Testosterone treatment and cardiometabolic health

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.

Key Points

  • Sex steroid hormones play an important role in modulating vascular function in men, given that reduced levels of plasma testosterone are linked with several conditions including obesity, metabolic syndrome, dyslipidemia, endothelial cell dysfunction, diabetes, vascular disease, insulin resistance and arterial stiffness1-4
  • Aortic elasticity can be investigated non-invasively (with equivalent accuracy as invasive measures)5 by transthoracic echocardiography
  • Aortic elasticity, measured by transthoracic echocardiography and blood pressure obtained by sphygmomanometer, was investigated in 22 men with hypogonadism and outcomes compared with 25 matched eugonadal healthy subjects. The relationship between aortic elastic properties (β index, AoS and AoD) and sex hormone levels in male patients with hypogonadism was also studied6

    • Hypogonadism was defined by symptoms of androgen deficiency and total morning serum testosterone levels <300 ng/dL7
    • Exclusion criteria included presence of hypertension, renal failure, diabetes, heart failure, valvular heart disease, coronary artery disease, chronic obstructive pulmonary disease and arrhythmia, e.g. atrial fibrillation
    • Serum samples were collected to measure total/free testosterone levels
    • In measuring the elastic properties of the aorta, AoD was calculated non-invasively based on the relationship between changes in aortic diameter and pressure with each cardiac cycle8
  • Patients with hypogonadism had increased arterial stiffness, as measured by AoS, AoD and β index

    • AoS (12.4 ± 3.9% vs 16.6 ± 4.2%, p< 0.001) and AoD (5.4 ± 1.9 vs 6.9 ± 2.3 10-6 cm2/dyn, p<0.001) were significantly decreased in the hypogonadism group. In addition, β index was increased in the hypogonadism group compared with the control group (3.1 ± 1.1 vs 2.3 ± 0.9, p=0.002)
    • Serum total testosterone level was significantly correlated with AoD, AoS and β index (respectively, relative risk [RR]=2.88, p=0.004; RR=3.45, p=0.001; RR=2.64, p=0.01)
  • The effect of testosterone therapy on cardiometabolic risk has not been systematically studied in obese men with OSA who are at increased cardiometabolic risk and who have some degree of relative androgen deficiency. To address this gap, a double-blind, placebo controlled, parallel-group study was conducted to examine the effects of testosterone on cardiometabolic parameters in this population9
  • Eligible adult obese men with OSA (defined as aged ≥18 years, body mass index [BMI] >30 kg/m2 and apnea hypopnea index [AHI] >10 events/h by in-laboratory polysomnography) recruited from sleep clinics at the Royal Prince Alfred Hospital and the Woolcock Institute of Medical Research, Sydney, Australia were enrolled into an 18-week weight loss program and randomized to receive three intramuscular injections (at 0, 6 and 12 weeks) of either Reandron™ (testosterone undecanoate 1,000 mg in 4 mL castor oil vehicle, n=33) or 4 mL oil vehicle placebo (n=34)

    • The weight loss program included a dietician-prescribed 2500 kJ (600 kcal) daily deficit diet plus increased physical activity (30 minutes daily walking)
    • Body composition included measures of abdominal, liver and total fat and total lean muscle mass by computerised tomography (CT) and dual energy X-ray absorptiometry (DXA) scanning performed at 0 and 18 weeks
    • Arterial stiffness and central blood pressure were measured at 0, 6 and 18 weeks in the supine position by pulse wave analysis10
    • Metabolic syndrome was defined according to international consensus guidelines and the National Cholesterol Education Program’s Adult Treatment Program Panel Criteria III11,12
    • Blood samples were taken at each visit and stored at –80°C for subsequent batched analysis of LH, FSH, total- and free-testosterone concentrations
  • Testosterone treatment significantly improved a number of cardiometabolic parameters compared with placebo treatment

    • Arterial stiffness (i.e. AIx) decreased by 3.2%, 95% confidence interval (CI) –6.01 to –0.46%, p=0.02 (Figure 1A)
    • Insulin sensitivity (HOMA-IR) increased (–1.14 units, 95% CI –2.27 to –0.01, p<0.05; Figure 1B), liver fat was reduced (0.09 Hounsfield attenuation ratio, 95% CI 0.009 to 0.17, p=0.03; Figure 1C), and lean muscle mass increased (1.6 kg, 95% CI 0.69 to 2.5, p=0.0009; Figure 1D)
    • Weight, BMI and waist circumference, as well as total fat, subcutaneous abdominal fat and visceral abdominal fat, significantly decreased over time due to the weight loss program (p<0.0001), but there were no significant differences between the treatment groups at any single time point or overall

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.

References

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Last updated: 2018
G.MKT.GM.MH.01.2018.0500