BERKELEY, CA (UroToday.com) - Testosterone (T) and its metabolite, 5α-dihydrotestosterone (5α-DHT) are metabolic and vascular hormones, responsible for regulating carbohydrate, lipid and protein metabolism and modulate sexual, reproductive, and vascular function. Testosterone deficiency (TD) is a medical condition with critical health implications. TD is associated with insulin resistance (IR), type 2 diabetes mellitus (T2DM), obesity, hypertension, inflammation, atherosclerosis and cardiovascular disease, erectile dysfunction, and increased incidence of mortality. TD is characterized by low circulating levels of plasma T, concomitant with a host of clinical signs and symptoms.[1, 2, 3, 4] Clinically, TD may be attributed to primary (testicular dysfunction), secondary (pituitary or hypothalamic failure) or mixed hypogonadism (a combination of testicular failure and pituitary hypothalamic failure). While reduced sexual desire and nocturnal penile erections are thought to be strong indications of TD, other signs and symptoms include diminished motivation, fatigue, decreased energy, reduced muscle mass and strength, depressed mood, irritability, and poor concentration.[5, 6] The overall incidence of TD increases with age. The prevalence of TD increases with age and comorbidities such as insulin resistance (IR) and type 2 diabetes (T2DM), obesity, hypertension, and cardiovascular disease (CVD).
TD & Inflammation
Several studies have reported an inverse relationship between T and free T with C-reactive protein (CRP) and IL-6, markers of inflammation.[8, 9, 10, 11] T therapy significantly attenuated IL-6 and hs-CRP levels. T treatment in men with metabolic syndrome (MetS) and TD shifts the cytokine balance to a state of reduced inflammation.
TD & Type 2 Diabetes (T2DM) and Obesity
Higher plasma T levels were associated with reduced risk of T2DM and vice versa, and low T levels are commonly noted in men with T2DM and IR. Equally, TD and T2DM are often diagnosed together in the same patient and TD may be more prevalent in men with T2DM, higher BMI, or severely obese (BMI > 40).[16, 17, 18] Laaksonen, et al. evaluated 1,896 non-diabetic middle-aged men according to the presence of MetS and observed that men with MetS had elevated fasting insulin levels and reduced total T. Elevated T led to increased insulin sensitivity and reduced risk of MetS. TD was a stronger risk factor in the development of elevated insulin and glucose levels compared to overweight/obesity. Acute T withdrawal markedly reduced insulin sensitivity in young, healthy, men with idiopathic hypogonadotropic hypogonadism (IHH), in absence of changes in BMI or detectable changes in body composition. IR is associated with a decrease in Leydig cell T secretion in men[22, 23] and TD is independently associated with IR in non-diabetic older men.
TD & Dyslipidemia
TD is associated with adverse plasma levels of triglycerides (TGs), insulin, and high density lipoprotein (HDL) in a young male population. Reductions in TGs, total cholesterol (TC) and low-density lipoprotein (LDL) and increases in HDL were noted in response to T therapy.[25, 26, 27] TG levels were negatively associated with quartile levels of T, and HDL levels were positively related to quartile levels of T. Interestingly, LDL levels were positively associated with quartile levels of T. After adjusting for age, BMI, and life-style factors (alcohol consumption, smoking and physical activity), total T and cFT were inversely correlated with TGs, insulin, systolic blood pressure and positively correlated with HDL. Men with an unfavorable lipid profile (HDL < 0.90 and TG >1.8) had significantly lower levels of total T and sex hormone binding globulin (SHBG). Androgen deprivation therapy (ADT) in men with prostate cancer produces elevated TC and LDL.[30, 31, 32, 33, 34, 35, 36, 37]
TD & Endothelial Dysfunction
TD contributes to endothelium damage and dysfunction and androgen therapy enhances endothelial repair and function and increases synthesis and release of endothelial NO in the vasculature.[38, 39, 40, 41, 42, 43, 44] Flow-mediated dilation (FMD) was reduced in patients with TD and was enhanced in response to T therapy.[45, 46] Acute and chronic  T therapy in men with TD enhanced %FMD without affecting the basal diameter of the brachial artery, suggesting an endothelium-dependent vasodilator action of T.
TD & Hypertension
In a study of 1 548 men aged 25–84 years, total T was inversely associated with systolic blood pressure, indicating that men with hypertension had lower levels of total and free T before and after adjusting for BMI, suggesting that low T may be related to higher blood pressure. Similarly, data from TRiUS (Testim® Registry study) showed significant decrease in blood pressure with T therapy after 12 months. Men treated with ADT for prostate cancer showed increased arterial stiffness.[30, 31, 50] In men with TD who received T therapy, improvement in systolic and diastolic blood pressure was noted.[51, 52, 53] TD & Vascular Stiffness Men with TD exhibited higher intima media thickness (IMT) compared with controls, and carotid IMT correlated inversely with T levels after adjustment for age, TC, BMI, blood pressure, and smoking.[54, 55, 56, 57, 58, 59] The progression of carotid intima-media thickness (IMT) and plaque was investigated in a cohort from the Tromsø study of 1 101 men. An inverse association was noted between T levels and total carotid plaque area, after adjusting for age, systolic blood pressure, smoking and use of lipid-lowering drugs. A significant negative correlation between T levels and thoracic aorta intima thickness (TAIT) was also demonstrated, suggesting an independent relationship between T and TAIT.
TD & CVD
Low circulating T levels are associated with increased risk for major adverse cardiovascular events (MACE) in hypertensive patients. Ohlsson, et al. reported that, after 5-year follow-up 2 416 men, age 69 to 81 years, total T levels were inversely associated with CV events risk. Men in the highest T quartile had significantly reduced CV events risk when compared with men in the 3 lower quartiles. This association remained significant even after adjustment for traditional CV risk factors. In patients with coronary artery disease (CAD), mean T levels were significantly lower than in the healthy subjects.[64, 65] T values were inversely correlated to the degree of CAD severity, suggesting that low T may contribute to the increased risk of CAD in men.
TD & Mortality
The reported mortality in men with physiologically normal T levels was 20.1% vs. 24.6% in men with equivocal T levels and 34.9% in men with reduced T levels. In a prospective, population-based study of 794 men aged 50-91 years and who were followed an average 11.8 years, the men with total T levels in the lowest quartile were 40% more likely to die than those with higher T levels, independent of age, adiposity, and lifestyle. In a cohort of 15 68 men (Tromsø study) there was a significant increase in all-cause mortality risk for men with free T in the lowest quartile compared with the highest quartiles after adjustment for age. Men with free T in the lowest quartile had a 24% increased risk of all-cause mortality. Men (n=930) with CAD followed up for a mean of 6.9±2.1 years showed increased mortality in the TD group (21%) compared with men with normal T levels (12%)/ In a group of men (n =1954) who were followed up for an average 7.2-years, the low T group had a significantly higher mortality, from all causes, compared with the group with higher T levels.
TD & Sexual Dysfunction
The relationship between TD and sexual function has been recognized for some time and a large number of studies have documented that androgens are critical for maintaining sexual function in men, and androgen deficiency contributes to sexual dysfunction.[71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85] Indeed, men with TD exhibit symptoms of low libido and erectile dysfunction and T therapy improves sexual desire and erectile function in men with TD.[71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85] The biochemical and physiological pathways underlying the role of androgens in sexual function have been reported by many investigators and are summarized in a number of recent publications.[71, 73, 80, 85]
TD is a common clinical condition and impacts men’s health [Figure 1]. TD is associated with diminished sexual desire and erectile function, increased disturbances in mood, and decline in cognitive and intellectual function, reduced energy, increased fatigue, depressed mood and vitality, anger and depression. TD is associated with decrease in lean body mass with associated decreases in muscle volume and strength, and decreased bone mineral density. TD is associated with increased T2DM, MetS, adiposity, altered lipid profile, inflammation, endothelial dysfunction, hypertension, increased risk of CVD, and mortality.
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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.
Professor of Biochemistry
Professor of Urology
Institute of Sexual Medicine
Boston University School of Medicine
Boston, MA USA