12-Month Observation of Testosterone Replacement Effectiveness in a General Population of Men Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial. Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial. Testosterone replacement therapy in older male subjective memory complainers: double-blind randomized crossover placebo-controlled clinical trial of physiological assessment and safety. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. The effect of hormone replacement therapy and route of administration on selected cardiovascular risk factors in post-menopausal women. The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. Testosterone therapy in women with chronic heart failure: a pilot double-blind, randomized, placebo-controlled study. Comparison of transdermal and oral estrogen-progestin replacement therapy: effects on cardiovascular risk factors Testosterone replacement in hypogonadal men with angina improves ischaemic threshold and quality of life Differing effects of oral and transdermal hormone replacement therapy on cardiovascular risk factors in healthy postmenopausal women. Risk factors associated with cardiovascular events during testosterone administration in older men with mobility limitation. Long-term benefits of testosterone replacement therapy on angina threshold and atheroma in men. Longitudinal relation between endogenous testosterone and cardiovascular disease risk factors in middle-aged men. A 13-year follow-up of former Multiple Risk Factor Intervention Trial participants. Acute haemodynamic effects of testosterone in men with chronic heart failure. Extremes of endogenous testosterone are associated with increased risk of incident coronary events in older women. Testosterone therapy during exercise rehabilitation in male patients with chronic heart failure who have low testosterone status: a double-blind randomized controlled feasibility study.
Abstract Background : Testosterone decline becomes more prevalent as men age and symptomatic testosterone deficiency is associated with potentially serious comorbidities . Despite limitations , registries can provide an opportunity to accumulate data regarding disease management in a typical patient population , including diagnosis , treatment , and outcomes . Material s and Methods : The Testim Registry in the United States ( TRiUS ) was a prospect i ve , 12-month , observational cohort registry of men prescribed Testim ® ( 1 % testosterone gel ; Auxilium Pharmaceuticals , Inc. ) for the first time ; patients previously on other forms of testosterone replacement therapy ( TRT )  were eligible to participate in the study as well . The registry recorded total testosterone ( TT ) and free testosterone ( FT ) levels , prostate-specific antigen ( PSA ) , sexual function , mood/depression , and cardiometabolic and anthropometric criteria before and after TRT . Changes over time were analyzed by analysis of variance , and linear regression and Pearson product-moment correlation coefficients were used to examine relationships between variables . Results : At baseline , 849 patients from 72 sites were enrolled , with 743 of 849 started on 5 g gel/day ( 50 mg testosterone/day ) and 106 of 849 started on 10 g gel/day ( 100 mg testosterone/day ) . Mean TT and FT levels increased significantly after 3 months of TRT ( TT level , 16.8 ± 9.87 nmol/L [ 485 ± 284 ng/dL ] , P < 0.001 ; FT level , 286.3 ± 224.9 pmol/L [ 82.5 ± 64.8 pg/mL ] , P < 0.001 ) and were maintained at eugonadal levels . Mean PSA levels increased significantly ( P = 0.004 ) from 1.12 ± 1.11 μg/L ( 1.12 + 1.11 ng/mL ) at baseline to 1.26 ± 1.22 μg/L ( 1.26 ± 1.22 ng/mL ) after 12 months of TRT , although changes were well within guidelines ( < 1.4 μg/L/year increase ) . Significant improvements were seen in sexual function and mood/depression at 3 months and in metabolic parameters at 12 months . Conclusion : Testosterone deficiency symptoms improved with TRT use in men ; sexual function and mood/depression improvements were seen before metabolic improvements . Prostate-specific antigen levels increased , although increases were within guideline -determined safety limits 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 CONTEXT Prostate safety is a primary concern when aging men receive testosterone replacement therapy ( TRT ) , but little information is available regarding the effects of TRT on prostate tissue in men . OBJECTIVE To determine the effects of TRT on prostate tissue of aging men with low serum testosterone levels . DESIGN , SETTING , AND PARTICIPANTS R and omized , double-blind , placebo-controlled trial of 44 men , aged 44 to 78 years , with screening serum testosterone levels lower than 300 ng/dL ( < 10.4 nmol/L ) and related symptoms , conducted at a US community-based research center between February 2003 and November 2004 . INTERVENTION Participants were r and omly assigned to receive 150 mg of testosterone enanthate or matching placebo intramuscularly every 2 weeks for 6 months . MAIN OUTCOME MEASURES The primary outcome measure was the 6-month change in prostate tissue and rogen levels ( testosterone and dihydrotestosterone ) . Secondary outcome measures included 6-month changes in prostate-related clinical features , histology , biomarkers , and epithelial cell gene expression . RESULTS Of the 44 men r and omized , 40 had prostate biopsies performed both at baseline and at 6 months and qualified for per- protocol analysis ( TRT , n = 21 ; placebo , n = 19 ) . Testosterone replacement therapy increased serum testosterone levels to the mid-normal range ( median at baseline , 282 ng/dL [ 9.8 nmol/L ] ; median at 6 months , 640 ng/dL [ 22.2 nmol/L ] ) with no significant change in serum testosterone levels in matched , placebo-treated men . However , median prostate tissue levels of testosterone ( 0.91 ng/g ) and dihydrotestosterone ( 6.79 ng/g ) did not change significantly in the TRT group . No treatment-related change was observed in prostate histology , tissue biomarkers ( and rogen receptor , Ki-67 , CD34 ) , gene expression ( including AR , PSA , PAP2A , VEGF , NXK3 , CLU [ Clusterin ] ) , or cancer incidence or severity . Treatment-related changes in prostate volume , serum prostate-specific antigen , voiding symptoms , and urinary flow were minor . CONCLUSIONS These preliminary data suggest that in aging men with late-onset hypogonadism , 6 months of TRT normalizes serum and rogen levels but appears to have little effect on prostate tissue and rogen levels and cellular functions . Establishment of prostate safety for large population s of older men undergoing longer duration of TRT requires further study . Trial Registration clinical trials.gov Identifier : NCT00161304 Testosterone replacement therapy ( TRT ) has been investigated in older men as a preventative treatment against Alzheimer 's disease and dementia . However , previous studies have been contradictory . We assessed TRT physiological effects in 44 older men ( aged 61 ± 7.7 years ) with subjective memory complaints using a double blind , r and omized , crossover , placebo-controlled study . Participants were r and omized into 2 groups , one group received transdermal testosterone ( 50 mg ) daily for 24 weeks , followed by a 4 week wash-out period , then 24 weeks of placebo ; the other group received the reverse treatment . Blood evaluation revealed significant increases in total testosterone , free ( calculated ) testosterone , dihydrotestosterone , and a decrease in luteinizing hormone levels ( p<0.001 ) following TRT . Although there were significant increases in red blood cell counts , hemoglobin and prostate specific antigen levels  following TRT , they remained within normal ranges . No significant differences in plasma amyloid beta , estradiol , sex hormone binding globulin , insulin levels , body fat percentage , or body mass index were detected . This is the first carefully controlled study that has investigated the influence of TRT in Indonesian men  on blood biomarkers linked to dementia risk . Our study suggests TRT is safe and well-tolerated in this Indonesian cohort , yet longitudinal studies with larger cohorts are needed to assess TRT further , and to establish whether TRT  reduces dementia risk OBJECTIVE Men with type 2 diabetes are known to have a high prevalence of testosterone deficiency . No long-term data are available regarding testosterone and mortality in men with type 2 diabetes or any effect of testosterone replacement therapy ( TRT ) . We report a 6-year follow-up study to examine the effect of baseline testosterone and TRT on all-cause mortality in men with type 2 diabetes and low testosterone . RESEARCH DESIGN AND METHODS A total of 581 men with type 2 diabetes who had testosterone levels performed between 2002 and 2005 were followed up for a mean period of 5.81.3 S.D. years . mortality rates were compared between total testosterone 10.4nmol/l ( 300ng/dl ; n=343 ) and testosterone 10.4nmol/l ( n=238 ) . the effect of TRT ( as per normal clinical practise : 85.9 % testosterone gel and 14.1 % intramuscular testosterone undecanoate ) was assessed retrospectively within the low testosterone group . RESULTS Mortality was increased in the low testosterone group ( 17.2 % ) compared with the normal testosterone group ( 9 % ; P=0.003 ) when controlled for covariates . In the Cox regression model , multivariate-adjusted hazard ratio ( HR ) for decreased survival was 2.02 ( P=0.009 , 95 % CI 1.2 - 3.4 ) . TRT ( mean duration 41.6±20.7 months ; n=64 ) was associated with a reduced mortality of 8.4 % compared with 19.2 % ( P=0.002 ) in the untreated group ( n=174 ) . The multivariate-adjusted HR for decreased survival in the untreated group was 2.3 ( 95 % CI 1.3 - 3.9 , P=0.004 ) . CONCLUSIONS Low testosterone levels predict an increase in all-cause mortality during long-term follow-up . Testosterone replacement may improve survival in hypogonadal men with type 2 diabetes BACKGROUND There is increasing use of hormone replacement therapy ( HRT ) by post-menopausal women . Observational epidemiological studies have shown reductions in cardiovascular risk factors in  HRT users in the USA , but no r and omized controlled trials of HRT have been carried out in the primary practice setting . Previous studies of cardiovascular risk factors have shown a variety of responses according to type of progestagen and oral or topical administration . None has examined the effect of route using an identical progestagen . OBJECTIVES Our aim was to establish differences , if any , in alteration in cardiovascular risk factors with HRT in post-menopausal women according to route of administration of HRT , oral , transdermal and implant , using first oestrogen alone then oestrogen plus norethisterone , or testosterone for implant . METHODS Subjects were recruited by letter of invitation to women aged 50 - 65 years from lists in general practice s local to the Charing Cross Hospital Lipid Clinic in West London . Their menopausal status was confirmed and they were r and omized to one of three treatment groups or acted as controls . They attended for three visits ; at baseline , HRT was initiated as oestrogen alone , oral or transdermal . At the 3-month visit , HRT with the progestagen , norethisterone , was given cyclically , continuously or transdermally until the final visit at 6 months . A separate group of women from the menopause clinic at Chelsea and Westminster Hospital were studied on oestrogen implant then on implanted oestrogen and testosterone . The outcome measures studied were the separate effects of the four regimes as compared with controls on lipoproteins , glucose , insulin , fibrinogen , factor VII and E-selectin , together with weight , waist : hip ratio and blood pressure . RESULTS The continuous combined oestrogen-progestagen therapy had similar effects on cardiovascular risk factors as oestrogen with cyclical progestagen . All regimes lowered low-density lipoprotein cholesterol , the oral route being more potent than the parenteral ; the effect of transdermal HRT was similar to the implant . Lp(a ) was reduced only with the oral route . Reductions in factor VII and E-selectin were observed in both the oral and transdermal routes . There was no increase in body mass index , waist : hip ratio , blood pressure or glucose and insulin levels with any of the HRT regimes used . Systolic blood pressure was reduced with the transdermal route . CONCLUSIONS This study supports the evidence that oestrogen-progestagen HRT , both oral and transdermal , although attenuating some of the benefit of oestrogen alone on fibrinogen and high-density lipoprotein , significantly reduces cardiovascular risk factors , which should diminish post-menopausal risk of coronary disease Testosterone has immune-modulating properties , and current in vitro evidence suggests that testosterone may suppress the expression of the proinflammatory cytokines TNFalpha , IL-1beta , and IL-6 and potentiate the expression of the antiinflammatory cytokine IL-10 . We report a r and omized , single-blind , placebo-controlled , crossover study of testosterone replacement ( Sustanon 100 ) vs. placebo in 27 men ( age , 62 + /- 9 yr ) with symptomatic and rogen deficiency ( total testosterone , 4.4 + /- 1.2 nmol/liter ; bioavailable testosterone , 2.4 + /- 1.1 nmol/liter ) . Compared with placebo , testosterone induced reductions in TNFalpha ( -3.1 + /- 8.3 vs. 1.3 + /- 5.2 pg/ml ; P = 0.01 ) and IL-1beta ( -0.14 + /- 0.32 vs. 0.18 + /- 0.55 pg/ml ; P = 0.08 ) and an increase in IL-10 ( 0.33 + /- 1.8 vs. -1.1 + /- 3.0 pg/ml ; P = 0.01 ) ; the reductions of TNFalpha and IL-1beta were positively correlated ( r(S ) = 0.588 ; P = 0.003 ) . In addition , a significant reduction in total cholesterol was recorded with testosterone therapy ( -0.25 + /- 0.4 vs. -0.004 + /- 0.4 mmol/liter ; P = 0.04 ) . In conclusion , testosterone replacement shifts the cytokine balance to a state of reduced inflammation and lowers total cholesterol .  Twenty of these men had established coronary disease , and because total cholesterol is a cardiovascular risk factor , and proinflammatory cytokines mediate the development and complications associated with atheromatous plaque , these properties may have particular relevance in men with overt vascular disease OBJECTIVES The primary objective of this study was to assess the effect of a 6-month testosterone supplementation therapy on functional capacity and insulin resistance in female patients with chronic heart failure ( CHF ) . BACKGROUND Patients with CHF show decreased exercise capacity and insulin sensitivity . Testosterone supplementation improves these variables in men with CHF . No study has evaluated the effects of testosterone supplementation on female patients with CHF . METHODS Thirty-six elderly female patients with stable CHF , ( ejection fraction 32.9 ± 6 ) were r and omly assigned ( 2:1 ratio ) to receive testosterone transdermal patch ( T group , n = 24 ) or placebo ( P group , n = 12 ) , both on top of optimal medical therapy . At baseline and after 6 months , patients underwent  6-min walking test  ( 6MWT ) , cardiopulmonary exercise test , echocardiogram , quadriceps maximal isometric voluntary contraction , dynamic quadriceps isokinetic strength ( peak torque ) , and insulin resistance assessment by homeostasis model . RESULTS Distance walked at 6MWT as well as peak oxygen consumption significantly improved in the T group , whereas they were unchanged in the P group ( p < 0.05 for all comparisons ) . The homeostasis model was significantly reduced in the T group in comparison with the P group ( -16.5 % vs. + 5 % , respectively ; p < 0.05 ) . Maximal voluntary contraction and peak torque increased significantly in the T group but did not change in the P group . Increase in distance walked at 6MWT was related to the increase in free testosterone levels ( r = 0.593 , p = 0.01 ) . No significant changes in echocardiographic parameters were observed in either group . No side effects requiring discontinuation of T were detected . CONCLUSIONS Testosterone supplementation improves functional capacity , insulin resistance , and muscle strength in women with advanced CHF .  Testosterone seems to be an effective and safe therapy for elderly women with CHF Objective To determine the effects of oral and transdermal hormone replacement therapy on lipid profile and hemostatic factors in postmenopausal women . Design Twenty subjects were treated with oral E2 valerate ( 2 mg ) combined with cyproterone acetate ( 1 mg ) ( group I ) and 21 with transdermal E2 ( 1.5 mg ) plus oral medroxyprogesterone acetate ( 5 mg ) ( group II ) . The effects on lipid profile and hemostatic parameters were evaluated at baseline and after 3 , 6 , and 12 months of treatment . Results Group I showed a stronger increase of high-density lipoprotein ( HDL ) cholesterol levels ( 2–8 % ) and stronger reduction of atherogenic indices ( total cholesterol/HDL cholesterol and low-density lipoprotein/HDL cholesterol ) than group II . Group II showed a more pronounced reduction of triglyceride ( 21–31 % ) and factor VII ( 6–10 % ) levels than group I. Both groups showed reduced concentrations of total cholesterol , low-density lipoprotein cholesterol , tissue plasminogen activator , plasminogen activator inhibitor-1 , antithrombin III , and protein S , whereas protein C was increased after 12 months of treatment . Conclusions The cardioprotective effects of hormone replacement therapy are demonstrated by favorable effects on lipid profile and fibrinolytic activity . Oral hormone replacement therapy showed a more prominent effect on lipoprotein metabolism than did transdermal administration , but transdermal medication had a stronger effect on triglyceride and coagulation factors . However , it needs to be considered that there is an increased risk of venous thrombotic events in the first year of treatment Background : Low serum testosterone is associated with several cardiovascular risk factors including dyslipidaemia , adverse clotting profiles , obesity , and insulin resistance . Testosterone has been reported to improve symptoms of angina and delay time to ischaemic threshold in unselected men with coronary disease . Objective : This r and omised single blind placebo controlled crossover study compared testosterone replacement therapy ( Sustanon 100 ) with placebo in 10 men with ischaemic heart disease and hypogonadism . Results : Baseline total testosterone and bioavailable testosterone were respectively 4.2 ( 0.5 ) nmol/l and 1.7 ( 0.4 ) nmol/l . After a month of testosterone , delta value analysis between testosterone and placebo phase showed that mean ( SD ) trough testosterone concentrations increased significantly by 4.8 ( 6.6 ) nmol/l ( total testosterone ) ( p = 0.05 ) and 3.8 ( 4.5 ) nmol/l ( bioavailable testosterone ) ( p = 0.025 ) , time to 1 mm ST segment depression assessed by Bruce protocol exercise treadmill testing increased by 74 ( 54 ) seconds ( p = 0.002 ) , and mood scores assessed with vali date d question naires all improved . Compared with placebo , testosterone therapy was also associated with a significant reduction of total cholesterol and serum tumour necrosis factor α with delta values of −0.41 ( 0.54 ) mmol/l ( p = 0.04 ) and −1.8 ( 2.4 ) pg/ml ( p = 0.05 ) respectively . Conclusion : Testosterone replacement therapy  in hypogonadal men delays time to ischaemia , improves mood , and is associated with potentially beneficial reductions of total cholesterol and serum tumour necrosis factor α P oral estrogen therapy exerts beneficial effects on serum lipids,1 providing one of the mechanisms used to explain the decreased cardiovascular risk associated with hormone replacement therapy ( HRT ) in observational studies ( e.g. , in the Nurses ’ Health Study 2 ) . However , recent r and omized clinical trials using estrogen – progestin combinations3–5 have changed the picture , and oral HRT is no longer recommended for cardiovascular prevention . The results of the estrogen arm of the Womens ’ Health Initiative study 4 are pending ; the jury is still out on the possible benefits of estrogen alone . Irrespective of the cardiovascular effects , HRT will continue to be used for the control of postmenopausal symptoms and questions of safety will persist . Oral and transdermal HRT result in quantitatively and qualitatively different lipid and other metabolic effects result ing from hepatic first-pass metabolism during oral therapy,6 as well as from different quantities of estrogen introduced into the body by the 2 routes of administration . The aim of the present investigation was to compare the effects of oral and transdermal HRT on serum lipids , glucose , and insulin as well as the novel cardiovascular risk factor serum highly sensitive C-reactive protein ( hs-CRP7 ) in healthy postmenopausal women . • • • Healthy postmenopausal white women were recruited for the study and all gave informed consent to participate in the study . The local ethics committee approved the study . The women were r and omly assigned to receive either oral or transdermal HRT . Details of the study procedures have been published earlier.8,9 For the present analysis , we included 64 participants for whom serum lipid and hs-CRP values at baseline and after 6 months were available . Thirtytwo women received transdermal estrogen and sequential progestin therapy in the form of 2 weeks of estradiol ( 50 g/day ) followed by 2 weeks of estradiol ( 50 g/day)/norethisterone acetate ( NETA , 0.25 mg/ day ) ( Estracomb ; Novartis Pharma AG , Basel , Switzerl and ) . Patches were changed twice a week . Another 32 women received continuous peroral estradiol ( 2 mg/day ) for the first 12 days , combined with cyclic peroral NETA ( 1 mg/day ) for the next 10 days , followed by estradiol ( 1 mg/day ) for 6 days ( Trisekvens ; Novo Nordisk , Copenhagen , Denmark ) . Both treatments led to similar increases in plasma estradiol levels.9 They also reduced climacteric symptoms and caused regular withdrawal bleeding,9 confirming compliance with the treatments . Blood sample s were obtained with venipuncture after an overnight fast at baseline and after 6 months ’ treatment during the last days of estradiol NETA intake . Plasma glucose , insulin , and serum lipids including total cholesterol , high-density lipoprotein ( HDL ) cholesterol , triglycerides , and lipoprotein(a ) ( Lp[a ] ) were measured with st and ard methods . Low-density lipoprotein ( LDL ) cholesterol was calculated according to Friedewald ’s formula . Serum hs-CRP was measured as described earlier.10 Statistical analyses were performed with NCSS statistical program ( www.ncss.com ; Number Cruncher Statistical Systems , Kaysville , Utah ) using descriptive statistics , correlation analysis , analysis of covariance , and stepwise multivariate analysis . Because of the skewed distribution of serum triglycerides , Lp(a ) , and hs-CRP , logarithmic transformation of values was used where appropriate . In some of the analyses , only hs-CRP values 10 mg/L were included to exclude the effect of possible intervening infection . Nonparametric tests were used for statistical comparisons between groups . A p value 0.05 was considered statistically significant . Except for smoking and serum HDL-3 cholesterol , the groups were well balanced at baseline ( Table 1 ) . At baseline , hs-CRP correlated positively with body mass index ( r 0.34 , p 0.007 ) and plasma insulin ( r 0.36 , p 0.004 ) , but not with any other variables . hs-CRP did not differ significantly between smokers ( n 20 ) and nonsmokers ( n 44 ) ( 1.27 1.22 vs 1.28 1.19 mg/L [ mean SD ] ; p 0.36 ) . Effects of the 2 treatments on serum lipids and hs-CRP during 6 months are listed in Table 2 . In the analyses adjusted for age , smoking , body mass index , and baseline log-transformed hs-CRP as covariates , oral HRT was significantly associated with an hs-CRP increase ( p 0.02 ) . In the analysis of covariance , with baseline log-transformed hs-CRP as covariate and a single hs-CRP value 10 mg/L excluded , oral HRT was associated with a greater log-transformed hs-CRP increase during 6 months of therapy than transdermal HRT ( 0.20 0.05 vs 0.06 0.05 [ mean SE ] ; p 0.03 ) . We also investigated factors related to hs-CRP change ( log-transformed , the single outlier excluded ) From the Departments of Medicine and Gynecology and Obstetrics , University of Helsinki , Helsinki , Finl and . This study was supported by grants from the Finnish Academy of Science and from the Research Council of Novartis Pharma , Helsinki , Finl and . Novartis also supplied the study medications . Dr. Str and berg is supported by Grant 48613 from the Academy of Finl and , Helsinki , Finl and . Dr. Str and berg ’s address is : Department of Medicine , Geriatric Clinic , University of Helsinki , PO Box 340 , FIN-00029 HUS , Finl and . E-mail : timo.str and berg@hus.fi . Manuscript received February 6 , 2003 ; revised manuscript received and accepted April 7 , 2003 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 INTRODUCTION In short-term studies , testosterone replacement therapy has been shown to protect male subjects from exercise-induced ischaemia and modify cardiovascular risk factors such as insulin resistance , fat mass and lipid profiles . METHODS This r and omised parallel group controlled trial was design ed to assess the treatment effect of testosterone therapy ( Nebido ) compared with placebo in terms of exercise-induced ischaemia , lipid profiles , carotid intima-media thickness ( CIMT ) and body composition during 12 months treatment in men with low testosterone levels and angina . RESULTS A total of 15 men were recruited but 13 ( n=13 ) reached adequate duration of follow-up ; seven were treated with testosterone  and six with placebo . Testosterone increased time to ischaemia ( 129+/-48 s versus 12+/-18 , P=0.02 ) and haemoglobin ( 0.4+/-0.6 g/dl versus -0.03+/-0.5 , P=0.04 ) , and reduced body mass index ( -0.3 kg/m(2 ) versus 1.3+/-1 , P=0.04 ) and triglycerides ( -0.36+/-0.4 mmol/l versus 0.3+/-1.2 , P=0.05 ) . The CIMT decreased in the testosterone group more than placebo , but full between group analyses suggested this was only a statistical trend ( -0.5+/-0.1 vs -0.09+/-0.06 , P=0.16 ) . There were no significant effects on serum prostate specific antigen , total or high-density lipoprotein cholesterol ; or on mood and symptom scores as assessed by Seattle Angina Score and EuroQol . CONCLUSION The protective effect of testosterone on myocardial ischaemia is maintained throughout treatment without decrement . Previously noted potentially beneficial effects of testosterone on body composition were confirmed and there were no adverse effects The present study examined lifestyle and behavioral correlates of the change in total testosterone over 13 years in 66 men aged 41 - 61 years who were former participants of the Multiple Risk Factor Intervention Trial ( MRFIT ) at the Pittsburgh , Pennsylvania , center . The authors also determined in these men if changes in total testosterone are related to changes in cardiovascular disease risk factors . The mean total testosterone level was 751 ( st and ard deviation , 248 ) ng/dl at baseline and decreased by 41 ( st and ard deviation , 314 ) ng/dl during follow-up . The correlation between measures was r = 0.44 ( p < 0.001 ) . In multivariate analysis , higher type A coronary-prone behavior score , greater pack-years of cigarette smoking , and the MRFIT special intervention group were associated with larger decreases in total testosterone . Age , body weight , weight change , leisure time activity level , and alcohol intake were not related to the change in total testosterone . The decrease in endogenous testosterone was associated with an increase in triglycerides and a decrease in high density lipoprotein cholesterol in multivariate analysis controlling for obesity and other lifestyle covariates . There was little relation between change in testosterone and change in total and low density lipoprotein cholesterol or blood pressure . This longitudinal study confirms a gradual decline in total testosterone levels with advancing age in older men and provides evidence that lifestyle and psychosocial factors are related to this decline . Decreases in endogenous testosterone levels with age in men are associated with potentially unfavorable changes in triglycerides and high density lipoprotein cholesterol AIMS Anabolic therapy with testosterone may be useful in the treatment of wasting associated with chronic heart failure but little is known about its cardiovascular actions . The aim of this study was to determine the acute haemodynamic effects of testosterone administration in men with heart failure . METHODS AND RESULTS Twelve men with stable chronic heart failure were enrolled in a double-blind , r and omised , placebo-controlled , cross-over trial . Subjects were given testosterone 60 mg or placebo via the buccal route and central haemodynamics were monitored over 6h , using a pulmonary flotation catheter . Subjects received the second treatment on day 2 and haemodynamic monitoring was repeated . Treatment was well tolerated . Compared with placebo , testosterone treatment result ed in a relative increase in cardiac output ( p<0.0001 , ANCOVA ) , with maximum treatment effect after 180 min ( 10.3+/-4.6 % increase from baseline , p=0.035 ; 95 % CI 0.8 - 19.8 ) . This was accompanied by reduction in systemic vascular resistance compared with baseline ( p<0.0001 , ANCOVA ) , with maximum treatment effect also at 180 min ( -17.4+/-9.6 % from baseline , p=0.085 ; 95 % CI -37.3 to + 2.6 ) . These maximal changes coincided with the peak elevation in serum bio-available testosterone . There was no significant change in any other haemodynamic parameter measured . CONCLUSIONS Administration of testosterone increases cardiac output acutely , apparently via reduction of left ventricular afterload CONTEXT Few studies have examined whether endogenous testosterone is associated with the development of  coronary heart disease ( CHD ) in women . OBJECTIVE This study tested the association of  total testosterone ( total T ) and bioavailable T ( BioT ) levels with risk of incident coronary events  among older community-dwelling women . DESIGN , SETTING , AND PARTICIPANTS This was a prospect i ve , population -based study of 639 postmenopausal women , aged 50 - 91 ( mean , 73.8 ) yr who had serum testosterone measurements at baseline ( 1984 - 87 ) and who were followed for incident CHD events through 2004 . MAIN OUTCOME MEASURES A total of 134 incident CHD events occurred during follow-up [ 45 nonfatal myocardial infa rct ions , 79 fatal myocardial infa rct ions , and 10 coronary revascularizations ] . RESULTS The median follow-up was 12.3 yr . Age-adjusted CHD risk estimates were similar for the four highest total T quintiles relative to the lowest , suggesting a low threshold . In age-adjusted analyses , the lowest total T quintile ( < /=80 pg/ml ) was associated with a 1.62-fold increased risk of incident CHD [ 95 % confidence interval ( CI ) , 1.10 - 2.39 ] compared to higher levels . BioT showed a U-shaped association with incident CHD . Age-adjusted risk for the lowest and highest BioT quintiles relative to the third were 1.79 ( 95 % CI , 1.03 - 3.16 ) and 1.96 ( 95 % CI , 1.13 - 3.41 ) , respectively . Additional adjustment for lifestyle , adiposity , estradiol , and ovarian status , or for CHD risk factor covariates , had minimal influence on results . CONCLUSIONS An optimal range of testosterone may exist for cardiovascular health in women , with increased risk of CHD events at low levels of testosterone overall and at high levels of the bioavailable fraction of testosterone 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
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 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 .