Testosterone treatment and cardiometabolic health
Body compositional and cardiometabolic effects of testosterone therapy in obese men with severe obstructive sleep apnoea: a randomised placebo-controlled trial.
Hoyos CM, Yee BJ, Phillips CL, Machan EA, Grunstein RR, Liu PY. Eur J Endocrinol 2012;167:531-541.
Impaired aortic elastic properties in patients with adult-onset hypogonadism. Canpolat U, Tokgözoğlu L, Aydin K, Dural M, Gϋrses KM, Yorgun H, et al. Blood Press 2013;22:114-119.
Reduced plasma testosterone levels can affect vascular function, as shown by the strong association with several conditions including obesity, metabolic syndrome, dyslipidemia, endothelial cell dysfunction, diabetes, vascular disease, insulin resistance and arterial stiffness. Studies have shown that testosterone therapy may improve cardiometabolic risk in some at-risk male populations. However, this effect of testosterone therapy has not been systematically studied in obese men with obstructive sleep apnoea (OSA) who are at greater cardiometabolic risk and who have some degree of relative androgen deficiency.
The effect of reduced plasma testosterone levels on aortic elasticity (measured by transthoracic echocardiography) was investigated in 22 men with hypogonadism and 25 matched eugonadal healthy subjects. In a separate randomized, placebo-controlled study, the effect of testosterone therapy on cardiometabolic health parameters was evaluated in obese men with severe OSA (the effects of testosterone therapy on sleep and breathing in this study have recently been published). Eligible subjects were enrolled into an 18-week weight loss program and randomized to receive three intramuscular injections of either testosterone undecanoate 1,000 mg or placebo. Assessments included precise measures of cardiometabolic risk including radiographically determined liver fat and tonometry determined arterial stiffness. Additional outcomes included changes in anthropometry, abdominal visceral fat, total body fat and lean muscle, basal metabolic rate, insulin sensitivity, blood lipids and metabolic syndrome status.
What is known
All cause and cardiovascular mortality is amplified when untreated OSA is combined with the risk factors of coexisting obesity and male gender.13,14 It is therefore important to understand the mechanisms and methods by which cardiometabolic risk may be reduced in this specific obese population.
Testosterone may play a direct role in the regulation of vascular tonus, as it has been shown to dilate aortic, brachial and coronary vascular systems by both endothelial-dependent and independent mechanisms.15-20 Thus, testosterone appears to be an important regulator of vascular compliance in large and medium-sized arteries. Arterial stiffening, an independent marker of cardiovascular risk,21,22 can result from impaired endothelial release of mediators contributing to reduced vascular compliance seen with this condition.23,24
What these studies add
Aortic stiffness has been shown to be associated with a variety of hormonal disturbances including hypogonadism. This was confirmed in a study of patients with hypogonadism which showed they had increased arterial stiffness, as measured by β index, AoS and AoD.6
Hoyos et al. conducted the first randomized placebo-controlled study to examine the body compositional and cardiometabolic effects of testosterone treatment in obese men with OSA.9 They demonstrated that 18 weeks of testosterone therapy in these men improved several important cardiometabolic parameters but did not differentially reduce overall weight or the metabolic syndrome. It is understood that this is also the first study using testosterone therapy to accurately measure liver fat by CT imaging.
There are a number of factors that encourage conducting larger and longer term studies with testosterone therapy in this population of adult obese men with OSA. For example, although no changes in metabolic syndrome were seen following 18 weeks of treatment,9 reductions in metabolic syndrome have been reported with longer duration treatment (1–2 years).25,26 Furthermore, non-alcoholic fatty liver disease (NAFLD) is becoming an increasingly prevalent condition, particularly in patients with cardiometabolic risk factors and is associated with increased risk of liver damage and possibly future cardiovascular disease, particularly in patients with cardiometabolic risk factors.27,28 Therefore, lowering liver fat (as seen after 18 weeks of testosterone treatment)9 could have an important impact on disease burden.
Figure 1: Changes (mean ± SEM) from baseline (week 0) for A) Augmentation index, B) HOMA-IR, C) Liver fat and D) Lean muscle mass. Overall between-group differences are indicated by the p value, determined by linear regression and adjusted for baseline waist circumference.