommendations that measurement of serum testosterone to diagnose androgen deficiency should be performed while fasting.