BERKELEY, CA (UroToday.com) - As far back as 1940, testosterone (T) therapy in men with T deficiency (TD), when administered in the physiological range, was deemed beneficial to overall health and had no demonstrable side effects.1, 2 These early observations pointed out that if T treatment was in the physiological range, no harm of T therapy was noted.1, 2 Over the past seven decades a large number of studies were published on T therapy in men with TD. While some of these studies had small numbers of patients, or were of short duration, and others may have been observational in nature, many of these studies have provided a wealth of information on the improvements in the overall health of men with TD.
T therapy in men with TD increases insulin sensitivity, attenuates inflammation, increases muscle mass, and reduces fat mass and adiposity. T therapy improves lipid profiles and endothelial function and reduces systolic and diastolic blood pressure. T therapy improves bone mineral density and increases energy and vitality and improves mood and sexual function and overall quality of life (see Figure). Furthermore, T therapy may reduce risk of vascular disease and mortality (see Figure). T therapy appears to be safe if treatment and monitoring are appropriately executed. The evidence available to date does not support alleged concerns regarding risk of cardiovascular disease (CVD) and prostate cancer.
T Therapy Reduces Inflammatory Biomarkers in Men with TD
Recently we have reported that T therapy reduces activities of liver enzymes and reduces C-reactive protein (CRP) levels in obese and diabetic men with TD, suggesting attenuation of the inflammatory response and improvement in various physiological functions.3-7 Long-term T therapy in men with TD markedly and significantly reduced CRP levels, suggesting T therapy reduces inflammatory responses.
T Therapy Improves Insulin Sensitivity and Reduces Glucose and HbA1c Levels
T therapy elicits positive effects on blood glucose levels, insulin sensitivity, and glycated hemoglobin (HbA1c) levels,8-21 suggesting that T therapy ameliorates hyperglycemia and insulin resistance (IR) in subjects with type 2 diabetes mellitus (T2DM).3, 7, 21, 22, 23 Hackett et al.,22 and Grossman et al.,23 reinforced the benefits of T in reducing IR and regulating hyperglycemia and HbA1c22, 23 These findings, together with data from other studies, strongly suggest that T therapy improves glycemic control and improves fasting blood sugar and also improves insulin sensitivity.
T Therapy Improves Body Weight, Waist Circumference (WC) and Body Mass Index (BMI) Men with TD
T therapy in men with TD produced significant decrease in weight, WC, and BMI,3-6 suggesting that T therapy produces improvement in metabolic function and results in lifestyle and behavioral modifications, such as increased energy and motivation and increased physical activity that are translated into changes in body composition, which are accompanied with increases in lean body mass and reduction in fat mass, as discussed previously.3-6 Reduced fat mass and increased lean body mass are the most common reported observations in men with TD treated with T.3-6, 20, 24, 25-43
T Therapy Improves Lipid Profile in Men with TD
Long-term T therapy in men with TD is associated with reduced levels of total cholesterol (TC), low-density lipoprotein (LDL), and triglycerides (TGs) coupled with beneficial increase in high-density lipoprotein (HDL).3, 7, 8, 13, 14, 20, 24, 44-53 Thus, T therapy appears to have a favorable impact on the lipid profile in men with TD. Treatment with intramuscular T undecanoate maintained LDL levels low and HDL levels high in men with TD for up to 9.5 years.44 The clinical implication of reduction in LDL and TGs and increased HDL is reduced CVD risk.3-8
T Therapy Improves Systolic and Diastolic Blood Pressure
In a study of 1 548 men aged 25–84 years, Svartberg et al.,54 reported that systolic blood pressure was inversely associated with T levels, inferring that TD is associated with higher blood pressure. Data from TRiUS (Testim® Registry study showed that blood pressure is reduced in response to T therapy after 12 months,20 supporting previous findings.16, 55 On the contrary, men treated with androgen deprivation therapy (ADT) for prostate cancer showed marked increased arterial stiffness,56, 57
T Therapy Improves CVD Risk in Men with TD
Although epidemiological studies have suggested that reduced T levels are associated with greater CVD risk,58 this area of investigation remained controversial.59 Hoyos et al.10 reported that T treatment decreased arterial stiffness and decreased the respiratory quotient compared with placebo. T therapy in men with TD reduced CVD risk factors with concomitant improvement in insulin sensitivity and glycemic control, even in studies of shorter duration.60, 61 Further, a marked decrease in visceral fat mass and circulating inflammatory cytokines concomitant with improvement in endothelial cell function have been reported.48, 62 T is well known to regulate a host of metabolic functions in liver, adipose tissue, muscles, coronary arteries, and the heart. Thus, it is not surprising that T therapy reduces the risk of CVD. An inverse relationship exists between T and obesity and TD is associated with dyslipidaemia, atherosclerosis, cardiovascular diseases, metabolic syndrome (MetS) and diabetes.63, 64, 65
T therapy Reduces Mortality and Improves Survival in Men with TD
Two recent studies demonstrated reduced mortality in men with TD who were treated with T.66, 67 Shores et al.66 demonstrated that mortality in T-treated men was 10.3% compared with 20.7% in untreated men (P < 0.0001). Muraleedharan et al.67 demonstrated increased mortality of 19.2% versus 9.0% in men with normal T and in men with low T receiving T therapy, mortality was reduced to 8.4%, compared with 19.2% in untreated men (P=0.002). These findings are consistent with several studies.34, 58, 68-87 CV benefits of T therapy have been shown in interventional studies, including benefits of in men with congestive heart failure (CHF), cardiac ischemia/angina, and reduced carotid intima media thickness (CIMT).59, 60, 61, 87-99 Most studies identified an inverse association between serum T concentration and all-cause or cardiovascular mortality.
T therapy Improves Sexual Function and Quality of Life in men with TD
T therapy in men with TD increases vigor and vitality.21 This, together with improvement in quality of life, explains, in part, the noted increase in physical activity subsequent to T treatment. Furthermore, the increased motivation, level of energy, and vigor associated with T treatment may explain the marked reduction in BW attributed to increased energy expenditure. Similar observations were made by Tong et al.,100 who examined the effect of long-acting T undecanoate therapy on quality of life in men with TD. After 48 weeks, the QoL of men treated with T improved significantly in five out of the eight domains on SF-12. The mental health composite scores also improved in the T group. After adjusting for baseline differences, significant improvement was observed only in mental health composite scores. Erectile dysfunction (ED) is thought to be one of the relevant signs and symptoms of TD deficiency. The role of T in erectile physiology has been the subject of a recent comprehensive review and it is clear that androgens play critical role in erections.101 The readers are advised to consult this review.101 For brevity’s sake, we will not elaborate on the relationship between erectile dysfunction and TD, since this topic is covered in detail in this current review.101
In summary, TD is a common clinical condition, which contributes to sexual dysfunction and is associated with a number of co-morbidities.102 In observational studies, long-term T therapy in men with TD restores physiological T levels and produced significant WL, reduced WC, and BMI. T therapy reduced inflammatory cytokines and fasting blood glucose and HbA1c levels concomitant with increased insulin sensitivity. More importantly, T therapy reduced TC, LDL, triglycerides and increased HDL levels and improved systolic and diastolic blood pressure.103-134 Finally, T therapy improved mineral bone density and increased energy and vitality and improved mood and sexual function and overall quality of life. T therapy appears to be safe, and risks, such as erythrocytosis, require appropriate monitoring.
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Abdulmaged M. Traish, PhD, MBA as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Department of Biochemistry, Boston University School of Medicine, Boston, MA USA; Department of Urology, Boston University School of Medicine, Boston, MA USA