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Abstracts

LE Magazine July 2008
Abstracts

Testosterone

Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective Population Study.

BACKGROUND: The relation between endogenous testosterone concentrations and health in men is controversial. METHODS AND RESULTS: We examined the prospective relationship between endogenous testosterone concentrations and mortality due to all causes, cardiovascular disease, and cancer in a nested case-control study based on 11,606 men aged 40 to 79 years surveyed in 1993 to 1997 and followed up to 2003. Among those without prevalent cancer or cardiovascular disease, 825 men who subsequently died were compared with a control group of 1,489 men still alive, matched for age and date of baseline visit. Endogenous testosterone concentrations at baseline were inversely related to mortality due to all causes (825 deaths), cardiovascular disease (369 deaths), and cancer (304 deaths). Odds ratios (95% confidence intervals) for mortality for increasing quartiles of endogenous testosterone compared with the lowest quartile were 0.75 (0.55 to 1.00), 0.62 (0.45 to 0.84), and 0.59 (0.42 to 0.85), respectively (P<0.001 for trend after adjustment for age, date of visit, body mass index, systolic blood pressure, blood cholesterol, cigarette smoking, diabetes mellitus, alcohol intake, physical activity, social class, education, dehydroepiandrosterone sulfate, androstanediol glucuronide, and sex hormone binding globulin). An increase of 6 nmol/L serum testosterone ( approximately 1 SD) was associated with a 0.81 (95% confidence interval 0.71 to 0.92, P<0.01) multivariable-adjusted odds ratio for mortality. Inverse relationships were also observed for deaths due to cardiovascular causes and cancer and after the exclusion of deaths that occurred in the first 2 years. CONCLUSIONS: In men, endogenous testosterone concentrations are inversely related to mortality due to cardiovascular disease and all causes. Low testosterone may be a predictive marker for those at high risk of cardiovascular disease.

Circulation. 2007 Dec 4;116(23):2694-701

Risks of testosterone replacement therapy in ageing men.

Testosterone has been available to practitioners for several decades. However, testosterone prescriptions have increased in recent years partly because of the introduction of newer delivery systems that are topical and have good bioavailability. In the US alone, approximately 2 million prescriptions for testosterone were written in 2002. This represents a 30% increase from 2001 and a 170% increase from 1999. There has also been a 500% increase in prescription sales in the past 10 years. The rise in prescriptions may be in part due to the increasing recognition of hypogonadism in ageing males or andropause. Treatment relating to hypogonadism has relieved symptoms and improved the quality of life of many individuals. Epidemiological studies point toward an association with increased morbidity and mortality, with low testosterone states in ageing males. For example, there is a higher prevalence of depression, coronary heart disease, osteoporosis, fracture rates, frailty and even dementia with low testosterone states. Recently, there have been some concerns raised regarding the long-term safety of testosterone replacement therapy (TRT) from the Institute of Medicine. Current evidence suggests no causal relationship between prostate cancer and physiological dosing of testosterone, especially with careful selection and monitoring of patients. Cardiovascular risks have, overall, been neutral, although suggestions have been made that there are positive vasodilatory properties with testosterone. Mild eythrocytosis can be a common side effect of TRT, but thromboembolic events have rarely been reported in the literature. This paper addresses the evidence to date regarding the safety aspects of TRT. The medical-legal implications of TRT for men at this point in time is also discussed.

Expert Opin Drug Saf. 2004 Nov;3(6):599-606

Testosterone and ageing: what have we learned since the Institute of Medicine report and what lies ahead?

A 2003 report by the Institute of Medicine (IOM) surveyed the literature on the benefits and risks of testosterone replacement therapy in older men and identified knowledge gaps and research needs. This review summarises some key studies published since the IOM report. The possible relationship of testosterone to risk of prostate cancer remains a concern; however, no new evidence has emerged to suggest that testosterone replacement therapy increases the risk. Recent studies have demonstrated that hypogonadism in men may be more prevalent than previously thought, is strongly associated with metabolic syndrome, and may be a risk factor for type 2 diabetes and cardiovascular disease. Clinical studies have shown that testosterone replacement therapy in hypogonadal men improves metabolic syndrome indicators and cardiovascular risk factors. Maintaining testosterone concentrations in the normal range has been shown to contribute to bone health, lean muscle mass, and physical and sexual function, suggesting that testosterone replacement therapy may help to prevent frailty in older men. Based on current knowledge, testosterone replacement therapy is unlikely to pose major health risks in patients without prostate cancer and may offer substantial health benefits. Larger, longer-term randomised studies are needed to fully establish the effects of testosterone replacement therapy.

Int J Clin Pract. 2007 Apr;61(4):622-32

Testosterone and atherosclerosis in aging men: purported association and clinical implications.

Two of the strongest independent risk factors for coronary heart disease (CHD) are increasing age and male sex. Despite a wide variance in CHD mortality between countries, men are consistently twice as likely to die from CHD than their female counterparts. This sex difference has been attributed to a protective effect of female sex hormones, and a deleterious effect of male sex hormones, upon the cardiovascular system. However, little evidence suggests that testosterone exerts cardiovascular harm. In fact, serum levels of testosterone decline with age, and low testosterone is positively associated with other cardiovascular risk factors. Furthermore, testosterone exhibits a number of potential cardioprotective actions. For example, testosterone treatment is reported to reduce serum levels of the pro-inflammatory cytokines interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha, and to increase levels of the anti-inflammatory cytokine IL-10; to reduce vascular cell adhesion molecule (VCAM)-1 expression in aortic endothelial cells; to promote vascular smooth muscle and endothelial cell proliferation; to induce vasodilatation and to improve vascular reactivity, to reduce serum levels of the pro-thrombotic factors plasminogen activator inhibitor (PAI)-1 and fibrinogen; to reduce low-density lipoprotein-cholesterol (LDL-C); to improve insulin sensitivity; and to reduce body mass index and visceral fat mass. These actions of testosterone may confer cardiovascular benefit since testosterone therapy reduces atheroma formation in cholesterol-fed animal models, and reduces myocardial ischemia in men with CHD. Consequently, an alternative hypothesis is that an age-related decline in testosterone contributes to the atherosclerotic process. This is supported by recent findings, which suggest that as many as one in four men with CHD have serum levels of testosterone within the clinically hypogonadal range. Consequently, restoration of serum levels of testosterone via testosterone replacement therapy could offer cardiovascular, as well as other, clinical advantages to these individuals.

Am J Cardiovasc Drugs. 2005;5(3):141-54

Testosterone, diabetes mellitus, and the metabolic syndrome.

Metabolic syndrome is characterized by insulin insensitivity, central obesity dyslipidemia, and hypertension. It is recognized as a risk factor for cardiovascular disease in men; by the time metabolic syndrome is diagnosed, however, most men already have entrenched cardiovascular disease. A reliable early warning sign is needed to alert physicians to those at risk for metabolic syndrome and cardiovascular disease. Low serum testosterone level has emerged as a reliable prognosticator of metabolic syndrome in men whose testosterone deficiency is genetic (Klinefelter syndrome), iatrogenic following surgery for testicular cancer, pharmacologically induced by gonadotropin-releasing hormone during prostate cancer treatment, or a natural consequence of aging. One third of men with type 2 diabetes mellitus are now recognized as testosterone deficient. Emerging evidence suggests that testosterone therapy may be able to reverse some aspects of metabolic syndrome.

Curr Urol Rep. 2007 Nov;8(6):467-71

Androgen deficiency, diabetes, and the metabolic syndrome in men.

PURPOSE OF REVIEW: The burden of androgen deficiency in men with diabetes and the metabolic syndrome has become increasingly apparent in population-based studies. This article focuses on the mechanisms underlying the interdependent relationship between these conditions. RECENT FINDINGS: Various definitions of hypogonadism, the metabolic syndrome and diabetes have been proposed and are used in the literature. Cross-sectional studies have found that between 20 and 64% of men with diabetes have hypogonadism, with higher prevalence rates found in the elderly. Hypogonadism can be a risk factor for the development of diabetes and the metabolic syndrome through various mechanisms including changes in body composition; androgen receptor polymorphisms; glucose transport; and reduced antioxidant effect. Conversely, diabetes and the metabolic syndrome can be risk factors for hypogonadism through some similar but mostly distinct mechanisms, such as increased body weight; decreased sex hormone binding globulin levels; suppression of gonadotrophin release or Leydig cell testosterone production; cytokine-mediated inhibition of testicular steroid production; and increased aromatase activity contributing to relative estrogen excess. SUMMARY: The relationship between diabetes, the metabolic syndrome and androgen deficiency is complex. Testosterone supplementation, by either oral or intramuscular routes and through exogenous or endogenous delivery, has a promising role in this population although further clinical trials are needed.

Curr Opin Endocrinol Diabetes Obes. 2007 Jun;14(3):226-34

Effect of testosterone on insulin sensitivity in men with idiopathic hypogonadotropic hypogonadism.

OBJECTIVE: To assess the presence of insulin resistance (IR) among a homogeneous cohort of male patients with idiopathic hypogonadotropic hypogonadism (IHH) and to investigate the effects of testosterone therapy on IR in this specific group. METHODS: Twenty-four male patients with untreated IHH and 20 age-, sex-, and weight-matched eugonadal healthy control subjects were recruited for the study. Plasma glucose, plasma insulin, total and free testosterone, follicle-stimulating hormone, luteinizing hormone, estradiol, and sex hormone-binding globulin levels were measured in fasting blood samples, and biochemical and hormonal analyses were performed for all study participants. IR was calculated by the homeostasis model assessment of insulin resistance (HOMA-IR) formula and the quantitative insulin sensitivity check index (QUICKI). Body mass index was calculated by weighing and measuring the heights of all study participants at the beginning of the investigation. Body fat mass and body lean mass were calculated as percentages of body weight by bioelectrical impedance analysis of body composition. Sustanon 250 (a combination of 4 testosterones) was administered intramuscularly once every 3 weeks for 6 months to male patients with IHH after a basal anthropometric, biochemical, and hormonal evaluation. The response to therapy was monitored by regular clinical examinations and serum testosterone measurements. After 6 months of testosterone treatment, the entire anthropometric, biochemical, and hormonal evaluation was repeated 14 days after the last injection of testosterone. RESULTS: Before treatment, male patients with IHH had higher fasting plasma glucose concentrations, higher fasting plasma insulin levels, a higher HOMA-IR score, and a lower QUICKI when compared with the control group. After testosterone treatment in the patient group, the HOMA-IR score decreased dramatically to the level in the control group. The high body fat mass of the male patients with IHH was reduced significantly after testosterone treatment, concomitant with significant increases in body mass index and body lean mass. CONCLUSION: Insulin sensitivity improves and body fat mass decreases with long-term testosterone replacement therapy.

Endocr Pract. 2007 Oct;13(6):629-35

A dose-response study of testosterone on sexual dysfunction and features of the metabolic syndrome using testosterone gel and parenteral testosterone undecanoate.

The objective of this study was to observe the dose-response effects of testosterone (T) treatment on symptoms of sexual dysfunction and the metabolic syndrome. Two cohorts of elderly men with late-onset hypogonadism were followed over 9 months. Group 1, consisting of 28 men (mean age, 61 years; mean T level, 2.07 +/- 0.50 ng/mL), received long-acting T undecanoate (TU; 1000 mg); group 2, composed of 27 men (mean age, 60 years; mean T level, 2.24 +/- 0.41 ng/mL), received T gel (50 mg/day) for 9 months. In patients treated with T gel, plasma T levels rose from 2.24 +/- 0.41 to 2.95 +/- 0.52 (statistically significant) at 3 months, 3.49 +/- 0.89 (statistically significant) at 6 months, and 3.80 +/- 0.73 ng/mL at 9 months (T level at 6 months was compared with T level at 3 months). With TU, plasma T levels rose from 2.08 +/- 0.56 to 4.81 +/- 0.83 (statistically significant) at 3 months, 5.29 +/- 0.91 at 6 months, and 5.40 +/- 0.77 ng/mL at 9 months. With TU, the plasma T levels were statistically significantly higher than with T gel With TU, there was a greater improvement in sexual symptoms and in symptoms of the metabolic syndrome. With both treatments, changes in waist circumference correlated with changes in total, low-density, and high-density lipoprotein cholesterol. Parameters of safety were not different between the 2 treatments. T administration had a beneficial effect on sexual dysfunction and symptoms of the metabolic syndrome in elderly men. The higher plasma levels of T generated with TU than with T gel were clearly more effective, indicating that there is a T dose-effect relationship.

J Androl. 2008 Jan-Feb;29(1):102-5

Body composition, metabolic syndrome and testosterone in ageing men.

The ageing process in men is marked by changes in body composition (loss of fat-free mass (FFM) and skeletal muscle, and gain in fat mass (FM)) and is associated with a decline in serum testosterone. Correlations between these aspects of ageing and the acknowledged role of exogenous testosterone in reversing the loss of FFM and gain in FM seen in adult men with congenital or acquired hypoandrogenism have led to the hypothesis that testosterone therapy in ageing men will result in favourable changes in body composition and may improve metabolic status and/or cardiovascular risk. Data from randomized controlled trials of testosterone therapy in ageing men addressing the endpoints of body composition and components of the metabolic syndrome and cardiovascular risk factors are reviewed, and the impact of the increasing prevalence of obesity on these relationships is considered.

Int J Impot Res. 2007 Sep-Oct;19(5):448-57