What are the potential side effects and management strategies for a 40-70 year old male patient with hypogonadism (low testosterone levels) considering Testosterone Replacement Therapy (TRT)?

Testosterone Replacement Therapy Side Effects

Primary Side Effects and Risks

Erythrocytosis (elevated red blood cell count) is the most common and clinically significant side effect of TRT, occurring in 3-18% of men on transdermal preparations and up to 44% with injectable testosterone. 1, 2

Hematologic Complications

• Polycythemia/erythrocytosis represents the most frequent dose-dependent adverse effect, with injectable formulations carrying substantially higher risk than transdermal preparations 1, 2
• Increased risk of venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), has been reported in postmarketing surveillance 3
• Treatment must be withheld if hematocrit exceeds 54%, and phlebotomy should be considered in high-risk cases with persistent erythrocytosis 1, 2

Cardiovascular Concerns

• Low-certainty evidence suggests a small increase to no difference in major adverse cardiovascular events (MACE), including non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, with a Peto odds ratio of 1.22 2
• The FDA required labeling changes in 2015 regarding possible increased cardiovascular risk, though multiple professional societies note conflicting data and potential confounding by high-risk patient populations 1, 2
• Injectable testosterone may carry higher cardiovascular risk than transdermal preparations due to supraphysiologic and subtherapeutic fluctuations between doses 1
• Sodium and water retention can precipitate or worsen congestive heart failure in susceptible patients 2, 3

Prostate-Related Effects

• Benign prostatic hyperplasia (BPH) symptoms may worsen, though this is rarely of clinical significance 1, 2
• Current evidence does not support testosterone causing prostate cancer, but it may theoretically accelerate growth of existing disease 2
• PSA monitoring is mandatory in men over 40 years, with urologic referral required if PSA increases >1.0 ng/mL in the first 6 months or >0.4 ng/mL per year thereafter 1

Reproductive System Effects

• Testosterone therapy causes suppression of spermatogenesis and can lead to prolonged or potentially irreversible azoospermia 1
• This represents an absolute contraindication in men actively seeking fertility preservation 1
• Testicular atrophy commonly occurs due to suppression of the hypothalamic-pituitary-gonadal axis 1

Dermatologic Side Effects

• Acne or oily skin develops in a subset of patients 1
• Gynecomastia frequently develops and occasionally persists in patients being treated for hypogonadism 3
• Male-pattern baldness acceleration has not been documented in clinical studies, though this has not been carefully studied 1

Respiratory Complications

• Testosterone may potentiate or worsen obstructive sleep apnea, especially in men with obesity or chronic lung disease 2
• Untreated severe obstructive sleep apnea represents an absolute contraindication to initiating TRT 1
• Rare postmarketing reports describe transient reactions involving urge to cough, coughing fits, and respiratory distress immediately after injection of testosterone enanthate 3

Metabolic Effects

• Fluid retention is common and can be problematic in patients with preexisting cardiac, renal, or hepatic disease 3
• Hypercalcemia may occur in immobilized patients or those with breast cancer through stimulation of osteolysis 3

Hepatic Risks

• Prolonged use of high doses has been associated with peliosis hepatis and hepatic neoplasms, including hepatocellular carcinoma 3
• Cholestatic hepatitis with jaundice may develop, requiring immediate discontinuation 3
• Note: These hepatic complications are primarily associated with alkylated oral testosterone preparations, which should not be prescribed 1

Management Strategies

Pre-Treatment Screening

• Document baseline hematocrit/hemoglobin before initiating therapy 1
• Perform baseline PSA and digital rectal examination in men over 40 years 1, 2
• Assess for contraindications: active desire for fertility, active/treated male breast cancer, hematocrit >54%, untreated severe sleep apnea, recent cardiovascular events within 3-6 months 1

Monitoring Protocol

• Measure testosterone levels at 2-3 months after initiation or dose change, then every 6-12 months once stable 1
• For injectable testosterone: measure levels midway between injections (days 5-7), targeting 500-600 ng/dL 1
• Monitor hematocrit at each visit—withhold treatment if >54% 1, 2
• Check PSA every 6-12 months in men over 40 years 2
• Perform digital rectal examination periodically to assess for prostate abnormalities 1

Risk Mitigation Strategies

• Use transdermal preparations (gel, patch) over injectable testosterone when possible, as they provide more stable day-to-day levels and lower erythrocytosis risk 1, 2
• Target mid-normal testosterone levels (450-600 ng/dL) rather than higher physiologic ranges, especially in elderly patients or those with chronic illness 2, 4
• In patients with congestive heart failure, use caution and target mid-range levels (350-600 ng/dL) 1
• If erythrocytosis develops, withhold therapy until hematocrit normalizes and consider dose reduction or formulation change 1, 2
• Therapeutic phlebotomy may be necessary in high-risk cases with persistent erythrocytosis 1

Formulation Selection to Minimize Side Effects

• Transdermal testosterone gel (1.62% at 40.5 mg daily) represents first-line therapy with lower erythrocytosis risk 1
• Injectable testosterone cypionate/enanthate (100-200 mg every 2 weeks) is more economical but carries higher erythrocytosis and cardiovascular fluctuation risk 1
• Extra-long-acting testosterone undecanoate (750 mg initially, repeat at 4 weeks, then every 10 weeks) provides fewer injections and more stable levels 1

When to Discontinue Therapy

• Reassess treatment benefit at 12 months and discontinue if no improvement in sexual function, to prevent unnecessary long-term exposure without benefit 1, 2
• Discontinue immediately if hematocrit exceeds 54% and does not normalize with temporary cessation 1
• Stop therapy if venous thromboembolic event is suspected and initiate appropriate workup 3
• Discontinue if cholestatic hepatitis or abnormal liver function tests develop 3

Critical Pitfalls to Avoid

• Never initiate TRT in men actively seeking fertility—use gonadotropin therapy (hCG plus FSH) instead 1
• Do not start therapy within 3-6 months of cardiovascular events 1, 4
• Avoid prescribing alkylated oral testosterone due to hepatotoxicity risk 1
• Do not monitor testosterone levels at peak (days 2-5) or trough (days 13-14) for injectable formulations, as this leads to inappropriate dosing adjustments 1
• Nearly half of men on TRT never have their levels checked—this represents dangerous practice 1
• Approximately 20-30% of men receiving testosterone lack documented low testosterone before treatment initiation, violating evidence-based guidelines 1, 2