Adverse events associated with testosterone administration. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. Effect of transdermal testosterone treatment on serum lipid and apolipoprotein levels in men more than 65 years of age. Testosterone addition to estrogen therapy – Effects on inflammatory markers for cardiovascular disease Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique--a prospective, randomized, double-blind study. Prospective Study of Effect of Androgens on Serum Inflammatory Markers in Men Testosterone therapy increases sexual desire in ageing men with low–normal testosterone levels and symptoms of androgen deficiency Risk factors associated with cardiovascular events during testosterone administration in older men with mobility limitation. Testosterone therapy prevents gain in visceral adipose tissue and loss of skeletal muscle in nonobese aging men. Testosterone increases human platelet thromboxane A2 receptor density and aggregation responses. Effect of androgen suppression compared with androgen receptor blockade on arterial stiffness in men with prostate cancer. Osteoprotegerin levels decrease during testosterone therapy in aging men and are associated with changed distribution of regional fat. Oral testosterone undecanoate (Andriol®) supplement therapy improves the quality of life for men with testosterone deficiency Effect of oral administration of testosterone on brachial arterial vasoreactivity in men with coronary artery disease. The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. Sex Hormone Levels and Risk of Cardiovascular Events in Postmenopausal Women Effects of transdermal testosterone on lipids and vascular reactivity in older men with low bioavailable testosterone levels. The Effects of Growth Hormone and Sex Steroid on Lean Body Mass, Fat Mass, Muscle Strength, Cardiovascular Endurance and Adverse Events in Healthy Elderly Women and Men Testosterone patch for low sexual desire in surgically menopausal women: a randomized trial. Androgens promote oocyte insulin-like growth factor I expression and initiation of follicle development in the primate ovary. Relationship between serum levels of sex hormones and progression of subclinical atherosclerosis in postmenopausal women. Testosterone suppression in men with prostate cancer is associated with increased arterial stiffness Serum testosterone levels decrease in middle age in women with the polycystic ovary syndrome.
BACKGROUND Testosterone supplementation has been shown to increase muscle mass and strength in healthy older men . The safety and efficacy of testosterone treatment in older men who have limitations in mobility have not been studied . METHODS Community-dwelling men , 65 years of age or older , with limitations in mobility and a total serum testosterone level of 100 to 350 ng per deciliter ( 3.5 to 12.1 nmol per liter ) or a free serum testosterone level of less than 50 pg per milliliter ( 173 pmol per liter ) were r and omly assigned to receive placebo gel or testosterone gel , to be applied daily for 6 months . Adverse events were categorized with the use of the Medical Dictionary for Regulatory Activities classification . The data and safety monitoring board recommended that the trial be discontinued early because there was a significantly higher rate of adverse cardiovascular events in the testosterone group than in the placebo group . RESULTS A total of 209 men ( mean age , 74 years ) were enrolled at the time the trial was terminated . At baseline , there was a high prevalence of hypertension , diabetes , hyperlipidemia , and obesity among the participants . During the course of the study , the testosterone group had higher rates of cardiac , respiratory , and dermatologic events than did the placebo group . A total of 23 subjects in the testosterone group , as compared with 5 in the placebo group , had cardiovascular-related adverse events . The relative risk of a cardiovascular-related adverse event remained constant throughout the 6-month treatment period . As compared with the placebo group , the testosterone group had significantly greater improvements in leg-press and chest-press strength and in stair climbing while carrying a load . CONCLUSIONS In this population of older men with limitations in mobility and a high prevalence of chronic disease , the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events . The small size of the trial and the unique population prevent broader inferences from being made about the safety of testosterone therapy . ( Clinical Trials.gov number , NCT00240981 . 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 PURPOSE Because the effects of and rogen replacement on lipoprotein levels are uncertain , we sought to determine the effect of transdermal testosterone treatment on serum lipid and apolipoprotein levels in elderly men . SUBJECTS AND METHODS One hundred and eight healthy men more than 65 years of age who had serum testosterone concentrations > 1 SD below the mean for young men were r and omly assigned to receive either testosterone ( 54 men ; 6 mg/day ) or placebo ( 54 men ) transdermally in a double-blind fashion for 36 months . Serum concentrations of lipids and apolipoproteins were measured , and cardiovascular events recorded . RESULTS Serum total cholesterol concentrations decreased in both the testosterone-treated men and placebo-treated men , but the 3-year mean ( + /- SD ) decreases in the two groups ( testosterone treated , -17 + /- 29 mg/dL ; placebo treated , -12 + /- 38 mg/dL ) were not significantly different from each other ( P = 0.4 ) . Similarly , serum low-density lipoprotein ( LDL ) cholesterol levels decreased in both treatment groups , but the decreases in the two groups ( testosterone treated , -16 + /- 24 mg/dL ; placebo treated , -16 + /- 33 mg/dL ) were similar ( P = 1.0 ) . Levels of high-density lipoprotein ( HDL ) cholesterol , triglycerides , and apolipoproteins A-I and B did not change . Lipoprotein(a ) levels increased in both groups by similar amounts ( testosterone treated , 3 + /- 9 mg/dL ; placebo treated , 4 + /- 6 mg/dL ; P = 1.0 ) . The number of cardiovascular events was small and did not differ significantly between the  testosterone-treated  men ( 9 events ) and the placebo-treated men ( 5 events ) during the 3-year study ( relative risk = 1.8 ; 95 % confidence interval : 0.7 to 5.0 ) . CONCLUSIONS As compared with placebo , transdermal testosterone treatment of healthy elderly men for 3 years did not affect any of the lipid or apolipoprotein parameters that we measured . The effect of testosterone treatment on cardiovascular events was unclear , because the number of events was small Objective . To analyze the effects of testosterone addition to estrogen therapy in comparison with estrogen alone on cardiovascular risk factors in postmenopausal women . Methods . Fifty surgically postmenopausal women were included in this double-blind , placebo-controlled and r and omized study to receive daily oral treatment with estradiol valerate 2 mg + placebo ( E/P ) or estradiol valerate 2 mg + testosterone undecanoate 40 mg ( E/T ) for 24 weeks and then switched to the other regimen for another 24 weeks . Sex hormones , High sensitivity CRP ( hsCRP ) , Interleukin-6 ( IL-6 ) , Tissue necrosis factor (TNF)-α , Insulin-like growth factor binding globulin ( IGFBP-1 ) , vascular cell adhesion molecule (VCAM)- 1 , and homocysteine were analyzed at baseline and after 6 and 12 months . Results . Estradiol and and rogens increased as expected during the treatments . After 6 months of E/P , increases of hsCRP and IGFBP-1 and a decline of VCAM were recorded , whereas IL-6 , TNF-α , and homocysteine were unchanged . When testosterone was added to estrogen , the increase of IGFBP-1 and decline in VCAM was similar as with estrogen treatment alone . However , testosterone addition counteracted the estrogen-induced rise in hsCRP but had no effects on IL-6 , TNF-α , and homocysteine . Conclusion . Data suggest that testosterone addition to estrogen treatment in postmenopausal women has a modest influence on inflammatory markers and there were no apparent adverse effects . On the contrary , the estrogen-induced increase in hsCRP was suppressed BACKGROUND In primates , and rogens can play a synergistic role with FSH in promoting the early follicular recruitment , which is critical in assisted reproduction technique programmes . OBJECTIVE To assess whether poor responders can benefit from and rogen application . METHODS Inclusion criteria were a previous poor ovarian response to controlled ovarian stimulation and a decreased hormonal ovarian reserve . Selected women were r and omized to receive either transdermal application of testosterone ( n = 24 ) or placebo ( n = 25 ) gel for 15 days before FSH treatment for a second IVF cycle . Similar GnRH analogue and equivalent FSH daily doses were used in both cycles . The primary outcome was the total number of oocytes retrieved . RESULTS Testosterone gel application result ed in a significant increase in plasma testosterone levels but did not significantly improve the antral follicle count . Furthermore , after gel application , the main parameters of the ovarian response ( numbers of pre-ovulatory follicles , total and mature oocytes and embryos ) did not significantly differ between testosterone and placebo-treated patients . CONCLUSION No significant beneficial effects of and rogen administration on the ovarian response to FSH could be demonstrated . However , subsequent clinical trials are needed to determine whether an optimal dose and /or a longer duration of testosterone administration may be helpful Objective —Because male sex is an independent risk factor for the severity of atherosclerosis , it is possible that and rogens may be proatherogenic . There is evidence that sex hormones , particularly estrogens , regulate ( or modulate ) inflammation , a process integral to atherogenesis . Because levels of serum inflammatory markers predict cardiovascular outcomes , we prospect ively assessed the effects of and rogen therapy on these markers in older men . Methods and Results —Levels of high-sensitivity C-reactive protein ( CRP ) , soluble intracellular adhesion molecule-1 ( sICAM-1 ) , and soluble vascular cell adhesion molecule-1 ( sVCAM-1 ) were measured from sera collected at baseline and at the end of 2 r and omized double-blind placebo-controlled trials evaluating the effects of 3 months of and rogen treatment with either dihydrotestosterone ( DHT ) or recombinant human chorionic gonadotropin ( rhCG ) in healthy men aged > 60 years with partial and rogen deficiency ( serum testosterone levels < 15 nmol/L ) . For the DHT study ( 70 mg transdermally daily ) , 33 men completed 3 months of treatment ( 16 men were treated with DHT , and there were 17 controls ) . For the rhCG ( 250 & mgr;g twice weekly ) study , 20 men were treated with rhCG , and there were 20 controls . In both studies , groups were well matched for age and vascular risk factors . And rogen levels ( DHT and testosterone ) were consistently maintained at eugonadal levels throughout the trials , with estradiol markedly increased by rhCG but not DHT .  Baseline CRP levels were 0.74 to 1.49 mg/L , sVCAM-1 levels were 847 to 950 ng/mL , and sICAM-1 levels were 256 to 292 ng/mL in all groups . Neither DHT nor rhCG result ed in significant changes in CRP , sVCAM-1 , or sICAM-1 compared with placebo ( P > 0.3 in both studies ) . Conclusions —Exogenous and rogen therapy with or without increased estradiol levels does not alter serum inflammatory markers in older men ; this finding is in contrast to the effects of estrogens on inflammatory markers that have been found in postmenopausal women . These data provide a measure of reassurance concerning potential adverse cardiovascular effects of and rogen therapy in older men Although decline in sexual function is a common reason for ageing men to seek advice regarding testosterone therapy , placebo-controlled trial data have been unable to show a consistent , beneficial role for testosterone . The objective of this study was to determine the effect of testosterone therapy on sexual function in non-obese ageing men with symptoms of and rogen deficiency and low – normal serum testosterone levels . A total of 60 men aged 55 years or older in good general health with total testosterone ( TT ) levels < 15 nM , and with symptoms suggestive of and rogen deficiency , were r and omized in a double-blinded protocol to transdermal testosterone patches or placebo for 12 months  . Sexual function was assessed using the International Index of Erectile Function at weeks 0 , 26 and 52 . In men receiving testosterone TT levels increased by 30 % ( P=0.01 ) and luteinizing hormone decreased by 50 % ( P<0.001 ) . Relative to placebo , testosterone therapy improved sexual desire ( P=0.04 ) ; however other parameters of sexual function including erectile function were unaffected by the treatment . Ageing men in good general health and with symptoms of and rogen deficiency and low – normal serum testosterone levels receiving 12 months of transdermal testosterone therapy experienced , relative to placebo , improved sexual desire but no effect on other parameters of sexual function BACKGROUND Testosterone in Older Men with Mobility Limitations Trial found an increased incidence of  cardiovascular events in men r and omized to testosterone  , result ing in enrollment cessation by trial 's Data and Safety Monitoring Board . We evaluated changes in gonadal hormones and markers of inflammation and coagulation to eluci date risk factors associated with cardiovascular events . METHODS Men aged 65 years or more , with mobility limitation , total testosterone 100 - 350 ng/dL , or free testosterone less than 50 pg/mL  , were r and omized to placebo or 10 g testosterone gel daily for 6 months . Changes in total and free testosterone , estradiol and estrone , C-reactive protein , interleukin 6 , fibrinogen , plasminogen activator inhibitor-1 , and pro-brain naturetic peptide were compared between groups and within the testosterone group between subjects who experienced cardiovascular events and those who did not . RESULTS Of 209 men r and omized ( mean age 74 years ) , gonadal hormones and biomarkers were available in 179 men . Baseline body mass index , gonadal hormones , lipids , Framingham risk scores , and other biomarkers were similar in the two treatment groups . Within the testosterone group , the 6-month increase in free testosterone was significantly greater in men who experienced cardiovascular events than in those who did not [ mean ( 95 % confidence interval ) , 10.6 ( 4.6 - 16.7 ) vs 5.2 ( 3.0 - 7.5 ) ng/dL , p = .05 ] . In multivariable logistic regression analysis , the change in the serum levels of free testosterone was associated with cardiovascular events . CONCLUSION Mobility-limited older men who experienced cardiovascular events had greater increases in serum free testosterone levels than those who did not BACKGROUND Trials of testosterone therapy in aging men have demonstrated increases in fat-free mass ( FFM ) and skeletal muscle and decreases in fat mass ( FM ) but have not reported the impact of baseline body composition . OBJECTIVE The objective of the study was to determine the effect , in nonobese aging men with symptoms of and rogen deficiency and low-normal serum testosterone levels , of testosterone therapy on total and regional body composition and hormonal and metabolic indices . METHODS Sixty healthy but symptomatic , nonobese men aged 55 yr or older with total testosterone ( TT ) levels less than 15 nm were r and omized to transdermal testosterone patches or placebo for 52 wk . Body composition , by dual-energy x-ray absorptiometry ( FM , FFM , skeletal muscle ) and magnetic resonance imaging ( abdominal sc and visceral adipose tissue , thigh skeletal muscle , and intermuscular fat ) and hormonal and metabolic parameters were measured at wk 0 and 52 . RESULTS Serum TT increased by 30 % ( P = 0.01 ) , and LH decreased by 50 % ( P < 0.001 ) . Relative to placebo , total body FFM ( P = 0.03 ) and skeletal muscle ( P = 0.008 ) were increased and thigh skeletal muscle loss was prevented ( P = 0.045 ) with testosterone therapy and visceral fat accumulation decreased ( P = 0.001 ) without change in total body or abdominal sc FM ; change in visceral fat was correlated with change in TT levels ( r2 = 0.36 ; P = 0.014 ) . There was a trend to increasing total and low-density lipoprotein cholesterol with placebo . CONCLUSION Testosterone therapy , relative to placebo , selectively lessened visceral fat accumulation without change in total body FM and increased total body FFM and total body and thigh skeletal muscle mass . Further studies are needed to determine the impact of these body compositional changes on markers of metabolic and cardiovascular risk 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 Endogenous testosterone and estradiol are thought to be cardio-protective in men . We wanted to determine the effects of 2 different anti- and rogen therapies on arterial stiffness as one suppresses ( goserelin -- a gonadotrophin-releasing hormone analog ) while the other increases ( bicalutamide -- an and rogen receptor blocker ) both testosterone and estradiol . We conducted a r and omized trial on 43 men ( mean age , 71.2 + /- 6.2 years ) with localized prostate cancer . They received either goserelin or bicalutamide for 24 weeks . Carotid-femoral ( C-F ) and carotid-radial ( C-R ) pulse wave velocities ( PWVs ) were measured . Twenty age- and disease-matched men with prostate cancer on no active treatment were studied in a similar manner . After 12 weeks of goserelin , radial artery PWV increased significantly from baseline and a nonsignificant increase was observed in femoral PWV ( change from baseline radial : + 1.4 m/s , P = .002 , femoral : + 0.9 m/s , P = .127 ) Both PWV measures increased significantly with bicalutamide ( change from baseline radial : + 0.8 , femoral : + 0.9 m/s , P < or= .049 ) . PWV increased further after 24 weeks with goserelin ( change from baseline radial : + 1.7 , femoral : + 1.3 m/s , P < or= .049 for both ) but not bicalutamide ( change from baseline radial : + 0.4 , femoral : + 0.4 m/s , P not significant [ NS ] ) ; however , comparison of changes between the 2 drugs were not significantly different at either 12 or 24 weeks ( P > or= .967 at 12 weeks and P > or= .07 at 24 weeks ) . The untreated men studied in parallel showed no changes at 12 or 24 weeks in either PWV measure .  Anti- and rogen treatment in men might increase large artery stiffness , an adverse cardiovascular risk factor ; however , the effect was not maintained with testosterone receptor blockade , in the longer term , but tended to be sustained with suppression therapy . This could relate to the different sex hormone effects of the 2 therapies The cardiovascular effects of testosterone treatment are debated . Osteoprotegerin ( OPG ) is an independent marker of cardiovascular risk . We investigated the effect of testosterone therapy on OPG levels in aging men with low normal bioavailable testosterone levels . A r and omized , double-blinded , placebo-controlled study of 6 months testosterone therapy ( gel )  in 38 men aged 60 - 78 years with bioavailable testosterone < 7.3 nmol/l and waist circumference > 94 cm was performed .  Clinical evaluation , OPG , and C-reactive protein ( CRP ) measurements were carried out . Lean body mass ( LBM ) , total fat mass , and bone mineral density ( BMD ) were established by dual X-ray absorptiometry . Visceral adipose tissue ( VAT ) and subcutaneous adipose tissue ( SAT ) were measured by magnetic resonance imaging . Power calculation was based on an increase in LBM during testosterone therapy and responders were defined as testosterone treated patients with increased LBM ( Δ LBM positive ) , n=14 . Data are presented as median ( interquartile range ) . Testosterone therapy  decreased total fat mass and SAT , whereas VAT was unchanged ( n=38 ) . OPG levels decreased during testosterone therapy ( from 2.0 ( 1.9 - 2.5 ) to 1.9 ( 1.6 - 2.2 ) ng/ml , p<0.05 vs. placebo ) , whereas CRP levels were unchanged ( n=38 ) . In responders to testosterone therapy ( n=14 ) , ΔOPG levels were inversely associated with ΔSAT ( r= - 0.60 , p=0.03 ) and positively associated with ΔVAT ( r=0.56 , p=0.04 ) . OPG levels  decreased during testosterone therapy suggesting decreased cardiovascular risk . Decreased OPG levels were associated with changes in regional fat distribution and future studies are needed to further evaluate the association between OPG and regional fat mass distribution In a single-blind , placebo-controlled study , the effects of a 3-month oral administration of 160 mg/day testosterone undecanoate ( And riol ® ) on the quality of life of men with testosterone deficiency were evaluated . The subjects included ten men with primary hypogonadism and 29 with and ropause with sexual dysfunction as the most common problem . The changes in subjective symptoms were evaluated by the PNUH QoL scoring system and the St. Louis University Question naire for and rogen deficiency in aging males ( ADAM ) . Digital rectal examination ( DRE ) was performed and serum testosterone , prostate-specific antigen ( PSA ) and liver profile were monitored . Testosterone undecanoate treatment ( n = 33 ) significantly improved sexual dysfunction and symptom scores of metabolic , cardiopulmonary , musculo-skeletal and gastrointestinal functions compared to baseline and to placebo ( n = 6 ) . ADAM score also significantly improved after 3 months of treatment . Serum testosterone was significantly increased compared to pretreatment levels only in the testosterone undecanoate group . In the placebo group , no significant changes compared to baseline were found for testosterone levels and QoL question naires . No abnormal findings were detected on DRE or laboratory findings in either group . Adverse events , such as gastrointestinal problems and fatigue , were mild and self-limiting . It is concluded that and rogen supplement therapy with oral testosterone undecanoate ( And riol ) restores the quality of life through improvement of general body functions in men with testosterone deficiency H igh and rogen levels in men have been regarded as a risk factor for coronary artery disease ( CAD ) . However , it has recently been demonstrated that supplements of and rogens inhibit atheroma formation in castrated male animals , suggesting that testosterone may be antiatherosclerotic . In men with angina pectoris , a significant inverse correlation was found between plasma testosterone levels and the extent of CAD , demonstrating that low testosterone levels could be a risk factor for CAD . Other reports suggest that testosterone replacement therapy in men with CAD has a beneficial effect on angina pectoris and exercise-induced ST-segment depression . Another study showed that testosterone enhanced endotheliumindependent coronary artery dilation and flow-mediated brachial arterial vasoreactivity in men with CAD . In this study , we assessed the effects of oral testosterone administration on brachial arterial vasoreactivity in men with CAD . • • • Thirty-five men ( aged 58 8 years ) with CAD were r and omized to placebo ( n 17 ) or treatment group ( n 18 ) . Demographics of the study group are summarized in Table 1 . Diagnostic criteria of CAD are a history of unstable and stable angina pectoris with angiographic evidence ( 50 % stenosis of lumen diameter ) . Exclusion criteria were inflammatory disease or malignancy , ejection fraction 45 % , clinical evidence of heart failure , and Q-wave myocardial infa rct ion within 3 months before the study . The treatment group completed oral administration of 160 mg of testosterone undecanoate ( And riol , N.V. Organon , Oss , The Netherl and s ) daily for 4 weeks followed by 80 mg testosterone undecanoate for 8 weeks , in addition to their current medication . Using high-resolution ultrasound , we assessed brachial arterial vasoreactivity to reactive hyperemia ( flow-mediated dilation ) and sublingual nitroglycerin ( nitroglycerin-mediated dilation ) at baseline and after 12 weeks of treatment . Patients taking nitrates discontinued therapy 24 hours before the study to avoid nitrate tolerance . A 10-MHz linear phased-array ultrasound transducer ( GE Vigmed Ultrasound , Horten , Norway ) was used to image the dominant arm brachial artery longitudinally 3 to 5 cm just above the antecubital fossa . All patients rested in the supine position for 10 minutes in a quiet room . After the depth and gain setting were optimized to identify the vessel wall , the brachial artery diameter was measured from the anterior to the posterior interface between the media and the adventitia and determined at end-diastole on B mode . Reactive hyperemia was induced by inflation and then deflation of a pneumatic cuff placed around the upper arm . The blood pressure cuff was inflated to 250 mm Hg for 5 minutes . After release of the cuff , brachial artery diameter was measured within the first 15 seconds of reactive hyperemia . The brachial artery was allowed to return to the baseline level until 10 minutes after cuff release . Then , a further baseline brachial artery diameter was obtained . Nitroglycerin , 0.6 mg , was then given sublingually , and the brachial artery diameter was measured for the ensuing 3 minutes . The percent change in diameter caused by reactive hyperemia was calculated by dividing the difference from baseline end-diastolic diameter by the baseline value . The percent change in diameter caused by nitroglycerin administration was also calculated in the same way . Blood pressure and heart rate were measured before the examination . All data were calculated as an average of 4 consecutive cardiac cycles . Early morning blood sampling for fasting lipid profiles was performed and plasma-free testosterone levels were obtained immediately before ultrasound imaging and 12 weeks later . A st and ard radioimmunoassay method was used for analysis ( DSL-4900 kit , Diagnostic System Laboratory Inc. , Houston , Texas ) . All descriptive data are presented as mean SD and analyzed using SPSS for Windows 9.0 ( SPSS Inc. , Chicago , Illinois ) From the Cardiology Division , Yonsei Cardiovascular Center and Cardiovascular Research Institute , College of Medicine , Seoul ; and Department of Food and Nutrition , College of Ecology , Yonsei University , Seoul , South Korea . Dr. Jang ’s address is : Cardiology Division , Yonsei Cardiovascular Center , Yonsei University College of Medicine , 134 , Shinchon-Dong , Seodaemun-Gu , Seoul 120 - 752 , South Korea . E-mail : jangys1212@yumc.yonsei.ac.kr . Manuscript received August 10 , 2001 ; revised manuscript received and accepted December 10 , 2001 . TABLE 1 Clinical Characteristics of Study Testosterone has immune-modulating properties , and current in vitro evidence suggests that testosterone may suppress the expression of the proinflammatory cytokines TNFalpha , IL-1beta , and IL-6 and potentiate the expression of the antiinflammatory cytokine IL-10 . We report a r and omized , single-blind , placebo-controlled , crossover study of testosterone replacement ( Sustanon 100 ) vs. placebo in 27 men ( age , 62 + /- 9 yr ) with symptomatic and rogen deficiency ( total testosterone , 4.4 + /- 1.2 nmol/liter ; bioavailable testosterone , 2.4 + /- 1.1 nmol/liter ) . Compared with placebo , testosterone induced reductions in TNFalpha ( -3.1 + /- 8.3 vs. 1.3 + /- 5.2 pg/ml ; P = 0.01 ) and IL-1beta ( -0.14 + /- 0.32 vs. 0.18 + /- 0.55 pg/ml ; P = 0.08 ) and an increase in IL-10 ( 0.33 + /- 1.8 vs. -1.1 + /- 3.0 pg/ml ; P = 0.01 ) ; the reductions of TNFalpha and IL-1beta were positively correlated ( r(S ) = 0.588 ; P = 0.003 ) . In addition , a significant reduction in total cholesterol was recorded with testosterone therapy ( -0.25 + /- 0.4 vs. -0.004 + /- 0.4 mmol/liter ; P = 0.04 ) . In conclusion , testosterone replacement shifts the cytokine balance to a state of reduced inflammation and lowers total cholesterol .  Twenty of these men had established coronary disease , and because total cholesterol is a cardiovascular risk factor , and proinflammatory cytokines mediate the development and complications associated with atheromatous plaque , these properties may have particular relevance in men with overt vascular disease Background —Despite diffuse effects of sex hormones on the cardiovascular system , few prospect i ve studies have examined the relationship of plasma and rogens and estrogens with risk of cardiovascular disease ( CVD ) in postmenopausal women . Methods and Results —A nested case-control study was performed among women in the Women ’s Health Study . Two hundred women who developed CVD were matched 1:1 by age , smoking , and postmenopausal hormone therapy ( HT ) to controls who remained free of CVD . We measured testosterone , estradiol , and sex hormone binding globulin ( SHBG ) levels and calculated free and rogen index ( FAI ) , free estradiol index , and the FAI/free estradiol index ratio .  Results were stratified by HT use . Among HT nonusers , cases had significantly higher and rogen profiles ( higher median FAI and lower SHBG levels ) than controls . After adjustment for age , smoking , use of aspirin , vitamin E , and alcohol , family history of myocardial infa rct ion , and physical activity , nonusers in the lowest SHBG quartile had an OR of 2.25 ( 95 % CI , 1.03 to 4.91 ) for CVD , and there were significant trends across FAI quartiles ( P for trend=0.03 ) . Additional adjustment for body mass index , hypertension , diabetes , and elevated cholesterol eliminated associations with SHBG and FAI . Among women using HT , no significant differences in hormones or SHBG were observed among women who developed CVD and controls . Conclusions —Among HT nonusers , lower SHBG and higher FAI levels were noted among postmenopausal women who developed CVD events , but this was not independent of body mass index and other cardiovascular risk factors . Estradiol levels were not associated with risk of CVD in  HT  users or nonusers BACKGROUND Sex hormones are known to affect cholesterol levels and vascular tone in women . The effects of testosterone on cholesterol and vascular tone in men are less well understood . Low testosterone levels have been associated with higher cholesterol levels in epidemiologic studies , but testosterone replacement has result ed in variable changes in cholesterol levels . Similarly , clinical studies suggest that testosterone may be vasodilatory , but few studies have directly evaluated the effects of testosterone on vascular tone . METHODS Sixty-seven men ( mean age 76 + /- 4 years , range 65 - 87 ) with bioavailable testosterone levels below 4.44 nmol/l ( lower limit for adult normal range ) were r and omized to receive transdermal testosterone  ( 2 - 2.5 mg patches/d ) or placebo patches for 1 year . Twenty-three men ( 34 % ) withdrew from the study ; 44 men completed the trial . RESULTS While total cholesterol , triglyceride , and low-density lipoprotein cholesterol levels did not significantly change during the year of therapy , high-density lipoprotein ( HDL ) levels ( p = .004 ) and , specifically , HDL(2 ) subfraction ( p = .02 ) decreased in men receiving testosterone supplementation . Vascular tone was measured by brachial artery reactivity in 36 men . Endothelium-dependent brachial artery reactivity did not change from baseline measurements in men receiving transdermal testosterone  ( 0.3 + /- 6.7 % to 1.6 + /- 4.6 % ; p = .58 ) or in the placebo group ( 3.2 + /- 5.5 % to 0.7 + /- 5.5 % ; p = .23 ) . CONCLUSIONS Transdermal testosterone decreased HDL(2 ) cholesterol but did not affect vascular reactivity in men older than 65 years selected for low testosterone levels . No study to date has addressed the direct relationship between testosterone replacement and cardiovascular events Decreases in growth hormone ( GH ) and insulin-like growth factor I occur with age , in addition to oestrogen deficiency in women and a reduction in the levels of testosterone in men . These age-related hormonal changes may contribute to reductions in lean body mass , muscle strength and cardiac endurance , which can be partially reversed in elderly people with GH treatment , and testosterone supplements and oestrogen/progestin hormone replacement therapy in men and women , respectively . These treatments are , however , thought to have potentially serious adverse effects . We conducted a study to evaluate the separate and interactive effects of GH and sex steroids on body composition , muscle strength and cardiac endurance as well as the rate of adverse events in healthy elderly people . The results of the study showed that although there were beneficial effects with GH and sex steroid treatment , a high percentage of adverse effects occurred after 26 weeks of treatment , demonstrating a need for more research on the safety of hormonal therapy in the elderly population OBJECTIVE To assess the efficacy and safety of a 300 mug/d testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women on concomitant estrogen therapy . METHODS Five hundred thirty-three women with hypoactive sexual desire disorder who had undergone previous hysterectomy and bilateral oophorectomy were enrolled in a 24-week , multicenter , double-blind , placebo-controlled trial . Patients were r and omly assigned to receive placebo or the testosterone patch twice weekly . The primary efficacy endpoint was change from baseline at week 24 in the frequency of total satisfying sexual activity , measured by the Sexual Activity Log . Secondary measures included sexual desire using the Profile of Female Sexual Function and personal distress as measured by the Personal Distress Scale . Hormone levels , adverse events , and clinical laboratory measures were review ed . RESULTS Total satisfying sexual activity significantly improved in the testosterone patch group compared with placebo after 24 weeks ( mean change from baseline , 1.56 compared with 0.73 episodes per 4 weeks , P = .001 ) . Treatment with the testosterone patch also significantly improved sexual desire ( mean change , 10.57 compared with 4.29 , P < .001 ) and decreased personal distress ( P = .009 ) . Serum free , total , and bioavailable testosterone concentrations increased from baseline . Overall , adverse events were similar in both groups ( P > .05 ) . The incidence of and rogenic adverse events was higher in the testosterone group ; most and rogenic adverse events were mild . CONCLUSION In surgically menopausal women with hypoactive sexual desire disorder , a 300 mug/d testosterone patch significantly increased satisfying sexual activity and sexual desire , while decreasing personal distress , and was well tolerated through up to 24 weeks of use In the study reported here , we investigated the effect of and rogens on recruitment of resting , primordial follicles into the actively growing pool . Healthy , r and om-cycling female rhesus monkeys were treated with testosterone , dihydrotestosterone ( DHT ) , or vehicle for 3 - 10 days , after which ovaries were collected for histological analysis . The first stage of follicle growth is the formation of the primary follicle , consisting of an oocyte surrounded by a single layer of cuboidal granulosa cells . The number of primary follicles was significantly increased over time in testosterone-treated animals . In situ hybridization showed that and rogen treatment result ed in an increase to 3-fold in insulin-like growth factor I ( IGF-I ) and to 5-fold in IGF-I receptor mRNA in primordial follicle oocytes . DHT effects were comparable to those of testosterone , showing that these are and rogen receptor-mediated phenomena . These data show that and rogens promote initiation of primordial follicle growth and implicate oocyte-derived IGF-I in this activation process BACKGROUND Postmenopausal hormone therapy has been examined extensively in relation to cardiovascular disease . However , research relating serum levels of sex hormones to cardiovascular disease is sparse , and the results are inconclusive . METHODS We measured sex hormones in longitudinally collected sample s of 180 postmenopausal women , 91 r and omized to 17beta-estradiol and 89 to placebo , in the Estrogen in the Prevention of Atherosclerosis Trial . Repeated measures of sex hormone levels were tested for an association with carotid artery intima-media thickness ( CIMT ) , which was also assessed longitudinally over 2 yr . RESULTS In all women , changes in serum estrone ( P = 0.02 ) , total estradiol ( P = 0.01 ) , free estradiol ( P = 0.02 ) , and SHBG ( P = 0.005 ) were significantly inversely associated with CIMT progression , controlling for age and body mass index . All the estrogen compounds and SHBG were significantly inversely related with low-density lipoprotein cholesterol and positively associated with high-density lipoprotein cholesterol ( all P < 0.0001 ) , whereas free testosterone was positively related with low-density lipoprotein cholesterol and inversely associated with high-density lipoprotein cholesterol ( P < 0.003 ) . Despite an increase in serum-free estradiol with estradiol therapy , women with unchanged SHBG and free testosterone levels had an average ( se ) progression in CIMT of 8.53 ( 4.72 ) microm/yr , whereas women with increased free estradiol and SHBG and decreased free testosterone had the largest reduction in CIMT progression [ -5.45 ( 2.77 ) microm/yr ; trend P = 0.03 ] . CONCLUSION Estrogen and SHBG are associated with reduced sub clinical atherosclerosis progression in healthy postmenopausal women . These associations are partially mediated by their beneficial effects on lipids . Among women taking estradiol , the most beneficial hormone profile for CIMT progression was increased free estradiol and SHBG with concomitant decreased free testosterone Low and rogen levels in men are associated with increased cardiovascular risk , through unclear mechanisms . We measured arterial stiffness ( ' compliance ' ) in 21 men receiving complete testosterone suppression therapy for prostate cancer , and in 25 controls .  Systemic arterial compliance ( SAC ) , which assesses proximal aortic stiffness , was calculated by simultaneous recording of aortic flow and carotid artery pressure ( the ' area method ' ) . Aorto – femoral ( A – F ) , aorto – radial ( A – R ) and femoral – dorsalis pedis ( F – DP ) pulse-wave velocities ( PWVs ) were recorded using the ' Complior ' system . SAC was significantly lower in the and rogen-depleted men compared to controls ( 0.81 ± 0.53 vs. 1.18 ± 0.43 arbitrary compliance units , p = 0.01 , mean ± SD ) . Correspondingly , their A – F PWV was higher ( 14.1 ( 10.1–21.8 ) vs. 12.4 ( 9.6–17.4 ) m/s , p = 0.03 , median ( range ) ) . Cases tended to be older ( 75 ± 7 vs. 71 ± 6 years , p = 0.07 ) , and to have higher systolic blood pressure ( 148 ± 22 vs. 143 ± 17 mmHg , p = 0.40 ) ; however , SAC was still significantly lower ( p = 0.03 ) after adjustment for age and stratification for central systolic pressure ( ≤ or > the median ) . Adjustment of A – F PWV for age and central systolic pressure reduced significance to p = 0.07 . There was no significant difference in peripheral PWVs between groups . In conclusion , testosterone suppression is associated with increased aortic stiffness , only partly explained by age and blood pressure . Loss of and rogens in men might therefore adversely affect cardiovascular risk OBJECTIVE To determine whether testosterone levels change as women with the polycystic ovary syndrome ( PCOS ) grow older . DESIGN A follow-up cross-sectional study of a cohort of women with PCOS identified up to 20 - 25 years ago . SETTING Women with PCOS were recruited primarily from practice records between 1970 and 1990 .  Voter registration tapes and household directories were used to identify age- , race- , and neighborhood-matched controls . PARTICIPANT(S ) Eighty-four women with PCOS , 20 - 57 years of age , and 37 age-matched controls participating in a study of the risk for cardiovascular disease in women with PCOS . INTERVENTION(S ) Clinical data were collected by question naire and fasting blood sample s were obtained r and omly throughout the menstrual cycle . MAIN OUTCOME MEASURE(S ) Total and non-SHBG-bound testosterone levels . RESULT ( S ) Total and non-SHBG-bound testosterone levels were similar in women with PCOS who were 20 - 42 years of age but were reduced by approximately 50 % among women 42 - 47 years of age and remained stable in women older than 47 years of age . Testosterone levels were increased in younger and older women with PCOS compared with controls but were similar to controls in women 42 - 47 years of age . CONCLUSION ( S ) Hyper and rogenism partly resolves before menopause in women with PCOS . This change may explain the tendency of women with PCOS to cycle regularly as they grow older . Testosterone levels remain elevated in older women with PCOS , however , and may contribute to their increased risk for cardiovascular disease , endometrial cancer , and other diseases
Conclusions The effects of testosterone on cardiovascular-related events varied with source of funding .
Nevertheless , overall and particularly in trials not funded by the pharmaceutical industry , exogenous testosterone increased the risk of cardiovascular-related events , with corresponding implication s for the use of testosterone therapy
Background Testosterone therapy is increasingly promoted .
No r and omized placebo-controlled trial has been implemented to assess the effect of testosterone therapy on cardiovascular events , although very high levels of and rogens are thought to promote cardiovascular disease .