Low Testosterone Levels in Male Patients Linked to Increased Risk of CVD

All male patients with low testosterone levels are at a higher risk for cardiovascular disease (CVD), especially those with type 2 diabetes mellitus.  

Diabetes mellitus is a chronic debilitating condition that can cause co-morbidities. One example is hypogonadism in male patients, which is often overlooked but could have profound implications long term. “Male hypogonadism is a medical condition that results from either an absent or an inadequate and an impaired secretion of hypothalamic gonadotropin-releasing hormone (GnRH) or of pituitary gonadotropins (follicular stimulating hormone and luteinizing hormone [LH]) or, finally, from a testicular deficiency in sex steroid/sperm production” (Livingston et al., 2017). Studies conducted previously have established an association between hypogonadism and coronary artery disease, but none have specifically looked at patients with type 2 diabetes mellitus.  

For the 100 participants in this study, a previous diagnosis of T2DM had already been established by their primary care providers. The participants were separated into two groups (eugonadal and hypogonadal) with 28-85. Additionally, all participants with coronary artery disease had their diagnosis confirmed by a corresponding specialist with CT or angiography. Two criteria were used to identify hypogonadism: total serum testosterone <10.4 nmol/L or calculated free testosterone of 226 pmol/L. According to Livingston et al., “We found a statistically significant difference in the prevalence of CAD between hypogonadal and eugonadal T2DM males. No difference was found in the prevalence of macroalbuminuria, retinopathy, stroke, abnormal LFT and hypertension.” It can be concluded that a male patient with T2DM and hypogonadism is 33% more likely to have CAD compared to a patient who had normal testosterone levels. A negative correlation was found between testosterone levels and age, waist circumference, fasting blood sugar, and serum triglycerides. Patients with a reduced eGFR due to diabetic nephropathy also had lower testosterone levels.  

Serum testosterone has many impacts on the cardiovascular system and coronary arteries. While its complete mechanism of action is unknown, some studies have suggested it is associated with increased vasodilation via endothelial independent non-genomic means via the classical androgen receptor. Testosterone also upregulates the expression of endothelial nitric oxide synthase (eNOS), the enzyme responsible for synthesizing nitric oxide (NO). NO, in turn, brings about the relaxation of SMCs and subsequent vasodilatation by activating guanylate cyclase, which produces cGMP, which in turn activates cGMP-dependent protein kinase (PKG). PKG phosphorylates and activates sarcoplasmic reticulum- ATPase (SERCA), which augments calcium levels in the sarcoplasmic reticulum, leading to vasodilation (Saluja et al., 2021). A study by Soisson et al. showed an inverse relationship between total testosterone and intima-media thickness. They imply a preventive role of endogenous testosterone in coronary artery disease.  

Long-term trials and meta-analyses are required to further assess the efficacy of testosterone replacement therapy (TRT) in cardiovascular disease prevention in T2DM males with hypogonadism. Among men with androgen deficiency, testosterone replacement therapy is associated with a lower risk of cardiovascular outcomes. There was a reduction in acute MI, revascularization, sudden cardiac death, unstable angina, and all-cause mortality in hypogonadal patients who have ever taken testosterone treatment. Therefore, further research is needed for testosterone replacement therapy in males with type 2 diabetes with androgen deficiency concerning the prevention of coronary artery disease. 

Practice Pearls:  

• Male patients with type 2 diabetes mellitus should be monitored for hypogonadism and coronary artery disease.  
• Male patients with type 2 diabetes mellitus and hypogonadism have a 33% higher chance of developing coronary artery disease. 
• Testosterone replacement therapy needs to be studied further to assess its CVD prevention impacts.  

References for “Low Testosterone Levels in Male Patients Linked to Increased Risk of CVD”:
Livingston M, Kalansooriya A, Hartland A, Ramachandran S, Heald A. Serum testosterone levels in male hypogonadism: why and when to check-a review. Int J Clin Pract 2017; 71:e12995. 

Saluja M, Galav V, Pillai D, Chittora S. Low Serum Testosterone Levels in Male Patients with Type 2 Diabetes Mellitus as a Risk Factor for Coronary Artery Disease. J Assoc Physicians India. 2021 Sep;69(9):11-12. PMID: 34585886. 

Soisson V,  Brailly-Tabard S, Helmer C, Rouaud O, Ancelin ML,  Zerhouni C,  et al. A J-shaped association between plasma testosterone and risk of an ischemic arterial event in elderly men: the French 3C cohort study. Maturitas 2013; 75:282-288. 

Grace Behr, PharmD/MBA Candidate, Creighton University  

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