Is daily macrodosing of testosterone (intramuscular (IM) or topical) superior to weekly intramuscular (IM) injections of testosterone (such as testosterone cypionate or enanthate) for patients undergoing testosterone replacement therapy?

Daily Testosterone Dosing vs Weekly IM Injections

Weekly intramuscular injections of testosterone (50-100 mg) are superior to biweekly dosing and provide more stable levels than traditional biweekly regimens, while daily transdermal testosterone gel offers the most physiologically stable testosterone concentrations with lower risk of erythrocytosis compared to any injectable regimen. 1, 2

Optimal Dosing Frequency for Injectable Testosterone

Weekly dosing (50-100 mg IM) provides significantly more stable testosterone levels compared to biweekly administration (100-200 mg every 2 weeks), reducing the problematic peak-trough fluctuations that cause mood swings and adverse effects. 1

• The traditional biweekly dosing creates unsatisfactory fluctuations in serum testosterone that result in shifts in mood and sexual function in some men 3
• Weekly injections can be self-administered in the thighs or given by another person in the gluteal region 1
• Testosterone levels should be measured midway between injections, targeting mid-normal values of 450-600 ng/dL 1, 2

Transdermal Gel: The Superior Daily Option

The Endocrine Society recommends transdermal testosterone gels as first-line therapy due to stable physiologic testosterone levels and patient convenience, with intramuscular injections reserved for those with cost constraints or adherence issues. 2

Pharmacokinetic Advantages

• Daily testosterone gel (AndroGel 1% at 50-100 mg daily or AndroGel 1.62% at 20.25-81 mg daily) produces sustained physiologic concentrations without the extraphysiologic variations seen with injections 1, 4
• In a direct comparison study, mean peak-trough fluctuations in free testosterone were 2.7 ± 10.7 pg/mL with gel versus 26.7 ± 12.8 pg/mL with intramuscular injections (p < .001) 4
• Quality-of-life scores indicated more improved physical and emotional well-being with gel versus intramuscular testosterone 4

Safety Profile Favors Daily Transdermal Administration

Erythrocytosis occurs significantly more frequently with injectable formulations compared to transdermal preparations, representing a critical safety distinction. 5

• Erythrocytosis occurred in 43.8% of patients receiving intramuscular injections versus only 15.4% with transdermal patches 5
• Dose-dependent erythrocytosis with gels ranges from 2.8% at 5 mg/day delivered to 17.9% at 10 mg/day delivered, still substantially lower than injectable rates 1
• The risk of hemoconcentration from elevated hematocrit could aggravate vascular disease in coronary, cerebrovascular, or peripheral circulation, particularly in elderly patients 5

Practical Considerations

Cost and Access

• Transdermal formulations cost approximately $2,135 annually versus $156 for intramuscular injections per Medicare data 1
• For cost-sensitive patients or those with poor adherence to daily application, weekly intramuscular injections represent a reasonable alternative 2

Administration Ease

• Transdermal gels offer easy application and good skin tolerability, avoiding intramuscular injection discomfort 1
• Approximately 5% of gel users experience skin reactions compared to 66% with patches 1
• The main disadvantage is potential for transfer to partners or children through skin-to-skin contact, requiring the gel to dry completely and application sites to be covered with clothing 1

Clinical Algorithm for Formulation Selection

Start with transdermal gel (AndroGel 1% at 50 mg daily) as first-line unless cost prohibits, then use weekly IM injections (50-100 mg) rather than biweekly dosing. 1, 2

1. First-line: Transdermal gel 50-100 mg daily for stable levels and lowest erythrocytosis risk 2
2. Second-line (cost constraints): Weekly IM testosterone cypionate/enanthate 50-100 mg for more stable levels than biweekly 1
3. Avoid: Biweekly IM dosing (100-200 mg every 2 weeks) due to excessive fluctuations 1, 3

Monitoring Protocol

• Measure testosterone levels at 2-3 months after initiation or dose change 1, 2
• For IM injections, measure midway between injections targeting 450-600 ng/dL 1, 2
• For transdermal preparations, measure at any time (peak occurs 6-8 hours after application) 2
• Monitor hematocrit/hemoglobin at each visit given dose-dependent erythrocytosis risk 1
• Once stable, monitor every 6-12 months including testosterone levels, hematocrit, PSA, and lipid panel 1, 2

Common Pitfalls to Avoid

• Do not use biweekly IM dosing when weekly dosing provides superior stability with the same medication 1
• Do not ignore erythrocytosis risk with injectable formulations—this occurs in nearly half of patients on IM therapy and carries cardiovascular consequences 5
• Do not assume all gel formulations are interchangeable—the 1.62% formulation delivers more testosterone per gram than 1% formulation, requiring different dosing 1
• Do not continue supraphysiological dosing even if patients report feeling well, as levels >1000 ng/dL significantly increase adverse event risk 1