What are the potential side effects of testosterone replacement therapy?

Testosterone Replacement Therapy Side Effects

Testosterone replacement therapy carries several well-documented side effects, with erythrocytosis (elevated red blood cell count) being the most common and clinically significant, occurring in 2.8% to 43.8% of patients depending on formulation and dose, followed by local skin reactions, prostate enlargement, and potential worsening of sleep apnea. 1

Hematologic Effects

Erythrocytosis is the most frequent and dose-dependent side effect requiring active monitoring:

• Intramuscular testosterone injections carry the highest risk, with 43.8% of patients experiencing at least one elevated hematocrit (>52%) during treatment 1
• Transdermal gel preparations show intermediate risk: 11.3% at 50 mg/day and 17.9% at 100 mg/day 1
• Nonscrotal patches have the lowest incidence at 2.8% 1
• Most hemoglobin/hematocrit elevations occur within the first three months of therapy 1
• When hematocrit exceeds 54%, immediate intervention is mandatory: dose reduction, temporary discontinuation, therapeutic phlebotomy, or blood donation 2
• No testosterone-associated thromboembolic events have been reported to date, despite theoretical concerns 1

Prostate-Related Effects

Prostate volume increases but voiding symptoms typically do not worsen:

• Prostate volume increases significantly during the first six months of therapy to levels equivalent to eugonadal men 1
• Multiple studies demonstrate no exacerbation of voiding symptoms or increased urinary retention rates compared to placebo 1
• Individual patients may occasionally experience increased voiding symptoms 1
• The relationship between testosterone and prostate cancer remains controversial, with prospective studies showing only 1.1% cancer incidence (5 cases among 461 men over 6-36 months), similar to the general population 1
• Case reports suggest potential unmasking of occult prostate cancer, though causality is difficult to establish 1

Dermatologic and Local Reactions

Skin reactions vary dramatically by formulation:

• Transdermal patches cause reactions in up to 66% of users (erythema, pruritus) 1
• Gel preparations cause skin reactions in only 5% of users 1
• Intramuscular injections commonly cause local pain, soreness, bruising, erythema, swelling, nodules, or furuncles 1, 3
• Ice application provides symptomatic relief for injection site reactions 3
• Switching to transdermal formulations eliminates injection site complications entirely 3

Respiratory Effects

Sleep apnea may worsen or develop, particularly with higher doses:

• Testosterone has been associated with exacerbation or new development of sleep apnea 1
• Risk is highest in men receiving higher doses of parenteral testosterone who have other identifiable risk factors 1
• Mechanism involves central respiratory control rather than anatomical airway changes 1
• History of sleep apnea must be ascertained before initiating therapy 1

Cardiovascular and Fluid Balance

Fluid retention occurs but is generally mild:

• Fluid retention is uncommon and typically mild 1
• Use cautiously in men with congestive heart failure or renal insufficiency 1
• Leg swelling may indicate testosterone-induced erythrocytosis contributing to symptoms through increased blood viscosity 2
• Hypertension is rarely reported 1

Reproductive Effects

Fertility is significantly compromised during therapy:

• Testicular size and consistency diminish due to gonadotropin down-regulation 1
• Fertility will be greatly compromised during treatment 1
• This effect may be irreversible with prolonged use 4

Endocrine and Metabolic Effects

Gynecomastia and minor androgenic effects occur:

• Small number of men report breast tenderness and swelling 1
• Acne, oily skin, increased body hair, and flushing are minor inconveniences 1
• No data indicate acceleration of male-pattern baldness, though this has not been carefully studied 1

Formulation-Specific Risk Stratification

Choose formulation based on side effect profile:

• Injectable testosterone: Highest erythrocytosis risk (43.8%), highest local reaction rates, supraphysiologic peak levels 1
• Transdermal gels: Intermediate erythrocytosis risk (11.3-17.9%), lowest skin reaction rate (5%), more stable levels 1, 3
• Transdermal patches: Lowest erythrocytosis risk (2.8%), highest skin reaction rate (66%) 1

Critical Monitoring Requirements

Mandatory baseline and follow-up assessments:

• Baseline: PSA, hematocrit/hemoglobin, digital rectal exam, voiding symptoms, sleep apnea history 1
• First follow-up at 1-2 months to assess efficacy and early side effects 1, 2
• Subsequent visits every 3-6 months for first year, then yearly: symptomatic response, voiding symptoms, sleep apnea assessment, digital rectal exam, serum testosterone, PSA, hematocrit/hemoglobin 1
• If hematocrit rises above reference range: temporarily withhold therapy, reduce dose, or perform phlebotomy 1

Abuse and Dependence Risks

Testosterone is a Schedule III controlled substance with abuse potential:

• Serious adverse reactions from abuse include cardiac arrest, myocardial infarction, hypertrophic cardiomyopathy, congestive heart failure, cerebrovascular accident, hepatotoxicity, and psychiatric manifestations (major depression, mania, paranoia, psychosis) 4
• Withdrawal symptoms after abrupt discontinuation include depressed mood, fatigue, craving, restlessness, irritability, anorexia, insomnia, decreased libido 4

Key Clinical Pitfalls to Avoid

• Never continue testosterone at current dose if hematocrit exceeds 54% - increases thrombotic risk 2
• Do not ignore persistent cough or leg swelling - may indicate erythrocytosis-related complications requiring immediate hematocrit assessment 2
• Do not restart therapy without confirmed testosterone deficiency (<230 ng/dL) 2
• Switch from injectable to transdermal formulations if recurrent problematic reactions occur 3