What are the risks of excessive supplemental testosterone (testosterone replacement therapy) in adult males with hypogonadism or low testosterone levels, particularly those with pre-existing conditions such as prostate cancer, sleep apnea, or cardiovascular disease?

Risks of Excessive Supplemental Testosterone

Excessive supplemental testosterone carries well-defined risks including erythrocytosis (3-44% depending on formulation), potential worsening of sleep apnea and heart failure, benign prostatic hyperplasia progression, and the unmasking of occult prostate cancer, though testosterone does not cause prostate cancer. 1, 2

Hematologic Risks

Erythrocytosis (Primary Concern)

• Erythrocytosis is the most common and clinically significant risk, occurring in 3-18% with transdermal formulations and up to 43.8% with intramuscular injections. 1, 3, 4
• The risk is dose-dependent: 2.8% with 5mg/day transdermal patches, 11.3% with 50mg/day gel, and 17.9% with 100mg/day gel. 1
• Elevated hematocrit (>52%) increases blood viscosity and could aggravate coronary, cerebrovascular, or peripheral vascular disease, particularly in elderly patients. 4
• Injectable testosterone carries 4-fold higher erythrocytosis risk compared to transdermal preparations, making transdermal formulations strongly preferred for patients with cardiovascular disease or risk factors. 1, 4
• Despite theoretical thrombotic concerns, no testosterone-associated thromboembolic events have been reported in clinical trials to date. 1

Cardiovascular Considerations

Evidence Shows Neutral to Beneficial Effects

• Contrary to historical concerns, testosterone replacement therapy does not increase cardiovascular risk or stroke in appropriately selected patients, based on the 2023 TRAVERSE trial (highest quality evidence). 4
• Men with chronic stable angina treated with transdermal testosterone showed greater angina-free exercise tolerance compared to placebo. 4
• Physiologic replacement doses show no clinically significant worsening of lipid profiles, with HDL unchanged in 15 of 18 studies. 4

Specific Cardiovascular Risks to Monitor

• Fluid retention can occur but is rarely clinically significant. 3, 4
• Edema with or without congestive heart failure may be a serious complication in patients with pre-existing cardiac, renal, or hepatic disease. 2
• Worsening of untreated severe heart failure is a relative contraindication. 5, 6, 7

Prostate-Related Risks

Prostate Cancer: Unmasking vs. Causation

• There is no compelling evidence that testosterone causes prostate cancer or that men with higher testosterone levels are at greater risk. 1
• Prospective studies examining stored plasma samples found no difference in testosterone levels between men who developed prostate cancer 7-25 years later and those who did not. 1
• Of 12 prospective studies reviewed, only one (Physicians' Health Study) suggested any relation, and this was only after simultaneous adjustment for four other hormones—clinically uncertain significance. 1
• Testosterone may unmask occult prostate cancer by promoting growth of pre-existing microscopic disease, with 4.9% developing prostate cancer in one long-term study. 8
• In men who developed prostate cancer during therapy, PSA increased by 1.8 ng/mL at 18 months and 3.2 ng/mL at 36 months, while PSA remained stable in those without cancer. 8

Benign Prostatic Hyperplasia

• Prostate volume increases significantly during the first six months of therapy to levels equivalent to men without hypogonadism. 1
• Despite increased prostate volume, multiple studies failed to demonstrate worsening voiding symptoms, and urinary retention has not occurred at higher rates than placebo. 1
• Urine flow rates, post-void residual volumes, and prostate symptoms did not change significantly in clinical trials. 1
• Individual men may occasionally experience increased voiding symptoms requiring clinical awareness. 1

Hepatic Risks

• Prolonged use of high doses of androgens (principally 17-α alkyl-androgens) has been associated with hepatic adenomas, hepatocellular carcinoma, and peliosis hepatis—all potentially life-threatening complications. 2
• This risk is primarily associated with oral alkylated androgens, not injectable or transdermal testosterone esters. 2

Metabolic and Endocrine Effects

• Hypercalcemia may occur in immobilized patients, requiring drug discontinuation. 2
• Gynecomastia may develop and occasionally persists in patients treated for hypogonadism. 2

Sleep Apnea

• Worsening of untreated sleep apnea is a recognized risk and relative contraindication. 5, 6, 7
• Baseline sleep apnea history should be determined before initiating therapy. 1

Special Population Risks

Geriatric Patients

• Geriatric patients may be at increased risk of developing prostatic hypertrophy and prostatic carcinoma, although conclusive evidence is lacking. 2

Pediatric/Adolescent Patients

• In children, androgen treatment may accelerate bone maturation without producing compensatory gain in linear growth, compromising final adult stature. 2
• The younger the child, the greater the risk of compromising final mature height. 2

Contraindications and High-Risk Scenarios

Absolute Contraindications

• Prostate cancer (though debated for men deemed cured). 1, 7
• Breast cancer. 7
• Erythrocytosis (hematocrit >50% at baseline). 4, 7
• Recent myocardial infarction. 7

Relative Contraindications Requiring Careful Assessment

• Untreated severe obstructive sleep apnea. 7
• Severe congestive heart failure. 7
• Severe lower urinary tract symptoms. 7
• Pre-existing cardiac, renal, or hepatic disease. 2

Monitoring Algorithm to Mitigate Risks

Baseline Assessment

• Digital rectal examination and PSA (biopsy if PSA >4.0 ng/mL or abnormal examination). 1
• Baseline testosterone levels, hematocrit/hemoglobin. 1
• Voiding history or standardized questionnaire. 1
• Sleep apnea history. 1

Follow-Up Monitoring

• Hematocrit at 2-3 months, then every 6-12 months (most critical for detecting erythrocytosis). 4
• PSA and digital rectal examination every 3-6 months for first year, then annually. 1
• Low threshold for prostate biopsy if PSA rises substantially or digital rectal examination changes (nodule, asymmetry, increased firmness). 1

Management of Complications

• For erythrocytosis: dosage reduction, withholding testosterone, therapeutic phlebotomy, or blood donation. 1
• Transdermal testosterone gel is strongly preferred over injections for all patients, especially those with cardiovascular disease or risk factors, due to lower erythrocytosis risk. 4