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1.  Clinical Meaningfulness of the Changes in Muscle Performance and Physical Function Associated With Testosterone Administration in Older Men With Mobility Limitation 
Testosterone in Older Men with Mobility Limitations Trial determined the effects of testosterone on muscle performance and physical function in older men with mobility limitation. Trial’s Data and Safety Monitoring Board recommended enrollment cessation due to increased frequency of adverse events in testosterone arm. The changes in muscle performance and physical function were evaluated in relation to participant’s perception of change.
Men aged 65 years and older, with mobility limitation, total testosterone 100–350 ng/dL, or free testosterone less than 50 pg/mL, were randomized to placebo or 10 g testosterone gel daily for 6 months. Primary outcome was leg-press strength. Secondary outcomes included chest-press strength, stair-climb, 40-m walk, muscle mass, physical activity, self-reported function, and fatigue. Proportions of participants exceeding minimally important difference in study arms were compared.
Of 209 randomized participants, 165 had follow-up efficacy measures. Mean (SD) age was 74 (5.4) years and short physical performance battery score 7.7 (1.4). Testosterone arm exhibited greater improvements in leg-press strength, chest-press strength and power, and loaded stair-climb than placebo. Compared with placebo, significantly greater proportion of men receiving testosterone improved their leg-press and chest-press strengths (43% vs 18%, p = .01) and stair-climbing power (28% vs 10%, p = .03) more than minimally important difference. Increases in leg-press strength and stair-climbing power were associated with changes in testosterone levels and muscle mass. Physical activity, walking speed, self-reported function, and fatigue did not change.
Testosterone administration in older men with mobility limitation was associated with patient-important improvements in muscle strength and stair-climbing power. Improvements in muscle strength and only some physical function measures should be weighed against the risk of adverse events in this population.
PMCID: PMC3202898  PMID: 21697501
Testosterone; Minimally important difference; Mobility limitation; Older men; Function promoting therapies
2.  Risk Factors Associated With Cardiovascular Events During Testosterone Administration in Older Men With Mobility Limitation 
Testosterone in Older Men with Mobility Limitations Trial found an increased incidence of cardiovascular events in men randomized to testosterone, resulting in enrollment cessation by trial's Data and Safety Monitoring Board. We evaluated changes in gonadal hormones and markers of inflammation and coagulation to elucidate risk factors associated with cardiovascular events.
Men aged 65 years or more, with mobility limitation, total testosterone 100–350 ng/dL, or free testosterone less than 50 pg/mL, were randomized to placebo or 10 g testosterone gel daily for 6 months. Changes in total and free testosterone, estradiol and estrone, C-reactive protein, interleukin 6, fibrinogen, plasminogen activator inhibitor-1, and pro-brain naturetic peptide were compared between groups and within the testosterone group between subjects who experienced cardiovascular events and those who did not.
Of 209 men randomized (mean age 74 years), gonadal hormones and biomarkers were available in 179 men. Baseline body mass index, gonadal hormones, lipids, Framingham risk scores, and other biomarkers were similar in the two treatment groups. Within the testosterone group, the 6-month increase in free testosterone was significantly greater in men who experienced cardiovascular events than in those who did not [mean (95% confidence interval), 10.6 (4.6–16.7) vs 5.2 (3.0–7.5) ng/dL, p = .05]. In multivariable logistic regression analysis, the change in the serum levels of free testosterone was associated with cardiovascular events.
Mobility-limited older men who experienced cardiovascular events had greater increases in serum free testosterone levels than those who did not.
PMCID: PMC3598355  PMID: 22562960
Testosterone; Older men; Mobility limitation; Cardiovascular disease
3.  Does testosterone supplementation improve health and function in elderly men? 
Low serum testosterone levels are associated with age-related changes in physical and cognitive function. Replacement therapy could, therefore, help alleviate symptoms of aging.
To determine whether 6 months’ supplementation with testosterone improved signs of aging in a population of elderly men with low-normal testosterone levels.
This was a double-blind, randomized, placebo-controlled trial of testosterone supplementation conducted at a single center in the Netherlands between January 2004 and April 2005. Participants were recruited by direct mailing. Inclusion criteria included age 60–80 years and a serum testosterone level below the 50th percentile of the study population-based testosterone distribution (cutoff 13.7 nmol/l). Exclusion criteria included myocardial infarction, heart failure, malignancy, serious liver or renal disease, epilepsy, diabetes mellitus, elevated prostate-specific antigen, use of corticosteroids, and use of testosterone esters within the previous 60 days. Eligible participants were randomly allocated to receive either 80 mg oral testosterone undecenoate or placebo twice daily for 6 months. Functional ability was measured with the timed ‘get up and go’ test, the Stanford Health Assessment Questionnaire, an isometric handgrip strength test, and a maximal voluntary isometric leg strength test. Cognitive parameters assessed included verbal episodic memory, cognitive and perceptual speed, attention and mental flexibility, extrapersonal spatial perception, and visuospatial performance. BMD and total body composition were measured by dual-energy X-ray absorptiometry. Quality of life was assessed with the Short-Form 36 Health Survey (SF-36) and the Questions on Life Satisfaction Modules questionnaires.
The main outcome measures were functional mobility, cognitive function, BMD, anthropometry, body composition, biochemical measures, quality of life, and safety parameters.
The study enrolled 113 men in the testosterone group (mean age 67.1 years; mean serum testosterone level 11.0 nmol/l) and 110 men in the placebo group (mean age 67.4 years; mean serum testosterone level 10.4 nmol/l). Treatment adherence was >90% for both groups. When compared with the placebo group, treatment with testosterone was associated with increased lean body mass, decreased body fat mass and decreased body fat percentage (P <0.001 for all comparisons); however, no significant changes in parameters of functional ability were observed in either group. Total cholesterol and HDL cholesterol decreased in the testosterone group, whereas insulin and glucose concentrations and measures of insulin resistance increased in the placebo group. Cognitive function improved in both groups but BMD and quality of life were unchanged. The mean number of adverse events per participant was 0.87 in the testosterone group and 0.90 in the placebo group.
The results of this study suggest that eugonadal or slightly hypogonadal men might not benefit substantially from short-term, low-dose testosterone supplementation.
PMCID: PMC2657091  PMID: 18493229
aging; androgen; supplementation; testosterone
4.  Effect of Testosterone Administration on Liver Fat in Older Men With Mobility Limitation: Results From a Randomized Controlled Trial 
Androgen receptor (AR) knockout male mice display hepatic steatosis, suggesting that AR signaling may regulate hepatic fat. However, the effects of testosterone replacement on hepatic fat in men are unknown. The aim of this study was to determine the effects of testosterone administration on hepatic fat in older men with mobility limitation and low testosterone levels who were participating in a randomized trial (the Testosterone in Older Men trial).
Two hundred and nine men with mobility limitation and low total or free testosterone were randomized in the parent trial to either placebo or 10-g testosterone gel daily for 6 months. Hepatic fat was determined by magnetic resonance imaging in 73 men (36 in placebo and 37 in testosterone group) using the volumetric method. Insulin sensitivity (homeostatic model assessment–insulin resistance) was derived from fasting glucose and insulin.
Baseline characteristics were similar between the two groups, including liver volumes (1583±363 in the testosterone group vs 1522±271mL in the placebo group, p = .42). Testosterone concentrations increased from 250±72 to 632±363ng/dL in testosterone group but did not change in placebo group. Changes in liver volume during intervention did not differ significantly between groups (p = .5) and were not related to on-treatment testosterone concentrations. The change in homeostatic model assessment–insulin resistance also did not differ significantly between groups and was not related to either baseline or change in liver fat.
Testosterone administration in older men with mobility limitation and low testosterone levels was not associated with a reduction in hepatic fat. Larger trials are needed to determine whether testosterone replacement improves liver fat in men with nonalcoholic hepatic steatosis.
PMCID: PMC3826861  PMID: 23292288
Testosterone; Older men; Liver fat; Insulin resistance.
5.  Gonadal Steroids and Body Composition, Strength, and Sexual Function in Men 
The New England journal of medicine  2013;369(11):1011-1022.
Current approaches to diagnosing testosterone deficiency do not consider the physiological consequences of various testosterone levels or whether deficiencies of testosterone, estradiol, or both account for clinical manifestations.
We provided 198 healthy men 20 to 50 years of age with goserelin acetate (to suppress endogenous testosterone and estradiol) and randomly assigned them to receive a placebo gel or 1.25 g, 2.5 g, 5 g, or 10 g of testosterone gel daily for 16 weeks. Another 202 healthy men received goserelin acetate, placebo gel or testosterone gel, and anastrozole (to suppress the conversion of testosterone to estradiol). Changes in the percentage of body fat and in lean mass were the primary outcomes. Subcutaneous- and intraabdominal-fat areas, thigh-muscle area and strength, and sexual function were also assessed.
The percentage of body fat increased in groups receiving placebo or 1.25 g or 2.5 g of testosterone daily without anastrozole (mean testosterone level, 44±13 ng per deciliter, 191±78 ng per deciliter, and 337±173 ng per deciliter, respectively). Lean mass and thigh-muscle area decreased in men receiving placebo and in those receiving 1.25 g of testosterone daily without anastrozole. Leg-press strength fell only with placebo administration. In general, sexual desire declined as the testosterone dose was reduced.
The amount of testosterone required to maintain lean mass, fat mass, strength, and sexual function varied widely in men. Androgen deficiency accounted for decreases in lean mass, muscle size, and strength; estrogen deficiency primarily accounted for increases in body fat; and both contributed to the decline in sexual function. Our findings support changes in the approach to evaluation and management of hypogonadism in men.
PMCID: PMC4142768  PMID: 24024838
6.  Effects of Testosterone Therapy on Muscle Performance and Physical Function in Older Men with Mobility Limitations (The TOM Trial): Design and Methods 
Contemporary clinical trials  2008;30(2):133-140.
The TOM study is the first, single-site, placebo-controlled, randomized clinical trial designed to comprehensively determine the effects of testosterone administration on muscle strength and physical function in older men with mobility limitations. A total of 252 community dwelling individuals aged 65 and older with low testosterone levels and self-reported limitations in mobility and short physical performance battery (SPPB) score between 4 and 9 will be randomized to receive either placebo or testosterone therapy for 6 months. The primary objective is to determine whether testosterone therapy improves maximal voluntary muscle strength as quantified by the one repetition maximum. Secondary outcomes will include measures of physical function (walking, stair climbing and a lifting and lowering task), habitual physical activity and self-reported disability. The effects of testosterone on affect, fatigue and sense of well being will also be assessed. Unique aspects of the TOM Trial include selection of men with self-reported as well as objectively demonstrable functional limitations, community-based screening and recruitment, adjustment of testosterone dose to ensure serum testosterone levels in the target range while maintaining blinding, and inclusion of a range of self-reported and performance-based physical function measures as outcomes. identifier: NCT00240981.
PMCID: PMC3031114  PMID: 18996225
testosterone; mobility limitations; physical function; strength; aging; sarcopenia; anabolic therapies
7.  The Safety, Pharmacokinetics, and Effects of LGD-4033, a Novel Nonsteroidal Oral, Selective Androgen Receptor Modulator, in Healthy Young Men 
Concerns about potential adverse effects of testosterone on prostate have motivated the development of selective androgen receptor modulators that display tissue-selective activation of androgenic signaling. LGD-4033, a novel nonsteroidal, oral selective androgen receptor modulator, binds androgen receptor with high affinity and selectivity.
To evaluate the safety, tolerability, pharmacokinetics, and effects of ascending doses of LGD-4033 administered daily for 21 days on lean body mass, muscle strength, stair-climbing power, and sex hormones.
In this placebo-controlled study, 76 healthy men (21–50 years) were randomized to placebo or 0.1, 0.3, or 1.0 mg LGD-4033 daily for 21 days. Blood counts, chemistries, lipids, prostate-specific antigen, electrocardiogram, hormones, lean and fat mass, and muscle strength were measured during and for 5 weeks after intervention.
LGD-4033 was well tolerated. There were no drug-related serious adverse events. Frequency of adverse events was similar between active and placebo groups. Hemoglobin, prostate-specific antigen, aspartate aminotransferase, alanine aminotransferase, or QT intervals did not change significantly at any dose. LGD-4033 had a long elimination half-life and dose-proportional accumulation upon multiple dosing. LGD-4033 administration was associated with dose-dependent suppression of total testosterone, sex hormone–binding globulin, high density lipoprotein cholesterol, and triglyceride levels. follicle-stimulating hormone and free testosterone showed significant suppression at 1.0-mg dose only. Lean body mass increased dose dependently, but fat mass did not change significantly. Hormone levels and lipids returned to baseline after treatment discontinuation.
LGD-4033 was safe, had favorable pharmacokinetic profile, and increased lean body mass even during this short period without change in prostate-specific antigen. Longer randomized trials should evaluate its efficacy in improving physical function and health outcomes in select populations.
PMCID: PMC4111291  PMID: 22459616
Selective androgen receptor modulators; SARMs; Sarcopenia; Function promoting anabolic therapies; Cachexia
8.  Effects of Transdermal Testosterone on Bone and Muscle in Older Men with Low Bioavailable Testosterone Levels, Low Bone Mass and Physical Frailty 
To investigate the effects of testosterone supplementation on bone, body composition, muscle, physical function, and safety in older men.
Design, Setting, Participants
Double-blind, randomized, placebo-controlled trial was done at a major medical institution of 131 men (mean 77.1 ± 7.6 yr) with low testosterone level, history of fracture or bone mineral density (BMD) T-score of < −2.0 AND frailty.
Participants received 5 mg/d testosterone (AndroGel™) or placebo for 12–24 months; all received calcium (1500 mg/d diet and supplement) and cholecalciferol (1000 IU/d).
BMD of hip, lumbar spine, and mid-radius, body composition, sex and calcium regulating hormones, bone turnover markers, strength, physical performance, and safety parameters.
Ninety -nine men (75.6%) completed 12 months and 62 men (47.3%) completed end therapy (mean 23 months; range 16–24 months for 62 men in this group). Study adherence was 54%, 40% of subjects maintaining 70% or greater adherence. Testosterone and bioavailable testosterone levels at 12 months were 583 ng/dL and 157 ng/dL in the treatment group. BMD on testosterone increased 1.38% at the femoral neck, 3.25% at the lumbar spine (p=.005) and decreased by 1.29% at the mid-radius (p=.0008). There was an increase in lean mass and decrease in fat mass in the testosterone group, but no differences in strength or physical performance. Finally, there were no differences in safety parameters.
Older, frail men receiving testosterone replacement increased testosterone levels, had favorable changes in body composition, modest changes in axial BMD, and no substantial changes physical function.
PMCID: PMC3014265  PMID: 20722847
testosterone; osteoporosis; frailty; hypogonadism
9.  Testosterone Replacement and Resistance Exercise in HIV-Infected Men With Weight Loss and Low Testosterone Levels 
Previous studies of testosterone supplementation in HIV-infected men failed to demonstrate improvement in muscle strength. The effects of resistance exercise combined with testosterone supplementation in HIV-infected men are unknown.
To determine the effects of testosterone replacement with and without resistance exercise on muscle strength and body composition in HIV-infected men with low testosterone levels and weight loss.
Design and Setting
Placebo-controlled, double-blind, randomized clinical trial conducted from September 1995 to July 1998 at a general clinical research center.
Sixty-one HIV-infected men aged 18 to 50 years with serum testosterone levels of less than 12.1 nmol/L (349 ng/dL) and weight loss of 5% or more in the previous 6 months, 49 of whom completed the study.
Participants were randomly assigned to 1 of 4 groups: placebo, no exercise (n = 14); testosterone enanthate (100 mg/wk intramuscularly), no exercise (n = 17); placebo and exercise (n = 15); or testosterone and exercise (n = 15). Treatment duration was 16 weeks.
Main Outcome Measures
Changes in muscle strength, body weight, thigh muscle volume, and lean body mass compared among the 4 treatment groups.
Body weight increased significantly by 2.6 kg (P<.001) in men receiving testosterone alone and by 2.2 kg (P = .02) in men who exercised alone but did not change in men receiving placebo alone (−0.5 kg; P = .55) or testosterone and exercise (0.7 kg; P = .08). Men treated with testosterone alone, exercise alone, or both experienced significant increases in maximum voluntary muscle strength in leg press (range, 22%–30%), leg curls (range, 18%–36%), bench press (range, 19%–33%), and latissimus pulls (range, 17%–33%). Gains in strength in all exercise categories were greater in men assigned to the testosterone-exercise group or to the exercise-alone group than in those assigned to the placebo-alone group. There was a greater increase in thigh muscle volume in men receiving testosterone alone (mean change, 40 cm3; P<.001 vs zero change) or exercise alone (62 cm3; P = .003) than in men receiving placebo alone (5 cm3; P = .70). Average lean body mass increased by 2.3 kg (P = .004) and 2.6 kg (P<.001), respectively, in men who received testosterone alone or testosterone and exercise but did not change in men receiving placebo alone (0.9 kg; P = .21). Hemoglobin levels increased in men receiving testosterone but not in those receiving placebo.
Our data suggest that testosterone and resistance exercise promote gains in body weight, muscle mass, muscle strength, and lean body mass in HIV-infected men with weight loss and low testosterone levels. Testosterone and exercise together did not produce greater gains than either intervention alone.
PMCID: PMC3173037  PMID: 10683055
10.  Durability of the Effects of Testosterone and Growth Hormone Supplementation in Older Community Dwelling Men: The HORMA Trial 
Clinical endocrinology  2011;75(1):103-111.
Determine the durability of anabolic effects and adverse events (AEs) after stopping testosterone and growth hormone supplementation in older men.
Secondary analysis of a double-masked, randomized controlled trial of testosterone gel (5g or 10g/daily) plus rhGH (0, 3, or 5ug/kg/day) with follow-up of outcomes 3-months later.
108 community-dwelling 65-90 year-old-men.
Testosterone and IGF-1 levels, body composition (DEXA), 1-repetition maximum (1-RM) strength, stair-climbing power, quality-of-life (QOL) and activity questionnaires, AEs.
Despite improvements in body composition during treatment, residual benefits 3-months later (week-28) were variable. For participants with improvements exceeding their week-17 median changes, benefits were sustained at week 28 for lean body mass (LBM, 1.45±1.63kg, 45% of week-17 values, p<0.0001-vs-baseline), appendicular skeletal muscle mass (ASMM, 0.71±1.01kg, 42%, p<0.0001), total fat (-1.06±2.18kg, 40%, p<0.0001,), and trunk fat (-0.89±1.42kg, 50%, p<0.0001,); retention of ASMM was associated with greater week-16 protein intake (p=0.01). For 1-RM strength, 39%-43% of week-17 improvements (p≤0.05) were retained and associated with better week-17 strength (p<0.0001), change in testosterone from week-17-to-28 (p=0.004) and baseline PASE (p=0.04). Framingham 10-year cardiovascular risks were low (~14%), didn’t worsen, and improved by week-28 (p=0.0002). The hypothalamic-pituitary-gonadal axis recovered completely.
Durable improvements in muscle mass, strength, and fat mass were retained 3-months after discontinuing hormone supplementation in participants with greater than median body composition changes during treatment, but not in others with smaller gains. AEs largely resolved after intervention discontinuation. Additional strategies may be needed to sustain or augment muscle mass and strength gains achieved during short-term hormone therapy.
PMCID: PMC3529980  PMID: 21521283
Lean body mass; fat mass; muscle performance; quality of life; cardiovascular risks
11.  Dutasteride Reduces Prostate Size and Prostate Specific Antigen in Older Hypogonadal Men With Benign Prostatic Hyperplasia Undergoing Testosterone Replacement Therapy 
The Journal of Urology  2011;186(1):191-197.
Benign prostatic hyperplasia and hypogonadism are common disorders in aging men. There is concern that androgen replacement in older men may increase prostate size and symptoms of benign prostatic hyperplasia. We examined whether combining dutasteride, which inhibits testosterone to dihydrotestosterone conversion, with testosterone treatment in older hypogonadal men with benign prostatic hyperplasia reduces androgenic stimulation of the prostate compared to testosterone alone.
Materials and Methods
We conducted a double-blind, placebo controlled trial of 53 men 51 to 82 years old with symptomatic benign prostatic hyperplasia, prostate volume 30 cc or greater and serum total testosterone less than 280 ng/dl (less than 9.7 nmol/l). Subjects were randomized to daily transdermal 1% T gel plus oral placebo or dutasteride for 6 months. Testosterone dosing was adjusted to a serum testosterone of 500 to 1,000 ng/dl. The primary outcomes were prostate volume measured by magnetic resonance imaging, serum prostate specific antigen and androgen levels.
A total of 46 subjects completed all procedures. Serum testosterone increased similarly into the mid-normal range in both groups. Serum dihydrotestosterone increased in the testosterone only but decreased in the testosterone plus dutasteride group. In the testosterone plus dutasteride group prostate volume and prostate specific antigen (mean ± SEM) decreased 12% ± 2.5% and 35% ± 5%, respectively, compared to the testosterone only group in which prostate volume and prostate specific antigen increased 7.5% ± 3.3% and 19% ± 7% (p = 0.03 and p = 0.008), respectively, after 6 months of treatment. Prostate symptom scores improved in both groups.
Combined treatment with testosterone plus dutasteride reduces prostate volume and prostate specific antigen compared to testosterone only. Coadministration of a 5α-reductase inhibitor with testosterone appears to spare the prostate from androgenic stimulation during testosterone replacement in older, hypogonadal men with symptomatic benign prostatic hyperplasia.
PMCID: PMC3353656  PMID: 21575967
testosterone; prostate; 5-alpha reductase inhibitors; dihydrotestosterone
12.  Testosterone restoration using enclomiphene citrate in men with secondary hypogonadism: a pharmacodynamic and pharmacokinetic study 
Bju International  2013;112(8):1188-1200.
To determine the pharmacodynamic profile of serum total testosterone and luteinizing hormone (LH) levels in men with secondary hypogonadism after initial and chronic daily oral doses of enclomiphene citrate vs transdermal testosterone.To determine the effects of daily oral doses of enclomiphene citrate in comparison with transdermal testosterone on other hormones and markers in men with secondary hypogonadism.
Patients and Methods
This was a randomized, single-blind, two-centre, phase II study to evaluate the effects of three different doses of enclomiphene citrate (6.25, 12.5 and 25 mg) vs transdermal testosterone on 24-h LH and total testosterone in otherwise normal healthy men with secondary hypogonadism.Forty-eight men were enrolled in the trial (the intent-to-treat population), but four men had testosterone levels >350 ng/dL at baseline. Forty-four men completed the study per protocol. All subjects enrolled in this trial had serum total testosterone in the low range (<350 ng/dL) and had low to normal LH (<12 IU/L) on at least two occasions.Total testosterone and LH levels were assessed each hour for 24 h to examine the effects at each of three treatment doses of enclomiphene citrate vs a standard dose (5 g) of transdermal testosterone. In the initial profile, total testosterone and LH were determined in a naïve population after a single initial oral or transdermal treatment (day 1). This was contrasted to that seen after 6 weeks of continuous daily oral or transdermal treatment (day 42).The pharmacokinetics of enclomiphene citrate were assessed in a select subpopulation.Serum samples were obtained over the course of the study to determine the levels of various hormones and lipids.
After 6 weeks of continuous use, the mean (sd) concentration of total testosterone at day 42 was 604 (160) ng/dL for men taking the highest dose of enclomiphene citrate (enclomiphene citrate, 25 mg daily) and 500 (278) ng in those men treated with transdermal testosterone. These values were higher than day 1 values but not different from each other (P = 0.23, t-test).All three doses of enclomiphene citrate increased the testosterone concentration at time 0 of each 24-h sampling period, and the mean, maximum, minimum and range of testosterone concentrations over the 24-h sampling period. Transdermal testosterone also raised total testosterone, albeit with more variability, and with suppressed LH levels.The patterns of total testosterone over the 24-h period after 6 weeks of dosing could be fit to a nonlinear function with morning elevations, mid-day troughs, and rising night-time levels.Enclomiphene citrate and transdermal testosterone increased levels of total testosterone within 2 weeks, but they had opposite effects on FSH and LH.Treatment with enclomiphene citrate did not significantly affect levels of thyroid-stimulating hormone, adenocorticotropic hormone, cortisol, lipids or bone markers. Both transdermal testosterone and enclomiphene citrate decreased insulin-like growth factor-1 levels (P < 0.05) but suppression was greater in the enclomiphene citrate groups.
Enclomiphene citrate increased serum LH and total testosterone; however, there was not a temporal association between the peak drug levels and the maximum concentration levels of LH or total testosterone.Enclomiphene citrate consistently increased serum total testosterone into the normal range and increased LH and FSH above the normal range. The effects on LH and total testosterone persisted for at least 1 week after stopping treatment.
PMCID: PMC4155868  PMID: 23875626
serum testosterone; LH; secondary hypogonadism; transdermal testosterone; testosterone restoration
13.  Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials 
BMC Medicine  2013;11:108.
Testosterone therapy is increasingly promoted. No randomized placebo-controlled trial has been implemented to assess the effect of testosterone therapy on cardiovascular events, although very high levels of androgens are thought to promote cardiovascular disease.
A systematic review and meta-analysis was conducted of placebo-controlled randomized trials of testosterone therapy among men lasting 12+ weeks reporting cardiovascular-related events. We searched PubMed through the end of 2012 using “(“testosterone” or “androgen”) and trial and (“random*”)” with the selection limited to studies of men in English, supplemented by a bibliographic search of the World Health Organization trial registry. Two reviewers independently searched, selected and assessed study quality with differences resolved by consensus. Two statisticians independently abstracted and analyzed data, using random or fixed effects models, as appropriate, with inverse variance weighting.
Of 1,882 studies identified 27 trials were eligible including 2,994, mainly older, men who experienced 180 cardiovascular-related events. Testosterone therapy increased the risk of a cardiovascular-related event (odds ratio (OR) 1.54, 95% confidence interval (CI) 1.09 to 2.18). The effect of testosterone therapy varied with source of funding (P-value for interaction 0.03), but not with baseline testosterone level (P-value for interaction 0.70). In trials not funded by the pharmaceutical industry the risk of a cardiovascular-related event on testosterone therapy was greater (OR 2.06, 95% CI 1.34 to 3.17) than in pharmaceutical industry funded trials (OR 0.89, 95% CI 0.50 to 1.60).
The effects of testosterone on cardiovascular-related events varied with source of funding. Nevertheless, overall and particularly in trials not funded by the pharmaceutical industry, exogenous testosterone increased the risk of cardiovascular-related events, with corresponding implications for the use of testosterone therapy.
PMCID: PMC3648456  PMID: 23597181
Testosterone; Cardiovascular; Men; Trial
14.  Testosterone Supplementation Improves Carbohydrate and Lipid Metabolism in Some Older Men with Abdominal Obesity 
The effects of testosterone supplementation on carbohydrate and lipid metabolism in obese older men are uncertain. We conducted a single-arm open-label prospective pilot study to investigate the effects of testosterone supplementation on central and peripheral insulin sensitivity in older men with upper body obesity and insulin resistance.
Twenty men (62–78 years-old) with morning testosterone levels <13.9 nmol/L (400 ng/dL), waist circumference ≥ 102 cm, and HOMA-IR ≥ 4.0 or HgbA1C 5.7–6.4% applied transdermal testosterone (10 mg) daily for 20 weeks. Insulin sensitivity (Si) was determined by a 2-stage glucose clamp, liver and intramyocellular lipid by 1H-MR spectroscopy and body composition by DEXA.
Testosterone supplementation significantly reduced total fat (−.9 ± 2.4 kg, p=0.002), trunk fat (−1.3 ± 1.4 kg, p=0.0007) and extremity fat (−0.7 ± 1.1 kg, p=0.01), and increased extremity lean tissue (+1.3 ± 1.4 kg, p=0.0006). Whole body (WB) Si improved by 21% (0.76 ± 1.57 dL/min per µU/mL, p=0.04) and insulin-stimulated glucose uptake (Rd) by 24% (0.91 ± 1.74 dL/min per µU/mL, p=0.03). Improvements in glucose kinetics were limited to men with reductions in trunk and extremity fat greater than median declines for the entire group. Reductions in intramyocellular lipid were associated with improvements in WB Si (p=0.04) and Rd (p=0.03). Change in Rd accounted for 90% of the change in WB Si. Hepatic glucose output and liver lipid/H2O were unchanged (p>0.05). Multivariable analyses revealed that reductions in extremity fat, trunk fat, and FFA levels during the clamp accounted for 45% (p=0.004), 31% (p=0.002) and 8% (p=0.04) of respective changes in Rd. Triglycerides decreased by −0.40 ± 0.67mmol/L (p=0.02), LDL-C by-0.35 ± 0.57 mmol/L (p=0.02), and HDL-C by −0.14 ± 0.19 mmol/L (p=0.004).
Testosterone supplementation that resulted in greater reductions in regional adiposity was associated with improved insulin sensitivity, lower LDL-C and fasting triglycerides, but lower HDL-C. Placebo controlled trials need to further examine the potential cardiometabolic risks/benefits of androgen supplementation for older men with low testosterone levels, central obesity, and insulin resistance.
PMCID: PMC4225803  PMID: 25392748
Obesity; Insulin resistance; Testosterone; Aging; Metabolism
15.  Testosterone Threshold Levels and Lean Tissue Mass Targets Needed to Enhance Skeletal Muscle Strength and Function: The HORMA Trial 
In the HORMA (Hormonal Regulators of Muscle and Metabolism in Aging) Trial, supplemental testosterone and recombinant human growth hormone (rhGH) enhanced lean body mass, appendicular skeletal muscle mass, muscle performance, and physical function, but there was substantial interindividual variability in outcomes.
One hundred and twelve men aged 65–90 years received testosterone gel (5 g/d vs 10 g/d via Leydig cell clamp) and rhGH (0 vs 3 vs 5 μg/kg/d) in a double-masked 2 × 3 factorial design for 16 weeks. Outcomes included lean tissue mass by dual energy x-ray absorptiometry, one-repetition maximum strength, Margaria stair power, and activity questionnaires. We used pathway analysis to determine the relationship between changes in hormone levels, muscle mass, strength, and function.
Increases in total testosterone of 1046 ng/dL (95% confidence interval = 1040–1051) and 898 ng/dL (95% confidence interval = 892–904) were necessary to achieve median increases in lean body mass of 1.5 kg and appendicular skeletal muscle mass of 0.8 kg, respectively, which were required to significantly enhance one-repetition maximum strength (≥30%). Co-treatment with rhGH lowered the testosterone levels (quantified using liquid chromatography–tandem mass spectrometry) necessary to reach these lean mass thresholds. Changes in one-repetition maximum strength were associated with increases in stair climbing power (r = .26, p = .01). Pathway analysis supported the model that changes in testosterone and insulin-like growth factor 1 levels are related to changes in lean body mass needed to enhance muscle performance and physical function. Testosterone’s effects on physical activity were mediated through a different pathway because testosterone directly affected Physical Activity Score of the Elderly.
To enhance muscle strength and physical function, threshold improvements in lean body mass and appendicular skeletal muscle mass are necessary and these can be achieved by targeting changes in testosterone levels. rhGH augments the effects of testosterone. To maximize functional improvements, the doses of anabolic hormones should be titrated to achieve target blood levels.
PMCID: PMC3032430  PMID: 21059836
Testosterone; Growth hormone; Lean body mass; Muscle performance; Physical function
16.  Sex steroids and cardiovascular disease 
Asian Journal of Andrology  2013;16(2):239-247.
As men grow older, testosterone (T) levels decline and the significance of this change is debated. The evidence supporting a causal role for lower circulating T, or its metabolites dihydrotestosterone (DHT) and estradiol, in the genesis of atherosclerosis and cardiovascular disease (CVD) in men is limited. Observational studies associate low baseline T levels with carotid atherosclerosis, aortic and peripheral vascular disease, and with the incidence of cardiovascular events and mortality. Studies using mass spectrometry suggest that when total T is assayed optimally, calculation of free T might not necessarily improve risk stratification. There is limited evidence to support an association of estradiol with CVD. Interventional studies of T therapy in men with coronary artery disease have shown beneficial effects on exercise-induced myocardial ischemia. However, placebo-controlled, randomized clinical trials (RCTs) of T therapy in men with the prespecified outcomes of cardiovascular events or deaths are lacking. Meta-analyses of randomized controlled trials of T published up to 2010 found no increase in cardiovascular events, mortality, or prostate cancer with therapy. Recently, in a trial of older men with mobility limitations, men randomized to receive a substantial dose of T reported cardiovascular adverse effects. This phenomenon was not reported from a comparable trial where men received a more conservative dose of T, suggesting a prudent approach should be adopted when considering therapy in frail older men with existing CVD. Adequately powered RCTs of T in middle-aged and older men are needed to clarify whether or not hormonal intervention would reduce the incidence of CVD.
PMCID: PMC3955333  PMID: 24407188
atherosclerosis; cardiovascular disease; dihydrotestosterone; estradiol; mortality; testosterone
17.  The Impact of Drug Reimbursement Policy on Rates of Testosterone Replacement Therapy among Older Men 
PLoS ONE  2014;9(7):e98003.
Despite a lack of data describing the long-term efficacy and safety of testosterone replacement therapy (TRT), prescribing of testosterone to older men has increased with the availability of topical formulations. The magnitude of this increase and the impact of formulary restrictions on testosterone prescribing are poorly characterized.
We conducted a time series analysis using the linked health administrative records of men aged 66 years or older in Ontario, Canada between January 1, 1997 and March 31, 2012. We used interventional autoregressive integrated moving average models to examine the impact of a restrictive drug reimbursement policy on testosterone prescribing and examined the demographic profile of men initiating testosterone in the final 2 years of the study period.
A total of 28,477 men were dispensed testosterone over the study period. Overall testosterone prescribing declined 27.9% in the 6 months following the implementation of the restriction policy (9.5 to 6.9 men per 1000 eligible; p<0.01). However, the overall decrease was temporary and testosterone use exceeded pre-policy levels by the end of the study period (11.0 men per 1000 eligible), largely driven by prescriptions for topical testosterone (4.8 men per 1000 eligible). Only 6.3% of men who initiated testosterone had a documented diagnosis of hypogonadism, the main criteria for TRT reimbursement according to the new policy.
Government-imposed restrictions did not influence long-term prescribing of testosterone to older men. By 2012, approximately 1 in every 90 men aged 66 or older was being treated with TRT, most with topical formulations.
PMCID: PMC4100730  PMID: 25029014
18.  Changes in Muscle Mass, Muscle Strength and Power, but not Physical Function are Related to Testosterone Dose in Healthy Older Men 
To examine the effect of graded doses of testosterone on physical function (PF) and muscle performance in healthy, older men.
Randomized, double-blind, placebo controlled clinical trial.
General Clinical Research Center
Community-dwelling healthy older men aged 60-75 yr, N=44.
Monthly treatment with a gonadotropin releasing hormone agonist plus 25, 50, 125, or 300 mg/wk testosterone enanthate IM for 20 weeks.
Skeletal muscle mass (SMM) was estimated by DEXA. Leg press strength was measured by 1-RM, leg power by Nottingham Leg Rig, and muscle fatigability by repetitions to failure in the leg press exercise. Stair climbing, 6-m and 400-m walking speed, and a timed-up-and-go (TUG) were used to assess PF.
Significant T dose- and concentration-dependent increases were observed in SMM (P<0.001) and maximal strength (P=0.001), but not muscle fatigability. Leg power also increased dose-dependently (P=0.048). In contrast, changes in self-selected normal and fast walking speed over 6-m or 400-m, stair climbing power, and time for the TUG were not significantly related to T-dose, T-concentrations, or changes in muscle strength or power, or SMM.
Testosterone administration was associated with dose-dependent increases in SMM, leg strength and power, but did not improve muscle fatigability or physical function. The observation that physical function scores did not improve linearly with strength suggests that our high functioning older men were already in the asymptotic region of the curve describing the physical function – strength relationship.
PMCID: PMC2585153  PMID: 18795988
stair climb; timed up-and-go; timed walk test
19.  Double blind randomized placebo-controlled trial on the effects of testosterone supplementation in elderly men with moderate to low testosterone levels: design and baseline characteristics [ISRCTN23688581] 
Trials  2006;7:24.
In ageing men testosterone levels decline, while cognitive function, muscle and bone mass, sexual hair growth, libido and sexual activity decline and the risk of cardiovascular diseases increase. We set up a double-blind, randomized placebo-controlled trial to investigate the effects of testosterone supplementation on functional mobility, quality of life, body composition, cognitive function, vascular function and risk factors, and bone mineral density in older hypogonadal men.
We recruited 237 men with serum testosterone levels below 13.7 nmol/L and ages 60–80 years. They were randomized to either four capsules of 40 mg testosterone undecanoate (TU) or placebo daily for 26 weeks. Primary endpoints are functional mobility and quality of life. Secondary endpoints are body composition, cognitive function, aortic stiffness and cardiovascular risk factors and bone mineral density. Effects on prostate, liver and hematological parameters will be studied with respect to safety.
Measure of effect will be the difference in change from baseline visit to final visit between TU and placebo. We will study whether the effect of TU differs across subgroups of baseline waist girth (< 100 cm vs. ≥ 100 cm; testosterone level (<12 versus ≥ 12 nmol/L), age (< median versus ≥ median), and level of outcome under study (< median versus ≥ median).
At baseline, mean age, BMI and testosterone levels were 67 years, 27 kg/m2 and 10.72 nmol/L, respectively.
PMCID: PMC1563476  PMID: 16887030
20.  Testosterone Administration Inhibits Hepcidin Transcription and is Associated with Increased Iron Incorporation into Red Blood Cells 
Aging cell  2013;12(2):280-291.
Testosterone administration increases hemoglobin levels and has been used to treat anemia of chronic disease. Erythrocytosis is the most frequent adverse event associated with testosterone therapy of hypogonadal men, especially older men. However, the mechanisms by which testosterone increases hemoglobin remain unknown.
Testosterone administration in male and female mice was associated with a greater increase in hemoglobin and hematocrit, reticulocyte count, reticulocyte hemoglobin concentration, and serum iron and transferring saturation than placebo. Testosterone downregulated hepatic hepcidin mRNA expression, upregulated renal erythropoietin mRNA expression, and increased erythropoietin levels. Testosterone-induced suppression of hepcidin expression was independent of its effects on erythropoietin or hypoxia-sensing mechanisms. Transgenic mice with liver-specific constitutive hepcidin over-expression failed to exhibit the expected increase in hemoglobin in response to testosterone administration. Testosterone upregulated splenic ferroportin expression and reduced iron retention in spleen. After intravenous administration of transferrin-bound 58Fe, the amount of 58Fe incorporated into red blood cells was significantly greater in testosterone-treated mice than in placebo-treated mice. Serum from testosterone-treated mice stimulated hemoglobin synthesis in K562 erythroleukemia cells more than that from vehicle-treated mice. Testosterone administration promoted the association of androgen receptor (AR) with Smad1 and Smad4 to reduce their binding to BMP-response elements in hepcidin promoter in the liver. Ectopic expression of AR in hepatocytes suppressed hepcidin transcription; this effect was blocked dose-dependently by AR antagonist flutamide. Testosterone did not affect hepcidin mRNA stability. Conclusion: Testosterone inhibits hepcidin transcription through its interaction with BMP-Smad signaling. Testosterone administration is associated with increased iron incorporation into red blood cells.
PMCID: PMC3602280  PMID: 23399021
21.  Gonadal Status and physical performance in older men 
Male aging is characterized by a progressive decline in serum testosterone levels and physical performance. Low testosterone levels may be implicated in the decline of physical performance and consequent mobility disability that occurs with aging. During the recent years many consensus reports have advocated that one of the potential effects of testosterone supplementation is the improvement in mobility. However, to the best of our knowledge no study has fully investigated the relationship between gonadal status and objective measures of physical performance in older men and their determinants.
We evaluated 455 ≥ 65 year old male participants of InCHIANTI study a population based study in two municipalities of Tuscany, Italy with complete data on testosterone levels, hand grip strength, cross-sectional muscle area (CSMA), short physical performance battery (SPPB). Linear models were used to test the relationship between gonadal status and determinants of physical performance.
According to baseline serum levels of total testosterone, three different groups of older men were created: 1) severely hypogonadal (N= 23),total testosterone levels ≤230 ng /dl; 2) moderately hypogonadal (N=88), total testosterone >230 and <350 ng/dL), and 3) eugonadal (N=344), testosterone levels ≥350 ng/dL. With increased severity of hypogonadal status, participants were significantly older while their BMI was substantially similar. In the age and BMI adjusted analysis, there was a significant difference in hemoglobin levels, hand grip strength and SPPB score (p for trend<0.001) among −3 groups, with severely hypogonadal men having lower values of hemoglobin, muscle strength and physical performance. We found no association between testosterone group assignment and calf muscle mass and 4 meter walking speed. In the multivariate analysis grip strength (p for trend=0.004) and haemoglobin (p for trend <0.0001) but not SPPB and other determinants of physical performance were significantly different between the 3 groups.
In older men, gonadal status is independently associated with some determinants (hemoglobin and muscle strength) of physical performance.
PMCID: PMC3142745  PMID: 20937007
testosterone; physical performance; older men
22.  Testosterone depot injection in male hypogonadism: a critical appraisal 
Clinical Interventions in Aging  2007;2(4):577-590.
Testosterone compounds have been available for almost 70 years, but the pharmaceutical formulations have been less than ideal. Traditionally, injectable testosterone esters have been used for treatment, but they generate supranormal testosterone levels shortly after the 2- to 3-weekly injection interval and then testosterone levels decline very rapidly, becoming subnormal in the days before the next injection. The rapid fluctuations in plasma testosterone are subjectively experienced as disagreeable. Testosterone undecanoate is a new injectable testosterone preparation with a considerably better pharmacokinetic profile. After 2 initial injections with a 6-week interval, the following intervals between two injections are almost always 12-weeks, amounting eventually to a total of 4 injections per year. Plasma testosterone levels with this preparation are nearly always in the range of normal men, so are its metabolic products estradiol and dihydrotestosterone. The “roller coaster” effects of traditional parenteral testosterone injections are not apparent. It reverses the effects of hypogonadism on bone and muscle and metabolic parameters and on sexual functions. Its safety profile is excellent due to the continuous normalcy of plasma testosterone levels. No polycythemia has been observed, and no adverse effects on lipid profiles. Prostate safety parameters are well within reference limits. There was no impairment of uroflow. Testosterone undecanoate is a valuable contribution to the treatment options of androgen deficiency.
PMCID: PMC2686335  PMID: 18225458
testosterone treatment; testosterone undecanoate; pharmacokinetic profile; clinical efficacy; side effects; sexual dysfunction
23.  Testosterone replacement in hypogonadal men with angina improves ischaemic threshold and quality of life 
Heart  2004;90(8):871-876.
Background: Low serum testosterone is associated with several cardiovascular risk factors including dyslipidaemia, adverse clotting profiles, obesity, and insulin resistance. Testosterone has been reported to improve symptoms of angina and delay time to ischaemic threshold in unselected men with coronary disease.
Objective: This randomised single blind placebo controlled crossover study compared testosterone replacement therapy (Sustanon 100) with placebo in 10 men with ischaemic heart disease and hypogonadism.
Results: Baseline total testosterone and bioavailable testosterone were respectively 4.2 (0.5) nmol/l and 1.7 (0.4) nmol/l. After a month of testosterone, delta value analysis between testosterone and placebo phase showed that mean (SD) trough testosterone concentrations increased significantly by 4.8 (6.6) nmol/l (total testosterone) (p  =  0.05) and 3.8 (4.5) nmol/l (bioavailable testosterone) (p  =  0.025), time to 1 mm ST segment depression assessed by Bruce protocol exercise treadmill testing increased by 74 (54) seconds (p  =  0.002), and mood scores assessed with validated questionnaires all improved. Compared with placebo, testosterone therapy was also associated with a significant reduction of total cholesterol and serum tumour necrosis factor α with delta values of −0.41 (0.54) mmol/l (p  =  0.04) and −1.8 (2.4) pg/ml (p  =  0.05) respectively.
Conclusion: Testosterone replacement therapy in hypogonadal men delays time to ischaemia, improves mood, and is associated with potentially beneficial reductions of total cholesterol and serum tumour necrosis factor α.
PMCID: PMC1768369  PMID: 15253956
24.  Testosterone Replacement in Hypogonadal Men With Type 2 Diabetes and/or Metabolic Syndrome (the TIMES2 Study) 
Diabetes Care  2011;34(4):828-837.
This study evaluated the effects of testosterone replacement therapy (TRT) on insulin resistance, cardiovascular risk factors, and symptoms in hypogonadal men with type 2 diabetes and/or metabolic syndrome (MetS).
The efficacy, safety, and tolerability of a novel transdermal 2% testosterone gel was evaluated over 12 months in 220 hypogonadal men with type 2 diabetes and/or MetS in a multicenter, prospective, randomized, double-blind, placebo-controlled study. The primary outcome was mean change from baseline in homeostasis model assessment of insulin resistance (HOMA-IR). Secondary outcomes were measures of body composition, glycemic control, lipids, and sexual function. Efficacy results focused primarily on months 0−6 (phase 1; no changes in medication allowed). Medication changes were allowed in phase 2 (months 6−12).
TRT reduced HOMA-IR in the overall population by 15.2% at 6 months (P = 0.018) and 16.4% at 12 months (P = 0.006). In type 2 diabetic patients, glycemic control was significantly better in the TRT group than the placebo group at month 9 (HbA1c: treatment difference, −0.446%; P = 0.035). Improvements in total and LDL cholesterol, lipoprotein a (Lpa), body composition, libido, and sexual function occurred in selected patient groups. There were no significant differences between groups in the frequencies of adverse events (AEs) or serious AEs. The majority of AEs (>95%) were mild or moderate.
Over a 6-month period, transdermal TRT was associated with beneficial effects on insulin resistance, total and LDL-cholesterol, Lpa, and sexual health in hypogonadal men with type 2 diabetes and/or MetS.
PMCID: PMC3064036  PMID: 21386088
25.  Testosterone therapy increased muscle mass and lipid oxidation in aging men 
Age  2011;34(1):145-156.
The indication for testosterone therapy in aging hypogonadal men without hypothalamic, pituitary, or testicular disease remains to be elucidated. The aim of this study was to investigate the effect of testosterone therapy on insulin sensitivity, substrate metabolism, body composition, and lipids in aging men with low normal bioavailable testosterone levels using a predefined cutoff level for bioavailable testosterone. A randomized, double-blinded, placebo-controlled study of testosterone treatment (gel) was done on 38 men, aged 60–78 years, with bioavailable testosterone <7.3 nmol/l and a waist circumference >94 cm. Insulin-stimulated glucose disposal (Rd) and substrate oxidation were assessed by euglycemic hyperinsulinemic clamps combined with indirect calorimetry. Lean body mass (LBM) and total fat mass (TFM) were measured by dual x-ray absorptiometry, and serum total testosterone was measured by tandem mass spectrometry. Bioavailable testosterone was calculated. Coefficients (b) represent the placebo-controlled mean effect of intervention. LBM (b = 1.9 kg, p = 0.003) increased while HDL–cholesterol (b = −0.12 mmol/l, p = 0.043) and TFM decreased (b = −1.2 kg, p = 0.038) in the testosterone group compared to placebo. Basal lipid oxidation (b = 5.65 mg/min/m2, p = 0.045) increased and basal glucose oxidation (b = −9.71 mg/min/m2, p = 0.046) decreased in response to testosterone therapy even when corrected for changes in LBM. No significant changes in insulin-stimulated Rd was observed (b = −0.01mg/min/m2, p = 0.92). Testosterone therapy increased muscle mass and lipid oxidation in aging men with low normal bioavailable testosterone levels; however, our data did not support an effect of testosterone on whole-body insulin sensitivity using the euglycemic hyperinsulinemic clamp technique.
PMCID: PMC3260358  PMID: 21347608
Testosterone therapy; Insulin sensitivity; Substrate oxidation; Aging men

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