T. Hugh Jones

Low-Dose Transdermal Testosterone Therapy Improves Angina Threshold in Men With Chronic Stable Angina A Randomized, Double-Blind, Placebo-Controlled Study

BackgroundExperimental studies suggest that androgens induce coronary vasodilatation. We performed this pilot project to examine the clinical effects of long-term low-dose androgens in men with angina. Methods and ResultsForty-six men with stable angina completed a 2-week, single-blind placebo run-in, followed by double-blind randomization to 5 mg testosterone daily by transdermal patch or matching placebo for 12 weeks, in addition to their current medication. Time to 1-mm ST-segment depression on treadmill exercise testing and hormone levels were measured and quality of life was assessed by SF-36 at baseline and after 4 and 12 weeks of treatment. Active treatment resulted in a 2-fold increase in androgen levels and an increase in time to 1-mm ST-segment depression from (mean±SEM) 309±27 seconds at baseline to 343±26 seconds after 4 weeks and to 361±22 seconds after 12 weeks. This change was statistically significant compared with that seen in the placebo group (from 266±25 seconds at baseline to 284±23 seconds after 4 weeks and to 292±24 seconds after 12 weeks;P =0.02 between the 2 groups by ANCOVA). The magnitude of the response was greater in those with lower baseline levels of bioavailable testosterone (r =−0.455, P <0.05). There were no significant changes in prostate specific antigen, hemoglobin, lipids, or coagulation profiles during the study. There were significant improvements in pain perception (P =0.026) and role limitation resulting from physical problems (P =0.024) in the testosterone-treated group. ConclusionsLow-dose supplemental testosterone treatment in men with chronic stable angina reduces exercise-induced myocardial ischemia.

The Effect of Testosterone Replacement on Endogenous Inflammatory Cytokines and Lipid Profiles in Hypogonadal Men

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 randomized, single-blind, placebo-controlled, crossover study of testosterone replacement (Sustanon 100) vs. placebo in 27 men (age, 62 +/- 9 yr) with symptomatic androgen 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.

Clinical and biochemical assessment of hypogonadism in men with type 2 diabetes: correlations with bioavailable testosterone and visceral adiposity.

OBJECTIVE—The aim of our study was to assess the prevalence of clinical hypogonadism, based on both symptoms and biochemical available measures of testosterone deficiency, in men with type 2 diabetes. RESEARCH DESIGN AND METHODS—In a cross-sectional study of 355 type 2 diabetic men aged >30 years, total and bioavailable testosterone, sex hormone–binding globulin, BMI, and waist circumference were measured and free testosterone was calculated. Overt hypogonadism was defined as the presence of clinical symptoms of hypogonadism and low testosterone level (total testosterone <8 nmol/l and/or bioavailable testosterone <2.5 nmol/l). Borderline hypogonadism was defined as the presence of symptoms and total testosterone of 8–12 nmol/l or bioavailable testosterone of 2.5–4 nmol/l. RESULTS—A low blood testosterone level was common in diabetic men, and a significant proportion of these men had symptoms of hypogonadism. Overt hypogonadism was seen in 17% of men with total testosterone <8 nmol/l and 14% with bioavailable testosterone <2.5 nmol/l. Borderline hypogonadism was found in 25% of men with total testosterone 8–12 nmol/l and bioavailable testosterone between 2.5 and 4 nmol/l; 42% of the men had free testosterone <0.255 nmol/l. BMI and waist circumference were both significantly negatively correlated with testosterone levels in men, with the association being stronger for waist circumference. CONCLUSIONS—Testosterone levels are frequently low in men with type 2 diabetes, and the majority of these men have symptoms of hypogonadism. Obesity is associated with low testosterone levels in diabetic men.

Testosterone Replacement in Hypogonadal Men With Type 2 Diabetes and/or Metabolic Syndrome (the TIMES2 Study)

OBJECTIVE This study evaluated the effects of testosterone replacement therapy (TRT) on insulin resistance, cardiovascular risk factors, and symptoms in hypogonadal men with type 2 diabetes and/or metabolic syndrome (MetS). RESEARCH DESIGN AND METHODS The efficacy, safety, and tolerability of a novel transdermal 2% testosterone gel was evaluated over 12 months in 220 hypogonadal men with type 2 diabetes and/or MetS in a multicenter, prospective, randomized, double-blind, placebo-controlled study. The primary outcome was mean change from baseline in homeostasis model assessment of insulin resistance (HOMA-IR). Secondary outcomes were measures of body composition, glycemic control, lipids, and sexual function. Efficacy results focused primarily on months 0−6 (phase 1; no changes in medication allowed). Medication changes were allowed in phase 2 (months 6−12). RESULTS TRT reduced HOMA-IR in the overall population by 15.2% at 6 months (P = 0.018) and 16.4% at 12 months (P = 0.006). In type 2 diabetic patients, glycemic control was significantly better in the TRT group than the placebo group at month 9 (HbA1c: treatment difference, −0.446%; P = 0.035). Improvements in total and LDL cholesterol, lipoprotein a (Lpa), body composition, libido, and sexual function occurred in selected patient groups. There were no significant differences between groups in the frequencies of adverse events (AEs) or serious AEs. The majority of AEs (>95%) were mild or moderate. CONCLUSIONS Over a 6-month period, transdermal TRT was associated with beneficial effects on insulin resistance, total and LDL-cholesterol, Lpa, and sexual health in hypogonadal men with type 2 diabetes and/or MetS.

Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes

OBJECTIVE Men with type 2 diabetes are known to have a high prevalence of testosterone deficiency. No long-term data are available regarding testosterone and mortality in men with type 2 diabetes or any effect of testosterone replacement therapy (TRT). We report a 6-year follow-up study to examine the effect of baseline testosterone and TRT on all-cause mortality in men with type 2 diabetes and low testosterone. RESEARCH DESIGN AND METHODS A total of 581 men with type 2 diabetes who had testosterone levels performed between 2002 and 2005 were followed up for a mean period of 5.81.3 S.D. years. mortality rates were compared between total testosterone 10.4nmol/l (300ng/dl; n=343) and testosterone 10.4nmol/l (n=238). the effect of TRT (as per normal clinical practise: 85.9% testosterone gel and 14.1% intramuscular testosterone undecanoate) was assessed retrospectively within the low testosterone group. RESULTS Mortality was increased in the low testosterone group (17.2%) compared with the normal testosterone group (9%; P=0.003) when controlled for covariates. In the Cox regression model, multivariate-adjusted hazard ratio (HR) for decreased survival was 2.02 (P=0.009, 95% CI 1.2-3.4). TRT (mean duration 41.6±20.7 months; n=64) was associated with a reduced mortality of 8.4% compared with 19.2% (P=0.002) in the untreated group (n=174). The multivariate-adjusted HR for decreased survival in the untreated group was 2.3 (95% CI 1.3-3.9, P=0.004). CONCLUSIONS Low testosterone levels predict an increase in all-cause mortality during long-term follow-up. Testosterone replacement may improve survival in hypogonadal men with type 2 diabetes.

Low Testosterone Associated With Obesity and the Metabolic Syndrome Contributes to Sexual Dysfunction and Cardiovascular Disease Risk in Men With Type 2 Diabetes

Men with obesity, the metabolic syndrome, and type 2 diabetes have low total and free testosterone and low sex hormone–binding globulin (SHBG). Conversely, the presence of low testosterone and/or SHBG predicts the development of metabolic syndrome and type 2 diabetes. Visceral adiposity present in men with low testosterone, the metabolic syndrome, and/or type 2 diabetes acts through proinflammatory factors. These inflammatory markers contribute to vascular endothelial dysfunction with adverse sequelae such as increased cardiovascular disease (CVD) risk and erectile dysfunction. This review focuses on the multidirectional impact of low testosterone associated with obesity and the metabolic syndrome and its effects on erectile dysfunction and CVD risk in men with type 2 diabetes. Whenever possible in this review, we will cite recent reports (after 2005) and meta-analyses. ### Epidemiological studies of low testosterone, obesity, metabolic status, and erectile dysfunction Epidemiological studies support a bidirectional relationship between serum testosterone and obesity as well as between testosterone and the metabolic syndrome. Low serum total testosterone predicts the development of central obesity and accumulation of intra-abdominal fat (1–3). Also, low total and free testosterone and SHBG levels are associated with an increased risk of developing the metabolic syndrome, independent of age and obesity (1–3). Lowering serum T levels in older men with prostate cancer treated with androgen deprivation therapy increases body fat mass (4). Conversely, high BMI, central adiposity, and the metabolic syndrome are associated with and predict low serum total and to a lesser extent free testosterone and SHBG levels (1–3,5). Because obesity suppresses SHBG and as a result total testosterone concentrations, alterations in SHBG confound the relationship between testosterone and obesity. Low total testosterone or SHBG levels are associated with type 2 diabetes, independent of age, race, obesity, and criteria for diagnosis of diabetes (6,7). In longitudinal studies, low serum total and free testosterone …

Low serum testosterone and increased mortality in men with coronary heart disease

Background To examine the effect of serum testosterone levels on survival in a consecutive series of men with confirmed coronary disease and calculate the prevalence of testosterone deficiency. Design Longitudinal follow-up study. Setting Tertiary referral cardiothoracic centre. Patients 930 consecutive men with coronary disease referred for diagnostic angiography recruited between June 2000 and June 2002 and followed up for a mean of 6.9±2.1 years. Outcome All-cause mortality and vascular mortality. Prevalence of testosterone deficiency. Results The overall prevalence of biochemical testosterone deficiency in the coronary disease cohort using bio-available testosterone (bio-T) <2.6 nmol/l was 20.9%, using total testosterone <8.1 nmol/l was 16.9% and using either was 24%. Excess mortality was noted in the androgen-deficient group compared with normal (41 (21%) vs 88 (12%), p=0.002). The only parameters found to influence time to all-cause and vascular mortality (HR ± 95% CI) in multivariate analyses were the presence of left ventricular dysfunction (3.85; 1.72 to 8.33), aspirin therapy (0.63; 0.38 to 1.0), β-blocker therapy (0.45; 0.31 to 0.67) and low serum bio-T (2.27; 1.45 to 3.6). Conclusions In patients with coronary disease testosterone deficiency is common and impacts significantly negatively on survival. Prospective trials of testosterone replacement are needed to assess the effect of treatment on survival.

Acute haemodynamic effects of testosterone in men with chronic heart failure

AIMS Anabolic therapy with testosterone may be useful in the treatment of wasting associated with chronic heart failure but little is known about its cardiovascular actions. The aim of this study was to determine the acute haemodynamic effects of testosterone administration in men with heart failure. METHODS AND RESULTS Twelve men with stable chronic heart failure were enrolled in a double-blind, randomised, placebo-controlled, cross-over trial. Subjects were given testosterone 60 mg or placebo via the buccal route and central haemodynamics were monitored over 6h, using a pulmonary flotation catheter. Subjects received the second treatment on day 2 and haemodynamic monitoring was repeated. Treatment was well tolerated. Compared with placebo, testosterone treatment resulted in a relative increase in cardiac output (p<0.0001, ANCOVA), with maximum treatment effect after 180 min (10.3+/-4.6% increase from baseline, p=0.035; 95% CI 0.8-19.8). This was accompanied by reduction in systemic vascular resistance compared with baseline (p<0.0001, ANCOVA), with maximum treatment effect also at 180 min (-17.4+/-9.6% from baseline, p=0.085; 95% CI -37.3 to +2.6). These maximal changes coincided with the peak elevation in serum bio-available testosterone. There was no significant change in any other haemodynamic parameter measured. CONCLUSIONS Administration of testosterone increases cardiac output acutely, apparently via reduction of left ventricular afterload.

Testosterone: a metabolic hormone in health and disease

Testosterone is a hormone that plays a key role in carbohydrate, fat and protein metabolism. It has been known for some time that testosterone has a major influence on body fat composition and muscle mass in the male. Testosterone deficiency is associated with an increased fat mass (in particular central adiposity), reduced insulin sensitivity, impaired glucose tolerance, elevated triglycerides and cholesterol and low HDL-cholesterol. All these factors are found in the metabolic syndrome (MetS) and type 2 diabetes, contributing to cardiovascular risk. Clinical trials demonstrate that testosterone replacement therapy improves the insulin resistance found in these conditions as well as glycaemic control and also reduces body fat mass, in particular truncal adiposity, cholesterol and triglycerides. The mechanisms by which testosterone acts on pathways to control metabolism are not fully clear. There is, however, an increasing body of evidence from animal, cell and clinical studies that testosterone at the molecular level controls the expression of important regulatory proteins involved in glycolysis, glycogen synthesis and lipid and cholesterol metabolism. The effects of testosterone differ in the major tissues involved in insulin action, which include liver, muscle and fat, suggesting a complex regulatory influence on metabolism. The cumulative effects of testosterone on these biochemical pathways would account for the overall benefit on insulin sensitivity observed in clinical trials. This review discusses the current knowledge of the metabolic actions of testosterone and how testosterone deficiency contributes to the clinical disease states of obesity, MetS and type 2 diabetes and the role of testosterone replacement.

The vasodilatory action of testosterone: a potassium-channel opening or a calcium antagonistic action?

British Journal of Pharmacology (2003) 138, 733–744. doi:10.1038/sj.bjp.0705141