What are the risks and considerations for initiating testosterone replacement therapy (TRT) in a middle-aged man with hypogonadism?

Risks and Considerations for Testosterone Replacement Therapy

Testosterone replacement therapy carries significant cardiovascular risks, including blood pressure increases that can lead to major adverse cardiovascular events (MACE), and should only be initiated in men with confirmed biochemical hypogonadism (testosterone <300 ng/dL on two separate morning measurements) plus associated symptoms, after careful cardiovascular risk assessment. 1

Absolute Contraindications

TRT must not be initiated in men with:

• Breast or prostate cancer 1
• Pregnancy in female partners (testosterone causes fetal virilization) 1
• "Age-related hypogonadism" without structural or genetic etiologies - the FDA explicitly prohibits this indication due to cardiovascular risks 1

Major Cardiovascular Risks

Blood Pressure and MACE

• The FDA issued a black box warning stating that TRT can cause blood pressure increases that elevate the risk of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death 1
• Before initiating therapy, assess baseline cardiovascular risk and ensure blood pressure is adequately controlled 1
• After starting TRT, monitor for new-onset hypertension or worsening of pre-existing hypertension and re-evaluate whether benefits outweigh risks if cardiovascular risk factors develop 1
• The FDA Safety Announcement in March 2015 mandated labeling changes reflecting increased risk of heart attack and stroke 2

Conflicting Evidence on Cardiovascular Outcomes

• Some retrospective studies (Vigen et al., Finkle et al.) showed increased cardiovascular adverse outcomes in men receiving TRT 2
• Conversely, Baillargeon et al. found no increased myocardial infarction risk and even suggested relative risk reduction in high-risk men 2
• Most level 1 trials found no difference in cardiovascular adverse events compared to placebo, except for the TOM trial 2

Hematologic Risks

Erythrocytosis

• Erythrocytosis is the most common serious adverse effect, with risk varying by formulation: 3-18% with transdermal administration and up to 44% with injectable testosterone 3
• Elevated hematocrit increases risk of thromboembolic events 3
• Monitor hematocrit at 2-3 months after initiation or dose adjustment, then every 6-12 months 3

Venous Thromboembolism

• Evaluate patients reporting lower extremity pain, edema, warmth, and erythema for deep vein thrombosis 1
• Evaluate patients with acute shortness of breath for pulmonary embolism 1
• If venous thromboembolic event is suspected, discontinue TRT immediately and initiate appropriate workup 1

Prostate-Related Risks

Benign Prostatic Hyperplasia and Prostate Cancer

• Perform baseline PSA and digital rectal examination in men over 40 years before initiating therapy 3
• Monitor PSA levels every 6-12 months 3
• While evidence does not support testosterone causing prostate cancer, it may accelerate growth of existing disease 3
• The FDA warns about potential worsening of benign prostatic hyperplasia 1

Other Significant Risks

Fluid Retention and Heart Failure

• Testosterone promotes sodium and water retention, which may precipitate or worsen congestive heart failure in susceptible patients 3, 1
• Edema can be a serious complication in patients with pre-existing cardiac, renal, or hepatic disease 1
• Diuretic therapy may be required in addition to drug discontinuation 1

Sleep Apnea

• TRT may potentiate sleep apnea, especially in men with obesity or chronic lung disease 1
• However, recent trials cast doubt on significant effects on sleep architecture in patients with untreated obstructive sleep apnea 2

Reproductive Effects

• Large doses suppress spermatogenesis through feedback inhibition of pituitary FSH, potentially leading to reduced sperm count 1
• Inform patients of this risk before initiating therapy, particularly those desiring fertility 1

Metabolic Effects

• TRT causes reductions in total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides 1
• Monitor lipid profile periodically, particularly after starting therapy, as changes may require dose adjustment of lipid-lowering drugs or discontinuation of testosterone 1

Other Adverse Effects

• Gynecomastia may develop and persist in men being treated for hypogonadism 1
• Hepatic adverse effects are possible, though testosterone undecanoate is not a 17-alpha-alkyl androgen and is not known to cause hepatic toxicity 1
• Hypercalcemia risk in cancer patients requires periodic monitoring of serum calcium 1

Critical Monitoring Requirements

Establish a structured monitoring protocol:

• Testosterone levels at 7 days after starting or dose adjustment (3-5 hours after morning dose for oral formulations) 1
• Hematocrit at 2-3 months, then every 6-12 months 3
• PSA and digital rectal examination every 6-12 months in men over 40 3
• Blood pressure monitoring at each visit to detect new-onset or worsening hypertension 1
• Lipid profile periodically, especially after starting therapy 1
• Reassess treatment benefit at 12 months and discontinue if no improvement in sexual function to prevent unnecessary long-term exposure 3

Common Pitfalls to Avoid

• Do not prescribe TRT for "anti-aging" or age-related hypogonadism alone - this violates FDA indications and exposes patients to cardiovascular risks without proven benefit 1
• Do not rely on single testosterone measurement - confirm with two separate morning measurements 3
• Do not initiate TRT without documenting both low testosterone AND associated symptoms 3
• Do not neglect cardiovascular risk assessment before initiating therapy 1
• Do not continue therapy beyond 12 months without documented symptom improvement 3