Comparative Side Effects of Testosterone Therapies

Introduction to Testosterone Replacement Therapy

• The American College of Physicians recommends considering the risk of erythrocytosis when choosing between intramuscular testosterone injections and transdermal patches, with injections carrying a significantly higher risk of 43.8% compared to 15.4% with patches 1, 2
• The Endocrine Society suggests that the elevated hematocrit risk with injections stems from supraphysiologic testosterone peaks followed by subtherapeutic troughs, creating prolonged exposure to both extremes 1, 3

Key Side Effect Differences

• Intramuscular injections produce erythrocytosis in 43.8% of patients, versus 15.4% with transdermal patches—a nearly 3-fold higher risk that directly impacts cardiovascular morbidity and mortality 1, 2
• The American Heart Association notes that evidence suggests IM injections may carry higher cardiovascular event risk than transdermal preparations due to time spent in both supratherapeutic and subtherapeutic ranges between injections 3

Formulation-Specific Side Effects

• Transdermal patches have a lower risk of erythrocytosis, with a rate of 15.4% compared to 43.8% with intramuscular injections, and also minimize mood/energy fluctuations due to stable testosterone levels 1, 2, 3
• The European Association of Urology states that intramuscular injections require intramuscular injection technique and can cause fluctuating serum testosterone with peaks and valleys, leading to mood/sexual function shifts in some men 3

Shared Side Effects

• Both formulations show neutral effects on HDL cholesterol and total cholesterol/HDL ratio at physiologic doses, according to the American College of Cardiology 1, 2
• The American Urological Association notes that benign prostatic hyperplasia exacerbation is rare with both formulations, and prostate cancer risk remains theoretical and unproven 1, 2

Clinical Decision Algorithm

• The American Geriatrics Society recommends choosing transdermal patches when patients have cardiovascular risk factors, such as elderly, diabetes, hypertension, or known CAD 1, 3
• The European Society of Endocrinology suggests choosing intramuscular injections when cost is a primary concern, or when patients have a history of significant skin reactions to adhesives 3

Critical Monitoring Requirements

• The American Society of Clinical Oncology recommends monitoring hematocrit at each visit for patients on intramuscular injections, withholding if >54% and considering phlebotomy 1, 2
• The Endocrine Society suggests measuring testosterone anytime for transdermal patches, and monitoring hematocrit periodically due to lower but still present risk 1, 2, 3

Testosterone Replacement Therapy Options

Introduction to Testosterone Replacement

• For patients who refuse intramuscular testosterone injections, transdermal testosterone preparations are the recommended first-line alternative due to their ease of application, good skin tolerability, and ability to maintain stable testosterone levels 4

Transdermal Testosterone Options

• Transdermal testosterone preparations provide stable serum testosterone levels with once-daily application to the upper arms and shoulders 4, 5
• Testosterone gels are available in various formulations, including AndroGel 1% and 1.62%, Testim 1% gel, Fortesta 2% gel, and Axiron 2% solution for axillary application 5
• The American College of Physicians recommends considering the advantages and disadvantages of transdermal testosterone preparations, including easy application, good skin tolerability, and potential for transfer to partners or children through skin contact 5, 6, 7
• Transdermal testosterone preparations have a higher cost compared to injectable options, with an annual cost in 2016 per Medicare beneficiary of $2,135.32 for transdermal formulations versus $156.24 for intramuscular formulations 6, 7

Testosterone Patch Options

• Testosterone patches, such as Androderm, are applied to dry, intact skin of the back, abdomen, upper thighs, or upper arms, and provide stable day-to-day testosterone levels 4, 5
• The Endocrine Society recommends considering the advantages and disadvantages of testosterone patches, including easy application, no risk of secondary transfer to others, and potential skin rash or irritation at the application site 4, 5

Monitoring and Safety Considerations

• Testosterone levels should be tested 2-3 months after treatment initiation and after any dose change, with a target mid-normal testosterone value of 500-600 ng/dL 4
• The American Urological Association recommends monitoring for potential adverse effects, including cardiovascular events and polycythemia, and targeting mid-normal testosterone values 4, 5

Patient Preference Considerations

• Patient preference should be considered when choosing a testosterone replacement therapy, with 71% of patients preferring topical gel over injections or patches due to convenience, ease of use, and non-staining of clothes 6, 7
• The method of testosterone replacement should be individualized based on patient preference, cost considerations, and clinical factors, according to the American College of Physicians 4

Evidence‑Based Decision Factors for Testosterone Replacement Formulations

Patient Preference

• Approximately 71 % of individuals initiating testosterone therapy prefer transdermal gel because it is perceived as more convenient and easier to use than injections. 8
• About 53 % of individuals choose injectable testosterone primarily due to its lower out‑of‑pocket cost. 8

Cost Considerations

• The average annual expense for transdermal gel is roughly US $2,100, whereas injectable testosterone costs about US $160 per year, representing a more than ten‑fold price difference. 8
• This large cost disparity (≈13‑fold) is a significant barrier; roughly 35 % of patients who opt for injections cite affordability as the decisive factor. 8
• In patients with severe financial constraints, injectable testosterone is the only economically feasible option, with an annual cost of about US $160. 8

Treatment Adherence and Continuity

• Discontinuation of testosterone replacement therapy occurs in 30 %–62 % of patients, regardless of the formulation used. 8

Comparative Efficacy

• Both transdermal gel and injectable testosterone produce comparable modest improvements in sexual function (standardized mean difference ≈ 0.35) and quality of life, with minimal impact on energy, physical function, mood, or cognition. 8