title: Increased survival with enzalutamide in prostate cancer after chemotherapy. 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. Risk factors associated with cardiovascular events during testosterone administration in older men with mobility limitation. Sex steroid hormone concentrations and risk of death in US men. Testosterone increases human platelet thromboxane A2 receptor density and aggregation responses. Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. Androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. Testosterone therapy increased muscle mass and lipid oxidation in aging men Randomized placebo-controlled trial of androgen effects on muscle and bone in men requiring long-term systemic glucocorticoid treatment. Efficacy and safety study of 1.62% testosterone gel for the treatment of hypogonadal men. When is a further clinical trial justified? Effect of testosterone treatment on bone mineral density in men over 65 years of age. Low-Dose Transdermal Testosterone Therapy Improves Angina Threshold in Men With Chronic Stable Angina: A Randomized, Double-Blind, Placebo-Controlled Study Effects of transdermal testosterone on cognitive function and health perception in older men with low bioavailable testosterone levels. A randomized trial of testosterone therapy in males with rheumatoid arthritis. Effects of transdermal testosterone on lipids and vascular reactivity in older men with low bioavailable testosterone levels. Adverse events associated with testosterone administration. Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial. The Delphi list: a criteria list for quality assessment of randomized clinical trials for conducting systematic reviews developed by Delphi consensus. Effects of muscle strength training and testosterone in frail elderly males. Double-blind placebo-controlled study of testosterone patch therapy on bone turnover in men with borderline hypogonadism. Reporting of safety results in published reports of randomized controlled trials. Association between industry funding and statistically significant pro-industry findings in medical and surgical randomized trials. Effects of testosterone on behavior, depression, and cognitive function in older men with mild cognitive loss. Assimilation and mobilization of triglycerides in subcutaneous abdominal and femoral adipose tissue in vivo in men: effects of androgens. The effects of transdermal dihydrotestosterone in the aging male: a prospective, randomized, double blind study. Transdermal androgen therapy to augment EPO in the treatment of anemia of chronic renal disease. Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. Effect of transdermal testosterone treatment on serum lipid and apolipoprotein levels in men more than 65 years of age. Commentary: hormone replacement therapy and coronary heart disease: four lessons. Testosterone treatment of men with alcoholic cirrhosis: a double-blind study. The Copenhagen Study Group for Liver Diseases. Understanding why evidence from randomised clinical trials may not be retrieved from Medline: comparison of indexed and non-indexed records DHEA in elderly women and DHEA or testosterone in elderly men. A double-blind, placebo-controlled, randomized clinical trial of transdermal dihydrotestosterone gel on muscular strength, mobility, and quality of life in older men with partial androgen deficiency. Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure a double-blind, placebo-controlled, randomized study. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels, low bone mass, and physical frailty. Oral testosterone replacement in symptomatic late-onset hypogonadism: effects on rating scales and general safety in a randomized, placebo-controlled study. Effect of Testosterone Replacement on Response to Sildenafil Citrate in Men With Erectile Dysfunction
abstract: BACKGROUND Enzalutamide ( formerly called MDV3100 ) targets multiple steps in the and rogen-receptor-signaling pathway , the major driver of prostate-cancer growth . We aim ed to evaluate whether enzalutamide prolongs survival in men with castration-resistant prostate cancer after chemotherapy . METHODS In our phase 3 , double-blind , placebo-controlled trial , we stratified 1199 men with castration-resistant prostate cancer after chemotherapy according to the Eastern Cooperative Oncology Group performance-status score and pain intensity . We r and omly assigned them , in a 2:1 ratio , to receive oral enzalutamide at a dose of 160 mg per day ( 800 patients ) or placebo ( 399 patients ) . The primary end point was overall survival . RESULTS The study was stopped after a planned interim analysis at the time of 520 deaths . The median overall survival was 18.4 months ( 95 % confidence interval [ CI ] , 17.3 to not yet reached ) in the enzalutamide group versus 13.6 months ( 95 % CI , 11.3 to 15.8 ) in the placebo group ( hazard ratio for death in the enzalutamide group , 0.63 ; 95 % CI , 0.53 to 0.75 ; P<0.001 ) . The superiority of enzalutamide over placebo was shown with respect to all secondary end points : the proportion of patients with a reduction in the prostate-specific antigen ( PSA ) level by 50 % or more ( 54 % vs. 2 % , P<0.001 ) , the soft-tissue response rate ( 29 % vs. 4 % , P<0.001 ) , the quality -of-life response rate ( 43 % vs. 18 % , P<0.001 ) , the time to PSA progression ( 8.3 vs. 3.0 months ; hazard ratio , 0.25 ; P<0.001 ) , radiographic progression-free survival ( 8.3 vs. 2.9 months ; hazard ratio , 0.40 ; P<0.001 ) , and the time to the first skeletal-related event ( 16.7 vs. 13.3 months ; hazard ratio , 0.69 ; P<0.001 ) . Rates of fatigue , diarrhea , and hot flashes were higher in the enzalutamide group . Seizures were reported in five patients ( 0.6 % ) receiving enzalutamide . CONCLUSIONS Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer after chemotherapy . ( Funded by Medivation and Astellas Pharma Global Development ; AFFIRM Clinical Trials.gov number , NCT00974311 . ) CONTEXT Steroid 5α-reductase inhibitors are used to treat benign prostatic hyperplasia and and rogenic alopecia , but the role of 5α-dihydrotestosterone ( DHT ) in mediating testosterone 's effects on muscle , sexual function , erythropoiesis , and other and rogen-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 r and omized 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 r and omized ; 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 grade d 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 clinical trials.gov Identifier : NCT00493987 BACKGROUND Testosterone in Older Men with Mobility Limitations Trial found an increased incidence of  cardiovascular events in men r and omized to testosterone  , result ing in enrollment cessation by trial 's Data and Safety Monitoring Board . We evaluated changes in gonadal hormones and markers of inflammation and coagulation to eluci date 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 r and omized 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 r and omized ( 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 The association of sex hormone levels with mortality over a median of 16 years of follow-up was evaluated in a prospect i ve cohort study . The study included 1,114 US men who participated in phase 1 ( 1988 - 1991 ) of the Third National Health and Nutrition Examination Survey Mortality Study and had no history of cardiovascular disease or cancer at baseline .  Multivariable adjusted hazard ratios for all-cause mortality associated with a decrease in hormone concentration equal to the difference between the 90th and 10th percentiles of the sex hormone distributions were estimated by using proportional hazards regression . The hazard ratios associated with low free testosterone and low bioavailable testosterone levels were 1.43 ( 95 % confidence interval ( CI ) : 1.09 , 1.87 ) and 1.52 ( 95 % CI : 1.15 , 2.02 ) , respectively , for follow-up between baseline and year 9 ; they were 0.94 ( 95 % CI : 0.51 , 1.72 ) and 0.98 ( 95 % CI : 0.56 , 1.72 ) , respectively , for follow-up between year 9 and year 18 . Men with low free and bioavailable testosterone levels may have a higher risk of mortality within 9 years of hormone measurement . Future studies should be conducted to fully characterize the association of low free and bioavailable testosterone concentrations and  mortality in men and to describe the mechanism underlying the association BACKGROUND The incidence of thrombotic cardiovascular disease is greater in men than in premenopausal women .  Testosterone has been implicated as a significant risk factor for cardiovascular disease and for acute myocardial infa rct ions and strokes in young male athletes who abuse anabolic steroids . Thromboxane A2 ( TXA2 ) is a vasoconstrictor and platelet proaggregatory agent that has been implicated in the pathogenesis of cardiovascular disease . We therefore tested the hypothesis that testosterone regulates the expression of human platelet TXA2 receptors . METHODS AND RESULTS In a double-blind , placebo-controlled , r and omized , parallel-group study , we determined the effects of testosterone cypionate 200 mg IM given twice , 2 weeks apart , or saline placebo in 16 healthy men .  Platelet TXA2 receptor density ( Bmax ) and dissociation constant ( Kd ) were measured by use of the TXA2 mimetic 125I-BOP . Platelet aggregation responses to I-BOP and to thrombin and plasma testosterone concentrations were measured before treatment ( pretreatment phase ) , at 2 and 4 weeks ( active phase ) , and again at 8 weeks ( recovery phase ) . Treatment with testosterone was associated with an increase in the Bmax value from 0.95 + /- 0.13 to 2.10 + /- 0.4 pmol/mg protein ( n = 9 ) , with a peak effect at 4 weeks ( P = .001 ) , returning to baseline by 8 weeks . There was no significant change in Bmax values in the saline-treated group . The Kd values were unchanged . Testosterone treatment was associated with a significant increase in the maximum platelet aggregation response to I-BOP ( P < .001 ) at 4 weeks and returned to baseline at 8 weeks . The EC50 values were not significantly changed . Platelet TXA2 receptor density was positively correlated ( r = .56 , P < .001 , n = 32 measurements ) with pretreatment ( endogenous ) plasma testosterone levels ( range , 215 to 883 ng/dL ) but not Kd . CONCLUSIONS Testosterone regulates the expression of platelet TXA2 receptors in humans . This may contribute to the thrombogenicity of and rogenic steroids Older men , particularly those with low serum testosterone ( T ) levels , might benefit from T therapy to improve bone mineral density ( BMD ) and reduce fracture risk . Concerns exist , however , about the impact of T therapy on the prostate in older men . We hypothesized that the combination of T and finasteride ( F ) , a 5 alpha-reductase inhibitor , might increase BMD in older men without adverse effects on the prostate . Seventy men aged 65 yr or older , with a serum T less than 12.1 nmol/liter on two occasions , were r and omly assigned to receive one of three regimens for 36 months : T enanthate , 200 mg i m every 2 wk with placebo pills daily ( T-only ) ; T enanthate , 200 mg every 2 wk with 5 mg F daily ( T+F ) ; or placebo injections and pills ( placebo ) . Low BMD was not an inclusion criterion . We obtained serial measurements of BMD of the lumbar spine and hip by dual x-ray absorptiometry . Prostate-specific antigen ( PSA ) and prostate size were measured at baseline and during treatment to assess the impact of therapy on the prostate . Fifty men completed the 36-month protocol . By an intent-to-treat analysis including all men for as long as they contributed data , T therapy for 36 months increased BMD in these men at the lumbar spine [ 10.2 + /- 1.4 % ( mean percentage increase from baseline + /- SEM ; T-only ) and 9.3 + /- 1.4 % ( T+F ) vs. 1.3 + /- 1.4 % for placebo ( P < 0.001 ) ] and in the hip [ 2.7 + /- 0.7 % ( T-only ) and 2.2 + /- 0.7 % ( T+F ) vs. -0.2 + /- 0.7 % for placebo , ( P < or = 0.02 ) ] . Significant increases in BMD were seen also in the intertrochanteric and trochanteric regions of the hip . After 6 months of therapy , urinary deoxypyridinoline ( a bone-resorption marker ) decreased significantly compared with baseline in both the T-only and T+F groups ( P < 0.001 ) but was not significantly reduced compared with the placebo group . Over 36 months , PSA increased significantly from baseline in the T-only group ( P < 0.001 ) . Prostate volume increased in all groups during the 36-month treatment period , but this increase was significantly less in the T+F group compared with both the T-only and placebo groups ( P = 0.02 ) . These results demonstrate that T therapy in older men with low serum T  increases vertebral and hip BMD over 36 months , both when administered alone and when combined with F. This finding suggests that dihydrotestosterone is not essential for the beneficial effects of T on BMD in men . In addition , the concomitant administration of F with T appears to attenuate the impact of T therapy on prostate size and PSA and might reduce the chance of benign prostatic hypertrophy or other prostate-related complications in older men on T therapy . These findings have important implication s for the prevention and treatment of osteoporosis in older men with low T levels And rogen-deprivation therapy ( ADT ) is a widely used treatment for prostate cancer . Recently , several studies have reported an association between ADT and an increased risk of cardiovascular events , including myocardial infa rct ion and cardiovascular mortality.1 - 5 These reports have led to increased interest and discussion regarding the metabolic effects of ADT and its possible association with increased cardiovascular risk . In addition , likely as a result of these reports , internists , endocrinologists , and cardiologists are now being consulted regarding the evaluation and management of patients in whom ADT is being initiated . Most of these physicians are not aware of the possible effects of ADT on cardiovascular risk factors or the issues regarding ADT and cardiovascular disease . Therefore , this multidisciplinary writing group has been commissioned to review and summarize the metabolic effects of ADT , to evaluate the data regarding a possible relation between ADT and cardiovascular events in patients with prostate cancer , and to generate suggestions regarding the evaluation and management of patients , both with and without known cardiac disease , in whom ADT is being initiated ( Table 1 ) . TABLE 1 Prospect i ve Studies of the Effects of ADT on Cardiac Risk Factors  ADT was first used in prostate cancer for patients with overt metastatic disease,7 and it remains the mainstay of therapy for this group . ADT combined with external-beam radiation therapy is a st and ard of care in the treatment of men with high-risk prostate cancer , on the basis of evidence that shows a survival benefit in multiple r and omized controlled trials.8 - 13 However , ADT is also often used for other prostate cancer states ( eg , for prostate volume reduction in men planning to undergo definitive local therapy with brachytherapy , or in the case of rising prostate-specific antigen after definitive local treatment),14,15 and in these cases , its role in prolonging survival is less certain BACKGROUND A large proportion of men over 65 years of age have bioavailable testosterone levels below the reference range of young adult men . The impact of this on musculoskeletal health and the potential for improvement in function in this group with testosterone supplementation require investigation . METHODS Sixty-seven men ( mean age 76 + /- 4 years , range 65 - -87 ) with bioavailable testosterone levels below 4.44 nmol/l ( lower limit for adult normal range ) were r and omized to receive transdermal testosterone  ( two 2.5-mg patches per day ) or placebo patches for 1 year . All men received 500 mg supplemental calcium and 400 IU vitamin D. Outcome measures included sex hormones ( testosterone , bioavailable testosterone , sex-hormone binding globulin [ SHBG ] , estradiol , and estrone ) , bone mineral density ( BMD ; femoral neck , Ward 's triangle , trochanter , lumbar spine , and total body ) , bone turnover markers , lower extremity muscle strength , percent body fat , lean body mass , hemoglobin , hematocrit , prostate symptoms , and prostate specific antigen ( PSA ) levels . RESULTS Twenty-three men ( 34 % ) withdrew from the study ; 44 men completed the trial . In these men , bioavailable testosterone levels increased from 3.2 + /- 1.2 nmol/l ( SD ) to 5.6 + /- 3.5 nmol/l ( p < .002 ) at 12 months in the testosterone group , whereas no change occurred in the control group . Although there was no change in estradiol levels in either group , estrone levels increased in the testosterone group ( 103 + /- 26 pmol/l to 117 + /- 33 pmol/l ; p < .017 ) . The testosterone group had a 0.3 % gain in femoral neck BMD , whereas the control group lost 1.6 % over 12 months ( p = .015 ) . No significant changes were seen in markers of bone turnover in either group . Improvements in muscle strength were seen in both groups at 12 months compared with baseline scores . Strength increased 38 % ( p = .017 ) in the testosterone group and 27 % in the control group ( p = .06 ) , with no statistical difference between the groups . In the testosterone group , body fat decreased from 26.3 + /- 5.8 % to 24.6 + /- 6.5 % ( p = .001 ) , and lean body mass increased from 56.2 + /- 5.3 kg to 57.2 + /- 5.1 kg ( p = .001 ) , whereas body mass did not change . Men receiving testosterone had an increase in PSA from 2.0 + /- 1.4 microg/l to 2.6 + /- 1.8 microg/l ( p = .04 ) , whereas men receiving placebo had an increase in PSA from 1.9 + /- 1.0 microg/l to 2.2 + /- 1.5 microg/l ( p = .09 ) . No significant differences between groups were seen in hemoglobin , hematocrit , symptoms or signs of benign prostate hyperplasia , or PSA levels . CONCLUSIONS Transdermal testosterone ( 5 mg/d ) prevented bone loss at the femoral neck , decreased body fat , and increased lean body mass in a group of healthy men over age 65 with low bioavailable testosterone levels . In addition , both testosterone and placebo groups demonstrated gains in lower extremity muscle strength , possibly due to the beneficial effects of vitamin D. Testosterone did result in a modest increase in PSA levels but result ed in no change in signs or symptoms of prostate hyperplasia The indication for testosterone therapy in aging hypogonadal men without hypothalamic , pituitary , or testicular disease remains to be eluci date d. 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 r and omized , 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 t and em 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 Long-term glucocorticoid therapy  in men is associated with loss of bone and muscle mass as well as a decrease in serum testosterone . We tested the effect of two and rogens , testosterone and its minimally aromatizable analog n and rolone , on muscle mass ( dual x-ray absorptiometry ) , muscle strength ( knee flexion and extension by isokinetic dynamometry ) , bone mineral density ( BMD ) , and quality of life ( Qualeffo-41 question naire ) in 51 men on a mean daily prednisone dose of 12.6 + /- 2.2 mg . Men were r and omized , double blind , to testosterone ( 200 mg mixed esters ) , n and rolone decanoate ( 200 mg ) , or placebo given every fortnight by i m injection for 12 months . At 12 months , both and rogens increased muscle mass ( mean change from baseline + 3.5 % , + 5.8 % , and -0.9 % in testosterone , n and rolone , and placebo groups , respectively , P < 0.0001 ) and muscle strength ( P < 0.05 ) . Lumbar spine BMD increased significantly only in men treated with testosterone ( 4.7 + /- 1.1 % , P < 0.01 ) . There was no significant change in hip or total body BMD . Testosterone , but not n and rolone or placebo , improved overall quality of life ( P < 0.001 ) . These results suggest that and rogen therapy may have a role in ameliorating adverse effects of glucocorticoid therapy such as muscle and bone loss and aromatization is necessary for and rogen action on bone but not on muscle INTRODUCTION Male hypogonadism is a significant and growing problem that can be successfully treated with testosterone replacement therapy . A new formulation of testosterone gel ( 1.62 % ) was developed with increased viscosity , reduced volume of application , and increased skin permeation compared with other currently available testosterone gels . AIM To evaluate the efficacy and safety of titrated doses of 1.62 % testosterone gel after daily application to the skin of hypogonadal men for 182 days . METHODS This was a multicenter , r and omized , double-blind , placebo-controlled study in hypogonadal men ( 234 active ; 40 placebo ) , 18 to 80 years of age with average serum total testosterone concentrations < 300 ng/dL and prostate-specific antigen < 2.5 ng/mL.  Topical testosterone gel ( 1.62 % ) , 1.25 g , 2.5 g , 3.75 g , and 5.0 g , or placebo gel was applied once daily to either upper arms/shoulders or abdomen . Dose adjustments were made on days 14 , 28 , and 42 . Main Outcome Measures . The percentage of subjects with serum total testosterone average concentrations ( C(av ) ) within the normal range of 300 - 1,000 ng/dL on study days 14 , 56 , 112 , and 182 . RESULTS Following titration , significantly ( P < 0.0001 ) more subjects receiving active treatment had testosterone C(av ) values ( range 81.6 % to 82.5 % ) within the eugonadal range compared with placebo ( range 28.6 % to 37.0 % ) on all study days . The 1.62 % gel was safe and well tolerated . CONCLUSIONS In this study , treatment with 1.62 % testosterone gel was safe and efficacious , result ing in an acceptable percentage of hypogonadal males achieving eugonadal serum testosterone levels High quality r and omised trials provide unbiased estimates of the effects of health interventions , but the findings of a single trial are rarely conclusive . Usually data from several similar trials must be pooled together to draw firm conclusions about the effectiveness of an intervention . This article considers how to determine whether data from existing trials are conclusive and , if not , whether a further trial is justified . As men age , their serum testosterone concentrations decrease , as do their bone densities . Because bone density is also low in hypogonadal men , we hypothesized that increasing the serum testosterone concentrations of men over 65 yr to those found in young men would increase their bone densities . We r and omized 108 men over 65 yr of age to wear either a testosterone patch or a placebo patch double blindly for 36 months . We measured bone mineral density by dual energy x-ray absorptiometry before and during treatment . Ninety-six men completed the entire 36-month protocol . The mean serum testosterone concentration in the men treated with testosterone increased from 367 + /- 79 ng/dL ( + /-SD ; 12.7 + /- 2.7 nmol/L ) before treatment to 625 + /- 249 ng/dL ( 21.7 + /- 8.6 nmol/L ; P < 0.001 ) at 6 months of treatment and remained at that level for the duration of the study . The mean bone mineral density of the lumbar spine increased ( P < 0.001 ) in both the placebo-treated ( 2.5 + /- 0.6 % ) and testosterone-treated ( 4.2 + /- 0.8 % ) groups , but the mean changes did not differ between the groups . Linear regression analysis , however , demonstrated that the lower the pretreatment serum testosterone concentration , the greater the effect of testosterone treatment on lumbar spine bone density from 0 - 36 months ( P = 0.02 ) . This analysis showed a minimal effect ( 0.9 + /- 1.0 % ) of testosterone treatment on bone mineral density for a pretreatment serum testosterone concentration of 400 ng/dL ( 13.9 nmol/L ) , but an increase of 5.9 + /- 2.2 % for a pretreatment testosterone concentration of 200 ng/dL ( 6.9 nmol/L ) . Increasing the serum testosterone concentrations of normal men over 65 yr of age to the midnormal range for young men did not increase lumbar spine bone density overall , but did increase it in those men with low pretreatment serum testosterone concentrations Background Experimental studies suggest that and rogens induce coronary vasodilatation . We performed this pilot project to examine the clinical effects of long-term low-dose and rogens in men with angina . Methods and Results Forty-six men with stable angina completed a 2-week , single-blind placebo run-in , followed by double-blind r and omization to 5 mg testosterone daily by transdermal patch or matching placebo for 12 weeks , in addition to their current medication . Time to 1-mm ST-segment depression on treadmill exercise testing and hormone levels were measured and quality of life was assessed by SF-36 at baseline and after 4 and 12 weeks of treatment . Active treatment result ed in a 2-fold increase in and rogen levels and an increase in time to 1-mm ST-segment depression from ( mean±SEM ) 309±27 seconds at baseline to 343±26 seconds after 4 weeks and to 361±22 seconds after 12 weeks . This change was statistically significant compared with that seen in the placebo group ( from 266±25 seconds at baseline to 284±23 seconds after 4 weeks and to 292±24 seconds after 12 weeks;P = 0.02 between the 2 groups by ANCOVA ) . The magnitude of the response was greater in those with lower baseline levels of bioavailable testosterone ( r = −0.455 , P < 0.05 ) . There were no significant changes in prostate specific antigen , hemoglobin , lipids , or coagulation profiles during the study . There were significant improvements in pain perception ( P = 0.026 ) and role limitation result ing from physical problems ( P = 0.024 ) in the testosterone-treated group . Conclusions Low-dose supplemental testosterone treatment in men with chronic stable angina  reduces exercise-induced myocardial ischemia BACKGROUND Many men older than 50 years have bioavailable testosterone levels below the reference range for young adult men . The impact of the decreased and rogen levels on cognition and health perception has received little attention . METHODS Sixty-seven men ( mean age 76 + /- 4 years , range 65 - 87 ) with bioavailable testosterone levels below 128 ng/dl ( lower limit for adult normal range ) were r and omized to receive transdermal testosterone ( 2 - 2.5 mg patches/d ) or placebo patches for 1 year . All men received 500 mg supplemental calcium and 400 IU vitamin D. Outcome measures included sex hormones [ testosterone , bioavailable testosterone , sex hormone binding globulin ( SHBG ) , estradiol , and estrone ] , cognitive tests ( Digit Symbol , Digit Span , Trailmaking A and B ) , health perception ( Medical Outcome Survey Short-form 36 or SF-36 ) , lower extremity muscle strength and power , and calcium intake . RESULTS Twenty-three men ( 34 % ) withdrew from the study ; 44 men completed the trial .  Bioavailable testosterone levels increased from 93 + /- 34 ( SD ) to 162 + /- 100 ng/dl ( p < .002 ) at 12 months in the testosterone group ( n = 24 ) while no change occurred in the control group ( n = 20 ) . While there was no change in estradiol levels in either group , estrone levels increased in the testosterone group ( 28 + /- 7 to 32 + /- 9 pg/dl , p = .017 ) . Scores on the Digit Symbol test improved in both the testosterone and placebo groups . Scores on Trailmaking B improved in men treated with testosterone ( p < .005 ) , although the changes were not statistically different from the changes seen in the placebo group . Twelve-month scores on Trailmaking B for the entire group were correlated with 12-month testosterone levels ( p = .016 ) . Scores for health perception measured by SF-36 did not change significantly , though scores of mental and general health declined in both groups during the 12-month intervention . Twelve-month bioavailable testosterone scores were directly correlated with scores for physical role ( p = .022 ) , vitality ( p = .036 ) , and the physical composite score ( p = .010 ) . CONCLUSIONS Transdermal testosterone treatment in men with low bioavailable testosterone levels does not impair and may improve cognitive function . Treatment did not improve health perception but this may have been due to the side effects of skin irritation suggested by similar reactions in both the testosterone and placebo groups Thirty-five male patients , aged 34 - 79 yr , with definite rheumatoid arthritis ( RA ) were recruited from out-patient clinics and r and omized to receive monthly injections of testosterone enanthate 250 mg or placebo as an adjunct therapy for 9 months . Endpoints included disease activity parameters and bone mineral density ( BMD ) . At baseline , there were negative correlations between the ESR and serum testosterone ( r = -0.42 , P < 0.01 ) and BMD ( hip , r = -0.65 , P < 0.01 ) . A total of 29.6 % of all patients had at least one vertebral fracture , most having multiple fractures . Back pain , however , was not more prevalent in fracture patients ( 55 % vs 50 % ) . Disease activity was significantly higher in the fracture group ( joint score P < 0.05 , rheumatoid factor P < 0.01 ) . Thirty patients completed the trial , 15 receiving testosterone and 15 receiving placebo . There were significant rises in serum testosterone , dihydrotestosterone and oestradiol in the treatment group . There was no significant effect of treatment on disease activity overall , five patients receiving testosterone underwent a " flare ' . Differences in mean BMD following testosterone or placebo were non-significant ( spine : + 1.2 % vs -1.1 % ; femur : -0.3 % vs + 0.3 % ) . There was no suggestion of a positive effect of testosterone on disease activity in men with RA BACKGROUND Sex hormones are known to affect cholesterol levels and vascular tone in women . The effects of testosterone on cholesterol and vascular tone in men are less well understood . Low testosterone levels have been associated with higher cholesterol levels in epidemiologic studies , but testosterone replacement has result ed in variable changes in cholesterol levels . Similarly , clinical studies suggest that testosterone may be vasodilatory , but few studies have directly evaluated the effects of testosterone on vascular tone . METHODS Sixty-seven men ( mean age 76 + /- 4 years , range 65 - 87 ) with bioavailable testosterone levels below 4.44 nmol/l ( lower limit for adult normal range ) were r and omized to receive transdermal testosterone  ( 2 - 2.5 mg patches/d ) or placebo patches for 1 year . Twenty-three men ( 34 % ) withdrew from the study ; 44 men completed the trial . RESULTS While total cholesterol , triglyceride , and low-density lipoprotein cholesterol levels did not significantly change during the year of therapy , high-density lipoprotein ( HDL ) levels ( p = .004 ) and , specifically , HDL(2 ) subfraction ( p = .02 ) decreased in men receiving testosterone supplementation . Vascular tone was measured by brachial artery reactivity in 36 men . Endothelium-dependent brachial artery reactivity did not change from baseline measurements in men receiving transdermal testosterone  ( 0.3 + /- 6.7 % to 1.6 + /- 4.6 % ; p = .58 ) or in the placebo group ( 3.2 + /- 5.5 % to 0.7 + /- 5.5 % ; p = .23 ) . CONCLUSIONS Transdermal testosterone decreased HDL(2 ) cholesterol but did not affect vascular reactivity in men older than 65 years selected for low testosterone levels . No study to date has addressed the direct relationship between testosterone replacement and cardiovascular events BACKGROUND Testosterone supplementation has been shown to increase muscle mass and strength in healthy older men . The safety and efficacy of testosterone treatment in older men who have limitations in mobility have not been studied . METHODS Community-dwelling men , 65 years of age or older , with limitations in mobility and a total serum testosterone level of 100 to 350 ng per deciliter ( 3.5 to 12.1 nmol per liter ) or a free serum testosterone level of less than 50 pg per milliliter ( 173 pmol per liter ) were r and omly assigned to receive placebo gel or testosterone gel , to be applied daily for 6 months . Adverse events were categorized with the use of the Medical Dictionary for Regulatory Activities classification . The data and safety monitoring board recommended that the trial be discontinued early because there was a significantly higher rate of adverse cardiovascular events in the testosterone group than in the placebo group . RESULTS A total of 209 men ( mean age , 74 years ) were enrolled at the time the trial was terminated . At baseline , there was a high prevalence of hypertension , diabetes , hyperlipidemia , and obesity among the participants . During the course of the study , the testosterone group had higher rates of cardiac , respiratory , and dermatologic events than did the placebo group . A total of 23 subjects in the testosterone group , as compared with 5 in the placebo group , had cardiovascular-related adverse events . The relative risk of a cardiovascular-related adverse event remained constant throughout the 6-month treatment period . As compared with the placebo group , the testosterone group had significantly greater improvements in leg-press and chest-press strength and in stair climbing while carrying a load . CONCLUSIONS In this population of older men with limitations in mobility and a high prevalence of chronic disease , the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events . The small size of the trial and the unique population prevent broader inferences from being made about the safety of testosterone therapy . ( Clinical Trials.gov number , NCT00240981 . AIMS Chronic heart failure is associated with maladaptive and prolonged neurohormonal and pro-inflammatory cytokine activation causing a metabolic shift favouring catabolism , vasodilator incapacity , and loss of skeletal muscle bulk and function . In men , and rogens are important determinants of anabolic function and physical strength and also possess anti-inflammatory and vasodilatory properties . METHODS AND RESULTS We conducted a r and omized , double-blind , placebo-controlled parallel trial of testosterone replacement therapy ( 5 mg And roderm ) at physiological doses in 76 men ( mean+/-SD , age 64+/-9.9 ) with heart failure ( ejection fraction 32.5+/-11 % ) over a maximum follow-up period of 12 months . The primary endpoint was functional capacity as assessed by the incremental shuttle walk test ( ISWT ) . At baseline , 18 ( 24 % ) had serum testosterone below the normal range and bioavailable testosterone correlated with distance walked on the initial ISWT ( r=0.3 , P=0.01 ) . Exercise capacity significantly improved with testosterone therapy compared with placebo over the full study period ( mean change + 25+/-15 m ) corresponding to a 15+/-11 % improvement from baseline ( P=0.006 ANOVA ) . Symptoms improved by at least one functional class on testosterone in 13 ( 35 % ) vs. 3 ( 8 % ) on placebo ( P=0.01 ) . No significant changes were found in h and grip strength , skeletal muscle bulk by cross-sectional computed tomography , or in tumour necrosis factor levels .  Testosterone therapy was safe with no excess of adverse events although the patch preparation was not well tolerated by the study patients . CONCLUSION Testosterone replacement therapy improves functional capacity and symptoms in men with moderately severe heart failure Most systematic review s rely substantially on the assessment of the method ological quality of the individual trials . The aim of this study was to obtain consensus among experts about a set of generic core items for quality assessment of r and omized clinical trials ( RCTs ) . The invited participants were experts in the field of quality assessment of RCTs . The initial item pool contained all items from existing criteria lists . Subsequently , we reduced the number of items by using the Delphi consensus technique . Each Delphi round comprised a question naire , an analysis , and a feedback report . The feedback report included staff team decisions made on the basis of the analysis and their justification . A total of 33 international experts agreed to participate , of whom 21 completed all question naires . The initial item pool of 206 items was reduced to 9 items in three Delphi rounds . The final criteria list ( the Delphi list ) was satisfactory to all participants . It is a starting point on the way to a minimum reference st and ard for RCTs on many different research topics . This list is not intended to replace , but rather to be used alongside , existing criteria lists PURPOSE Determine the independent and combined effects of progressive resistance muscle strength training ( PRMST ) and testosterone on strength , muscle mass , and function in hypogonadal elderly male recuperative care patients . METHODS Between 1999 and 2004 , 71 subjects ( mean age 78.2 + /- 6.4 yr , 86 % white ) were enrolled . After baseline one-repetition maximum ( 1RM ) strength testing and then r and omization to one of four treatment groups ( low-resistance ( 20 % of the 1RM ) exercises and weekly injections of either 100 mg of testosterone enanthate or placebo or high-intensity PRMST ( > or = 80 % 1RM ) and weekly injections ) , each subject received training and injections for 12 wk . RESULTS Ten subjects withdrew from the study before its completion . Based on intent-to-treat analyses , strength improved in all groups , but was greater with high-intensity PRMST compared with low-resistance exercise ( e.g. , leg press , ( mean + /- SE ) , 28 + /- 4 vs 13 + /- 4 % , P = 0.009 ) . Although testosterone led to significantly greater increases in midthigh cross-sectional muscle area compared with placebo ( 7.9 + /- 1.3 vs 2.4 + /- 1.4 % , P = 0.005 ) , it produced only a nonsignificant trend toward greater strength gains ( e.g. , leg press 25 + /- 4 vs 16 + /- 4 % , P = 0.144 ) . Change in aggregate functional performance score ( the sum of 4 functional performance test scores ) did not differ between the four intervention groups nor with high-intensity PRMST compared with low-resistance exercise ( 7 + /- 5 vs 15 + /- 5 % , P = 0.263 ) . There was not a significant interaction between exercise and testosterone for any outcome . CONCLUSION High-intensity PRMST is as safe and well tolerated as a similarly structured low-resistance exercise regimen for very frail elderly patients , but produces greater muscle strength improvements . The addition of testosterone leads to greater muscle size and a trend toward greater strength but did not produce a synergistic interaction with exercise . Neither intervention had a significant effect on functional performance Clinical studies suggest there may be a threshold concentration of serum testosterone below which replacement will result in skeletal and psychological benefit . We evaluated the response to testosterone in men with borderline hypogonadism . A r and omized double-blind placebo-controlled trial in 39 men over age 40 years presenting with sexual dysfunction and a borderline low testosterone level ( total testosterone < 10 nmol/L or free and rogen index < 30 % ) . Patients were r and omized to Testoderm TTS body patch ( 5 mg/day , n = 20 ) or a placebo patch ( n = 19 ) for 6 months , followed by open-label testosterone replacement for a further 6 months in all patients . During the placebo-controlled phase of the study serum testosterone increased significantly on testosterone vs. placebo treatment ( p = 0.004 ) ; this was associated with a decrease in total body fat mass ( p = 0.019 ) and increase in haemoglobin level ( p = 0.036 ) . There were no significant changes in lean body mass , markers of bone turnover , and measures of bone mineral density ( BMD ) . There was evidence of difference in quality of life according to the Male Erectile Dysfunction Quality of Life question naire ( MEDQoL score , p = 0.017 ) , mainly accounted for by deterioration in the placebo arm . When the active treatment period was combined for placebo and testosterone groups , the within-patient analysis showed a significant effect of testosterone to decrease markers of bone resorption ( uNTX/Cr , p = 0.007 ; iFDPD/Cr , p = 0.0006 ) and to increase lean body mass ( p = 0.001 ) . There was little convincing evidence from this study that testosterone replacement is likely to have major benefit in men over age 40 years with borderline hypogonadism and sexual dysfunction . However , there was evidence of suppression in bone resorption and hence longer and larger studies are needed to examine its effect on BMD BACKGROUND Reports of clinical trials usually emphasize efficacy results , especially when results are statistically significant . Poor safety reporting can lead to misinterpretation and inadequate conclusions about the interventions assessed . Our aim was to describe the reporting of harm-related results from r and omized controlled trials ( RCTs ) . METHODS We search ed the MEDLINE data base for reports of RCTs published from January 1 , 2006 , through January 1 , 2007 , in 6 general medical journals with a high impact factor . Data were extracted by use of a st and ardized form to appraise the presentation of safety results in text and tables . RESULTS Adverse events were mentioned in 88.7 % of the 133 reports . No information on severe adverse events and withdrawal of patients owing to an adverse event was given in 27.1 % and 47.4 % of articles , respectively . Restrictions in the reporting of harm-related data were noted in 43 articles ( 32.3 % ) with a description of the most common adverse events only ( n = 17 ) , severe adverse events only ( n = 16 ) , statistically significant events only ( n = 5 ) , and a combination of restrictions ( n = 5 ) . The population considered for safety analysis was clearly reported in 65.6 % of articles . CONCLUSION Our review reveals important heterogeneity and variability in the reporting of harm-related results in publications of RCTs BACKGROUND Conflicting reports exist in the medical literature regarding the association between industry funding and published research findings . In this study , we examine the association between industry funding and the statistical significance of results in recently published medical and surgical trials . METHODS We examined a consecutive series of 332 r and omized trials published between January 1999 and June 2001 in 8 leading surgical journals and 5 medical journals . Each eligible study was independently review ed for method ological quality using a 21-point index with 5 domains : r and omization , outcomes , eligibility criteria , interventions and statistical issues . Our primary analysis included studies that explicitly identified the primary outcome and reported it as statistically significant . For studies that did not explicitly identify a primary outcome , we defined a " positive " study as one with at least 1 statistically significant outcome measure . We used multivariable regression analysis to determine whether there was an association between reported industry funding and trial results , while controlling for study quality and sample size . RESULTS Among the 332 r and omized trials , there were 158 drug trials , 87 surgical trials and 87 trials of other therapies . In 122 ( 37 % ) of the trials , authors declared industry funding . An unadjusted analysis of this sample of trials revealed that industry funding was associated with a statistically significant result in favour of the new industry product ( odds ratio [ OR ] 1.9 , 95 % confidence interval [ CI ] 1.3 - 3.5 ) . The association remained significant after adjustment for study quality and sample size ( adjusted OR 1.8 , 95 % CI 1.1 - 3.0 ) . There was a nonsignificant difference between surgical trials ( OR 8.0 , 95 % CI 1.1 - 53.2 ) and drug trials ( OR 1.6 , 95 % CI 1.1 - 2.8 ) , both of which were likely to have a pro-industry result ( relative OR 5.0 , 95 % CI 0.7 - 37.5 , p = 0.14 ) . INTERPRETATION Industry-funded trials are more likely to be associated with statistically significant pro-industry findings , both in medical trials and surgical interventions BACKGROUND The role of sex hormones in the prevention of cognitive decline is uncertain . Animal studies suggest mechanisms for sex hormones including testosterone to maintain optimal cognitive function . But , there are studies to suggest that endogenous testosterone levels are associated with aggression in men with cognitive impairment . METHODS In this pilot study , 11 men ( mean age 80 + /- 5 years , range 73 - 87 years ) with early cognitive decline and bioavailable testosterone levels below 128 ng/dl ( lower limit for adult normal range ) were r and omized to receive intramuscular testosterone ( 200 mg every 3 weeks ) or placebo for 12 weeks . Outcome measures included sex hormones ( testosterone , bioavailable testosterone , sex hormone binding globulin , estradiol , and estrone ) , Behave AD Question naire , Katz Activities of Daily Living , Geriatric Depression Scale , Digit Span , Clock Face Drawing , Clock Face Perception , Verbal Fluency , Trail-Making B , and International Prostate Symptom Score at baseline , 4 weeks , and 10 weeks . RESULTS All men completed the study . Total and bioavailable testosterone , estrone , and estradiol levels increased in men receiving testosterone , but no changes were detected in men receiving placebo . No significant changes were found in behavior following testosterone supplementation , nor was there evidence of change in depression or activities of daily living . No discernable changes were found in any of the cognitive tests . Symptoms of prostate hyperplasia remained unchanged in the testosterone ( 6.6 + 5.8 to 5.2 + 3.6 ; p = .39 ) and placebo ( 8.8 + 6.4 to 6.4 + 3.8 ; p = .15 ) groups , and prostate-specific antigen levels did not change significantly . CONCLUSION No significant changes in behavior , function , depression , or cognitive performance occurred following 12 weeks of testosterone replacement in men with low testosterone levels and early-to-moderate cognitive impairment . This pilot work suggests that testosterone can be given to men with early cognitive impairment without significant concern about worsening aggressive or unwanted behaviors Studies on regional differences of adipose tissue metabolism have mainly been performed in vitro . To allow measurements of lipid uptake in vivo in man , radioactive label from [9,10 - 3H]oleic acid in 80 g orally administered milk fat was measured after 4 h in abdominal and femoral sc adipose tissues in 28 middle-aged , abdominally obese men . Radioactivity was measured in adipose tissue triglycerides extracted from needle biopsies . Lipoprotein lipase ( LPL ) activity was also measured . Uptake of label in triglycerides and LPL activity were higher ( 20 % and 15 % , respectively ; P < 0.05 ) in the abdominal compared to the femoral adipose tissue region . The men were then r and omly assigned to three groups , receiving testosterone ( T ) , dihydrotestosterone , or placebo , for 9 months . After 2 months of treatment , the procedure of administration of label was repeated , this time using [U-14C]oleic acid as a marker . Measurements of radioactive label was then performed after 4 h and monthly up to 7 months . Supplementation with T was followed by an inhibited uptake of label in triglycerides ( 34 % ; P < 0.05 ) , lower LPL activity ( 48 % ; P < 0.05 ) , and a shorter t1/2 ( 30 % ; P < 0.05 ) in the abdominal adipose tissue region compared with the dihydrotestosterone and placebo groups . No significant effect of T on triglyceride uptake , LPL activity , or t1/2 was found in sc femoral adipose tissue . It was concluded that the turnover rate of depot triglycerides is more rapid in abdominal compared to femoral sc adipose tissue in men . Furthermore , T supplementation inhibits triglyceride uptake and LPL activity and causes a more rapid turnover of triglycerides only in the sc abdominal adipose tissue region . These results demonstrate the marked effects of T on adipose tissue metabolism in vivo and suggest that T is an important regulator of the proportion of depot fat mass in central and peripheral adipose tissue in men The objective of the study was to investigate the effects of dihydrotestosterone ( DHT ) gel on general well-being , sexual function , and the prostate in aging men . A total of 120 men participated in this r and omized , placebo-controlled study ( 60 DHT and 60 placebo ) . All subjects had nocturnal penile tumescence once per week or less , and ropause symptoms , and a serum T level of 15 nmol/liter or less and /or a serum SHBG level greater than 30 nmol/liter . The mean age was 58 yr ( range , 50 - 70 yr ) . Of these subjects , 114 men completed the study .  DHT was administered transdermally for 6 months , and the dose varied from 125 - 250 mg/d . General well-being symptoms and sexual function were evaluated using a question naire , and prostate symptoms were evaluated using the International Prostate Symptoms Score , transrectal ultrasonography , and assay of serum prostate-specific antigen . Early morning erections improved transiently in the DHT group at 3 months of treatment ( P < 0.003 ) , and the ability to maintain erection improved in the DHT group compared with the placebo group ( P < 0.04 ) . No significant changes were observed in general well-being between the placebo and the DHT group . Serum concentrations of LH , FSH , E2 , T , and SHBG decreased significantly during DHT treatment . Treatment with DHT did not affect liver function or the lipid profile . Hemoglobin concentrations increased from 146.0 + /- 8.2 to 154.8 + /- 11.4 g/liter , and hematocrit from 43.5 + /- 2.5 % to 45.8 + /- 3.4 % ( P < 0.001 ) . Prostate weight and prostate-specific antigen levels did not change during the treatment . No major adverse events were observed . Transdermal administration of DHT improves sexual function and may be a useful alternative for and rogen replacement . As estrogens are thought to play a role in the pathogenesis of prostate hyperplasia , DHT may be beneficial , compared with aromatizing and rogens , in the treatment of aging men BACKGROUND Hypogonadism and anemia are common comorbid conditions in dialysis patients .  Testosterone replacement may improve such clinical parameters as anemia , sarcopenia , and low libido . Additionally , by increasing hemoglobin levels , testosterone replacement may allow for a dose reduction in recombinant human erythropoietin ( rHuEPO ) , thereby reducing cost . METHODS This phase IV , single-center , placebo-controlled , double-blind study assessed the effect of transdermal testosterone on serum testosterone levels , rHuEPO dose required to maintain hemoglobin level , bone mineral content , lean body mass and fat content , cholesterol level , sexual function , and mood . Forty hypogonadal male hemodialysis patients who were administered rHuEPO were r and omly assigned to 100 mg of topical 1 % testosterone gel ( Testim ; Auxilium Pharmaceuticals , Norristown , PA ) or placebo , applied daily for 6 months . RESULTS Forty men with a mean age of 56 years and baseline serum testosterone level less than 300 ng/dL ( < 10.4 nmol/L ) participated in this trial . In men assigned to administration of transdermal testosterone , there was an increase beyond that in the placebo group in mean serum testosterone ( 77.1 ng/dL [ 2.7 nmol/L ] ) , dihydrotestosterone ( DHT ; 0.8 nmol/L ) , and estradiol levels ( 6.3 pg/mL [ 23.0 pmol/L ] ) and a decrease in mean serum luteinizing hormone levels ( -3.1 IU/L ) . Compared with subjects administered placebo , participants on testosterone replacement therapy did not show an appreciable change in  rHuEPO dose ( mean difference adjusted for baseline values , 12.6 U/kg/wk ; P = 0.73 ) , bone mineral density , lean body mass or fat content , cholesterol level , sexual function , or mood . CONCLUSION Daily administration of 100 mg of topical 1 % testosterone gel for 6 months failed to significantly increase serum testosterone or DHT levels in hypogonadal men with end-stage renal disease . Treatment with transdermal testosterone did not impact on rHuEPO requirement or clinical parameters in this small placebo-controlled study . Greater serum testosterone levels may be required to show clinical benefit in men with end-stage renal disease As men age , serum testosterone concentrations decrease , the percentage of body mass that is fat increases , the percentage of lean body mass decreases , and muscle strength decreases . Because these changes are similar to those that occur in hypogonadal men , we hypothesized that increasing the serum testosterone concentration of men over 65 yr of age to that in young men would decrease their fat mass , increase their lean mass , and increase their muscle strength . We r and omized 108 men over 65 yr of age to wear either a testosterone patch or a placebo patch in a double blind study for 36 months . We measured body composition by dual energy x-ray absorptiometry and muscle strength by dynamometer before and during treatment . Ninety-six men completed the entire 36-month protocol .  Fat mass decreased ( -3.0+/-0.5 kg ) in the testosterone-treated men during the 36 months of treatment , which was significantly different ( P = 0.001 ) from the decrease ( -0.7+/-0.5 kg ) in the placebo-treated men . Lean mass increased ( 1.9+/-0.3 kg ) in the testosterone-treated men , which was significantly different ( P < 0.001 ) from that ( 0.2+/-0.2 kg ) in the placebo-treated men . The decrease in fat mass in the testosterone-treated men was principally in the arms ( -0.7+/-0.1 kg ; P < 0.001 compared to the placebo group ) and legs ( -1.1+/-0.2 kg ; P < 0.001 ) , and the increase in lean mass was principally in the trunk ( 1.9+/-0.3 kg ; P < 0.001 ) . The change in strength of knee extension and flexion at 60 degrees and 180 degrees angular velocity during treatment , however , was not significantly different between the two groups . We conclude that increasing the serum testosterone concentrations of normal men over 65 yr of age to the midnormal range for young men decreased fat mass , principally in the arms and legs , and increased lean mass , principally in the trunk , but did not increase the strength of knee extension and flexion , as measured by dynamometer A decline in testicular function is recognized as a common occurrence in older men . However data are sparse regarding the effects of hypogonadism on age-associated physical and cognitive declines . This study was undertaken to examine the year-long effects of testosterone administration in this patient population . Fifteen hypogonadal men ( mean age 68 + /- 6 yr ) were r and omly assigned to receive a placebo  , and 17 hypogonadal men ( mean age 65 + /- 7 yr ) were r and omly assigned to receive testosterone .  Hypogonadism was defined as a bioavailable testosterone < 60 ng/dL. The men received injections of placebo or 200 mg testosterone cypionate biweekly for 12 months . The main outcomes measured included grip strength , hemoglobin , prostate-specific antigen , leptin , and memory .  Testosterone improved bilateral grip strength ( P < 0.05 by ANOVA ) and increased hemoglobin ( P < 0.001 by ANOVA ) . The men assigned to testosterone had greater decreases in leptin than those assigned to the control group ( mean + /- SEM : -2.0 + /- 0.9 ng/dL vs. 0.8 + /- 0.7 ng/dL ; P < 0.02 ) . There were no significant changes in prostate-specific antigen or memory .  Three subjects receiving placebo and seven subjects receiving  testosterone  withdrew from the study . Three of those seven withdrew because of an abnormal elevation in hematocrit .  Testosterone supplementation improved strength , increased hemoglobin , and lowered leptin levels in older hypogonadal men .  Testosterone may have a role in the treatment of frailty in males with hypogonadism ; however , older men receiving testosterone must be carefully monitored because of its potential risks CONTEXT Physical frailty is associated with reduced muscle strength , impaired physical function , and quality of life .  Testosterone ( T ) increases muscle mass and strength in hypogonadal patients . It is unclear whether T has similar effects in intermediate-frail and frail elderly men with low to borderline-low T. OBJECTIVE Our objective was to determine the effects of 6 months T treatment in intermediate-frail and frail elderly men , on muscle mass and strength , physical function , and quality of life . DESIGN AND SETTING We conducted a r and omized , double-blind , placebo-controlled , parallel-group , single-center study . PARTICIPANTS PARTICIPANTS were community-dwelling intermediate-frail and frail elderly men at least 65 yr of age with a total T at or below 12 nmol/liter or free T at or below 250 pmol/liter . METHODS Two hundred seventy-four participants were r and omized to transdermal T ( 50 mg/d ) or placebo gel for 6 months . Outcome measures included muscle strength , lean and fat mass , physical function , and self-reported quality of life . RESULTS Isometric knee extension peak torque improved in the T group ( vs. placebo at 6 months ) , adjusted difference was 8.6 ( 95 % confidence interval , 1.3 - 16.0 ; P = 0.02 ) Newton-meters . Lean body mass increased and fat mass decreased significantly in the T group by 1.08 + /- 1.8 and 0.9 + /- 1.6 kg , respectively . Physical function improved among older and frailer men . Somatic and sexual symptom scores decreased with T treatment ; adjusted difference was -1.2 ( -2.4 to -0.04 ) and -1.3 ( -2.5 to -0.2 ) , respectively . CONCLUSIONS T treatment in intermediate-frail and frail elderly men with low to borderline-low T for 6 months may prevent age-associated loss of lower limb muscle strength and improve body composition , quality of life , and physical function . Further investigations are warranted to extend these results PURPOSE Because the effects of and rogen replacement on lipoprotein levels are uncertain , we sought to determine the effect of transdermal testosterone treatment on serum lipid and apolipoprotein levels in elderly men . SUBJECTS AND METHODS One hundred and eight healthy men more than 65 years of age who had serum testosterone concentrations > 1 SD below the mean for young men were r and omly assigned to receive either testosterone ( 54 men ; 6 mg/day ) or placebo ( 54 men ) transdermally in a double-blind fashion for 36 months . Serum concentrations of lipids and apolipoproteins were measured , and cardiovascular events recorded . RESULTS Serum total cholesterol concentrations decreased in both the testosterone-treated men and placebo-treated men , but the 3-year mean ( + /- SD ) decreases in the two groups ( testosterone treated , -17 + /- 29 mg/dL ; placebo treated , -12 + /- 38 mg/dL ) were not significantly different from each other ( P = 0.4 ) . Similarly , serum low-density lipoprotein ( LDL ) cholesterol levels decreased in both treatment groups , but the decreases in the two groups ( testosterone treated , -16 + /- 24 mg/dL ; placebo treated , -16 + /- 33 mg/dL ) were similar ( P = 1.0 ) . Levels of high-density lipoprotein ( HDL ) cholesterol , triglycerides , and apolipoproteins A-I and B did not change . Lipoprotein(a ) levels increased in both groups by similar amounts ( testosterone treated , 3 + /- 9 mg/dL ; placebo treated , 4 + /- 6 mg/dL ; P = 1.0 ) . The number of cardiovascular events was small and did not differ significantly between the  testosterone-treated  men ( 9 events ) and the placebo-treated men ( 5 events ) during the 3-year study ( relative risk = 1.8 ; 95 % confidence interval : 0.7 to 5.0 ) . CONCLUSIONS As compared with placebo , transdermal testosterone treatment of healthy elderly men for 3 years did not affect any of the lipid or apolipoprotein parameters that we measured . The effect of testosterone treatment on cardiovascular events was unclear , because the number of events was small In 1991 , Stampfer and Colditz , 1 review ing epidemiological studies of the effect of postmenopausal oestrogen on coronary heart disease concluded that : ‘ … the bulk of evidence strongly supports a protective effect of estrogens that is unlikely to be explained by confounding factors … ’ Their best estimate of the relative risk of coronary heart disease ( CHD ) in postmenopausal oestrogen users was calculated using meta-analytical techniques applied to the epidemiological studies they deemed to be of high quality based on their design s— prospect i ve studies with internal controls and angiographic studies . This estimate was 0.50 . The CI was narrow � 0.43 to 0.56 A double-blind , placebo-controlled multicenter trial was conducted to determine the efficacy of oral testosterone treatment ( 200 mg three times daily ) in men with alcoholic cirrhosis . By skewed r and omization ( 3:2 ) , 134 patients received testosterone and 87 placebo .  Patients were followed from 8 to 62 months ( median = 28 months ) . In the testosterone group , 33 patients died ( 25 % ; 95 % confidence limits = 18 to 33 % ) as compared to 18 ( 21 % ; 95 % confidence limits = 13 to 31 % ) in the placebo group . Taking age and significant prognostic variables into consideration , this corresponds with a relative mortality risk of 1.17 ( 95 % confidence limits = 0.65 to 2.15 ) in the testosterone group vs. the placebo group . Testosterone treatment did not significantly affect liver biochemistry , prevalence of complications to cirrhosis or causes of death . Patients treated with testosterone developed significantly ( p less than 0.05 ) higher serum testosterone and blood hemoglobin concentrations and significantly ( p less than 0.05 ) lower plasma IgM concentrations as compared to the placebo group . The prevalence of gynecomastia decreased significantly ( p less than 0.05 ) in the testosterone group as compared to the placebo group . We conclude that oral testosterone treatment has no beneficial effect on survival and liver biochemistry in men with alcoholic cirrhosis , and adverse effects can not be excluded Objective To explore why reports that seem to describe r and omised controlled trials are sometimes not indexed ( “ tagged ” ) with RCT ( r and omised controlled trial ) [ pt ] ( publication type ) in Medline . Design Cross sectional study . Setting The Cochrane Collaboration and US National Library of Medicine worked together to identify and retag records of r and omised controlled trials with RCT [ pt ] , 1994 to 2006 . Data source Published reports entered into Medline in 2005 . Main outcome measures Type of trial information presented ( for example , main results , design , and methods ) , trial design , and other Medline indexing terms applied . Results 572/591 ( 97 % ) untagged records and 578/594 ( 97 % ) tagged records contained information from r and omised controlled trials . Type of trial information and design differed between untagged and tagged reports . Fewer than half ( 234/572 , 41 % , 95 % confidence interval 37 % to 45 % ) of untagged reports but most tagged reports ( 526/578 , 91 % , 89 % to 93 % ) described the main results of the trial . Untagged reports were more likely than tagged reports to contain information on design and methods , baseline characteristics , long term follow-up , and secondary analyses . Untagged reports of main results were more likely than tagged reports to be from trials using a crossover design ( 36 % v 10 % , difference 25 % , 95 % confidence interval 19 % to 32 % ) . The Medical Subject Heading “ R and omized Controlled Trials ” was the most common clinical trial term applied to untagged reports , although more than half of untagged reports had no indexing related to trials . Conclusion Based on the results for 2005 , at least 3000 records describing r and omised controlled trials but not indexed using RCT [ pt ] may have been entered into Medline between 2006 and 2011 . Research ers and healthcare decision makers relying on using RCT [ pt ] may be missing important evidence in their search es , particularly for design and methods , baseline characteristics , long term follow-up , and secondary data analyses BACKGROUND Dehydroepi and rosterone ( DHEA ) and testosterone are widely promoted as antiaging supplements , but the long-term benefits , as compared with potential harm , are unknown . METHODS We performed a 2-year , placebo-controlled , r and omized , double-blind study involving 87 elderly men with low levels of the sulfated form of DHEA and bioavailable testosterone and 57 elderly women with low levels of sulfated DHEA . Among the men , 29 received DHEA , 27 received testosterone , and 31 received placebo . Among the women , 27 received DHEA and 30 received placebo . Outcome measures included physical performance , body composition , bone mineral density ( BMD ) , glucose tolerance , and quality of life . RESULTS As compared with the change from baseline to 24 months in the placebo group , subjects who received DHEA for 2 years had an increase in plasma levels of sulfated DHEA by a median of 3.4 microg per milliliter ( 9.2 micromol per liter ) in men and by 3.8 microg per milliliter ( 10.3 micromol per liter ) in women . Among men who received testosterone , the level of bioavailable testosterone increased by a median of 30.4 ng per deciliter ( 1.1 nmol per liter ) , as compared with the change in the placebo group . A separate analysis of men and women showed no significant effect of DHEA on body-composition measurements . Neither hormone altered the peak volume of oxygen consumed per minute , muscle strength , or insulin sensitivity . Men who received testosterone had a slight increase in fat-free mass , and men in both treatment groups had an increase in BMD at the femoral neck . Women who received DHEA had an increase in BMD at the ultradistal radius . Neither treatment improved the quality of life or had major adverse effects . CONCLUSIONS Neither DHEA nor low-dose testosterone replacement in elderly people has physiologically relevant beneficial effects on body composition , physical performance , insulin sensitivity , or quality of life . ( Clinical Trials.gov number , NCT00254371 [ Clinical Trials.gov ] . ) The efficacy and safety of and rogen supplementation in older men remains controversial . Despite biochemical evidence of partial and rogen deficiency in older men , controlled studies using T demonstrate equivocal benefits . Furthermore , the importance of aromatization and 5alpha reduction in and rogen actions among older men remains unclear . Dihydrotestosterone is the highest potency natural and rogen with the additional features that it is neither aromatizable nor susceptible to potency amplification by 5alpha reduction . Therefore , the effects of dihydrotestosterone may differ from those of T in older men . This study evaluated the efficacy and safety of 3 months treatment with transdermal dihydrotestosterone gel on muscle strength , mobility , and quality of life in ambulant , community-dwelling men aged 60 yr or older . Eligible men ( plasma T < or = 15 nmol/liter ) were r and omized to undergo daily dermal application of 70 mg dihydrotestosterone gel ( n = 18 ) or vehicle ( n = 19 ) and were studied before , monthly during , and 1 month after treatment . Among 33 ( 17 dihydrotestosterone , 16 placebo ) men completing the study with a high degree of compliance , dihydrotestosterone had significant effects on circulating hormones ( increased dihydrotestosterone ; decreased total and free testosterone , LH , and FSH ; unchanged SHBG and estradiol ) , lipid profiles ( decreased total and low-density lipoprotein cholesterols ; unchanged high-density lipoprotein cholesterol and triglycerides ) , hematopoiesis ( increased hemoglobin , hematocrit , and red cell counts ) , and body composition ( decreased skinfold thickness and fat mass ; unchanged lean mass and waist to hip ratio ) . Muscle strength measured by isokinetic peak torque was increased in flexion of the dominant knee but not in knee extension or shoulder contraction , nor was there any significant change in gait , balance , or mobility tests , in cognitive function , or in quality of life scales .  Dihydrotestosterone treatment had no adverse effects on prostate ( unchanged prostate volumes and prostate-specific antigen ) and cardiovascular ( no adverse change in vascular reactivity or lipids ) safety markers . We conclude that 3 months treatment with transdermal dihydrotestosterone gel demonstrates expected and rogenic effects , short-term safety , and limited improvement in lower limb muscle strength but no change in physical functioning or cognitive function OBJECTIVES This study investigated the effect of a 12-week long-acting testosterone administration on maximal exercise capacity , ventilatory efficiency , muscle strength , insulin resistance , and baroreflex sensitivity ( BRS ) in elderly patients with chronic heart failure ( CHF ) . BACKGROUND CHF is characterized by a metabolic shift favoring catabolism and impairment in skeletal muscle bulk and function that could be involved in the pathophysiology of heart failure . METHODS Seventy elderly patients with stable CHF-median age 70 years , ejection fraction 31.8 + /- 7%-were r and omly assigned to receive testosterone ( n = 35 , intramuscular injection every 6 weeks ) or placebo ( n = 35 ) , both on top of optimal medical therapy . At baseline and at the end of the study , all patients underwent echocardiogram , cardiopulmonary exercise test , 6-min walk test ( 6MWT ) , quadriceps maximal voluntary contraction ( MVC ) , and isokinetic strength ( peak torque ) and BRS assessment ( sequences technique ) . RESULTS Baseline peak oxygen consumption ( VO(2 ) ) and quadriceps isometric strength showed a direct relation with serum testosterone concentration . Peak VO(2 ) significantly improved in testosterone but was unchanged in placebo .  Insulin sensitivity was significantly improved in testosterone . The MVC and peak torque significantly increased in testosterone but not in placebo . The BRS significantly improved in testosterone but not in placebo . Increase in testosterone levels was significantly related to improvement in peak VO(2 ) and MVC . There were no significant changes in left ventricular function either in testosterone or placebo . CONCLUSIONS These results suggest that long-acting testosterone therapy improves exercise capacity , muscle strength , glucose metabolism , and BRS in men with moderately severe CHF .  Testosterone benefits seem to be mediated by metabolic and peripheral effects OBJECTIVES To investigate the effects of testosterone supplementation on bone , body composition , muscle , physical function , and safety in older men . DESIGN Double-blind , r and omized , placebo-controlled trial . SETTING A major medical institution . PARTICIPANTS One hundred thirty-one men ( mean age 77.1 + /- 7.6 ) with low testosterone , history of fracture , or bone mineral density ( BMD ) T-score less than -2.0 and frailty . INTERVENTION Participants received 5 mg/d of testosterone or placebo for 12 to 24 months ; all received calcium ( 1500 mg/d diet and supplement ) and cholecalciferol ( 1,000 IU/d ) . MEASUREMENTS BMD of hip , lumbar spine , and mid-radius ; body composition ; sex hormones , calcium-regulating hormones ; bone turnover markers ; strength ; physical performance ; and safety parameters . RESULTS Ninety-nine men ( 75.6 % ) completed 12 months , and 62 ( 47.3 % ) completed end therapy ( mean 23 months ; range 16 - 24 months for 62 who completed therapy ) . Study adherence was 54 % , with 40 % of subjects maintaining 70 % or greater adherence . Testosterone and bioavailable testosterone levels at 12 months were 583 ng/dL and 157 ng/dL , respectively , in the treatment group . BMD on testosterone  increased 1.4 % at the femoral neck and 3.2 % at the lumbar spine ( P=.005 ) and decreased 1.3 % at the mid-radius ( P<.001 ) . There was an increase in lean mass and a decrease in fat mass in the testosterone group but no differences in strength or physical performance . There were no differences in safety parameters . CONCLUSION Older , frail men receiving  testosterone replacement increased testosterone levels and had favorable changes in body composition , modest changes in axial BMD , and no substantial changes in physical function OBJECTIVE To investigate the effects of oral testosterone undecanoate ( TU ) on symptoms associated with late-onset hypogonadism ( LOH ) . Design Multicenter , r and omized , double-blind , placebo-controlled . METHODS The study was performed in 14 study centers in seven European countries . Men > or = 50 years ( n=322 ) with symptoms of hypogonadism and testosterone deficiency ( calculated free testosterone < 0.26 nmol/l ) were r and omized and treated for 12 months with placebo or oral TU 80 , 160 or 240 mg/day . Primary outcome was the total score on the Aging Males ' Symptoms ( AMS ) rating scale after six months of treatment . RESULTS Treatment of mild-to-moderate LOH symptoms in subjects with borderline hypogonadism with oral TU result ed in an improved total AMS score at month 6 , but differences between groups were not statistically significant . There was greater improvement in subjects < 60 years when compared with subjects > or = 60 years ( P=0.001 ) , but baseline testosterone level had no influence on treatment response . The AMS sexual symptoms domain improved with oral TU 160 mg/day at months 6 ( P=0.008 ) and 12 ( P=0.012 ) compared with placebo , but not with 80 and 240 mg/day . Treatment was well-tolerated and there were no between-group differences in adverse events or drop-out rates . CONCLUSIONS In one of the largest placebo-controlled studies of testosterone therapy in LOH , oral TU did not improve total AMS score in subjects with mild-to-moderate symptoms compared with placebo , except the sexual symptom sub-domain where a modest improvement was reported with oral TU 160 mg/day 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 R and omized , double-blind , parallel , placebo-controlled trial . ( Clinical Trials.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 r and omly 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 r and omization 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
target: Conclusions 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 implication s for the use of testosterone therapy
background: Background Testosterone therapy is increasingly promoted .
  No r and omized placebo-controlled trial has been implemented to assess the effect of testosterone therapy on cardiovascular events , although very high levels of and rogens are thought to promote cardiovascular disease .