title: Lower testosterone levels predict incident stroke and transient ischemic attack in older men. Low serum testosterone and mortality in older men. Low serum testosterone and mortality in male veterans. Cortisol, Testosterone, and Coronary Heart Disease: Prospective Evidence From the Caerphilly Study Low serum testosterone and estradiol predict mortality in elderly men. Serum sex hormone levels and myocardial infarction in the Honolulu Heart Program. Pitfalls in prospective studies on sex hormones. Relationship between androgenic hormones and arterial stiffness, based on longitudinal hormone measurements. Endogenous Sex Hormones and Cardiovascular Disease Incidence in Men Progression in intima media thickness—the significance of hormonal biomarkers of chronic stress A 5-year follow-up study of disease incidence in men with an abnormal hormone pattern. Circulating estradiol is an independent predictor of progression of carotid artery intima-media thickness in middle-aged men. Plasma levels of estradiol, testosterone, and DHEAS do not predict risk of coronary artery disease in men. Usefulness of sex steroid hormone levels in predicting coronary artery disease in men. Steroid sex hormones and peripheral arterial disease in the Edinburgh Artery Study Adrenal androgens and testosterone as coronary risk factors in the Helsinki Heart Study. Effect of intravenous testosterone on myocardial ischemia in men with coronary artery disease.
abstract: 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 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 BACKGROUND Low serum testosterone is a common condition in aging associated with decreased muscle mass and insulin resistance . This study evaluated whether low testosterone levels are a risk factor for mortality in male veterans . METHODS We used a clinical data base to identify men older than 40 years with repeated testosterone levels obtained from October 1 , 1994 , to December 31 , 1999 , and without diagnosed prostate cancer . A low testosterone level was a total testosterone level of less than 250 ng/dL ( < 8.7 nmol/L ) or a free testosterone level of less than 0.75 ng/dL ( < 0.03 nmol/L ) . Men were classified as having a low testosterone level ( 166 [ 19.3 % ] ) , an equivocal testosterone level ( equal number of low and normal levels ) ( 240 [ 28.0 % ] ) , or a normal testosterone level ( 452 [ 52.7 % ] ) . The risk for all-cause mortality was estimated using Cox proportional hazards regression models , adjusting for demographic and clinical covariates over a follow-up of up to 8 years . RESULTS Mortality in men with normal testosterone levels was 20.1 % ( 95 % confidence interval [ CI ] , 16.2%-24.1 % ) vs 24.6 % ( 95 % CI , 19.2%-30.0 % ) in men with equivocal testosterone levels and 34.9 % ( 95 % CI , 28.5%-41.4 % ) in men with low testosterone levels . After adjusting for age , medical morbidity , and other clinical covariates , low testosterone levels continued to be associated with increased mortality ( hazard ratio , 1.88 ; 95 % CI , 1.34 - 2.63 ; P<.001 ) while equivocal testosterone levels were not significantly different from normal testosterone levels ( hazard ratio , 1.38 ; 95 % CI , 0.99%-1.92 % ; P=.06 ) . In a sensitivity analysis , men who died within the first year ( 50 [ 5.8 % ] ) were excluded to minimize the effect of acute illness , and low testosterone levels continued to be associated with elevated mortality . CONCLUSIONS Low testosterone levels were associated with increased mortality in male veterans . Further prospect i ve studies are needed to examine the association between low testosterone levels and mortality Background —There is a popular belief that chronic stress causes heart disease through psychoneuroendocrine mechanisms . We have examined whether an elevated circulating cortisol-to-testosterone ratio increases the risk of ischemic heart disease . Methods and Results —We undertook a prospect i ve cohort study of 2512 men aged 45 to 59 years between 1979 and 1983 from Caerphilly , South Wales , with a mean follow-up of 16.5 years . Subjects underwent a clinical examination , and morning fasting blood sample s were taken for analysis of cortisol levels , testosterone levels , and other cardiovascular risk factors . The ratio of cortisol to testosterone showed weak associations with potential confounding factors but strong positive associations with components of the insulin resistance syndrome ( P<0.001 ) . A positive linear trend was seen across quintiles of cortisol : testosterone ratio for incident ischemic heart disease ( age-adjusted OR per z score change in ratio 1.22 , 95 % CI 1.07 to 1.38 , P=0.003 ) . This was markedly attenuated after adjustment for components of the insulin resistance syndrome ( age-adjusted OR per z score change in ratio 1.10 , 95 % CI 0.96 to 1.25 , P=0.18 ) . There was no association between the cortisol : testosterone ratio and other causes of death ( age-adjusted hazard ratio 0.99 , 95 % CI 0.88 to 1.11 , P=0.81 ) . Conclusions —This is the first population -based prospect i ve study that has found a specific association between cortisol : testosterone ratio and incident ischemic heart disease , apparently mediated through the insulin resistance syndrome . Whether this reflects the effects of chronic stress , behavioral factors , or genetic influences remains to be determined 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 It has been hypothesized that hyperestrogenemia may underlie myocardial infa rct ion . As a test of this hypothesis , the serum estradiol and testosterone levels were estimated in sample s collected prospect ively from 96 male patients aged 52 - 74 years [ mean age 60.8 + /- 6.3 ( SD ) ] who had had a myocardial infa rct ion and from 96 matched control subjects in the Honolulu Heart Program . Established risk factors for myocardial infa rct ion were measured prospect ively . No significant difference between patients and control subjects in mean estradiol or testosterone level was observed . The only established risk factor that was significantly different was blood pressure , which was higher in the patients . Thus , the data did not confirm the hypothesis . However , two major pitfalls for prospect i ve studies of estradiol in myocardial infa rct ion , which might have affected the validity of the results , were observed , namely , deterioration of estradiol values with prolonged storage ( 8.5 - 12 years in this study ) and intervention . The value of this study , therefore , may lie in pointing out difficulties in carrying out prospect i ve studies on sex hormones Circulating testosterone levels ( T ) decrease with age in men . Low T has been associated with coronary disease and with risk factors for atherosclerosis . This study examines the relationship in men between and rogenic hormones and arterial stiffness , a major risk factor for cardiovascular events . T , sex hormone-binding globulin ( SHBG ) , and dehydroepi and rosterone sulfate ( DHEAS ) were measured longitudinally over 33 yr ( follow-up 11.8 + /- 8.3 yr ) in 901 men from the Baltimore Longitudinal Study of Aging , of whom 206 ( 68.1 + /- 13.7 yr ) underwent carotid duplex ultrasonography .  The 901 men were used to characterize age-associated hormone levels by means of mixed-effects models . Hormone values were estimated for the 206 men at the time of ultrasonography . Free T index ( FTI ) was calculated by dividing T by SHBG . The arterial stiffness index was calculated from peak systolic and end diastolic diameters of the common carotid artery and simultaneous brachial artery blood pressure . T , FTI , and DHEAS were correlated negatively with age , pulse pressure ( PP ) , and stiffness index ( each P < 0.01 ) , whereas SHBG was correlated positively with age and stiffness index ( P < 0.01 ) . However , T was the only hormone that predicted the stiffness index after adjustment for age , PP , fasting plasma glucose , body mass index , and total cholesterol . T values 5 - 10 yr before the carotid study also predicted the stiffness index ( P < 0.05 ) . Thus the adverse influence of low T on the cardiovascular system in men may be mediated in part via the effects of T on vascular structure and function 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 ( OBJECTIVE The pathophysiological pathways from stress caused by psychosocial stress to IHD has not been dealt with very extensively . The objective of this study was to analyse the association between cortisol levels and progression in intima media thickness ( IMT ) . METHODS AND RESULTS In 1998 and 2002 , 95 participants went through a clinical investigation including ultrasound of the artery carotis communis .  Progression in IMT was analysed in relation to levels of salivary cortisol in 1998 and the average levels of salivary cortisol in 1998/2002 . Further , the significance of conventional coronary risk factors , testosterone and dehydro-epi and rosterone sulphate ( DHEAS ) were evaluated . Among the men , only age and HDL-cholesterol ( negative ) were significantly correlated with progression in IMT . Among the women , awakening cortisol response was significantly correlated with progression in IMT . Testosterone and DHEAS were borderline significantly associated ( negatively ) with progression in IMT in both genders . CONCLUSION Progression in atherosclerosis were determined by different risk factors in women and men . The awakening cortisol response was of great importance to IMT progression in women but not in men 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 CONTEXT Estrogen treatment of men with prostate cancer is associated with increased cardiovascular morbidity and mortality ; however , the role of endogenous estrogen levels for atherosclerotic disease in men is unknown . OBJECTIVE The objective of the study was to determine whether endogenous serum estradiol ( E2 ) levels predict the progression of carotid artery intima-media thickness in men . DESIGN , SETTING AND PARTICIPANTS This was a population -based , prospect i ve cohort study ( the Atherosclerosis and Insulin Resistance study ) conducted in Göteborg , Sweden , among 313 Caucasian men without cardiovascular or other clinical ly overt diseases .  Carotid artery intima-media thickness , an index of pre clinical atherosclerosis , was measured by ultrasound at baseline ( 58 yr of age ) and after 3 yr of follow-up .  Serum sex hormone levels and cardiovascular risk factors  ( body mass index , waist to hip ratio , systolic blood pressure , serum triglycerides  , plasma c-peptide , and smoking status ) were assessed at study entry . INTERVENTION There was no intervention . MAIN OUTCOME MEASURES Association between baseline total and free E2 levels and progression of carotid intima-media thickness over 3 yr with adjustments for cardiovascular risk factors was measured . RESULTS In univariate analyses , both total and free E2 levels at baseline were positively associated with the annual change in intima-media thickness . In linear regression models including E2 and cardiovascular risk factors , low-density lipoprotein and high-density lipoprotein cholesterol and E2 were identified as independent predictors of progression of carotid artery intima-media thickness ( total E2 beta = 0.187 , P = 0.001 ; and free E2 beta = 0.183 , P = 0.003 ) . CONCLUSIONS Circulating E2 is a predictor of progression of carotid artery intima-media thickness  in middle-aged men . Further studies are needed to investigate the role of endogenous E2 for incident cardiovascular disease events Prior studies have reported men with coronary artery disease ( CAD ) to have elevated plasma levels of estrogens and reduced concentrations of dehydroepi and rosterone ( DHEA ) or DHEA-sulfate ( DHEAS ) . We investigated whether gonadal steroids or DHEAS are risk factors for CAD in men , using a prospect i ve design , in a well characterized population studied at regular intervals . We studied 46 men ( Cardiac group ) who developed CAD and 124 men ( Control group ) who remained free of CAD ( mean follow-up , 9.5 years ) . We measured  testosterone ( T ) , estradiol ( E2 ) , and DHEAS  , as well as  plasma binding of T and E2  , in sample s stored before the onset of CAD ( Cardiac group ) or at matched times ( Control group ) . Body mass index , blood pressure , and total serum cholesterol were measured at each visit . Both systolic blood pressure ( SBP ; P less than 0.001 ) and cholesterol ( P less than 0.001 ) were increased in the Cardiac group , but no significant differences were found in total or free T or E2 , the ratio of E2/T , or DHEAS between the two groups . The difference in cholesterol was significant only in men less than or equal to 65 years old ( P less than 0.001 ) , and SBP only in men greater than 65 years old ( P less than 0.005 ) . Cholesterol ( P less than 0.05 ) and E2 ( P less than 0.001 ) appeared to decrease with age in the Cardiac , but not the Control , group . Moreover , total ( P less than 0.01 ) and free E2 ( P less than 0.05 ) were lower only in Cardiac men less than or equal to 55 years old . ( ABSTRACT TRUNCATED AT 250 WORDS The relation between sex hormone levels and subsequent risk of a major coronary event was studied in a nested case-control study among 163 men in the Multiple Risk Factor Intervention Trial who later had a major coronary event and in 163 controls . Cases and controls were matched for age , serum cholesterol level , r and omization group , r and omization date and clinic . Blood sample s were collected at baseline before r and omization and frozen at -70 degrees C. Follow-up extended over 6 to 8 years . Sixty-one patients had a nonfatal acute myocardial infa rct ion and 102 fatal infa rct ion .  Total and free testosterone , total and free estradiol , and rostenedione and estrone concentrations were measured . There were no significant differences between cases and controls for any sex hormone level . There was also no difference in the ratio of testosterone to estradiol . Controlling for other cardiovascular risk factors did not change these results . These results do not support previous case-control studies of a relation between sex hormone levels and risk of heart attack among men Although treatment with high dose exogenous sex hormones affects cardiovascular risk , the role of physiological levels of endogenous sex hormones in the development of atherosclerotic disease in men and women is unknown . Forty men and 43 women wit peripheral arterial disease and 88 age- and sex-matched controls were selected from participants in the Edinburgh Artery Study , a r and om survey of 1592 men and women ages 55 - 74 years from the general population . Compared with sex-matched controls , male cases had higher systolic blood pressure ( 155.5 mmHg vs. 138.7 mmHg ; p < or = 0.01 ) and waist hip ratio ( 0.92 vs. 0.89 ; p < or = 0.05 ) and female cases had higher lifetime smoking ( square root of packyears 2.14 vs. 1.03 ; p < or = 0.05 ) . Mean estrone levels were slightly higher in male cases than controls ( 101.9 pmol/Liter vs. 92.1 pmol/Liter ; p = 0.09 ) , but this association lost significance after multivariate adjustment for age and body mass index . Mean levels of total and free testosterone , estradiol , and sex hormone binding globulin were not significantly different in cases compared with controls in either sex ( p > 0.1 ) . These results , in accordance with previous prospect i ve studies on coronary artery disease , do not support a role for physiological levels of endogenous sex hormones in the development of peripheral arterial disease in men or postmenopausal women We investigated the role of adrenal and rogens , cortisol , testosterone and sex-hormone binding globulin ( SHBG ) as coronary risk factors using a nested case-control design . The study population consisted of 62 cases with cardiac end-points and 97 controls on placebo during the last 4 years in the Helsinki Heart Study .  Serum concentrations of dehydroepi and rosterone , dehydroepi and rosterone sulfate ( DHEAS ) , and rostenedione , and rostanediol glucuronide , cortisol , testosterone , and SHBG  at the first annual visit of the 5-year study period were determined by radioimmunoassays . The only significant difference was found in DHEAS , with cases having higher levels than controls ( P < 0.04 ) . DHEAS levels were positively associated with smoking ( P < 0.001 ) , alcohol consumption ( P < 0.04 ) and triglyceride levels ( P < 0.002 ) and with systolic ( P < 0.04 ) and diastolic ( P < 0.006 ) blood pressures , and negatively associated with age ( P < 0.01 ) and HDL-cholesterol ( P < 0.03 ) . The association between DHEAS and the CHD risk was studied using logistic regression analyses with the classical risk factors -- age , smoking , blood pressure , and lipid levels -- as covariates in the models . Studies of the joint effects of age and DHEAS disclosed that the risk associated with elevated DHEAS was confirmed to older men ( odds ratio ( OR ) 7.3 , 95 % , CI 2.3 - 23.3 ) . A similar analysis with smoking revealed that the DHEAS-related risk was mainly found in smokers ( OR 3.4 , 95 % CI 1.5 - 8.2 ) . One possible explanation for these results is that some form of mild steroid biosynthetic defect of the adrenals or functional adrenal hyperplasia associated with high DHEAS levels increases the CHD risk in this population 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
target: 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
background: 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 .