title: Testosterone dose-response relationships in healthy young men. Testosterone increases human platelet thromboxane A2 receptor density and aggregation responses. Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. The effect of androgen deprivation therapy on fasting serum lipid and glucose parameters. Acute sex steroid withdrawal reduces insulin sensitivity in healthy men with idiopathic hypogonadotropic hypogonadism. The Effect of Testosterone Supplement on Insulin Sensitivity, Glucose Effectiveness, and Acute Insulin Response After Glucose Load in Male Type 2 Diabetics Treatment of hypogonadism with testosterone in patients with type 2 diabetes mellitus. Testosterone suppression in men with prostate cancer leads to an increase in arterial stiffness and hyperinsulinaemia. Changes in muscle mass, muscle strength, and power but not physical function are related to testosterone dose in healthy older men. Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure a double-blind, placebo-controlled, randomized study.
abstract: Testosterone increases muscle mass and strength and regulates other physiological processes , but we do not know whether testosterone effects are dose dependent and whether dose requirements for maintaining various and rogen-dependent processes are similar . To determine the effects of grade d doses of testosterone on body composition , muscle size , strength , power , sexual and cognitive functions , prostate-specific antigen ( PSA ) , plasma lipids , hemoglobin , and insulin-like growth factor I ( IGF-I ) levels , 61 eugonadal men , 18 - 35 yr , were r and omized to one of five groups to receive monthly injections of a long-acting gonadotropin-releasing hormone ( GnRH ) agonist , to suppress endogenous testosterone secretion , and weekly injections of 25 , 50 , 125 , 300 , or 600 mg of testosterone enanthate for 20 wk . Energy and protein intakes were st and ardized . The administration of the GnRH agonist plus grade d doses of testosterone result ed in mean nadir testosterone concentrations of 253 , 306 , 542 , 1,345 , and 2,370 ng/dl at the 25- , 50- , 125- , 300- , and 600-mg doses , respectively . Fat-free mass increased dose dependently in men receiving 125 , 300 , or 600 mg of testosterone weekly ( change + 3.4 , 5.2 , and 7.9 kg , respectively ) . The changes in fat-free mass were highly dependent on testosterone dose ( P = 0.0001 ) and correlated with log testosterone concentrations ( r = 0.73 , P = 0.0001 ) . Changes in leg press strength , leg power , thigh and quadriceps muscle volumes , hemoglobin , and IGF-I were positively correlated with testosterone concentrations , whereas changes in fat mass and plasma high-density lipoprotein ( HDL ) cholesterol were negatively correlated . Sexual function , visual-spatial cognition and mood , and PSA levels did not change significantly at any dose . We conclude that changes in circulating testosterone concentrations , induced by GnRH agonist and testosterone administration , are associated with testosterone dose- and concentration-dependent changes in fat-free mass , muscle size , strength and power , fat mass , hemoglobin , HDL cholesterol , and IGF-I levels , in conformity with a single linear dose-response relationship . However , different and rogen-dependent processes have different testosterone dose-response relationships BACKGROUND 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 The objective of this study was to assess the effects of oral testosterone supplementation therapy on glucose homeostasis , obesity and sexual function in middle-aged men with type 2 diabetes and mild and rogen deficiency . Forty-eight middle-aged men , with type 2 diabetes , ( visceral ) obesity and symptoms of and rogen deficiency , were included in this open-label study . Twenty-four subjects received testosterone undecanoate ( TU ; 120 mg daily , for 3 months ) ; 24 subjects received no treatment .  Body composition was analyzed by bio-impedance . Parameters of metabolic control were determined . Symptoms of and rogen deficiency and erectile dysfunction were scored by self-administered question naires . TU had a positive effect on ( visceral ) obesity : statistically significant reduction in body weight ( 2.66 % ) , waist-hip ratio ( -3.96 % ) and body fat ( -5.65 % ) ; negligible changes were found in the control group . TU significantly improved metabolic control : decrease in blood glucose values and mean glycated hemoglobin ( HbA1c ) ( from 10.4 to 8.6 % ) . TU treatment significantly improved symptoms of and rogen deficiency ( including erectile dysfunction ) , with virtually no change in the control group . There were no adverse effects on blood pressure or hematological , biochemical and lipid parameters , and no adverse events . Oral TU treatment of type 2 diabetic men with and rogen deficiency  improves glucose homeostasis and body composition ( decrease in visceral obesity ) , and improves symptoms of and rogen deficiency ( including erectile dysfunction ) . In these men , the benefit of testosterone supplementation therapy exceeds the correction of symptoms of and rogen deficiency and also includes glucose homeostasis and metabolic control OBJECTIVE Low levels of testosterone in men have been shown to be associated with type 2 diabetes , visceral adiposity , dyslipidaemia and metabolic syndrome . We investigated the effect of testosterone treatment on insulin resistance and glycaemic control in hypogonadal men with type 2 diabetes . DESIGN This was a double-blind placebo-controlled crossover study in 24 hypogonadal men ( 10 treated with insulin ) over the age of 30 years with type 2 diabetes . METHODS Patients were treated with i.m . testosterone 200 mg every 2 weeks or placebo for 3 months in r and om order , followed by a washout period of 1 month before the alternate treatment phase . The primary outcomes were changes in fasting insulin sensitivity ( as measured by homeostatic model index ( HOMA ) in those not on insulin ) , fasting blood glucose and glycated haemoglobin . The secondary outcomes were changes in body composition , fasting lipids and blood pressure . Statistical analysis was performed on the delta values , with the treatment effect of placebo compared against the treatment effect of testosterone . RESULTS Testosterone therapy reduced the HOMA index ( -1.73 + /- 0.67 , P = 0.02 , n = 14 ) , indicating an improved fasting insulin sensitivity . Glycated haemoglobin was also reduced ( -0.37 + /- 0.17 % , P = 0.03 ) , as was the fasting blood glucose ( -1.58 + /- 0.68 mmol/l , P = 0.03 ) . Testosterone treatment result ed in a reduction in visceral adiposity as assessed by waist circumference ( -1.63 + /- 0.71 cm , P = 0.03 ) and waist/hip ratio ( -0.03 + /- 0.01 , P = 0.01 ) . Total cholesterol decreased with testosterone therapy ( -0.4 + /- 0.17 mmol/l , P = 0.03 ) but no effect on blood pressure was observed . CONCLUSIONS Testosterone replacement therapy reduces insulin resistance and improves glycaemic control in hypogonadal men with type 2 diabetes . Improvements in glycaemic control , insulin resistance , cholesterol and visceral adiposity together represent an overall reduction in cardiovascular risk PURPOSE Although prostate cancer specific mortality is decreasing , there is little effect on overall mortality in this population , suggesting the possibility of an increased risk of death from nonprostate cancer related causes . And rogen deprivation therapy could adversely affect cardiovascular health . We investigated changes in lipid and glucose during and rogen deprivation therapy . MATERIAL S AND METHODS We performed an exploratory analysis of pooled data from 3 prospect i ve clinical trials aim ed at achieving medical castration by comparing the gonadotropin releasing hormone antagonist abarelix , the gonadotropin releasing hormone agonist leuprolide acetate and leuprolide acetate plus the anti and rogen bicalutamide . Most patients were treated in the neoadjuvant setting or because of biochemical recurrence . Fasting serum lipid , glucose and hemoglobin A1C were determined in 1,102 men at baseline , and on treatment days 85 and 169 . In the current study men were categorized into 3 treatment groups according to the type of and rogen deprivation therapy , that is leuprolide acetate , leuprolide acetate plus bicalutamide or abarelix , and statin therapy . RESULTS Significant increases in total cholesterol , triglyceride and high density lipoprotein-cholesterol were observed in patients on leuprolide acetate or abarelix  but not in patients on leuprolide acetate plus bicalutamide . Consistent changes in low density lipoprotein-cholesterol were not detected . Increased total cholesterol was usually due to an increase in high density lipoprotein-cholesterol . Hemoglobin A1C increased from baseline to day 85 only and there were no significant changes in fasting glucose measurements . The type of and rogen deprivation therapy did not affect these parameters . CONCLUSIONS Short-term and rogen deprivation therapy affects serum lipid and hemoglobin A1C independent of statin therapy CONTEXT Evidence suggests that testosterone ( T ) influences insulin sensitivity in men . The mechanism of this effect is unclear but is thought to involve changes in body composition . OBJECTIVE The aim of this study was to determine whether acute sex steroid withdrawal decreases insulin sensitivity in young , healthy men with idiopathic hypogonadotropic hypogonadism ( IHH ) . DESIGN This was a 2-wk prospect i ve study . SETTING The study was conducted at a General Clinical Research Center . PATIENTS Twelve men with IHH ( age 40.8 + /- 2.8 yr ) were studied : 1 ) on hormone replacement with normal T levels and 2 ) 2 wk after discontinuing therapy . MAIN OUTCOME MEASURES Each evaluation comprised a 75-g oral glucose tolerance test with assessment of insulin sensitivity ( fasting insulin levels , homeostatic model assessment for insulin resistance , and Matsuda insulin sensitivity index ) and insulin secretion ( corrected insulin response ) . Serum cortisol , leptin , adiponectin , free fatty acids , IL-6 , C-reactive protein , and TNF-alpha levels were also measured . RESULTS Body mass index was unchanged ( 27.1 + /- 1.1 to 27.2 + /- 1.1 kg/m(2 ) ) . Serum T levels decreased from 529 + /- 65 to 28 + /- 8 ng/dl ( P < 0.00005 ) . Fasting insulin levels increased from 4.9 + /- 0.7 to 6.2 + /- 0.6 microU/ml ( P = 0.005 ) , homeostatic model assessment of insulin resistance increased from 1.07 + /- 0.2 to 1.4 + /- 1.01 ( P < 0.005 ) , and insulin sensitivity index decreased from 11.0 + /- 2.3 to 7.5 + /- 0.7 ( P < 0.05 ) . There was a trend for fasting glucose levels to increase , 86.7 + /- 1.3 to 90.8 + /- 1.7 mg/dl ( P = 0.09 ) . IL-6 levels increased from 1.2 + /- 0.2 to 2.4 + /- 0.5 pg/ml ( P < 0.01 ) , whereas TNF-alpha levels decreased from 1.0 + /- 0.1 to 0.6 + /- 0.1 pg/ml ( P < 0.05 ) . No other significant changes were observed . CONCLUSIONS 1 ) Acute sex steroid withdrawal reduces insulin sensitivity in young healthy IHH men . 2 ) The acuity of the hypogonadism and absence of changes in body mass index or leptin levels suggest that sex steroids modulate insulin sensitivity in the absence of apparent or detectable changes in body composition Our underst and ing of the effect of and rogens on insulin action and glucose metabolism is incomplete . Several different models and methods have been used to study and rogen effects , with some studies indicating that higher testosterone levels are associated with increased insulin resistance . In polycystic ovary syndrome , where high testosterone levels are frequently found , affected patients have a higher risk of diabetes . In contrast , increased insulin resistance was found in both hypergonadotropic and hypogonadotropic men with hypo and rogenism , patients with Klinefelter 's syndrome and men with idiopathic gonadotropin deficiency . Insulin resistance is considered to be one of the cornerstones in the state that ultimately leads to clinical ly established type 2 diabetes mellitus . In addition , men with type 2 diabetes have relative hypogonadism . Therefore , supplementation with testosterone might play a role in improving both insulin resistance and hypogonadism . The study population consisted of 11 male patients with type 2 diabetes . Their mean age was 57.7 ± 3.41 years , the body mass index ( BMI ) was 24.4 ± 1.02 kg/m2 , and the waist-to-hip ratio ( W/H ) was 0.91 ± 0.05 . The patients were all treated with oral hypoglycemic agents . The men received and rogen injections every 3 weeks intramuscularly for 12 weeks . The injections were testosterone depot 100 mg/3 weeks . Insulin sensitivity , glucose effectiveness and area under acute insulin response were calculated from " minimal model " algorithms . There were no significant differences in the value of BMI , W/H ratios , plasma lipid concentrations , testosterone , homeostasis model assessment ( HOMA ) of insulin sensitivity , and beta-cell function , before and after supplementation of testosterone . Furthermore , the insulin sensitivity ( SI ) ( 1.04 ± 0.25 , 1.11 ± 0.36 x 10−5 min−1/pM ; p = 0.43 ) , glucose effectiveness ( EG ) ( 0.018 ± 0.003 , 0.017 ± 0.002 min−1 ; p = 0.29 ) , and acute insulin response ( AIR ) after a glucose load ( 45.7 ± 24.3 , 50.1 ± 32.5 pM ; p = 0.45 ) did not change significantly after supplementation with testosterone . In our study , there was no improvement of SI , EG , and AIR after 3 months of Testosterone Depot treatment in type 2 diabetes , but we believe that duration and dosage of the and rogen therapy might play an important role in improving insulin sensitivity . The mechanisms by which testosterone causes insulin resistance is unknown , and larger studies on and rogen treatment in type 2 diabetic patients are necessary OBJECTIVE To investigate the effect of testosterone treatment on insulin resistance , glycemic control , and dyslipidemia in Asian Indian men with type 2 diabetes mellitus ( T2DM ) and hypogonadism . METHODS We conducted a double-blind , placebo-controlled , crossover study in 22 men , 25 to 50 years old , with T2DM and hypogonadism . Patients were treated with intramuscularly administered testosterone ( 200 mg every 15 days ) or placebo for 3 months in r and om order , followed by a washout period of 1 month before the alternative treatment phase . The primary outcomes were changes in fasting insulin sensitivity ( as measured by homeostasis model assessment [ HOMA ] in those patients not receiving insulin ) , fasting blood glucose , and hemoglobin A1c . The secondary outcomes were changes in fasting lipids , blood pressure , body mass index , waist circumference , waist-to-hip ratio , and and rogen deficiency symptoms . Statistical analysis was performed on the delta values , with the treatment effect of placebo compared with the effect of testosterone . RESULTS Treatment with testosterone did not significantly influence insulin resistance measured by the HOMA index ( mean treatment effect , 1.67 + /- 4.29 ; confidence interval , -6.91 to 10.25 ; P>.05 ) . Mean change in hemoglobin A1c ( % ) ( -1.75 + /- 5.35 ; -12.46 to 8.95 ) and fasting blood glucose ( mg/dL ) ( 20.20 + /- 67.87 ; -115.54 to 155.94 ) also did not reach statistical significance . Testosterone treatment did not affect fasting lipids , blood pressure , and anthropometric determinations significantly . CONCLUSION In this study , testosterone treatment showed a neutral effect on insulin resistance and glycemic control and failed to improve dyslipidemia , control blood pressure , or reduce visceral fat significantly in Asian Indian men with T2DM and hypogonadism The role of and rogens in cardiovascular disease is uncertain . We aim ed to determine the vascular effects of and rogen suppression in men with prostate cancer .  Arterial stiffness ( or ' compliance ' ) was measured in 16 men ( 71+/-9 years , mean+/-S.D. ) prior to , and 3 months after , complete and rogen suppression with gonadotrophin-releasing hormone analogues as treatment for prostate cancer . Fifteen control men ( 70+/-7 years ) also had arterial stiffness studies at baseline and 3 months later . Two measures of arterial stiffness were employed : systemic arterial compliance ( SAC ) was measured by simultaneous recording of aortic flow and carotid artery pressure ( ' area method ' ) , and pulse wave velocities ( PWVs ) were recorded with the ' Complior ' system . The 16 cases underwent glucose-tolerance and fasting-lipids tests on both visits . After 3 months of testosterone suppression , there was a significant fall in SAC , which was not seen in the controls [ mean change+/-S.E.M. , -0.26+/-0.09 a.c.u . ( arbitrary compliance unit ) in the cases versus + 0.06+/-0.11 in the controls ; P = 0.03 ) . Central , but not peripheral , PWVs tended to increase in the cases ( mean change+/-S.E.M. for aorto-femoral PWV , + 0.5+/-0.4 m/s for cases versus -0.3+/-0.3 m/s for controls ; P = 0.08 ) . After testosterone suppression , fasting insulin levels increased from 6.89+/-4.84 m-units/l to 11.34+/-8.16 m-units/l ( mean+/-S.D. ) , total cholesterol increased from 5.32+/-0.77 mmol/l to 5.71+/-0.82 mmol/l and high-density lipoprotein cholesterol increased from 1.05+/-0.24 mmol/l to 1.26+/-0.36 mmol/l ; P < 0.005 for all . No significant change occurred in body-mass index , serum glucose , low-density lipoprotein cholesterol or triacylglycerol ( triglyceride ) levels . Our results indicate that loss of and rogens in men leads to an increase in aortic stiffness and serum insulin levels , and may therefore adversely affect cardiovascular risk OBJECTIVES To examine the effect of grade d doses of testosterone on physical function and muscle performance in healthy , older men . DESIGN R and omized , double-blind , placebo-controlled clinical trial . SETTING General clinical research center . PARTICIPANTS Community-dwelling healthy men aged 60 to 75 ( N=44 ) . INTERVENTION Monthly treatment with a gonadotropin-releasing hormone agonist plus 25 , 50 , 125 , or 300 mg/wk of intramuscular injections of testosterone enanthate for 20 weeks . MEASUREMENTS Skeletal muscle mass ( SMM ) was estimated using dual-energy X-ray absorptiometry . Leg press strength was measured by one repetition maximum , leg power by Nottingham Leg Rig , and muscle fatigability by repetitions to failure in the leg press exercise .  Stair climbing , 6-meter and 400-meter walking speed , and a timed-up- and -go ( TUG ) test were used to assess physical function . RESULTS Significant testosterone dose- and concentration-dependent increases were observed in SMM ( P<.001 ) and maximal strength ( P=.001 ) but not muscle fatigability . Leg power also increased dose-dependently ( P=.048 ) . In contrast , changes in self-selected normal and fast walking speed over 6 or 400 meters , stair climbing power , and time for the TUG were not significantly related to testosterone dose , testosterone concentrations , or changes in muscle strength or power , or SMM . CONCLUSION Testosterone administration was associated with dose-dependent increases in SMM , leg strength , and power but did not improve muscle fatigability or physical function . The observation that physical function scores did not improve linearly with strength suggests that these high-functioning older men were already in the asymptotic region of the curve describing the relationship between physical function and strength OBJECTIVES This study investigated the effect of a 12-week long-acting testosterone administration on maximal exercise capacity , ventilatory efficiency , muscle strength , insulin resistance , and baroreflex sensitivity ( BRS ) in elderly patients with chronic heart failure ( CHF ) . BACKGROUND CHF is characterized by a metabolic shift favoring catabolism and impairment in skeletal muscle bulk and function that could be involved in the pathophysiology of heart failure . METHODS Seventy elderly patients with stable CHF-median age 70 years , ejection fraction 31.8 + /- 7%-were r and omly assigned to receive testosterone ( n = 35 , intramuscular injection every 6 weeks ) or placebo ( n = 35 ) , both on top of optimal medical therapy . At baseline and at the end of the study , all patients underwent echocardiogram , cardiopulmonary exercise test , 6-min walk test ( 6MWT ) , quadriceps maximal voluntary contraction ( MVC ) , and isokinetic strength ( peak torque ) and BRS assessment ( sequences technique ) . RESULTS Baseline peak oxygen consumption ( VO(2 ) ) and quadriceps isometric strength showed a direct relation with serum testosterone concentration . Peak VO(2 ) significantly improved in testosterone but was unchanged in placebo .  Insulin sensitivity was significantly improved in testosterone . The MVC and peak torque significantly increased in testosterone but not in placebo . The BRS significantly improved in testosterone but not in placebo . Increase in testosterone levels was significantly related to improvement in peak VO(2 ) and MVC . There were no significant changes in left ventricular function either in testosterone or placebo . CONCLUSIONS These results suggest that long-acting testosterone therapy improves exercise capacity , muscle strength , glucose metabolism , and BRS in men with moderately severe CHF .  Testosterone benefits seem to be mediated by metabolic and peripheral effects
target: The testosterone and control groups demonstrated no significant difference for other outcomes .
  In conclusion , we found that TRT can improve glycemic control and decrease triglyceride levels of hypogonadal men with T2DM .
background: This systematic review was aim ed at assessing the metabolic effects of testosterone replacement therapy ( TRT ) on hypogonadal men with type 2 diabetes mellitus ( T2DM ) .