What is the relationship between testosterone and cholesterol levels?

Testosterone and Cholesterol: Relationship and Clinical Implications

Testosterone replacement therapy at physiologic doses generally has a neutral effect on lipid profiles, with some evidence suggesting it may even reduce total cholesterol levels in men with hypogonadism. 1

Physiological Relationship Between Testosterone and Cholesterol

• Cholesterol serves as a precursor for testosterone synthesis, but research shows neither dietary cholesterol intake nor serum total cholesterol levels are associated with total testosterone levels in men 2
• Endogenous testosterone levels show positive correlation with HDL cholesterol levels in both white and black men, contrary to what might be expected 3
• Testosterone appears to stimulate cholesterol clearance from human macrophages by activating LXRα, which may explain some of its potential anti-atherogenic effects 4

Effects of Testosterone Replacement Therapy on Lipid Profiles

Physiologic Replacement Doses

• Multiple controlled studies using physiologic replacement doses of testosterone have shown:
  • No change or minimal reduction in HDL cholesterol
  • Often accompanied by reduction in total cholesterol
  • LDL levels unchanged or reduced in most studies 1

Dose-Dependent Effects

• The impact on lipid profiles appears dose-dependent:
  • Physiologic doses show minimal to no effects on lipid parameters
  • Only supraphysiologic doses (600 mg/week) were associated with significant HDL reduction
  • Lower doses may actually cause small, non-significant increases in HDL 1

Administration Route Considerations

• Transdermal testosterone administration shows minimal effects on lipid profiles:
  • A double-blind, placebo-controlled study of 108 men showed no significant differences in serum lipids over 36 months 1
  • No significant differences in HDL levels or total cholesterol/HDL ratio between transdermal and intramuscular administration 1

Cardiovascular Implications

• Higher testosterone levels may be associated with better cardiovascular outcomes:
  • Men in the highest two-thirds of testosterone levels had significantly lower risk of severe aortic atherosclerosis compared to those in the lowest third 1
  • Testosterone therapy improved angina-free exercise tolerance in men with chronic stable angina 1
  • Direct injection of physiologic testosterone levels into coronary arteries increased mean coronary-artery diameter and blood flow 1

Clinical Considerations and Cautions

• Single-dose effects: Even a single dose of testosterone enanthate (500mg) can increase total cholesterol by 15% and induce expression of HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis 5
• Polycythemia risk: Testosterone therapy can increase hematocrit, potentially increasing blood viscosity and aggravating vascular disease, particularly in elderly patients 1
• Formulation differences: Injectable testosterone appears associated with greater risk of erythrocytosis than topical preparations 1

Key Takeaways for Clinical Practice

• For men requiring testosterone replacement therapy, physiologic doses are unlikely to worsen lipid profiles
• Monitoring of lipid parameters is still recommended but major adverse effects are not expected at standard replacement doses
• Supraphysiologic doses (as used in abuse scenarios) may negatively impact HDL levels
• In men with cardiovascular disease, higher testosterone levels are associated with increased HDL-C, suggesting potential cardioprotective effects 6

The evidence strongly suggests that physiologic testosterone replacement therapy does not worsen cardiovascular risk through lipid profile changes and may actually provide modest benefits to overall cholesterol management in hypogonadal men.