Testosterone replacement therapy (TRT) in hypogonadal men was associated with a lower cardiovascular (CV) risk, according to a presentation at the recent Urological Association of Asia Annual Congress (UAA 2016) held in Singapore, allaying concerns about the safety of TRT amidst controversial findings from previous studies.

TRT has been associated with an increased risk of cardiovascular disease (CVD) in several clinical trials, but Dr. Gerald Brock, a professor from the Division of Urology, St. Joseph’s Health Centre in London, Ontario, Canada, noted that these studies were either conducted without randomization or placebo, or that CVD was not an endpoint in the design of the studies. [JAMA 2013;310:1829-1836;PLoS One 2014;9:e85805]

On the other hand, many other studies have showed that TRT was associated with either no increased risk or a reduced incidence of CV events. [Am J Cardiol 2016;117:794-799; Int J Clin Pract2016;70:244-253; Eur Heart J 2015;36:2706-2715]

“Evidence from epidemiological and observational studies shows that low testosterone is associated with a higher CV risk in men,” said Brock.

Low testosterone levels were associated with increased CV mortality, he added, as revealed by the EPIC-Norfolk* prospective population study which followed 2,314 men from 1993-2003 in Norfolk, UK. [Circulation 2007;116:2694-2701]

“Androgen deprivation therapy [ADT] in patients with prostate cancer has negative effects on all major CV risk factors.”

Previous studies have shown that men with obesity (body mass index [BMI] ≥30 kg/m²), a known risk factor for CVD, had lower testosterone levels than those with a lower BMI across all age groups, and that 52.4 percent of 2,162 obese men had low testosterone levels. [J Clin Endocrin Metab2008;93:2737-2745; Int J Clin Pract 2006;60:762-769]

On the contrary, testosterone therapy with testosterone undecanoate (TU) improved body composition in terms of reduced fat mass and increased fat-free mass in hypogonadal men (p<0.001 for both), as well as reduced waist circumference by 13 cm after 36 months of TU treatment (p<0.0001) compared with placebo. [Int J Impot Res 2008;20:378-387; Aging Male 2012;15:96-102]

According to Brock, men who underwent long-term ADT had a higher prevalence of metabolic syndrome including diabetes, and a higher CV mortality. [J Androl 2008;29:534-539; J Urol2009;181:1998-2006]

Conversely, TU significantly reduced fasting glucose levels (p=0.001 in insulin-resistant group) and decreased HbA_1c levels compared with baseline levels in hypogonadal men (p<0.0001). [J Sex Med2010;7:2253-2260; Endocr Rev 2012;33:MON-49]

TU also significantly improved lipid profile of 334 hypogonadal men in terms of decreased low-density lipoprotein (LDL) and triglycerides, and increased high-density lipoprotein (HDL) over a period of 15 years. [Endocr Rev 2012;33:SAT-117]

Supplementation of transdermal testosterone to a diet and exercise regime improved blood glucose control and HDL levels (p<0.001 for both) compared with a diet and exercise only intervention for 52 weeks in 32 hypogonadal men with type 2 diabetes.  [J Androl 2009;30:726-733]

TU administration significantly decreased inflammatory markers associated with CVD risk, such as C-reactive protein (CRP) and tumour necrosis factor-alpha (TNF-α; p<0.001 and p=0.03, respectively) compared with placebo in a double-blind randomized controlled trial involving 184 hypogonadal men with metabolic syndrome. [Clin Endocrinol (Oxf) 2010;73:602-612]

Lipids and inflammation constitute some of the risk factors for atherosclerosis, and hence development of CVD, said Brock.

Other CV risk factors such as blood pressure and carotid intima media thickness (CIMT) were also decreased in hypogonadal men receiving TU compared with baseline levels. [Endocr Rev2012;33:SAT-117; J Sex Med 2010;7:2253-2260]

“Normalization of testosterone improves all major CV risk factors, including body fat, insulin resistance, dyslipidemia, coagulation, inflammation, and blood pressure,” Brock concluded.