Endogenous Sex Hormones and Cardiovascular Disease Incidence 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. Extremes of endogenous testosterone are associated with increased risk of incident coronary events in older women. Endogenous Testosterone and Mortality Due to All Causes, Cardiovascular Disease, and Cancer in Men: European Prospective Investigation Into Cancer in Norfolk (EPIC-Norfolk) Prospective Population Study Endogenous testosterone levels, physical performance, and fall risk in older men. Lower testosterone levels predict incident stroke and transient ischemic attack in older men. Effects of Oral Testosterone Treatment on Myocardial Perfusion and Vascular Function in Men With Low Plasma Testosterone and Coronary Heart Disease Risk factors associated with cardiovascular events during testosterone administration in older men with mobility limitation. Effect of intravenous testosterone on myocardial ischemia in men with coronary artery disease. Low serum testosterone and mortality in older men. Testosterone therapy increased muscle mass and lipid oxidation in aging men The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. Testosterone replacement in hypogonadal men with angina improves ischaemic threshold and quality of life Testosterone does not adversely affect fibrinogen or tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) levels in 46 men with chronic stable angina. Testosterone dose-response relationships in healthy young men. Sex Hormone Levels and Risk of Cardiovascular Events in Postmenopausal Women Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T.
Context Studies of the role of endogenous sex hormones in  cardiovascular disease ( CVD ) in men have been inconclusive . Contribution A total of 2084 men from 2 Framingham Heart Study cohorts had levels of  total serum estrogen , testosterone , and dehydroepi and rosterone sulfate ( DHEA-S )  measured in 1981 to 1985 for the original cohort and in 1987 to 1991 for the offspring cohort . Testosterone and DHEA-S levels were not associated with CVD risk . Estrogen levels were inversely related : Risk for CVD in the highest quartile was 0.68 ( 95 % CI , 0.50 to 0.92 ) times that in the lowest level . Caution s Investigators studied only white men and did not study free unbound hormone levels . Implication s Endogenous estrogen may be vasculoprotective in men , which is in contrast to the effects of exogenous estrogen . The Editors Male sex is an independent risk factor for cardiovascular disease ( CVD ) ( 1 ) . Scientists have postulated that the 5- to 10-year lag period in CVD incidence in women ( compared with men ) may be related to differences in endogenous sex hormones ( 27 ) . Indeed , substantial evidence suggests that sex hormones ( testosterone , estrogen , and dehydroepi and rosterone sulfate [ DHEA-S ] ) influence traditional and newer CVD risk factors ( 27 ) . Interest in the role of sex hormones in the pathogenesis of CVD has been rekindled by the observation that men with genetic defects of estrogen synthesis ( 8) or action ( 9 ) develop premature atherosclerosis . In addition , genetic variation in estrogen receptor- has been associated with prevalent CVD ( 10 , 11 ) , and and rogen and estrogen receptor expression in coronary arteries has been reported to influence coronary atherosclerosis in men ( 12 ) . In contrast to the aforementioned data , prospect i ve studies relating circulating sex hormone levels to incident CVD in men have been inconclusive . For example , low serum testosterone levels have been associated with greater progression of sub clinical atherosclerosis in 2 previous investigations ( 13 , 14 ) , but other studies have reported no association of testosterone levels with CVD events ( 1521 ) . On a parallel note , low DHEA-S levels have been linked to greater CVD risk in some studies ( 18 , 2224 ) but not in other studies ( 13 , 20 , 2529 ) . Investigations relating serum estradiol levels to CVD risk in men have generally found no statistically significant association ( 1520 ) . Some previous investigations were limited by modest sample sizes ( 14 , 17 , 18 , 22 , 25 , 26 ) ; an insufficient number of CVD events ( 1518 , 22 , 23 , 26 ) ; and , in some instances , a retrospective study design ( 1721 , 25 , 26 ) . In addition , some reports ( 15 , 22 , 24 ) focused on CVD death ( they did not evaluate nonfatal CVD events ) . Thus , a large prospect i ve community-based study relating sex hormones to CVD risk with adequate power to detect modest potential associations is needed . Accordingly , we evaluated the associations of serum levels of sex hormones that were measured at a routine baseline examination with CVD incidence in a prospect ively assembled cohort of participants . Methods Study Sample The Framingham Heart Study , a prospect i ve study of the risk factors for the development of heart disease and stroke , began in 1948 with the recruitment of 5209 men and women between 30 and 60 years of age who resided in Framingham , Massachusetts ( 30 ) . The Framingham Offspring Study began in 1971 with the recruitment of 5124 participants who were the children of the original cohort and the spouses of the children ( 31 ) . Participants in the original cohort are examined every 2 years , while offspring cohort members are assessed every 4 years . At each Framingham Heart Study examination , attendees undergo a physical examination and laboratory assessment of risk factors ( 31 ) . We evaluated 2789 men who attended the 17th biennial examination ( 19811983 ) of the original cohort or the fourth quadrennial examination ( 19871991 ) of the offspring cohort . We measured serum total testosterone and estradiol levels at these examinations , and we measured DHEA-S levels at the 18th examination ( 19831985 ) for the original cohort and at the fourth examination for the offspring cohort . We excluded 705 men because of prevalent CVD ( n= 541 ) and nonavailable testosterone data ( n= 164 ) . After exclusions , 2084 men ( 74.7 % ; 525 original cohort participants ) without previous CVD were eligible . Data on serum estradiol levels and serum DHEA-S levels were available in 2047 men and 1928 participants , respectively . All participants gave written informed consent , and the institutional review board at the Boston Medical Center approved the study protocol . Biochemical Assessment of Sex Hormones As described previously ( 32 ) , we measured total testosterone , total estradiol , and DHEA-S levels from serum sample s by using radioimmunoassays ( Diagnostic Products Corp. , Los Angeles , California ) for total testosterone ( interassay coefficient of variation , 11 % ) , total estradiol ( interassay coefficient of variation , 4 % ) , and DHEA-S ( interassay coefficient of variation , 11 % ) . We also measured serum luteinizing hormone levels at the baseline examinations ( interassay coefficient of variation , 6 % ) . Cardiovascular Outcomes All participants were under continuous surveillance for the occurrence of  CVD events and death . Participants are evaluated periodically at the Framingham Heart Study and through health history up date s between examinations ( obtained via telephone interviews ) . Three experienced investigators obtained and review ed hospitalization and physician office visit records . We defined incident CVD as coronary heart disease ( recognized or unrecognized myocardial infa rct ion , angina pectoris , coronary insufficiency , or coronary heart disease death ) , cerebrovascular disease ( stroke or transient ischemic attack ) , congestive heart failure ( by Framingham criteria ) , or peripheral vascular disease ( intermittent claudication ) . Criteria for the diagnoses of cardiovascular events have been described elsewhere ( 33 ) . We considered that an unrecognized myocardial infa rct ion occurred if we found electrocardiographic evidence of clinical ly significant loss of R waves or appearance of pathologic Q waves on serial tracings in the absence of a clinical ly recognized event ( 33 ) . We defined the follow-up period a priori as 10 years from the baseline examination ( up to 1995 for the original cohort and 2002 for the offspring cohort ) to permit equal duration s of follow-up of original and offspring cohort participants and because sex hormone levels change considerably with age ( 34 ) . The analyses that combined the original and offspring cohorts had greater statistical power and allowed us to evaluate participants over a wider age range . Statistical Analyses Serum testosterone levels were normally distributed . Serum estradiol and DHEA-S levels were skewed and were log-transformed . We examined the associations between baseline sex hormone levels and CVD incidence during follow-up ( separate analyses for each hormone ) . We chose incident CVD as the outcome because the effects of sex hormones are not limited to a given vascular territory and this maximized our statistical power and limited multiple statistical testing ( as opposed to analysis for each CVD component ) . We stratified all analyses by the cohort ( offspring cohort vs. original cohort ) . We verified that the assumption of proportionality of hazards was satisfied for each hormone . We calculated age- and multivariable-adjusted 10-year incidence rates for CVD for each hormone quartile ( 35 ) . We prespecified 2 types of models : Primary analyses evaluated the sex hormones as continuous variables to maximize statistical power ( model A ) , and additional analyses compared CVD risk in hormone quartiles 2 to 4 with that in quartile 1 ( referent ) ( model B ) . These models facilitated assessment of potential nonlinear relations . For each hormone , we used proportional hazards regression ( 36 ) that adjusted for 1 ) age alone and 2 ) age , smoking , systolic and diastolic blood pressure , antihypertensive medication use , ratio of total and high-density lipoprotein ( HDL ) cholesterol , diabetes mellitus , and body mass index ( BMI ) . We evaluated models adjusted for age alone because some risk factors may fall along the causal pathway from estradiol to CVD . Adjustment for BMI was performed because adiposity is a strong correlate of sex hormone levels ( 37 ) and of sex hormonebinding globulin ( 38 ) . Sex hormonebinding globulin strongly influences measurements of total circulating sex hormone levels and the amount of bound hormone versus free hormone . We also evaluated models without BMI as a covariate to assess whether adjustment for BMI attenuated relations of sex hormones with CVD and models that were adjusted additionally for the use of aspirin or lipid-lowering medications , alcohol consumption , and education level . We incorporated statistical interaction terms to evaluate effect modification by age , BMI , smoking status , systolic blood pressure , and total cholesterolHDL cholesterol ratio . To gain additional insights into potential nonlinearity of associations between hormone levels and CVD risk , we examined generalized additive Cox models using penalized splines ( 39 , 40 ) for hormones that were statistically significantly related to CVD risk . Because potential relationships of sex hormones to CVD risk may be mediated by the development of risk factors during follow-up , we prespecified examination of time-dependent Cox models ( updating established CVD risk factors [ covariates in the multivariable-adjusted proportional hazards regression ] every 4 years at follow-up examinations ) for analyses of any sex hormone that was statistically significantly related to CVD events in the initial analyses . Additional Analyses We performed secondary analyses relating CVD risk to the estradioltestosterone ratio ( 37 , 41 ) . In addition , we investigated whether hypogonadism was related to CVD risk . We defined hypogonadism empirically as a serum testosterone level less than 10.4 nmol/L ( 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 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 — The relation between endogenous testosterone concentrations and health in men is controversial . Methods and Results — We examined the prospect i ve relationship between endogenous testosterone concentrations and mortality due to all causes , cardiovascular disease , and cancer in a nested case-control study based on 11 606 men aged 40 to 79 years surveyed in 1993 to 1997 and followed up to 2003 . Among those without prevalent cancer or cardiovascular disease , 825 men who subsequently died were compared with a control group of 1489 men still alive , matched for age and date of baseline visit .  Endogenous testosterone concentrations at baseline were inversely related to mortality due to all causes ( 825 deaths ) , cardiovascular disease ( 369 deaths ) , and cancer ( 304 deaths ) . Odds ratios ( 95 % confidence intervals ) for mortality for increasing quartiles of endogenous testosterone compared with the lowest quartile were 0.75 ( 0.55 to 1.00 ) , 0.62 ( 0.45 to 0.84 ) , and 0.59 ( 0.42 to 0.85 ) , respectively ( P<0.001 for trend after adjustment for age , date of visit , body mass index , systolic blood pressure , blood cholesterol , cigarette smoking , diabetes mellitus , alcohol intake , physical activity , social class , education , dehydroepi and rosterone sulfate , and rostanediol glucuronide , and sex hormone binding globulin ) . An increase of 6 nmol/L serum testosterone ( ≈1 SD ) was associated with a 0.81 ( 95 % confidence interval 0.71 to 0.92 , P<0.01 ) multivariable-adjusted odds ratio for mortality . Inverse relationships were also observed for deaths due to cardiovascular causes and cancer and after the exclusion of deaths that occurred in the first 2 years . Conclusions — In men  , endogenous testosterone concentrations are inversely related to mortality due to cardiovascular disease and all causes . Low testosterone may be a predictive marker for those at high risk of cardiovascular disease BACKGROUND Gonadal steroid levels decline with age in men . Whether low testosterone levels affect the development of common age-related disorders , including physical functioning and falling , is unclear . METHODS This longitudinal , observational follow-up study sought to determine whether low testosterone levels are associated with physical performance and fall risk in older men . A total of 2587 community-based men aged 65 to 99 years were selected using a stratified r and om sampling scheme from a study cohort of 5995 volunteers .  Bioavailable testosterone and estradiol levels and physical performance measures were determined from baseline . Incident falls were ascertained every 4 months during 4 years of follow-up . Generalized estimating equations were used to estimate risk ratios for the relation of sex steroids to falls . RESULTS Fifty-six percent of the men reported at least 1 fall ; many fell frequently . Lower bioavailable testosterone levels were associated with increased fall risk . Men with testosterone levels in the lowest quartile had a 40 % higher fall risk than those in the highest quartile . The effect of low testosterone levels was most apparent in younger men ( 65 - 69 years ) ( relative risk , 1.8 ; 95 % confidence interval , 1.2 - 2.7 ) ; testosterone level was not associated with falls in the oldest men ( > /=80 years ) . Lower testosterone concentrations were associated with reduced physical performance . However , the association between low testosterone levels and fall risk persisted despite adjustment for performance . CONCLUSIONS Falls were common among older men . Fall risk was higher in men with lower bioavailable testosterone levels . The effect of testosterone level was independent of poorer physical performance , suggesting that the effect of testosterone on fall risk may be mediated by other and rogen actions CONTEXT Lower circulating testosterone concentrations are associated with metabolic syndrome , type 2 diabetes , carotid intima-media thickness , and aortic and lower limb arterial disease in men . However , it is unclear whether lower testosterone levels predict major cardiovascular events . OBJECTIVE We examined whether lower serum testosterone was an independently significant risk factor for symptomatic cerebrovascular events  in older men . DESIGN This was a prospect i ve observational study with median follow-up of 3.5 yr . SETTING Community-dwelling , stroke-free older men were studied . PARTICIPANTS A total of 3443 men at least 70 yr of age participated in the study . MAIN OUTCOME MEASURES  Baseline serum total testosterone , SHBG , and LH were assayed . Free testosterone  was calculated using mass action equations . Incident stroke or transient ischemic attack ( TIA ) was recorded . RESULTS A first stroke or TIA occurred in 119 men ( 3.5 % ) .  Total and free testosterone concentrations in the lowest quartiles ( < 11.7 nmol/liter and < 222 pmol/liter ) were associated with reduced event-free survival ( P = 0.014 and P = 0.01 , respectively ) . After adjustment including age , waist-hip ratio , waist circumference , smoking , hypertension , dyslipidemia , and medical comorbidity , lower total testosterone predicted increased incidence of stroke or TIA ( hazard ratio = 1.99 ; 95 % confidence interval , 1.33 - 2.99 ) . Lower free testosterone was also associated ( hazard ratio = 1.69 ; 95 % confidence interval , 1.15 - 2.48 ) , whereas SHBG and LH were not independently associated with incident stroke or TIA . CONCLUSIONS In older men , lower total testosterone levels predict increased incidence of stroke or TIA after adjusting for conventional risk factors for cardiovascular disease . Men with low-normal testosterone levels had increased risk . Further studies are warranted to determine whether interventions that raise circulating testosterone levels might prevent cerebrovascular disease in men Intracoronary testosterone infusions induce coronary vasodilatation and increase coronary blood flow . Longer term testosterone supplementation favorably affected signs of myocardial ischemia in men with low plasma testosterone and coronary heart disease . However , the effects on myocardial perfusion are unknown . Effects of longer term testosterone treatment on myocardial perfusion and vascular function were investigated in men with CHD and low plasma testosterone . Twenty-two men ( mean age 57 ± 9 [ SD ] years ) were r and omly assigned to oral testosterone undecanoate ( TU ; 80 mg twice daily ) or placebo in a crossover study design . After each 8-week period , subjects underwent at rest and adenosine-stress first-pass myocardial perfusion cardiovascular magnetic resonance , pulse-wave analysis , and endothelial function measurements using radial artery tonometry , blood sampling , anthropomorphic measurements , and quality -of-life assessment . Although no difference was found in global myocardial perfusion after TU compared with placebo , myocardium supplied by unobstructed coronary arteries showed increased perfusion ( 1.83 ± 0.9 vs 1.52 ± 0.65 ; p = 0.037 ) . TU decreased basal radial and aortic augmentation indexes ( p = 0.03 and p = 0.02 , respectively ) , indicating decreased arterial stiffness , but there was no effect on endothelial function . TU significantly decreased high-density lipoprotein cholesterol and increased hip circumference , but had no effect on hemostatic factors , quality of life , and angina symptoms . In conclusion , oral TU had selective and modest enhancing effects on perfusion in myocardium supplied by unobstructed coronary arteries , in line with previous intracoronary findings . The TU-related decrease in basal arterial stiffness may partly explain previously shown effects of exogenous testosterone on signs of exercise-induced myocardial ischemia 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 BACKGROUND Studies on the effect of estrogen on atherosclerotic coronary artery disease ( CAD ) risk in women have produced conflicting results . Similar confusion , but fewer data , exists on the effect of testosterone on CAD risk in men . METHODS We used 99mTc sestamibi single-photon emission computed tomography ( SPECT ) myocardial perfusion imaging to examine the acute effect of intravenous testosterone in 32 men ( mean age , 69.1 + /- 6.4 years ) with provocable myocardial ischemia on st and ard medical therapy . Patients performed 3 exercise ( n = 18 ) or adenosine ( n = 16 ) stress tests during the infusion of placebo or 2 doses of testosterone design ed to increase testosterone 2 or 6 times baseline . RESULTS Serum testosterone increased 137 + /- 58 % and 488 + /- 113 % , and estradiol levels increased 27 + /- 46 % and 76 + /- 57 % , ( P < .001 for all ) during the 2 testosterone infusions . There were no differences among the placebo or testosterone groups in peak heart rate , systolic blood pressure , maximal rate pressure product , perfusion imaging scores , or the onset of ST-segment depression . CONCLUSIONS Acute testosterone infusion has neither a beneficial nor a deleterious effect on the onset and magnitude of stress-induced myocardial ischemia in men with stable CAD CONTEXT Declining testosterone levels in elderly men are thought to underlie many of the symptoms and diseases of aging ; however , studies demonstrating associations of low testosterone with clinical outcomes are few . OBJECTIVE The objective of the study was to examine the association of endogenous testosterone levels with mortality in older community-dwelling men . DESIGN , SETTING , AND PARTICIPANTS This was a prospect i ve , population -based study of 794 men , aged 50 - 91 ( median 73.6 ) yr who had serum testosterone measurements at baseline ( 1984 - 1987 ) and were followed for mortality through July 2004 . MAIN OUTCOME MEASURE All-cause mortality by serum testosterone level  was measured . RESULTS During an average 11.8-yr follow-up , 538 deaths occurred . Men whose total testosterone levels were in the lowest quartile ( < 241 ng/dl ) were 40 % [ hazards ratio ( HR ) 1.40 ; 95 % confidence interval ( CI ) 1.14 - 1.71 ] more likely to die than those with higher levels , independent of age , adiposity , and lifestyle . Additional adjustment for health status markers , lipids , lipoproteins , blood pressure , glycemia , adipocytokines , and estradiol levels had minimal effect on results . The low testosterone-mortality association was also independent of the metabolic syndrome , diabetes , and prevalent cardiovascular disease but was attenuated by adjustment for IL-6 and C-reactive protein . In cause-specific analyses , low testosterone predicted increased risk of cardiovascular ( HR 1.38 ; 95 % CI 1.02 - 1.85 ) and respiratory disease ( HR 2.29 ; 95 % CI 1.25 - 4.20 ) mortality but was not significantly related to cancer death ( HR 1.34 ; 95 % CI 0.89 - 2.00 ) . Results were similar for bioavailable testosterone . CONCLUSIONS Testosterone insufficiency in older men is associated with increased risk of death over the following 20 yr , independent of multiple risk factors and several preexisting health conditions The indication for testosterone therapy in aging hypogonadal men without hypothalamic , pituitary , or testicular disease remains to be eluci date d. The aim of this study was to investigate the effect of testosterone therapy on insulin sensitivity , substrate metabolism , body composition , and lipids in aging men with low normal bioavailable testosterone levels using a predefined cutoff level for bioavailable testosterone . A r and omized , double-blinded , placebo-controlled study of testosterone treatment ( gel ) was done on 38 men , aged 60–78 years , with bioavailable testosterone < 7.3 nmol/l and a waist circumference > 94 cm .  Insulin-stimulated glucose disposal ( Rd ) and substrate oxidation were assessed by euglycemic hyperinsulinemic clamps combined with indirect calorimetry . Lean body mass ( LBM ) and total fat mass ( TFM ) were measured by dual x-ray absorptiometry , and serum total testosterone was measured by t and em mass spectrometry . Bioavailable testosterone was calculated . Coefficients ( b ) represent the placebo-controlled mean effect of intervention . LBM ( b = 1.9 kg , p = 0.003 ) increased while HDL – cholesterol ( b = −0.12 mmol/l , p = 0.043 ) and TFM decreased ( b = −1.2 kg , p = 0.038 ) in the testosterone group compared to placebo . Basal lipid oxidation ( b = 5.65 mg/min/m2 , p = 0.045 ) increased and basal glucose oxidation ( b = −9.71 mg/min/m2 , p = 0.046 ) decreased in response to testosterone therapy even when corrected for changes in LBM . No significant changes in insulin-stimulated Rd was observed ( b = −0.01mg/min/m2 , p = 0.92 ) . Testosterone therapy increased muscle mass and lipid oxidation in aging men with low normal bioavailable testosterone levels ; however , our data did not support an effect of testosterone on whole-body insulin sensitivity using the euglycemic hyperinsulinemic clamp technique 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 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 OBJECTIVE In women , sex hormones cause increased morbidity and mortality in patients with coronary heart disease ( CHD ) and adversely affect the coagulation profile . We have studied the effect of physiological testosterone replacement therapy in men on coagulation factor expression , to determine if there is an increased risk of thrombosis . METHODS Double-blind , r and omized , placebo-controlled trial of testosterone in 46 men with chronic stable angina . Measurements of free , total and bioavailable testosterone , luteinising hormone ( LH ) and follicle-stimulating hormone ( FSH ) , estradiol , plasminogen activator inhibitor-1 ( PAI-1 ) , fibrinogen , tissue plasminogen activator ( tPA ) and full blood count were made at 0 , 6 and 14 weeks . RESULTS Bioavailable testosterone levels were : 2.58 + /- 0.58 nmol/l at baseline , compared with 3.35 + /- 0.31 nmol/l at week 14 ( P < 0.001 ) after treatment compared with 2.6 + /- 0.18 nmol/l and 2.44 + /- 0.18 nmol/l in the placebo group ( P was not significant ) . There was no change in fibrinogen ( 3.03 + /- 0.18 g/l at baseline and 3.02 + /- 0.18 g/l at week 14 , P = 0.24 ) , tPA activity ( 26.77 + /- 4.9 Iu/ml and 25.67 + /- 4.4 Iu/ml , P = 0.88 ) or PAI-1 activity ( 0.49 + /- 0.85 Iu/ml and 0.36 + /- 0.06 Iu/ml , P = 0.16 ) with active treatment and no differences between the groups ( at week 14 , P value 0.98 , 0.59 and 0.8 for fibrinogen , PAI-1 and tPA respectively ) . Haemoglobin concentration did not change over time , in the testosterone group ( 1.44 + /- 0.02 g/l and 1.45 + /- 0.02 g/l , P = 0.22 ) . CONCLUSION Physiological testosterone replacement does not adversely affect blood coagulation status Testosterone increases muscle mass and strength and regulates other physiological processes , but we do not know whether testosterone effects are dose dependent and whether dose requirements for maintaining various and rogen-dependent processes are similar . To determine the effects of grade d doses of testosterone on body composition , muscle size , strength , power , sexual and cognitive functions , prostate-specific antigen ( PSA ) , plasma lipids , hemoglobin , and insulin-like growth factor I ( IGF-I ) levels , 61 eugonadal men , 18 - 35 yr , were r and omized to one of five groups to receive monthly injections of a long-acting gonadotropin-releasing hormone ( GnRH ) agonist , to suppress endogenous testosterone secretion , and weekly injections of 25 , 50 , 125 , 300 , or 600 mg of testosterone enanthate for 20 wk . Energy and protein intakes were st and ardized . The administration of the GnRH agonist plus grade d doses of testosterone result ed in mean nadir testosterone concentrations of 253 , 306 , 542 , 1,345 , and 2,370 ng/dl at the 25- , 50- , 125- , 300- , and 600-mg doses , respectively . Fat-free mass increased dose dependently in men receiving 125 , 300 , or 600 mg of testosterone weekly ( change + 3.4 , 5.2 , and 7.9 kg , respectively ) . The changes in fat-free mass were highly dependent on testosterone dose ( P = 0.0001 ) and correlated with log testosterone concentrations ( r = 0.73 , P = 0.0001 ) . Changes in leg press strength , leg power , thigh and quadriceps muscle volumes , hemoglobin , and IGF-I were positively correlated with testosterone concentrations , whereas changes in fat mass and plasma high-density lipoprotein ( HDL ) cholesterol were negatively correlated . Sexual function , visual-spatial cognition and mood , and PSA levels did not change significantly at any dose . We conclude that changes in circulating testosterone concentrations , induced by GnRH agonist and testosterone administration , are associated with testosterone dose- and concentration-dependent changes in fat-free mass , muscle size , strength and power , fat mass , hemoglobin , HDL cholesterol , and IGF-I levels , in conformity with a single linear dose-response relationship . However , different and rogen-dependent processes have different testosterone dose-response relationships Background —Despite diffuse effects of sex hormones on the cardiovascular system , few prospect i ve studies have examined the relationship of plasma and rogens and estrogens with risk of cardiovascular disease ( CVD ) in postmenopausal women . Methods and Results —A nested case-control study was performed among women in the Women ’s Health Study . Two hundred women who developed CVD were matched 1:1 by age , smoking , and postmenopausal hormone therapy ( HT ) to controls who remained free of CVD . We measured testosterone , estradiol , and sex hormone binding globulin ( SHBG ) levels and calculated free and rogen index ( FAI ) , free estradiol index , and the FAI/free estradiol index ratio .  Results were stratified by HT use . Among HT nonusers , cases had significantly higher and rogen profiles ( higher median FAI and lower SHBG levels ) than controls . After adjustment for age , smoking , use of aspirin , vitamin E , and alcohol , family history of myocardial infa rct ion , and physical activity , nonusers in the lowest SHBG quartile had an OR of 2.25 ( 95 % CI , 1.03 to 4.91 ) for CVD , and there were significant trends across FAI quartiles ( P for trend=0.03 ) . Additional adjustment for body mass index , hypertension , diabetes , and elevated cholesterol eliminated associations with SHBG and FAI . Among women using HT , no significant differences in hormones or SHBG were observed among women who developed CVD and controls . Conclusions —Among HT nonusers , lower SHBG and higher FAI levels were noted among postmenopausal women who developed CVD events , but this was not independent of body mass index and other cardiovascular risk factors . Estradiol levels were not associated with risk of CVD in  HT  users or nonusers Testosterone ( T ) therapy in older men with low serum T levels increases lean body mass and decreases fat mass . These changes might improve physical performance and strength ; however , it has not been established whether T therapy improves functional outcome in older men . Moreover , concerns exist about the impact of T therapy on the prostate in older men . The administration of finasteride ( F ) , which partially blocks the conversion of T to the more potent and rogen , dihydrotestosterone , attenuates the impact of T replacement on prostate size and prostate-specific antigen . We hypothesized that T replacement in older , hypogonadal men would improve physical function and that the addition of F to this regimen would continue to provide the T-induced improvements in physical performance , strength , and body composition . Seventy men with low serum T ( < 350 ng/dl ) , age 65 yr and older , were r and omly assigned to receive one of three regimens for 36 months : 1 ) T enanthate , 200 mg i m every 2 wk , with placebo pills daily ( T-only ) ; 2 ) T enanthate , 200 mg every 2 wk , with 5 mg F daily ( T + F ) ; or 3 ) placebo injections and pills ( placebo ) . We obtained serial measurements of timed physical performance , grip strength , lower extremity strength , body composition ( by dual-energy x-ray absorptiometry ) , fasting cholesterol profiles , and hormones .  Fifty men completed the 36-month protocol . After 36 months , T therapy significantly improved performance in a timed functional test when compared with baseline and placebo [ 4.3 + /- 1.6 % ( mean + /- sem , T-only ) and 3.8 + /- 1.0 % ( T + F ) vs. -5.6 + /- 1.9 % for placebo ( P < 0.002 for both T and T + F vs. placebo ) ] and increased h and grip strength compared with baseline and placebo ( P < 0.05 ) . T therapy increased lean body mass [ 3.77 + /- 0.55 kg ( T-only ) and 3.64 + /- 0.56 kg ( T + F ) vs. -0.21 + /- 0.55 kg for placebo ( P < 0.0001 ) ] , decreased fat mass , and significantly decreased total cholesterol , low-density lipoprotein , and leptin , without affecting high-density lipoprotein , adiponectin , or fasting insulin levels . These results demonstrate that T therapy in older men with low serum T improves physical performance and strength over 36 months , when administered alone or when combined with F , and suggest that high serum levels of dihydrotestosterone are not essential for these beneficial effects of T in men
Age of study population and year of publication modified the relationship between testosterone and CVD .
Results were largely confirmed by separate analyses of free- and bioavailable testosterone .
The systematic review displayed no association between endogenous testosterone and risk for CVD in middle-aged men .
In elderly men , testosterone may weakly protect against CVD .
Alternatively , low testosterone may indicate a poor general health
CONTEXT The literature provides no clear answer as to whether low endogenous testosterone increases risk of cardiovascular disease ( CVD ) in healthy men .
OBJECTIVE Our purpose was to estimate the predictive value of testosterone for CVD and to identify study features explaining conflicting results .