How can hypogonadism (low sex hormone production) contribute to the development of cardiovascular disease (CVD) in individuals, particularly men with low testosterone levels?

How Hypogonadism Contributes to Cardiovascular Disease

Hypogonadism increases cardiovascular disease risk through multiple interconnected metabolic pathways, including insulin resistance, metabolic syndrome, visceral fat accumulation, and type 2 diabetes, with low testosterone levels consistently associated with increased all-cause and cardiovascular mortality in men. 1

Primary Metabolic Mechanisms

Insulin Resistance and Glucose Dysregulation

• Androgen deficiency directly causes insulin resistance, which serves as a central driver of cardiovascular risk 1
• Low testosterone levels are independently associated with type 2 diabetes mellitus development 1
• The TIMES2 study demonstrated that 6-12 months of testosterone replacement therapy significantly improved insulin resistance and glycemic control in hypogonadal men with metabolic syndrome or type 2 diabetes 1

Metabolic Syndrome Components

• Hypogonadism is strongly linked to metabolic syndrome, a constellation of cardiovascular risk factors 1
• Low testosterone promotes increased deposition of visceral fat, which is metabolically active and pro-inflammatory 1
• Visceral adiposity further perpetuates a vicious cycle by increasing aromatase activity, converting more testosterone to estradiol and worsening the hypogonadal state 2

Mortality Data

Epidemiological Evidence

• Multiple large prospective studies demonstrate hazard ratios ranging from 1.24 to 2.56 for all-cause mortality in men with low testosterone 1
• Cardiovascular-specific mortality shows hazard ratios between 1.38 and 2.56 across studies with follow-up periods of 4.3 to 20 years 1
• A meta-analysis of longitudinal studies confirmed that testosterone levels were significantly lower in patients with incident overall and cardiovascular mortality compared with controls 1

Cross-Sectional Associations

• Men with established cardiovascular disease have significantly lower testosterone and higher estradiol levels compared to those without CVD 3
• The association between low testosterone and CVD persists after adjusting for age and body mass index (HR=0.763 per increment of total testosterone; P<0.0001) 3
• High estradiol levels also independently correlate with CVD in cross-sectional studies (HR=1.015 per increment; P<0.0001) 3

Important Clinical Context

Marker vs. Causation Debate

• Low testosterone may function as a marker of poor general health rather than a direct cause of CVD 1
• The bidirectional relationship is complex: cardiovascular disease and chronic illness can suppress testosterone production through effects on the hypothalamic-pituitary-gonadal axis 4
• However, the consistent association across multiple large studies and the biological plausibility of metabolic mechanisms suggest testosterone deficiency contributes meaningfully to cardiovascular risk 5, 6

Prevalence in Heart Failure

• 30-50% of men with heart failure have testosterone deficiency, with 15% meeting criteria for symptomatic hypogonadism 4
• Low testosterone correlates with heart failure severity, NYHA class, reduced exercise functional capacity, and worse clinical prognosis 4

Body Composition Changes

Adverse Remodeling

• Hypogonadism causes decreased lean body mass and muscle strength, which impairs metabolic health 5
• Increased fat mass, particularly visceral adiposity, creates a pro-inflammatory state that accelerates atherosclerosis 5
• These body composition changes occur with aging-related testosterone decline, androgen deprivation therapy, and chronic disease-related hypogonadism 5

Therapeutic Implications

Safety of Testosterone Replacement

• The 2023 TRAVERSE trial (5,246 men, mean follow-up 21.7 months) found no significant difference in major adverse cardiac events or nonfatal stroke between testosterone gel and placebo in men 45-80 years with confirmed hypogonadism 1
• The 2024 AHA/ASA Stroke Prevention Guidelines give a Class 2a recommendation (Level B-R evidence) that testosterone replacement therapy is reasonable and does not increase stroke risk in appropriately selected men 1

Metabolic Benefits

• Testosterone replacement therapy improves insulin sensitivity and several biometric parameters in men with metabolic syndrome, though results vary across studies 1
• Treatment may improve bone mineral density, strength, frailty symptoms, and quality of life 1

Clinical Pitfall

Do not assume low testosterone is merely a consequence of poor health without clinical significance 1, 7. The metabolic derangements caused by hypogonadism—insulin resistance, visceral obesity, metabolic syndrome—are established cardiovascular risk factors that warrant evaluation and potential treatment 1, 5. Approximately 36% of men with erectile dysfunction have hypogonadism, and this population has documented increased cardiovascular mortality 1, 7.