human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 [  
    Output:
    
agent
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
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 [  
    Output:
    