Endogenous Sex Hormones and Cardiovascular Disease Incidence in Men 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 Low serum testosterone and mortality in older men. Testosterone and visceral fat in midlife women: the Study of Women's Health Across the Nation (SWAN) fat patterning study. Glycated hemoglobin measurement and prediction of cardiovascular disease. Impact of long-term testosterone treatment on plasma levels of free TFPI and TF-induced thrombin generation ex vivo in elderly men with low testosterone levels. 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. Low serum testosterone and estradiol predict mortality in elderly men. A 5-year follow-up study of disease incidence in men with an abnormal hormone pattern. Testosterone increases human platelet thromboxane A2 receptor density and aggregation responses. Lower testosterone levels predict incident stroke and transient ischemic attack in older men. Endocrine aspects of male sexual dysfunctions. Predictive value of waist-to-hip ratio on cardiovascular risk events Laboratory-based and office-based risk scores and charts to predict 10-year risk of cardiovascular disease in 182 countries: a pooled analysis of prospective cohorts and health surveys. Interrelation between plasma testosterone and plasma insulin in healthy adult men: the Telecom Study Extremes of endogenous testosterone are associated with increased risk of incident coronary events in older women. Short Adult Stature Predicts Impaired &bgr;-Cell Function, Insulin Resistance, Glycemia, and Type 2 Diabetes in Finnish Men Psychological distress as a risk factor for cardiovascular events: pathophysiological and behavioral mechanisms. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. L-arginine supplementation and risk factors of cardiovascular diseases in healthy men: a double-blind randomized clinical trial. Association between endogenous plasma hormone concentrations and fracture risk in men and women: the EPIC-Oxford prospective cohort study Mortality in participants and non-participants of a multifactorial prevention study of cardiovascular diseases: a 28 year follow up of the Helsinki Businessmen Study. Estimating the benefits of modifying risk factors of cardiovascular disease: a comparison of primary vs secondary prevention.
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 ( 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 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 Visceral fat ( VF ) increases with the menopause and is an independent predictor of the metabolic syndrome , diabetes , and cardiovascular disease ( CVD ) in women . Little is known about how hormonal changes during the menopausal transition are related to the increase in VF . We aim ed to determine the relationship between bioavailable testosterone and VF in middle-aged women at various stages of the menopausal transition and whether this relationship is independent of age and other CVD risk factors . The Study of Women 's Health Across the Nation ( SWAN ) is a longitudinal , community-based study . This report uses baseline data from a population -based longitudinal ancillary study at the Chicago site to examine the cross-sectional relationship between testosterone and computed tomography (CT)-assessed VF  in women at different stages of the menopausal transition . Included are 359 women ( 47.2 % black ) , aged 42 - 60 years , who were r and omly selected from a complete community census in which a 72 % participation rate was achieved . In multivariate models , bioavailable testosterone was associated with VF independent of age , race , percent total body fat , and other cardiovascular risk factors . Bioavailable testosterone was a stronger predictor than estradiol and was interchangeable in its strength of association with sex hormone-binding globulin ( SHBG ) . As bioavailable testosterone was associated with VF even after adjusting for insulin resistance , this suggests that it plays an important role in regional fat distribution . Our findings may have direct implication s in explaining the effect of menopause-related testosterone predominance on VF accumulation and subsequent cardiovascular risk IMPORTANCE The value of measuring levels of glycated hemoglobin ( HbA1c ) for the prediction of first cardiovascular events is uncertain . OBJECTIVE To determine whether adding information on HbA1c values to conventional cardiovascular risk factors is associated with improvement in prediction of cardiovascular disease ( CVD ) risk . DESIGN , SETTING , AND PARTICIPANTS Analysis of individual-participant data available from 73 prospect i ve studies involving 294,998 participants without a known history of diabetes mellitus or CVD at the baseline assessment . MAIN OUTCOMES AND MEASURES Measures of risk discrimination for CVD outcomes ( eg , C-index ) and reclassification ( eg , net reclassification improvement ) of participants across predicted 10-year risk categories of low ( < 5 % ) , intermediate ( 5 % to < 7.5 % ) , and high ( ≥ 7.5 % ) risk . RESULTS During a median follow-up of 9.9 ( interquartile range , 7.6 - 13.2 ) years , 20,840 incident fatal and nonfatal CVD outcomes ( 13,237 coronary heart disease and 7603 stroke outcomes ) were recorded . In analyses adjusted for several conventional cardiovascular risk factors , there was an approximately J-shaped association between HbA1c values and CVD risk . The association between HbA1c values and CVD risk changed only slightly after adjustment for total cholesterol and triglyceride concentrations or estimated glomerular filtration rate , but this association attenuated somewhat after adjustment for concentrations of high-density lipoprotein cholesterol and C-reactive protein . The C-index for a CVD risk prediction model containing conventional cardiovascular risk factors alone was 0.7434 ( 95 % CI , 0.7350 to 0.7517 ) . The addition of information on HbA1c was associated with a C-index change of 0.0018 ( 0.0003 to 0.0033 ) and a net reclassification improvement of 0.42 ( -0.63 to 1.48 ) for the categories of predicted 10-year CVD risk . The improvement provided by HbA1c assessment in prediction of CVD risk was equal to or better than estimated improvements for measurement of fasting , r and om , or postload plasma glucose levels . CONCLUSIONS AND RELEVANCE In a study of individuals without known CVD or diabetes , additional assessment of HbA1c values in the context of CVD risk assessment provided little incremental benefit for prediction of CVD risk Men have a higher incidence of cardiovascular disease ( CVD ) than women of similar age , and it has been suggested that testosterone may influence the development of CVD . Recently , we demonstrated that elderly men with low testosterone levels had lower plasma levels of free tissue factor pathway inhibitor ( TFPI ) Ag associated with shortened tissue factor (TF)-induced coagulation initiation in a population based case-control study . Our hypothesis was that one year of testosterone treatment to physiological levels in elderly men would increase the levels of free TFPI Ag in plasma and have a favorable effect on TF-induced coagulation .  Twenty-six men with low testosterone levels ( < or = 11.0 nM ) were r and omly assigned to treatment with intramuscular testosterone depot injections ( testosterone undecanoate 1,000 mg ) or placebo in a double-blinded study . Each participant received a total of five injections , at baseline , 6 , 16 , 28 and 40 weeks , and TF-induced thrombin generation ex vivo and plasma free TFPI Ag were measured after one year . At the end of the study total and free testosterone levels were significantly higher in the testosterone treated group ( 14.9 + /- 4.5 nM vs. 8.1 + /- 2.4 nM ; p < 0.001 , and 363.3 + /- 106.6 pM vs. 187.3 + /- 63.2 pM ; p < 0.001 , respectively ) . Testosterone treatment for one year did neither cause significant changes in TF-induced thrombin generation ex vivo nor changes in plasma levels of free TFPI Ag . In conclusion , normalising testosterone levels by testosterone treatment for 12 months in elderly men did not affect TF-induced coagulation or plasma TFPI levels . The potential antithrombotic role of testosterone therapy remains to be eluci date 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 Age-related reduction of serum testosterone may contribute to the signs and symptoms of aging , but previous studies report conflicting evidence about testosterone levels and male mortality . No large prospect i ve cohort study has determined a possible association between serum estradiol and mortality in men . OBJECTIVE The main objective was to examine the association between serum testosterone and estradiol and all-cause mortality  in elderly men . DESIGN , SETTING , AND PARTICIPANTS We used specific gas chromatography-mass spectrometry to analyze serum sex steroids at baseline in older men who participated in the prospect i ve population -based MrOS Sweden cohort ( n = 3014 ; mean age , 75 yr ; range , 69 - 80 yr ) . MAIN OUTCOME MEASURE All-cause mortality by serum testosterone and estradiol levels . RESULTS During a mean follow-up period of 4.5 yr , 383 deaths occurred . In multivariate hazards regression models , low levels ( within quartile 1 vs. quartiles 2 - 4 ) of both testosterone [ hazard ratio ( HR ) , 1.65 ; 95 % confidence interval ( CI ) , 1.29 - 2.12 ] and estradiol ( HR , 1.54 ; 95 % CI , 1.22 - 1.95 ) associated with mortality . A model including both hormones showed that both low testosterone ( HR , 1.46 ; 95 % CI , 1.11 - 1.92 ) and estradiol ( HR , 1.33 ; 95 % CI , 1.02 - 1.73 ) predicted mortality . Risk of death nearly doubled ( HR , 1.96 ; 95 % CI , 1.46 - 2.62 ) in subjects with low levels of both testosterone and estradiol compared with subjects within quartiles 2 - 4 of both hormones . CONCLUSIONS Elderly men with low serum testosterone and estradiol have increased risk of mortality , and subjects with low values of both testosterone and estradiol have the highest risk of mortality OBJECTIVES Previous studies have suggested that abnormal levels of cortisol and testosterone might increase the risk of serious somatic diseases . To test this hypothesis , we conducted a 5-year follow-up study in middle-aged men . METHODS A population -based cohort study conducted in 1995 amongst 141 Swedish men born in 1944 , in whom a clinical examination supplemented by medical history aim ed to disclose the presence of cardiovascular disease ( CVD ) ( myocardial infa rct ion , angina pectoris , stroke ) , type 2 diabetes and hypertension were performed at baseline and at follow-up in the year 2000 . In addition ,  salivary cortisol levels  were measured repeatedly over the day .  Serum testosterone concentrations  were also determined . Using the baseline data , an algorithm was constructed , which classified the secretion pattern of cortisol and testosterone from each individual as being normal or abnormal . RESULTS By the end of follow-up , men with an abnormal hormone secretion pattern ( n = 73 ) had elevated mean arterial pressure ( P = 0.003 ) , fasting insulin ( P = 0.009 ) and insulin : glucose ratio ( P = 0.005 ) compared with men with a normal secretion pattern ( n = 68 ) . Body mass index , waist circumference , and waist : hip ratio were significantly elevated in both groups . However , the 5-year incidence of CVD , type 2 diabetes , and hypertension were significantly higher ( P < 0.001 ) in men with an abnormal neuroendocrine secretory pattern compared to men with a normal pattern . CONCLUSIONS These data suggest that an abnormal neuroendocrine secretory pattern is prospect ively associated with an increased incidence of cardiovascular-related events and type 2 diabetes 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 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 INTRODUCTION Endocrine disorders may adversely affect men 's sexual function . AIM To provide recommendations based on best evidence for diagnosis and treatment of endocrine-related male sexual dysfunctions .  METHODS The Endocrine Aspects of Male Sexual Dysfunctions Committee , including 11 members from eight countries and four continents , collaborated with the Endocrine subcommittee of the St and ards Committee of the International Society for Sexual Medicine . Medical literature was review ed in detail , followed by extensive internal committee discussion over 2 years , then public presentation and discussion with the other experts before finalizing the report . MAIN OUTCOME MEASURE Recommendations based on grading of evidence -base medical literature and interactive discussion . RESULTS From animal studies , it is derived that testosterone modulates mechanisms involved in erectile machinery , including expression of enzymes that both initiate and terminate erection . In addition , testosterone is essential for sexual motivation . Whether these findings could be extrapolated to human erections is unclear . Testosterone plays a broad role in men 's overall health . Recent studies have established strong associations between low testosterone and metabolic and cardiovascular imbalances . In some studies , low testosterone decreased longevity ; however , longitudinal studies do not support the predictive value of low testosterone for further cardiovascular events . The article proposes a st and ardized process for diagnosis and treatment of endocrine-related male sexual dysfunctions , updating the knowledge on testosterone and prostate safety . There is no compelling evidence that testosterone treatment causes prostate cancer or its progression in men without severe testosterone deficiency ( TD ) . The possible roles of prolactin and thyroid hormones are also examined . CONCLUSIONS Men with erectile dysfunction , hypoactive sexual desire and retarded ejaculation  , as well as those with visceral obesity and metabolic diseases , should be screened for TD and treated . Prospect i ve interventional studies are required before screening for TD in more conditions , including cardiovascular diseases , and considering correction as preventive medicine as much data suggests BACKGROUND : A central distribution of adipose tissue is frequently associated with cardiovascular disease ( CVD ) and its risk factors . METHODS : Clinical usefulness of  waist-to-hip ratio ( WHR )  for predicting the risk of cardiovascular events , estimated with models based on data from the Framingham and Prospect i ve Cardiovascular Münster ( PROCAM ) studies was evaluated . SUBJECTS : These were 552 men and 160 women , asymptomatic and at risk for CVD , aged 30–74 y , recruited from an ongoing risk factor screening program conducted at worksites . RESULTS : Abdominal fatness was a strong predictor of cardiovascular complications in subjects whose WHR was in the top quintile ( > 0.98 for men and > ; 0.91 for women ) . The estimated percentage rate of coronary heart disease ( CHD , P<0.01 ) and death ( P<0.01 ) , myocardial infa rct ion ( P<0.01 ) , stroke ( P<0.01 ) , total CVD ( P<0.001 ) and death ( P<0.01 ) increased with increasing quintile of WHR in men and women . In the highest WHR , the number of subjects exceeding a 15 % risk of developing a coronary event over the next 10 y was more than two-fold greater ( odds ratio ( OR ) 2.60 ( confidence intervals ( CI ) 1.09–6.54 ) than in the lowest WHR quintiles . Similar six-year myocardial infa rct ion ( MI ) risks at each quintile of WHR were observed in men in both Framingham and PROCAM models . In the overall population , CHD estimates increased with increasing quintiles of WHR with the Framingham model and an adapted model for estimating probabilities of disease in the French population of the Prévention Cardiovasculaire en Médecine du Travail ( PCV-METRA ) group . CONCLUSION : Abdominal deposition of fat assessed by WHR may be of strong clinical value for predicting high risk of cardiovascular events BACKGROUND Worldwide implementation of risk-based cardiovascular disease ( CVD ) prevention requires risk prediction tools that are contemporarily recalibrated for the target country and can be used where laboratory measurements are unavailable . We present two cardiovascular risk scores , with and without laboratory-based measurements , and the corresponding risk charts for 182 countries to predict 10-year risk of fatal and non-fatal CVD in adults aged 40 - 74 years . METHODS Based on our previous laboratory-based prediction model ( Globorisk ) , we used data from eight prospect i ve studies to estimate coefficients of the risk equations using proportional hazard regressions . The laboratory-based risk score included age , sex , smoking , blood pressure , diabetes , and total cholesterol ; in the non-laboratory ( office-based ) risk score , we replaced diabetes and total cholesterol with BMI . We recalibrated risk scores for each sex and age group in each country using country-specific mean risk factor levels and CVD rates . We used recalibrated risk scores and data from national surveys ( using data from adults aged 40 - 64 years ) to estimate the proportion of the population at different levels of CVD risk  for ten countries from different world regions as examples of the information the risk scores provide ; we applied a risk threshold for high risk of at least 10 % for high-income countries ( HICs ) and at least 20 % for low-income and middle-income countries ( LMICs ) on the basis of national and international guidelines for CVD prevention . We estimated the proportion of men and women who were similarly categorised as high risk or low risk by the two risk scores . FINDINGS Predicted risks for the same risk factor profile were generally lower in HICs than in LMICs , with the highest risks in countries in central and southeast Asia and eastern Europe , including China and Russia . In HICs , the proportion of people aged 40 - 64 years at high risk of CVD ranged from 1 % for South Korean women to 42 % for Czech men ( using a ≥10 % risk threshold ) , and in low-income countries ranged from 2 % in Ug and a ( men and women ) to 13 % in Iranian men ( using a ≥20 % risk threshold ) . More than 80 % of adults were similarly classified as low or high risk by the laboratory-based and office-based risk scores . However , the office-based model substantially underestimated the risk among patients with diabetes . INTERPRETATION Our risk charts provide risk assessment tools that are recalibrated for each country and make the estimation of CVD risk possible without using laboratory-based measurements . FUNDING National Institutes of Health Summary Plasma insulin is a risk factor for diabetes mellitus and cardiovascular disease in men . We investigated the association between  plasma testosterone and plasma insulin  in an occupational sample of 1292 healthy adult men .  Total plasma testosterone  decreased with each decade of age and insulin increased with each decade of age . In these cross-sectional data , this significant grade d inverse association between testosterone and insulin was independent of age . The association was reduced but not explained by the addition of obesity and subscapular skinfold to the model . Adjustment for alcohol consumption , cigarette smoking and plasma glucose did not material ly alter the association . These results are the reverse of the positive association of and rogens with insulin in women and suggest alternative possible explanations for the effect of hyperinsulinaemia on cardiovascular disease risk . Prospect i ve studies will be necessary to determine the direction and causal nature of this association 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 Context : Recent studies have highlighted the role of height in complex diseases , but conflicting information has been reported on height as a predictor of changes in glycemia and risk of type 2 diabetes . Objective : Our aim was to investigate the association of height with insulin sensitivity , insulin secretion , glycemia , type 2 diabetes , and cardiovascular disease ( CVD ) in a large prospect i ve population -based study . Design : The study included 8746 Finnish men ( mean ± st and ard deviation , age 57.2 ± 7.1 years , body mass index , 26.8 ± 3.8 kg/m2 ) selected from a population -based Metabolic Syndrome in Men ( METSIM ) study . Setting : The study was conducted at Kuopio University Hospital and University of Eastern Finl and . Participants : The participants were nondiabetic at the recruitment , and 5401 subjects have participated in the follow-up study . During the follow-up , a total of 693 subjects converted to type 2 diabetes and 351 were diagnosed with a new CVD event during the follow-up . Main Outcome Measures : The main outcome measures were incidence of type 2 diabetes and CVD . Results : Height measured at baseline was significantly associated with lower levels of 2-hour glucose in an oral glucose tolerance test , an increase in insulin secretion , a decrease in the risk of type 2 diabetes [ hazard ratio ( HR ) = 0.83(confidence interval [ CI ] 0.77 to 0.90 ) ] and CVD [ HR = 0.75(CI 0.67 to 0.83 ) ] during the follow-up . Conclusion : Short stature is associated with unfavorable changes in glucose metabolism and predicts an increase in the risk of type 2 diabetes and cardiovascular events OBJECTIVES This study sought to estimate the extent to which behavioral and pathophysiological risk factors account for the association between  psychological distress  and incident cardiovascular events . BACKGROUND The intermediate processes through which psychological distress increases the risk of cardiovascular disease ( CVD ) are incompletely understood . An underst and ing of these processes is important for treating psychological distress in an attempt to reduce CVD risk . METHODS In a prospect i ve study of 6,576 healthy men and women ( ages 50.9 + /- 13.1 years ) , we measured psychological distress ( using the 12-item version of the General Health Question naire > or=4 ) and behavioral ( smoking , alcohol , physical activity ) and pathophysiological ( C-reactive protein , fibrinogen , total and high-density lipoprotein cholesterol , obesity , hypertension ) risk factors at baseline . The main outcome was CVD events ( hospitalization for nonfatal myocardial infa rct ion , coronary artery bypass , angioplasty , stroke , heart failure , and CVD-related mortality ) . RESULTS Cigarette smoking , physical activity , alcohol intake , C-reactive protein , and hypertension were independently associated with psychological distress . There were 223 incident CVD events ( 63 fatal ) over an average follow-up of 7.2 years . The risk of CVD increased in relation to presence of psychological distress in age- and sex-adjusted models ( hazard ratio : 1.54 , 95 % confidence interval : 1.09 to 2.18 , p = 0.013 ) . In models that were adjusted for potential mediators , behavioral factors explained the largest proportion of variance ( approximately 65 % ) , whereas pathophysiological factors accounted for a modest amount ( C-reactive protein approximately 5.5 % , hypertension , approximately 13 % ) . CONCLUSIONS The association between psychological distress and CVD risk is largely explained by behavioral processes . Therefore , treatment of psychological distress that aims to reduce CVD risk should primarily focus on health behavior change IMPORTANCE Rates of testosterone therapy are increasing and the effects of testosterone therapy on cardiovascular outcomes and mortality are unknown . A recent r and omized clinical trial of testosterone therapy in men with a high prevalence of cardiovascular diseases was stopped prematurely due to adverse cardiovascular events raising concerns about testosterone therapy safety . OBJECTIVES To assess the association between testosterone therapy and all-cause mortality , myocardial infa rct ion ( MI ) , or stroke among male veterans and to determine whether this association is modified by underlying coronary artery disease . DESIGN , SETTING , AND PATIENTS A retrospective national cohort study of men with low testosterone levels ( < 300 ng/dL ) who underwent coronary angiography in the Veterans Affairs ( VA ) system between 2005 and 2011 . MAIN OUTCOMES AND MEASURES Primary outcome was a composite of all-cause mortality , MI , and ischemic stroke . RESULTS Of the 8709 men with a total testosterone level lower than 300 ng/dL , 1223 patients started testosterone therapy after a median of 531 days following coronary angiography . Of the 1710 outcome events , 748 men died , 443 had MIs , and 519 had strokes . Of 7486 patients not receiving testosterone therapy  , 681 died , 420 had MIs , and 486 had strokes . Among 1223 patients receiving testosterone therapy , 67 died , 23 had MIs , and 33 had strokes . At 3 years after coronary angiography , the Kaplan-Meier estimated cumulative percentages with events were 19.9%in the no testosterone therapy group vs 25.7%in the testosterone therapy group , with an absolute risk difference of 5.8%(95%CI , -1.4%to 13.1 % ) [corrected].The Kaplan-Meier estimated cumulative percentages with events among the no testosterone therapy group vs testosterone therapy group at 1 year after coronary angiography were 10.1 % vs 11.3 % ; at 2 years , 15.4 % vs 18.5 % ; and at 3 years , 19.9 % vs 25.7 [corrected].There was no significant difference in the effect size of testosterone therapy among those with and without coronary artery disease ( test for interaction , P = .41 ) . CONCLUSIONS AND RELEVANCE Among a cohort of men in the VA health care system who underwent coronary angiography and had a low serum testosterone level , the use of testosterone therapy was associated with increased risk of adverse outcomes . These findings may inform the discussion about the potential risks of testosterone therapy Context : The effect of L-arginine on risk factors of cardiovascular diseases ( CVD ) has mostly focused on western countries . Since cardiovascular diseases is the second cause of death in Iran and , as far as we are aware , there have been no studies about the effect of L-arginine on CVD risk factors , the aim of this trial was to assess the effects of L-arginine supplementation on CVD risk factors in healthy men . Objective : The purpose of this study was to evaluate the effect of low-dose L-arginine supplementation on CVD risk factors ( lipid profile , blood sugar and blood pressure ) in Iranian healthy men . Design , setting , participants : We conducted a double-blind r and omized controlled trial in 56 patients selected from sport clubs at the Isfahan University of Medical Science between November 2013 and December 2013 . Interventions : Healthy men received L-arginine supplementation ( 2000 mg daily ) in the intervention group or placebo ( 2000 mg maltodextrin daily ) in the control group for 45 days . Main outcome measure : The primary outcome measures were we measured the levels of fasting blood sugar , blood pressure and lipid profile including triglyceride ( TG ) , cholesterol , LDL and HDL in healthy subjects . It was hypothesized that these measures would be significantly improved in those receiving L-arginine supplementation . at the beginning and end of the study . Results : In this trial , we had complete data for 52 healthy participants with mean age of 20.85±4.29 years . At the end of study , fasting blood sugar ( P=0.001 ) and lipid profile ( triglycerideTG ( P<0.001 ) , cholesterol ( P<0.001 ) , LDL ( P=0.04 ) , HDL ( P=0.015 ) ) decreased in the L-arginine group but we found no significant change in the placebo group . In addition , the reduction of fasting blood sugar and lipid profile in L-arginine was significant compared with placebo group . No significant changes were found about systolic ( P=0.81 ) and diastolic blood pressure either in L-arginine or placebo group . ( P=0.532 ) . Conclusion : The use of L-arginine significantly improved outcomes compared to placebo Sex steroids have an important role in bone health , however previous studies on fracture risk have been carried out in older population s. The EPIC-Oxford study is a prospect i ve cohort of men and women living in the UK . Five years after recruitment , participants self-reported previous fractures .  Sex steroid concentrations ( plasma estradiol , testosterone and sex hormone binding globulin )  were measured in 436 cases ( 155 men , 46 premenopausal women and 235 postmenopausal women ) with an incident fracture and 868 matched controls .  Fracture risk was inversely related to concentrations of estradiol among men ( RR for a doubling of estradiol 0.35 , 95 % CI 0.44–0.96 ) but there was no association between fracture risk and testosterone levels . There were no clear associations between fracture risk and hormone levels among postmenopausal women , however there was suggestion of an inverse association for both estradiol and testosterone as the RR in the highest compared with the lowest tertile for estradiol was 0.74 ( 95 % CI 0.46 , 1.18 ) and testosterone was 0.75 ( 95 % CI 0.49 , 1.16 ) . Among premenopausal women fracture risk was inversely associated with levels of testosterone ( RR for doubling of testosterone 0.46 , 95 % CI 0.26–0.81 ) , with no association between estradiol and fracture risk . SHBG was not associated with risk of fracture among either men or women . In summary , this study finds evidence of an inverse association between endogenous estradiol and risk of fracture in men , and between endogenous testosterone and risk of fracture in premenopausal women but no clear associations among postmenopausal women OBJECTIVE --To investigate pretrial risk factors and long term mortality ( 1964 - 1992 ) in participants and non- participants of a multifactorial primary prevention trial . DESIGN --A prospect i ve study among 3313 initially healthy businessmen . During the 1960s ( 1964 onwards ) , 3490 healthy male business executives born between 1919 and 1934 participated in voluntary health checks at the Institute of Occupational Health in Helsinki . From that period cardiovascular disease ( CVD ) risk factors were available in 3313 men . In the beginning of the 1970s these men were invited to join a multifactorial primary prevention trial of CVD . Six groups were formed : ( I ) healthy participants in a high risk intervention group ( n = 612 ) , and ( II ) their r and omised control group ( n = 610 ) ; ( III ) a non-participant low risk group ( n = 593 ) ; ( IV ) an excluded group with signs of CVD ( n = 563 ) ; ( V ) a refused group ( n = 867 ) ; and ( VI ) dead ( n = 68 ) . Groups I and II participated in the five year prevention trial which started in 1974 . Other groups were followed up through registers , with no personal contact . MEASUREMENTS --Cardiovascular risk factors during the 1960s . Mortality follow up using national registers up to 31 December , 1992 . MAIN RESULTS --Baseline risk factors were lowest in the low risk group , highest in the excluded group , intermediate and comparable in other groups . Eighteen-year ( 1974 - 1992 ) mortality ( per 1000 ) was 79.3 , 106.6 , 155.2 , 179.9 , and 259.3 in the low risk , control , intervention , refused , and excluded groups , respectively ( P < 0.001 ) . In the whole population of 3313 men , the 28-year ( 1964 - 1992 ) total ( n = 577 ) and coronary deaths ( n = 199 ) were significantly predicted by smoking , blood pressure , and cholesterol ; cancer deaths ( n = 163 ) by smoking only ; and violent deaths ( n = 83 ) by none of the risk factors . One-hour postload glucose was significantly associated with total mortality in the intervention group only . When the intervention and control groups were included in the same model , the effect of group on total mortality tended to be dependent on the 1 h blood glucose value ( P = 0.06 for the group by 1 h glucose interaction term ) . CONCLUSION --The traditional risk factors ( smoking , blood pressure , and cholesterol ) are significantly associated with 28-year mortality in this high social class population with previous health education . Conversely , a " clustering " of low risk factors predicted low total , coronary , and cancer mortality . The findings on 1 h blood glucose suggest that factors related to glucose tolerance explain in part the excess mortality in the intervention group compared with the control group OBJECTIVES To compare the potential years of life saved ( YOLS ) associated with risk factor modification in the primary and secondary prevention of cardiovascular disease ( CVD ) . METHODS The CVD life expectancy model estimates the risk of death due to coronary disease , stroke , and other causes based on the levels of independent risk factors ( such as age , blood pressure , and blood lipid levels ) found in the cohort of the Lipid Research Clinics . The model was vali date d by comparing its predictions with the observed fatal outcomes of 9 r and omized clinical trials . We then estimated the YOLS associated with treating hyperlipidemia or hypertension among hypothetical patient groups with and without CVD at baseline . We defined high-risk patients as those with 3 risk factors ( hyperlipidemia , cigarette smoking , and hypertension ) and low-risk patients as those with isolated hypertension or hyperlipidemia . RESULTS The fatal events predicted by the model were consistent with the clinical trial results . Among men and women with hyperlipidemia without CVD , the forecasted benefits of lipid therapy  were substantially greater among high-risk groups vs low-risk groups ( 4.74 - 0.78 YOLS vs 2.50 - 0.25 YOLS , respectively ) . Among those with CVD , the forecasted benefits of treatment were similar for both high-risk and low-risk groups ( 4.65 - 0.65 YOLS vs 3.84 - 0.58 YOLS , respectively ) . The results for  hypertension  therapy also demonstrated greater benefits for high-risk vs low-risk patients undergoing primary prevention therapy ( 1.34 - 0.29 YOLS vs 0.85 - 0.13 YOLS , respectively ) , and the forecasted benefits in secondary prevention were similar ( 1.26 - 0.23 YOLS vs 1.00 - 0.23 YOLS , respectively ) . CONCLUSIONS The clinical approach to risk factor modification in primary prevention should be different from that in secondary prevention . The forecasted benefits of therapy among patients without CVD are greatest in the presence of other risk factors . Among those with CVD , the benefits of therapy are equivalent , thereby obviating the need to target high-risk patients
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 .