Effect of testosterone replacement on response to sildenafil citrate in men with erectile dysfunction: a parallel, randomized trial.

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

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

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

Circulating Estrogen Levels and Self-Reported Health and Mobility Limitation in Community-Dwelling Men of the Framingham Heart Study.

BACKGROUND: Self-rated health is a commonly used global indicator of health status. Few studies have examined the association of self-rated health and mobility with estrone and estradiol in men. Accordingly, we determined the cross-sectional, incident, and mediating relations between circulating estrone and estradiol levels with self-rated health, mobility limitation, and physical performance in community-dwelling men. METHODS: The cross-sectional sample included 1,148 men, who attended Framingham Offspring Study Examinations 7 and 8. Estrone and estradiol levels were measured using liquid chromatography tandem mass spectrometry at Examination 7. Self-reported mobility limitation and self-rated health were assessed at Examinations 7 and 8. Additionally, short physical performance battery, usual walking speed, and grip strength were assessed at Examination 7. RESULTS: In incident analysis, estradiol levels at Examination 7 were associated with increased odds of fair or poor self-rated health at Examination 8, after adjusting for age, body mass index, comorbidities, and testosterone levels; in an individual with 50% greater estradiol than other, the odds of reporting "fair or poor" self-rated health increased by 1.78 (95% confidence interval: 1.25-2.55; p = .001). Neither estrone nor estradiol levels were associated with any physical performance measure at baseline. CONCLUSIONS: Higher circulating levels of estradiol are associated with increased risk of incident fair/poor self-rated health in community-dwelling men. The mechanisms by which circulating levels of estradiol are related to self-rated health in men need further investigation.

Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point.

BACKGROUND: The mechanisms by which testosterone increases hemoglobin and hematocrit remain unclear. METHODS: We assessed the hormonal and hematologic responses to testosterone administration in a clinical trial in which older men with mobility limitation were randomized to either placebo or testosterone gel daily for 6 months. RESULTS: The 7%-10% increase in hemoglobin and hematocrit, respectively, with testosterone administration was associated with significantly increased erythropoietin (EPO) levels and decreased ferritin and hepcidin levels at 1 and 3 months. At 6 months, EPO and hepcidin levels returned toward baseline in spite of continued testosterone administration, but EPO levels remained nonsuppressed even though elevated hemoglobin and hematocrit higher than at baseline, suggesting a new set point. Consistent with increased iron utilization, soluble transferrin receptor (sTR) levels and ratio of sTR/log ferritin increased significantly in testosterone-treated men. Hormonal and hematologic responses were similar in anemic participants. The majority of testosterone-treated anemic participants increased their hemoglobin into normal range. CONCLUSIONS: Testosterone-induced increase in hemoglobin and hematocrit is associated with stimulation of EPO and reduced ferritin and hepcidin concentrations. We propose that testosterone stimulates erythropoiesis by stimulating EPO and recalibrating the set point of EPO in relation to hemoglobin and by increasing iron utilization for erythropoiesis.

Testosterone dose-response relationships with cardiovascular risk markers in androgen-deficient women: a randomized, placebo-controlled trial.

OBJECTIVE: To determine dose-dependent effects of T administration on cardiovascular risk markers in women with low T levels. METHODS: Seventy-one hysterectomized women with or without oophorectomy with total T < 31 ng/dL and/or free T < 3.5 pg/mL received a standardized transdermal estradiol regimen during the 12-week run-in period and were then randomized to receive weekly im injections of placebo or 3-, 6.25-, 12.5-, or 25-mg T enanthate for 24 weeks. Total and free T levels were measured by liquid chromatography-tandem mass spectrometry and equilibrium dialysis, respectively. Insulin resistance and inflammatory markers were measured at baseline and 24 weeks. In a subset of women, magnetic resonance imaging of the abdomen was performed to quantify abdominal fat volume. RESULTS: Fifty-nine women who completed the 24-week intervention were included in the final analysis. The five groups were similar at baseline. Mean on-treatment nadir total T concentrations were 14, 79, 105, 130, and 232 ng/dL in the placebo group and the 3-, 6.25-, 12.5-, and 25-mg groups, respectively. No significant changes in fasting glucose, fasting insulin, homeostatic model assessment of insulin resistance, high sensitivity C-reactive protein, adiponectin, blood pressure, and heart rate were observed at any T dose when compared to placebo. Similarly, no dose- or concentration-dependent changes were observed in abdominal fat on magnetic resonance imaging. CONCLUSION: Short-term T administration over a wide range of doses for 24 weeks in women with low T levels was not associated with worsening of cardiovascular risk markers.

Testosterone dose-response relationships in hysterectomized women with or without oophorectomy: effects on sexual function, body composition, muscle performance and physical function in a randomized trial.

OBJECTIVE: This study aims to determine the dose-dependent effects of testosterone on sexual function, body composition, muscle performance, and physical function in hysterectomized women with or without oophorectomy. METHODS: Seventy-one postmenopausal women who previously underwent hysterectomy with or without oophorectomy and had total testosterone levels less than 31 ng/dL or free testosterone levels less than 3.5 pg/mL received a standardized transdermal estradiol regimen during the 12-week run-in period and were randomized to receive weekly intramuscular injections of placebo or 3, 6.25, 12.5, or 25 mg of testosterone enanthate for 24 weeks. Total and free testosterone levels were measured by liquid chromatography-tandem mass spectrometry and equilibrium dialysis, respectively. The primary outcome was change in sexual function measured by the Brief Index of Sexual Functioning for Women. Secondary outcomes included changes in sexual activity, sexual distress, Derogatis Interview for Sexual Functioning, lean body mass, fat mass, muscle strength and power, and physical function. RESULTS: Seventy-one women were randomized; five groups were similar at baseline. Sixty-two women with analyzable data for the primary outcome were included in the final analysis. The mean on-treatment total testosterone concentrations were 19, 78, 102, 128, and 210 ng/dL in the placebo, 3-mg, 6.25-mg, 12.5-mg, and 25-mg groups, respectively. Changes in composite Brief Index of Sexual Functioning for Women scores, thoughts/desire, arousal, frequency of sexual activity, lean body mass, chest-press power, and loaded stair-climb power were significantly related to increases in free testosterone concentrations; compared with placebo, changes were significantly greater in women assigned to the 25-mg group, but not in women in the lower-dose groups. Sexual activity increased by 2.7 encounters per week in the 25-mg group. The frequency of androgenic adverse events was low. CONCLUSIONS: Testosterone administration in hysterectomized women with or without oophorectomy for 24 weeks was associated with dose and concentration-dependent gains in several domains of sexual function, lean body mass, chest-press power, and loaded stair-climb power. Long-term trials are needed to weigh improvements in these outcomes against potential long-term adverse effects.

Risk factors associated with cardiovascular events during testosterone administration in older men with mobility limitation.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Mobility-limited older men who experienced cardiovascular events had greater increases in serum free testosterone levels than those who did not.

Effect of testosterone administration on liver fat in older men with mobility limitation: results from a randomized controlled trial.

BACKGROUND: 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). METHODS: 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. RESULTS: Baseline characteristics were similar between the two groups, including liver volumes (1583 ± 363 in the testosterone group vs 1522 ± 271 mL in the placebo group, p = .42). Testosterone concentrations increased from 250 ± 72 to 632 ± 363 ng/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. CONCLUSION: 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.

Age trends in estradiol and estrone levels measured using liquid chromatography tandem mass spectrometry in community-dwelling men of the Framingham Heart Study.

BACKGROUND: Age trends in estradiol and estrone levels in men and how lifestyle factors, comorbid conditions, testosterone, and sex hormone-binding globulin affect these age trends remain poorly understood, and were examined in men of the Framingham Heart Study. METHODS: Estrone and estradiol concentrations were measured in morning fasting samples using liquid chromatography tandem mass spectrometry in men of Framingham Offspring Generation. Free estradiol was calculated using a law of mass action equation. RESULTS: There were 1,461 eligible men (mean age [±SD] 61.1±9.5 years and body mass index [BMI] 28.8±4.5kg/m(2)). Total estradiol and estrone were positively associated with age, but free estradiol was negatively associated with age. Age-related increase in total estrone was greater than that in total estradiol. Estrone was positively associated with smoking, BMI, and testosterone, and total and free estradiol with diabetes, BMI, testosterone, and comorbid conditions; additionally, free estradiol was associated negatively with smoking. Collectively, age, BMI, testosterone, and other health and behavioral factors explained only 18% of variance in estradiol, and 9% of variance in estrone levels. Men in the highest quintile of estrone levels had significantly higher age and BMI, and a higher prevalence of smoking, diabetes, and cardiovascular disease than others, whereas those in the highest quintile of estradiol had higher BMI than others. CONCLUSIONS: Total estrone and estradiol levels in men, measured using liquid chromatography tandem mass spectrometry, revealed significant age-related increases that were only partially accounted for by cross-sectional differences in BMI, diabetes status, and other comorbidities and health behaviors. Longitudinal studies are needed to confirm these findings.

Circulating estrone levels are associated prospectively with diabetes risk in men of the Framingham Heart Study.

OBJECTIVE: In postmenopausal women and preclinical murine models, estrogen administration reduces diabetes risk; however, the relationship of estradiol and estrone to diabetes in men is poorly understood. We determined the relationship between circulating estradiol and estrone levels and diabetes risk in community-dwelling men of the Framingham Heart Study (FHS). RESEARCH DESIGN AND METHODS: Cross-sectional relationships of estradiol and estrone levels with diabetes were assessed at examination 7 (1998-2001) in FHS generation 2 men (n = 1,458); prospective associations between hormone levels at examination 7 and incident diabetes were assessed 6.8 years later at examination 8. Type 2 diabetes mellitus was defined as fasting glucose >125 mg/dL, medication use, or both. Estradiol, estrone, and testosterone levels were measured with liquid chromatography-tandem mass spectrometry, and free estradiol and estrone were calculated. RESULTS: In cross-sectional models, men with elevated estrone and estradiol had 40% and 62% increased likelihoods of existing diabetes per cross-sectional doubling of estrone and estradiol levels, respectively. Free estrone (cross-sectional odds ratio 1.28 [95% CI 1.02-1.62], P = 0.04) was associated with impaired fasting glucose at examination 7. There was an increase in risk of existing diabetes with increasing quartiles of total and free estrone and estradiol and an increase in risk of incident diabetes with increasing quartiles of estrone levels. In multivariate longitudinal analyses, a twofold increase in total or free estrone levels at examination 7 was associated with 77 and 93% increases, respectively, in odds of incident diabetes at examination 8. CONCLUSIONS: Although both estradiol and estrone exhibit cross-sectional associations with diabetes in men, in longitudinal analyses estrone is a more sensitive marker of diabetes risk than is estradiol.

Relation between sex hormone concentrations, peripheral arterial disease, and change in ankle-brachial index: findings from the Framingham Heart Study.

OBJECTIVE: Our objective was to investigate cross-sectional and longitudinal associations of sex hormone concentrations with ankle-brachial index (ABI) and peripheral arterial disease (PAD). METHODS AND RESULTS: We used data from 3034 (1612 women) participants of the Framingham Heart Study. ABI was measured and PAD defined as ABI below 0.90, intermittent claudication, or lower extremity revascularization. Sex hormone concentrations were measured by liquid chromatography-tandem mass spectrometry [total testosterone (T), total estradiol, and estrone], immunofluorometric assay (SHBG), or calculated (free T). Sex-specific multivariable linear and logistic regression models were conducted for each sex hormone separately. Cross-sectional multivariable analyses revealed that men with lower free T and higher estrone (E1) concentrations had a significantly lower ABI [for free T, lowest vs. higher quartiles, ß = -0.02, with 95% confidence interval (CI) = -0.04 to -0.001; and for E1, highest vs. lower quartiles, ß = -0.02, with 95% CI = -0.04 to -0.002, respectively). Lower total T and SHBG concentrations were also associated with prevalent PAD in age-adjusted [odds ratio (OR) = 2.24, 95% CI = 1.17-4.32; and OR = 2.06; 95% CI = 1.07-3.96, lowest vs. highest quartile, respectively), but not in multivariable logistic regression models. Longitudinal multivariable analyses showed an association of lower SHBG with ABI change (decline ≥ 0.15; n = 69) in men [OR for SHBG quartiles 1, 2, and 3 as compared with quartile 4 were 2.56 (95% CI = 1.01-6.45), 2.28 (95% CI = 0.98-5.32), and 2.93 (95% CI = 1.31-6.52), respectively]. In women, none of the investigated associations yielded statistically significant estimates. CONCLUSION: Our investigation of a middle-aged community-based sample suggests that sex hormone concentrations in men but not in women may be associated with PAD and ABI change.