Chris J. Malkin

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.

Neuroendocrine Effects on the Heart and Targets for Therapeutic Manipulation in Heart Failure

Chronic heart failure (CHF) involves derangements in multiple neurohormonal axes leading to a procatabolic state and wasting syndrome associated with significant mortality. Catabolic abnormalities include excess catecholamines and glucocorticoids. Anabolic defects include deficiencies of sex steroids, insulin resistance, and growth hormone (GH) resistance. These abnormalities are also correlated with increased morbidity and mortality in CHF. Anabolic axes have been augmented in pilot studies in CHF with testosterone, GH, insulin-like growth factor-1, and GH secretagogues. Results have been varied although some treatments have been associated with improved surrogate endpoints. This review article explores the current understanding of metabolic derangements in CHF and highlights potential neuroendocrine treatment strategies.

Androgens, insulin resistance and vascular disease in men

Type 2 diabetes mellitus is increasing globally and is an established risk factor for the development of atherosclerotic vascular disease. Insulin resistance is the hallmark feature of type 2 diabetes and is also an important component of the metabolic syndrome. There is evidence to suggest that testosterone is an important regulator of insulin sensitivity in men. Observational studies have shown that testosterone levels are low in men with diabetes, visceral obesity (which is strongly associated with insulin resistance), coronary artery disease and metabolic syndrome. Short‐term interventional studies have also demonstrated that testosterone replacement therapy produces an improvement in insulin sensitivity in men. Thus hypotestosteronaemia may have a role in the pathogenesis of insulin‐resistant states and androgen replacement therapy could be a potential treatment that could be offered for improvements in glycaemic control and reduction in cardiovascular risk, particularly in diabetic men.

Testosterone replacement in hypogonadal men with angina improves ischaemic threshold and quality of life

Background: Low serum testosterone is associated with several cardiovascular risk factors including dyslipidaemia, adverse clotting profiles, obesity, and insulin resistance. Testosterone has been reported to improve symptoms of angina and delay time to ischaemic threshold in unselected men with coronary disease. Objective: This randomised single blind placebo controlled crossover study compared testosterone replacement therapy (Sustanon 100) with placebo in 10 men with ischaemic heart disease and hypogonadism. Results: Baseline total testosterone and bioavailable testosterone were respectively 4.2 (0.5) nmol/l and 1.7 (0.4) nmol/l. After a month of testosterone, delta value analysis between testosterone and placebo phase showed that mean (SD) trough testosterone concentrations increased significantly by 4.8 (6.6) nmol/l (total testosterone) (p  =  0.05) and 3.8 (4.5) nmol/l (bioavailable testosterone) (p  =  0.025), time to 1 mm ST segment depression assessed by Bruce protocol exercise treadmill testing increased by 74 (54) seconds (p  =  0.002), and mood scores assessed with validated questionnaires all improved. Compared with placebo, testosterone therapy was also associated with a significant reduction of total cholesterol and serum tumour necrosis factor α with delta values of −0.41 (0.54) mmol/l (p  =  0.04) and −1.8 (2.4) pg/ml (p  =  0.05) respectively. Conclusion: Testosterone replacement therapy in hypogonadal men delays time to ischaemia, improves mood, and is associated with potentially beneficial reductions of total cholesterol and serum tumour necrosis factor α.

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.

The effect of testosterone on insulin sensitivity in men with heart failure

Resistance to insulin occurs in chronic heart failure (CHF) and is related to prognosis. Studies of testosterone in non‐(CHF) males suggest that physiological testosterone therapy improves insulin sensitivity. This was a single‐blind placebo controlled crossover trial to determine the effect of testosterone replacement on insulin sensitivity in 13 men with moderate to severe CHF (ejection fraction 30.5±1.3). The primary outcome was the homeostatic model index (HOMA‐IR) of fasting insulin sensitivity and secondary outcomes were body composition as measured by bioelectrical impedance and glucose tolerance to a standard 75 g oral glucose load. Analysis was performed on the delta values with the treatment effect of placebo compared with that of testosterone.

Testosterone and heart failure.

Purpose of reviewChronic heart failure (CHF) is a common condition with significant morbidity despite optimal medical therapy. Standard therapy involves inhibiting the maladaptive changes of metabolism and neuro-hormones that characterize the syndrome of CHF. Anabolic deficiency is a major component of the CHF syndrome and testosterone replacement therapy has been subject to recent trials. Recent findingsThe recent literature shows that physiological testosterone replacement therapy leads to modest improvements in voluntary muscle strength, lean muscle mass, endurance and positive effects on neuro-muscular and baro-receptor reflexes. Long-term efficacy and safety remain unstudied at present. SummaryTestosterone replacement therapy appears to improve metabolism and endurance in patients with CHF; further trials will be necessary before widespread use. Physicians who regularly treat patients with CHF may consider testosterone therapy but it is likely that they will require the advice and support from endocrine specialists.

Life-saving or life-prolonging? Interpreting trial data and survival curves for patients with congestive heart failure.

Chronic heart failure is responsible for considerable suffering and mortality throughout the world. Clinical trials have consistently demonstrated the benefits of pharmacological therapies such as angiotensin‐converting enzyme inhibitors and beta‐adrenoceptor blockers. These drugs are often quoted as reducing mortality from heart failure, yet all patients with heart failure deteriorate and most will die because of their disease. Therapies in heart failure are not truly life saving; they modify the natural history of the disease and delay the time to deterioration. The time benefit in survival is not usually reported in clinical trials, which are conducted over fixed time points and report risk reductions during this period only. In this paper, we discuss the use of prolongation of life statistics as an outcome measure in clinical trials and review simple techniques for calculating the lifetime benefit of pharmacological intervention in heart failure using data from a number of major studies.

Physiologic Testosterone Therapy has no Effect on Serum Levels of Tumour Necrosis Factor-α in Men with Chronic Heart Failure

Physiological testosterone therapy increases exercise capacity and reduces symptom scores in men with chronic heart failure (CHF). Tumour necrosis factor-alpha (TNF-α) exerts a significant pathologic activity in CHF, and physiologic testosterone replacement therapy is associated with reduced serum levels of TNF-α in hypogonadal men with concomitant coronary artery disease. It is unknown whether testosterone exerts a similar immunomodulatory action in men with CHF. Consequently, serum levels of TNF-α were measured in men with CHF, before and after physiologic testosterone therapy administered in three placebo-controlled studies, for either 6 hours (two 30-mg buccal tablets, n = 12) or 3 months (fortnightly 100 mg intra muscular injection, n = 20; or daily 5 mg transdermally, n = 62). The effects of testosterone were also assessed on lipopolysaccharide (LPS)-induced TNF-α production in whole blood obtained from 27 men with CHF. Incubation with testosterone (10 nM, 1 μM, and 100 μM) resulted in a reduction in LPS-induced TNF-α production from 12.6 ± 1.3 to 11.2 ± 1.1 (P = 0.053), 10.3 ± 1.1 (P = 0.0046), and 9.2 ± 1.1 (P = 0.000066) ng/ml, respectively. However in men with CHF, serum levels of TNF-α were similar before and after treatment with testosterone or placebo, irrespective of the length of study or route of administration. The clinically beneficial actions of testosterone in men with CHF are unlikely to be mediated by reducing TNF-α.