title: 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. Substitution therapy of hypogonadal men with transdermal testosterone over one year. Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. The effects of injected testosterone dose and age on the conversion of testosterone to estradiol and dihydrotestosterone in young and older men. Osteoporosis in Male Hypogonadism: Responses to Androgen Substitution Differ among Men with Primary and Secondary Hypogonadism Strength Training and Testosterone Treatment Have Opposing Effects on Migration Inhibitor Factor Levels in Ageing Men Effects of testosterone and progressive resistance exercise in healthy, highly functioning older men with low-normal testosterone levels. Efficacy and safety study of 1.62% testosterone gel for the treatment of hypogonadal men. Low-Dose Transdermal Testosterone Therapy Improves Angina Threshold in Men With Chronic Stable Angina: A Randomized, Double-Blind, Placebo-Controlled Study Cognitive changes associated with supplementation of testosterone or dihydrotestosterone in mildly hypogonadal men: a preliminary report. A randomized trial of testosterone therapy in males with rheumatoid arthritis. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. Adverse events associated with testosterone administration. Testosterone administration to older men improves muscle function: molecular and physiological mechanisms. 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. Pharmacokinetics and safety of long-acting testosterone undecanoate injections in hypogonadal men: an 84-week phase III clinical trial. Efficacy and safety of the 2% formulation of testosterone topical solution applied to the axillae in androgen‐deficient men Double-blind placebo-controlled study of testosterone patch therapy on bone turnover in men with borderline hypogonadism. Effects of testosterone on behavior, depression, and cognitive function in older men with mild cognitive loss. Effect of chronic oral testosterone undecanoate administration on the pituitary-testicular axes of hemodialyzed male patients. Transdermal androgen therapy to augment EPO in the treatment of anemia of chronic renal disease. Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. Testosterone with dutasteride, but not anastrazole, improves insulin sensitivity in young obese men: a randomized controlled trial. Efficacy and safety of a new testosterone-in-adhesive matrix patch applied every 2 days for 1 year to hypogonadal men Decline of plasma 5α‐dihydrotestosterone (DHT) levels upon testosterone administration to elderly men with subnormal plasma testosterone and high DHT levels Dutasteride reduces prostate size and prostate specific antigen in older hypogonadal men with benign prostatic hyperplasia undergoing testosterone replacement therapy. Long‐term efficacy and safety of a permeation‐enhanced testosterone transdermal system in hypogonadal men Testosterone treatment and mortality in men with low testosterone levels. 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. Pharmacokinetics of transdermal testosterone gel in hypogonadal men: application of gel at one site versus four sites: a General Clinical Research Center Study. Effect of transdermal testosterone treatment on serum lipid and apolipoprotein levels in men more than 65 years of age. Transdermal testosterone gel increases serum testosterone levels in hypogonadal men in Taiwan with improvements in sexual function Testosterone treatment of men with alcoholic cirrhosis: a double-blind study. The Copenhagen Study Group for Liver Diseases. Long-term pharmacokinetics of transdermal testosterone gel in hypogonadal men. DHEA in elderly women and DHEA or testosterone in elderly men. Testosterone therapy during exercise rehabilitation in male patients with chronic heart failure who have low testosterone status: a double-blind randomized controlled feasibility study. Invalidation of a commercially available human 5α-dihydrotestosterone immunoassay 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. A randomized pilot study of monthly cycled testosterone replacement or continuous testosterone replacement versus placebo in older men. 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: 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 Current testosterone substitution therapy either by injectable or oral testosterone esters suffers from markedly fluctuating serum testosterone levels often far above or below the physiological range . Recently , a transdermal therapeutic system ( TTS ) for the delivery of testosterone was developed which , when applied to the scrotum , provides smooth serum testosterone levels . Here we report results from seven hypogonadal men treated with the TTS for 14 months by applying a new patch every day . In all patients serum testosterone and dihydrotestosterone ( DHT ) determined 3 - 5 h after applying a new patch increased significantly and remained within the physiological range during the entire treatment period . The DHT/testosterone ratio remained constant . In 4 of these patients and 2 others under TTS treatment serum testosterone and DHT were also determined over a 24-h period at regular intervals . In these patients serum testosterone levels in the physiological range were seen during the entire observation period , whereas an increase in the DHT/testosterone ratio occurred towards the end of the one-day treatment phase . All patients in the 14-month treatment study were clinical ly well substituted and responded with good compliance . Clinical chemistry showed no abnormalities during treatment . Thus , the TTS appears to be an effective and safe new modality for the treatment of male hypogonadism 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 BACKGROUND During testosterone ( T ) therapy , T is partly converted to 17beta-estradiol ( E2 ) and 5alpha-dihydrotestosterone ( DHT ) . Effects of age , testosterone dose , and body composition on total and free E2 and DHT levels are unknown . OBJECTIVE We evaluated age and dose-related differences in E2 and DHT levels in response to grade d doses of testosterone enanthate in young and older men . METHODS Fifty-one young ( aged 19 - 35 yr ) and 52 older ( aged 59 - 75 yr ) men completed treatment with monthly injections of a GnRH agonist plus r and omly assigned weekly doses of testosterone enanthate ( 25 , 50 , 125 , 300 , or 600 mg ) for 5 months . RESULTS During testosterone administration , total and free E2 levels increased dose-dependently ( dose effect , P<0.001 ) in both young and older men . Total and free E2 levels and E2:T ratios during T administration were higher in older than young men , but age-related differences in free E2 and free E2:T ratios were not significant after adjusting for testosterone levels , percentage fat mass , and SHBG . DHT levels and DHT : T ratios were dose-related but did not differ between young and older men . Mechanistic modeling of free hormone data revealed that the conversions of T to E2 and DHT were both consistent with saturable Michaelis-Menten kinetics . The in vivo Km values were estimated to be 1.83 nm for aromatase and 3.35 nm for 5alpha-reductase , independent of age . The Vmax parameter for E2 was 40 % higher in older men than younger men , but Vmax for DHT was not significantly different between age groups . CONCLUSIONS During i m testosterone administration , E2 and DHT levels exhibit saturable increases with dose . The rate of whole body aromatization is higher in older men , partly related to their higher percentage fat mass , SHBG , and testosterone levels Background : No r and omized study exists comparing the effects of different modes of and rogen substitution on bone mineral density ( BMD ) . Methods : We performed a prospect i ve , r and omized , trial assigning 53 hypogonadal men to the following treatment groups : mesterolone 100 mg p.o . daily , testosterone undecanoate 160 mg p.o . daily , testosterone enanthate 250 mg i.m . every 21 days , or a single subcutaneous implantation of 1,200 mg crystalline testosterone .  The BMD was determined by peripheral quantitative computed tomography . Results : At baseline , men with secondary hypogonadism ( n = 33 ) had a lower BMD ( –1.52 ± 0.23 SDS ; Z-scores ) than men with primary hypogonadism ( n = 20 , –0.87 ± 0.23 SDS , p < 0.01 ) . In men with primary hypogonadism , the BMD increased dose dependently ( crystalline testosterone + 7.0 ± 1.3 % , testosterone enanthate + 4.8 ± 0.2 % , testosterone undecanoate + 3.4 ± 2.5 % , mesterolone + 0.8 ± 1.6 % ) after 6 months of therapy . Only secondary hypogonadal men treated with testosterone enanthate experienced an increase of the BMD . Conclusions : In primary hypogonadal men the BMD responds dose dependently to testosterone substitution , whereas in secondary hypogonadism only testosterone enanthate treatment significantly increased the BMD Background . The beneficial effects of testosterone treatment ( TT ) are debated . Methods . Double-blinded , placebo-controlled study of six months TT ( gel ) in 54 men aged 60–78 with bioavailable testosterone ( BioT ) < 7.3 nmol/L and waist > 94 cm r and omized to TT ( 50–100 mg/day , n = 20 ) , placebo ( n = 18 ) , or strength training ( ST ) ( n = 16 ) for 24 weeks . Moreover , the ST group was r and omized to TT ( n = 7 ) or placebo ( n = 9 ) after 12 weeks . Outcomes . Chemokines ( MIF , MCP-1 , and MIP-1α ) and lean body mass ( LBM ) , total , central , extremity , visceral , and subcutaneous ( SAT ) fat mass established by DXA and MRI . Results . From 0 to 24 weeks , MIF and SAT decreased during ST + placebo versus placebo , whereas BioT and LBM were unchanged . TT decreased fat mass ( total , central , extremity , and SAT ) and increased BioT and LBM versus placebo . MIF levels increased during TT versus ST + placebo . ST + TT decreased fat mass ( total , central , and extremity ) and increased BioT and LBM versus placebo . From 12 to 24 weeks , MCP-1 levels increased during TT versus placebo and MCP-1 levels decreased during ST + placebo versus placebo . Conclusion . ST + placebo was associated with decreased MIF levels suggesting decreased inflammatory activity . TT may be associated with increased inflammatory activity . This trial is registered with Clinical Trials.gov NCT00700024 CONTEXT Aging in men is associated with reduced testosterone ( T ) levels and physiological changes leading to frailty , but the benefits of T supplementation are inconclusive . OBJECTIVE We studied the effects of T supplementation with and without progressive resistance training ( PRT ) on functional performance , strength , and body composition . DESIGN , SETTING , AND PARTICIPANTS We recruited 167 generally healthy community-dwelling older men ( 66 ± 5 years ) with low-normal baseline total T levels ( 200 - 350 ng/dL ) . INTERVENTION Subjects were r and omized to placebo or transdermal T gel [ 2 doses targeting either a lower ( 400 - 550 ng/dL ) or higher ( 600 - 1000 ng/dL ) T range ] and to either PRT or no exercise for 12 months . MAIN OUTCOME MEASURE The primary outcome was functional performance , whereas secondary outcomes were strength and body composition . RESULTS A total of 143 men completed the study . At 12 months , total T was 528 ± 287 ng/dL in subjects receiving any T and 287 ± 65 ng/dL in the placebo group . In the PRT group , function and strength were not different between T- and placebo-treated subjects , despite greater improvements in fat mass ( P = .04 ) and fat-free mass ( P = .01 ) with T. In the non-PRT group , T did not improve function but improved fat mass ( P = .005 ) , fat-free mass ( P = .03 ) , and upper body strength ( P = .03 ) compared with placebo . There were fewer cardiovascular events in the T-treated groups compared with placebo . CONCLUSIONS T supplementation was well tolerated and improved body composition but had no effect on functional performance . T supplementation improved upper body strength only in nonexercisers compared with placebo 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 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 This study prospect ively examined changes in cognition in hypogonadal men given testosterone ( T ) or older hypogonadal men given dihydrotestosterone ( DHT ) gel .  A battery of cognitive tests assessing verbal and spatial memory , language , and attention was administered at baseline ( prior to medication ) and again at days 90 and 180 of treatment for men receiving T gel and at baseline and days 30 and 90 of treatment for men receiving DHT gel . For men receiving T gel , circulating total T and estradiol ( E(2 ) ) were significantly raised compared with baseline , and a significant improvement in verbal memory was observed . For men receiving DHT gel , serum DHT levels increased and T levels decreased significantly compared with baseline , and a significant improvement in spatial memory was observed . The results suggest that beneficial changes in cognition can occur in hypogonadal men using T replacement levels and DHT treatment , and these changes in cognition can be reliably measured during a relative steady-state dose level . Further , our results suggest that aromatization of T to E(2 ) may regulate verbal memory in men , whereas nonaromatizable and rogens may regulate spatial memory 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 IMPORTANCE Rates of testosterone therapy are increasing and the effects of testosterone therapy on cardiovascular outcomes and mortality are unknown . A recent r and omized clinical trial of testosterone therapy in men with a high prevalence of cardiovascular diseases was stopped prematurely due to adverse cardiovascular events raising concerns about testosterone therapy safety . OBJECTIVES To assess the association between testosterone therapy and all-cause mortality , myocardial infa rct ion ( MI ) , or stroke among male veterans and to determine whether this association is modified by underlying coronary artery disease . DESIGN , SETTING , AND PATIENTS A retrospective national cohort study of men with low testosterone levels ( < 300 ng/dL ) who underwent coronary angiography in the Veterans Affairs ( VA ) system between 2005 and 2011 . MAIN OUTCOMES AND MEASURES Primary outcome was a composite of all-cause mortality , MI , and ischemic stroke . RESULTS Of the 8709 men with a total testosterone level lower than 300 ng/dL , 1223 patients started testosterone therapy after a median of 531 days following coronary angiography . Of the 1710 outcome events , 748 men died , 443 had MIs , and 519 had strokes . Of 7486 patients not receiving testosterone therapy  , 681 died , 420 had MIs , and 486 had strokes . Among 1223 patients receiving testosterone therapy , 67 died , 23 had MIs , and 33 had strokes . At 3 years after coronary angiography , the Kaplan-Meier estimated cumulative percentages with events were 19.9%in the no testosterone therapy group vs 25.7%in the testosterone therapy group , with an absolute risk difference of 5.8%(95%CI , -1.4%to 13.1 % ) [corrected].The Kaplan-Meier estimated cumulative percentages with events among the no testosterone therapy group vs testosterone therapy group at 1 year after coronary angiography were 10.1 % vs 11.3 % ; at 2 years , 15.4 % vs 18.5 % ; and at 3 years , 19.9 % vs 25.7 [corrected].There was no significant difference in the effect size of testosterone therapy among those with and without coronary artery disease ( test for interaction , P = .41 ) . CONCLUSIONS AND RELEVANCE Among a cohort of men in the VA health care system who underwent coronary angiography and had a low serum testosterone level , the use of testosterone therapy was associated with increased risk of adverse outcomes . These findings may inform the discussion about the potential risks of testosterone therapy 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 . We investigated the effects of 6 mo of near-physiological testosterone administration  to older men on skeletal muscle function and muscle protein metabolism .  Twelve older men ( > or = 60 yr ) with serum total testosterone concentrations < 17 nmol/l ( 480 ng/dl ) were r and omly assigned in double-blind manner to receive either placebo ( n = 5 ) or testosterone enanthate ( TE ; n = 7 ) injections . Weekly intramuscular injections were given for the 1st mo to establish increased blood testosterone concentrations at 1 mo and then changed to biweekly injections until the 6-mo time point . TE doses were adjusted to maintain nadir serum testosterone concentrations between 17 and 28 nmol/l . Lean body mass ( LBM ) , muscle volume , prostate size , and urinary flow were measured at baseline and at 6 mo . Protein expression of and rogen receptor ( AR ) and insulin-like growth factor I , along with muscle strength and muscle protein metabolism , were measured at baseline and at 1 and 6 mo of treatment . Hematological parameters were followed monthly throughout the study . Older men receiving  testosterone increased total and leg LBM , muscle volume , and leg and arm muscle strength after 6 mo . LBM accretion result ed from an increase in muscle protein net balance , due to a decrease in muscle protein breakdown . TE treatment increased expression of AR protein at 1 mo , but expression returned to pre-TE treatment levels by 6 mo . IGF-I protein expression increased at 1 mo and remained increased throughout TE administration . We conclude that physiological and near-physiological increases of testosterone in older men will increase muscle protein anabolism and muscle strength 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 Currently available testosterone ( T ) injections in the United States are administered at 2 - 3 weekly intervals . Less frequent injections with favorable serum T pharmacokinetics would benefit hypogonadal men . The objective of this study is to assess the pharmacokinetics of long-acting testosterone undecanoate ( TU ) intramuscular ( IM ) injection in hypogonadal men . An unblinded , multicenter phase 3 clinical trial was conducted in 31 academic centers and contract research organizations . Males ( 130 ) more than 18 years of age with serum total T < 300 ng/dL were enrolled and received 750-mg injections of TU at weeks 0 and 4 and every 10 weeks thereafter for 9 injections over 84 weeks . The main outcome variables were serum total T , free T , dihydrotestosterone ( DHT ) , estradiol ( E(2 ) ) levels , and safety parameters . After the first injection , patients maintained average trough T concentrations in the adult male range ( 300 - 1000 ng/dL or 10.4 - 34.7 nmol/L ) before each injection and at multiple time points measured after the third and fourth injections . Serum free T , DHT , and E(2 ) levels and their ratios to serum T remained relatively consistent once steady state was attained . TU injections were generally well tolerated , with safety profiles similar to other T replacement . We conclude that hypogonadal patients treated for 84 weeks with a 750-mg IM injection of TU every 10 weeks demonstrated average concentrations of T , its metabolites ( DHT and E(2 ) ) , and ratios -- DHT : T and E(2):T -- within the adult male reference range at all time points measured . TU injections would be an acceptable alternative to the currently available 2 - 3 weekly injectables Objectives Testosterone replacement therapy in hypogonadal men relieves symptoms and restores serum testosterone levels to the physiological range . In this study , we assessed the safety , pharmacokinetics , and efficacy of the 2 % formulation of testosterone topical solution applied daily to the axillae 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 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 Testosterone undecanoate ( TU ) or placebo was administered orally ( for 12 weeks ) in a double blind study , to 19 patients with chronic renal insufficiency on hemodialysis in a daily dose of 240 mg . Effect on plasma testosterone ( T ) , dihydrotestosterone ( DHT ) , and rostenedione ( A ) , 110H and rostenedione ( 110A ) , FSH , LH and PRL concentration and the pituitary responsiveness to LH-RH/TRH stimulation was studied . These hormone levels were determined before the study and after 6 and 12 weeks of treatment . There was a rise in plasma and rogen concentration in all treated patients . Mean plasma DHT , A and 110A increased at 12 weeks from 0.3 , 0.85 and 1.13 ng/ml to 1.13 ( p less than 0.05 ) , 1.4 ( p less than 0.05 ) and 1.44 ( p less than 0.05 ) respectively . There was no change in plasma T or free testosterone . However , basal LH , FSH fell progressively from 5.51 and 5.51 ng/ml to 2.13 and 1.84 ng/ml ( p less than 0.05 ) . The level of significance of these changes was confirmed when the response to LH-RH was considered . Basal plasma PRL also decreased from 376 microU/nl to 306 ( p less than 0.05 ) , but PRL response to TRH remained unchanged . In contrast , none of these modifications were observed in placebo-treated patients . We conclude that oral TU restored to normal the pituitary-testicular axis . This form of treatment should be preferentially chosen instead of intramuscular injections in these frequently heparinized patients on hemodialysis 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 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 INTRODUCTION Testosterone ( T ) administration to men increases T , estradiol ( E2 ) , dihydrotestosterone ( DHT ) , and fat-free mass ( FFM ) , and decreases fat mass ( FM ) but does not consistently improve insulin sensitivity ( IS ) . AIM The aim of this study was to examine the effects of T administration in obese , nondiabetic men on body composition and IS , and to determine if inhibition ( i ) of metabolism of T to E2 with anastrazole or to DHT with dutasteride alters these effects . METHODS This was a 98-day r and omized , double-blind , parallel group , placebo-controlled trial of 57 men , 24 - 51 year , free T in the lower 25 % of normal range ( < 0.33 nmol/L ) , body mass index ≥ 30.0 kg/m(2 ) . Subjects were r and omized to one of four groups : ( i ) placebo : gel , pills , and injection ; ( ii ) T/DHT/iE2 : T gel , anastrazole , and acyline ( gonadotropin releasing-hormone antagonist to suppress endogenous T ) ; ( iii ) T/iDHT/E2 : T gel , dutasteride , and acyline ; ( iv ) T/DHT/E2 : T gel , placebo pills , and acyline . MAIN OUTCOME MEASURES Main outcome measures are insulin sensitivity as percent change ( % Δ ) in glucose disposal rates ( GDR ) from a two-step euglycemic clamp ( GDR1 and 2 ) , and % FM and % FFM by dual X-ray absorptiometry scan . RESULTS Insulin Sensitivity : % Δ GDR1 differed across groups ( P = 0.02 , anova ) and was significantly higher in the dutasteride ( T/iDHT/E2 ) compared with the placebo and T gel ( T/DHT/E2 ) groups . % ΔGDR2 was higher in the dutasteride ( T/iDHT/E2 ) compared with the anastrazole ( T/DHT/iE2 ) group . Body Composition : T gel alone ( T/DHT/E2 ) or with dutasteride ( T/iDHT/E2 ) significantly increased % FFM ( P < 0.05 ) and decreased % FM ( P < 0.05 ) . There was no change in % FFM or % FM  after placebo or anastrazole ( T/DHT/iE2 ) . CONCLUSIONS The combination of T plus dutasteride improved body composition and IS while T alone improved body composition but not IS , suggesting that when T is administered to men , reduction to DHT attenuates the beneficial effects of aromatization to E2 on IS but not body composition OBJECTIVES To study long-term efficacy and safety of a testosterone-in-adhesive matrix patch , delivering 4.8 mg of testosterone daily . METHODS R and omized , open label , multicenter 1-year study . 224 hypogonadal patients were included . 188 received 2 patches  of 60 cm2 every 48 h and 36 patients had IM testosterone enanthate injection every 3 weeks . T , bioavailable T ( BT ) , DHT , E2 , LH , FSH and SHBG and clinical symptom scores ( AMS and MSF-4 ) were assessed at 3 , 6 and 12 months . RESULTS In the patch group , T serum levels were above 3 ng/mL in 85 % of patients and remained stable over time . BT , DHT and E2 levels were restored within physiological range . BT/T ratio varied from 20 to 70 % . In the IM group , the percentages of " normalized " patients appeared to be lower , although the two groups can not be adequately compared due to the kinetic profile of T following IM administration , result ing in greater variations of serum T levels , blood samplings occurring r and omly at time of peak , trough , or in between . A significant correlation was found between T , BT and the MSF-4 changes . BT levels were significantly related to total AMS score . PSA values showed a mean ( S.D. ) increase of 0.13 ( 0.38 ) , 0.23 ( 0.79 ) and 0.30 (1.47)ng/mL at weeks 14 , 27 and 53 , respectively . The patch was well tolerated with no negative impact either on lipid profile , or red blood cells . Administration site reactions occurred in 35 patients ( 18.8 % ) . Adhesiveness was good ( > or=75 % ) in > 90 % patients over the 1 year application period . CONCLUSION Two 60 cm2 patches , allowed constant physiological levels of sexual hormones over time . This new patch was well tolerated , easy to use , well accepted by the patients and displayed a very good adhesiveness . Clinical efficacy was more related to BT than to The study was performed to measure the impact of testosterone ( T ) administration on circulating levels of 5α‐dihydrotestosterone ( DHT ) .  Group 1 ( 32 men ; mean age 61 years ; mean T 6.9 ± 1.9 nmol l−1 ) were treated for 15 months with long‐acting T undecanoate .  Group 2 ( 23 men , mean age 60 years , mean T 7.6 ± 2.0 nmol l−1 ) were treated for 9 months with T gel  . Plasma T and DHT were measured before and after 9 months T administration . In the men treated with T undecanoate  plasma T and DHT were also measured after 12 and 15 months . Before T administration , plasma DHT ranged from 0.39 to 1.76 nmol l−1 ( 0.30–1.90 nmol l−1 ) . Mean DHT declined upon T administration from 0.95 ± 0.50 to 0.55 ± 0.30 nmol l−1 ( P < 0.05 ) . With an arbitrary cut‐off at 0.60 nmol l−1 , all 21 values of DHT > 0.60 nmol l−1 had fallen from 1.29 ± 0.50 to 0.70 ± 0.60 nmol l−1 ( P < 0.01 ) . Below this cut‐off point 13 values rose and 21 fell upon T administration . Below this cut‐off point values on average declined from 0.39 ± 0.12 to 0.30 ± 0.14 nmol l−1 ( P < 0.05 ) . The study revealed that in a cohort  of elderly men with subnormal plasma T levels plasma DHT levels declined upon T administration when they were in the higher range of normal ( > 0.6 nmol l−1 ) , with a profound shift of DHT/T ratios presumed to be an indicator of a reduced 5α‐reductase activity . Below plasma DHT levels of 0.6 nmol l−1 , responses of plasma DHT to T administration varied PURPOSE Benign prostatic hyperplasia and hypogonadism are common disorders in aging men . There is concern that and rogen replacement in older men may increase prostate size and symptoms of benign prostatic hyperplasia . We examined whether combining dutasteride , which inhibits testosterone to dihydrotestosterone conversion , with testosterone treatment in older hypogonadal men with benign prostatic hyperplasia reduces and rogenic stimulation of the prostate compared to testosterone alone . MATERIAL S AND METHODS We conducted a double-blind , placebo controlled trial of 53 men 51 to 82 years old with symptomatic benign prostatic hyperplasia , prostate volume 30 cc or greater and serum total testosterone less than 280 ng/dl ( less than 9.7 nmol/l ) . Subjects were r and omized to daily transdermal 1 % T gel plus oral placebo or dutasteride for 6 months . Testosterone dosing was adjusted to a serum testosterone of 500 to 1,000 ng/dl . The primary outcomes were prostate volume measured by magnetic resonance imaging , serum prostate specific antigen and and rogen levels . RESULTS A total of 46 subjects completed all procedures . Serum testosterone increased similarly into the mid-normal range in both groups . Serum dihydrotestosterone increased in the testosterone only but decreased in the testosterone plus dutasteride group . In the testosterone plus dutasteride  group prostate volume and prostate specific antigen ( mean ± SEM ) decreased 12 % ± 2.5 % and 35 % ± 5 % , respectively , compared to the testosterone only group in which prostate volume and prostate specific antigen increased 7.5 % ± 3.3 % and 19 % ± 7 % ( p = 0.03 and p = 0.008 ) , respectively , after 6 months of treatment . Prostate symptom scores improved in both groups . CONCLUSIONS Combined treatment with testosterone plus dutasteride reduces prostate volume and prostate specific antigen compared to testosterone only . Coadministration of a 5α-reductase inhibitor with testosterone appears to spare the prostate from and rogenic stimulation during testosterone replacement in older , hypogonadal men with symptomatic benign prostatic hyperplasia An important aim in treating male hypogonadism is restoration of physiological concentrations of testosterone and its metabolites . We have assessed hormone levels , pharmacokinetics and clinical response , including safety , of a permeation‐enhanced testosterone transdermal system ( TTD ) in the treatment of hypogonadal men for a 12‐month period CONTEXT Low testosterone levels in men have been associated with increased mortality . However , the influence of testosterone treatment on mortality in men with low testosterone levels is not known . OBJECTIVE The objective of the study was to examine the association between testosterone treatment and mortality in men with low testosterone levels . DESIGN This was an observational study of mortality in testosterone-treated compared with untreated men , assessed with time-varying , adjusted Cox proportional hazards regression models . Effect modification by age , diabetes , and coronary heart disease was tested a priori . SETTING The study was conducted with a clinical data base that included seven Northwest Veterans Affairs medical centers . PATIENTS Patients included a cohort of 1031 male veterans , aged older than 40 yr , with low total testosterone [ ≤250 ng/dl ( 8.7 nmol/liter ) ] and no history of prostate cancer , assessed between January 2001 and December 2002 and followed up through the end of 2005 . MAIN OUTCOME MEASURE Total mortality in testosterone-treated compared with untreated men was measured . RESULTS Testosterone treatment was initiated in 398 men ( 39 % ) during routine clinical care . The mortality in testosterone-treated men was 10.3 % compared with 20.7 % in untreated men ( P<0.0001 ) with a mortality rate of 3.4 deaths per 100 person-years for testosterone-treated men and 5.7 deaths per 100 person-years in men not treated with testosterone . After multivariable adjustment including age , body mass index , testosterone level , medical morbidity , diabetes , and coronary heart disease , testosterone treatment was associated with decreased risk of death ( hazard ratio 0.61 ; 95 % confidence interval 0.42 - 0.88 ; P = 0.008 ) . No significant effect modification was found by age , diabetes , or coronary heart disease . CONCLUSIONS In an observational cohort of men with low testosterone levels  , testosterone treatment was associated with decreased mortality  compared with no testosterone treatment . These results should be interpreted cautiously because residual confounding may still be a source of bias . Large , r and omized clinical trials are needed to better characterize the health effects of testosterone treatment in older men with low testosterone levels 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 Testosterone ( T ) in a hydroalcoholic gel has been developed as an effective and convenient open system for transdermal delivery of the hormone to men . Because the gel can be applied either to small or large areas of skin , it was important to assess whether the skin surface area on which the gel was applied was an important determinant of serum T levels . To answer this question , the pharmacokinetics of a transdermal 1 % hydroalcoholic gel preparation of T was studied in nine hypogonadal men . The subjects applied in r and om order a 25-mg metered dose of T gel either four times at one site ( left arm/shoulder ) or at four different sites ( left and right arms/shoulders and left and right abdomen ) once daily ( 6 - 8 min ) for 7 consecutive days . After 7 days of washout , each subject was then crossed over to the opposite regimen for another 7 days of treatment . Serum sample s were collected for measurements of T , 5alpha dihydrotestosterone ( DHT ) , and estradiol before , during ( days 1 , 2 , 3 , 5 , and 7 ) , and after ( days 8 , 9 , 11 , 13 , and 15 ) application of T gel . Multiple blood sample s were drawn on the 1st and 7th day after gel application ; single sample s were obtained just before the next T gel application on other days ( 24 h after the previous gel application ) . The T gel dried in less than 5 min , left no residue , and produced no skin irritation in any of the subjects . Mean serum T levels , irrespective of application at one site or four sites followed the same pattern : rising to 2- to 3- and 4- to 5-fold above baseline at 0.5 and 24 h after first application , respectively . Thereafter , serum T levels reached steady state and remained at 4- to 5-fold above baseline ( at the upper limit of the normal adult range ) for the duration of gel application and returned to baseline within 4 days after stopping application . The application of T gel at four sites ( application skin area approximately four times that of one site ) result ed in a mean area under the curve ( AUC0 - 24h ) for serum T levels on the 7th day ( 868 + /- 72 nmol*h/L , mean + /- SEM ) , which was 23 % higher but not significantly different ( P = 0.06 ) than repeated application at one site ( 706 + /- 59 nmol*h/L ) . This could be due to the limited number of subjects studied ( n = 9 ) .  Mean serum DHT levels followed the same pattern as serum T , achieving steady-state levels by 2 days . The mean concentration of serum DHT on the 7th day was significantly higher after application at four sites ( 9.15 + /- 1.26 nmol/L , P < 0.05 ) than at one site ( 6.9 + /- 0.77 nmol/L ) . These serum DHT levels were at or above the normal adult male range . Serum DHT : T ratio was not significantly altered by T gel application . Serum estradiol levels followed the same pattern as serum T and showed no significant difference between the one- or four-site application . We conclude that transdermal daily application of 100 mg T gel result ed in similar steady levels of serum T. The surface area of the skin to which the gel was applied had only a modest impact on serum T and DHT levels . Mean serum levels of T and DHT was higher by 23 % and 33 % , respectively , despite application of the gel to four times the skin area in the four sites compared with the one site group . Because of the greater dosage flexibility provided , hydroalcoholic T gel application over multiple sites seems to be an effective and nonskin-irritating method of transdermal T delivery for hypogonadal men . Dose-ranging studies are required to determine dosage regimens for T gel application as a replacement therapy in hypogonadal men 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 A r and omized , double-blind , placebo-controlled trial was conducted to ( 1 ) evaluate efficacy and safety of transdermal testosterone gel ( And roGel )  for hypogonadal men in Taiwan , and ( 2 ) observe improvements in sexual function through international index of erectile function ( IIEF ) scores . Eligible hypogonadal men were r and omized to receive 50 mg/day transdermal testosterone gel ( TTG ) or placebo for 3 months . Primary end point was change from baseline in total testosterone ( TT ) and free testosterone ( FT ) . Secondary end points were change from baseline in serum hormone levels ( such as dihydrotestosterone ( DHT ) , estradiol ( E2 ) , luteinizing hormone ( LH ) , follicle-stimulating hormone ( FSH ) and sex-hormone-binding globulin ( SHBG ) ) and changes in IIEF scores . Safety evaluations included adverse events ( AEs ) and skin irritation assessment . Compared with baseline , the  TTG  group ( n=20 ) had statistically significant increases in mean TT levels at month 1 ( P=0.024 ) and month 2 ( P=0.025 ) , but no significant changes at month 3 . TT levels in the placebo group ( n=18 ) showed no statistically significant change at any visit . Changes in FT levels paralleled changes in TT levels in both groups . TTG group IIEF scores were significantly increased at month 3 ( P=0.01 ) , compared with a decline in placebo scores . No drug-related AEs occurred in the TTG group ; the placebo group had 2 AEs ( mild skin rash ) . In conclusion , TTG effectively restores serum TT and FT levels to a normal physiological range for hypogonadal men in Taiwan and improves sexual function 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 Transdermal delivery of testosterone ( T ) represents an effective alternative to injectable and rogens . Transdermal T patches normalize serum T levels and reverse the symptoms of and rogen deficiency in hypogonadal men . However , the acceptance of the closed system T patches has been limited by skin irritation and /or lack of adherence . T gels have been proposed as delivery modes that minimize these problems . In this study we examined the pharmacokinetic profiles after 1 , 30 , 90 , and 180 days of daily application of 2 doses of T gel ( 50 and 100 mg T in 5 and 10 g gel , delivering 5 and 10 mg T/day , respectively ) and a permeation-enhanced T patch ( 2 patches delivering 5 mg T/day ) in 227 hypogonadal men . This new 1 % hydroalcoholic T gel formulation when applied to the upper arms , shoulders , and abdomen dried within a few minutes , and about 9 - 14 % of the T applied was bioavailable . After 90 days of T gel treatment , the dose was titrated up ( 50 mg to 75 mg ) or down ( 100 mg to 75 mg ) if the preapplication serum T levels were outside the normal adult male range . Serum T rose rapidly into the normal adult male range on day 1 with the first T gel or patch application . Our previous study showed that steady state T levels were achieved 48 - 72 h after first application of the gel . The pharmacokinetic parameters for serum total and free T were very similar on days 30 , 90 , and 180 in all treatment groups . After repeated daily application of the T formulations for 180 days , the average serum T level over the 24-h sampling period ( C(avg ) ) was highest in the 100 mg T gel group ( 1.4- and 1.9-fold higher than the C(avg ) in the 50 mg T gel and T patch groups , respectively ) . Mean serum steady state T levels remained stable over the 180 days of T gel application . Upward dose adjustment from T gel 50 to 75 mg/day did not significantly increase the C(avg ) , whereas downward dose adjustment from 100 to 75 mg/day reduced serum T levels to the normal range for most patients . Serum free T levels paralleled those of serum total T , and the percent free T was not changed with transdermal T preparations . The serum dihydrotestosterone C(avg ) rose 1.3-fold above baseline after T patch application , but was more significantly increased by 3.6- and 4.6-fold with T gel 50 and 100 mg/day , respectively , result ing in a small , but significant , increase in the serum dihydrotestosterone/T ratios in the two T gel groups . Serum estradiol rose , and serum LH and FSH levels were suppressed proportionately with serum T in all study groups ; serum sex hormone-binding globulin showed small decreases that were significant only in the 100 mg T gel group . We conclude that transdermal T gel application can efficiently and rapidly increase serum T and free T levels in hypogonadal men to within the normal range . Transdermal T gel provided flexibility in dosing with little skin irritation and a low discontinuation rate 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 ] . ) BACKGROUND This study assessed the feasibility of a 12-week program of exercise , with and without intramuscular testosterone supplementation , in male patients with chronic heart failure ( CHF ) and low testosterone status and collected preliminary data for key health outcomes . METHODS Male patients with CHF ( n = 41 , age 67.2 years , range 51 - 84 years ) with mean ± SD testosterone levels of 10.7 ± 2.6 nmol/L ( 309 ± 76 ng/dL ) were r and omly allocated to exercise with testosterone or placebo groups . Feasibility was assessed in terms of recruitment , intervention compliance , and attrition . Outcomes included an incremental shuttle walk test , peak oxygen uptake , muscular strength , echocardiographic measures , N-terminal pro-brain natriuretic peptide , inflammatory markers , depression ( Beck Depression Inventory ) , and health-related quality of life ( Minnesota Living with Heart Failure Question naire and Medical Outcomes Study Short-Form ) . RESULTS Attrition was 30 % but with 100 % compliance to exercise and injections in patients who completed the study . Similar improvements in shuttle walk test ( 18 % vs 19 % ) , body mass ( -1.3 kg vs -1.0 kg ) , and h and grip strength ( 2.1 kg vs 2.5 kg ) from baseline were observed in both groups . The exercise with testosterone group showed improvements from baseline in peak oxygen uptake ( P < .01 ) , Beck Depression Inventory ( P < .05 ) , leg strength ( P < .05 ) , and several Medical Outcomes Study Short-Form quality of life domains ( P < .05 ) , which were generally not apparent in the exercise with placebo group . Echocardiographic measures , N-terminal pro-brain natriuretic peptide , and inflammatory markers were mostly unchanged . CONCLUSIONS This study shows for the first time that testosterone supplementation during a program of exercise rehabilitation is feasible and can positively impact on a range of key health outcomes in elderly male patients with CHF who have a low testosterone status Enzyme immunoassays ( EIA ) are commonly utilized for the evaluation of and rogens in biological fluids ; however , careful consideration must be given to cross-reactivity with other endogenous sex-steroid hormones . Our purpose was to determine the validity of a commonly-utilized commercially-available dihydrotestosterone ( DHT ) EIA . Serum sample s obtained from older hypogonadal men who participated in a 12-month r and omized controlled trial evaluating the effects of testosterone-enanthate ( 125 mg/week ) or vehicle in combination with finasteride ( 5mg/day ) or placebo  were assayed for DHT via EIA and using a vali date d gold-st and ard LC-MS/MS approach . Additionally , commercially-available ( DHT-free ) buffer containing grade d testosterone doses was evaluated by DHT immunoassay .  DHT concentrations measured via EIA were 79 % to > 1000 % higher than values obtained by LC-MS/MS ( p<0.05 ) , with the largest differences ( 415 - 1128 % ) occuring in groups receiving finasteride . Both LC-MS/MS and EIA indicated that testosterone-enanthate increased serum DHT to a similar magnitude . In contrast , finasteride-induced reductions in DHT were detected by LC-MS/MS , but not EIA ( p<0.05 ) . No significant associations were present for DHT concentrations between measurement techniques . Cross-reactivity of testosterone with the immunoassay ranged from 18 % to 99 % and DHT concentrations measured by EIA were highly associated with the spiked testosterone concentrations in DHT-free buffer ( r=0.885 , p<0.001 ) . In conclusion , we provide evidence invalidating a commonly-utilized commercially-available DHT immunoassay because significant cross-reactivity exists between testosterone and the EIA and because the changes in DHT observed via EIA were not associated with a vali date d gold-st and ard measurement technique . The cross-reactivity of testosterone is particularly concerning because testsoterone is present in 100-fold greater concentrations than is DHT within the circulation 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 CONTEXT Cycling and rogens has been reported by athletes to improve physical performance by enhancing muscle mass and strength , a paradigm that has not been studied , and may have clinical value in older men being treated with testosterone .  OBJECTIVE We investigated the efficacy of a monthly cycled testosterone regimen that uses half the testosterone dose as the current st and ard of care continuous therapy on body composition and muscle strength in older men . DESIGN , SETTING , AND PATIENTS Twenty-four community-dwelling older men 70 ± 2 yr of age with total testosterone levels below 500 ng/dl were r and omized at the Institute for Translational Sciences- Clinical Research Center into a 5-month double-blind placebo-controlled trial . INTERVENTION Subjects were dosed weekly for 5 months , receiving continuous testosterone ( TE , n = 8 ; 100 mg testosterone enanthate , i m injection ) , monthly cycled testosterone ( MO , n = 8 ; alternating months of testosterone and placebo ) , or placebo ( PL , n = 8) . MAIN OUTCOME MEASURES Main outcomes included body composition by dual-energy x-ray absorptiometry and upper and lower body muscle strength . Secondary outcomes included body weight , serum hormones , and mixed-muscle protein fractional synthesis rate ( FSR ) . RESULTS Total lean body mass was increased and percent fat was reduced after 5 months in TE and MO ( P < 0.05 ) . Upper body muscle strength increased in TE , and lower body muscle strength increased in TE and MO ( P < 0.05 ) . FSR increased in TE and MO ( P < 0.05 ) but not in PL . CONCLUSIONS Cycled testosterone  improved body composition and increased muscle strength compared with placebo and increased FSR similarly to continuous testosterone 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 Oral TRT produces significant CV risk .
  Differences in the degree to which serum DHT is elevated may underlie the varying CV risk by TRT administration route , as elevated serum dihydrotestosterone has been shown to be associated with CV risk in observational studies
background: Background Potential cardiovascular ( CV ) risks of testosterone replacement therapy ( TRT ) are currently a topic of intense interest .
  However , no studies have addressed CV risk as a function of the route of administration of TRT .