How can large variations in testosterone levels post-dosing be managed in testosterone replacement therapy (TRT) to achieve physiological levels?

Managing Large Testosterone Variations in TRT

While intramuscular testosterone injections do produce non-physiological fluctuations with peaks 2-5 days post-injection and troughs by 10-14 days, this limitation can be effectively managed by switching to transdermal preparations (gels/patches) or long-acting testosterone undecanoate injections, which maintain stable physiologic levels throughout the dosing interval. 1

Understanding the Fluctuation Problem with Standard Injections

Traditional intramuscular testosterone esters (enanthate, cypionate) create significant pharmacokinetic challenges:

• Peak levels occur 2-5 days after injection and often rise transiently above the upper limit of normal (>1000 ng/dL) with standard dosing 1
• Testosterone levels return to baseline by 10-14 days post-injection, meaning patients spend substantial time in subtherapeutic ranges 1
• Patients are outside the physiologic range at least 50% of the time with traditional 2-3 week injection protocols 2
• These fluctuations are associated with greater cardiovascular risk, hospitalizations, and deaths compared to transdermal preparations 1

The supraphysiologic peaks also generate elevated estradiol levels, which are typically above normal ranges with injection therapy 2.

Optimal Formulation Selection to Achieve Physiologic Levels

First-Line Recommendation: Transdermal Preparations

Transdermal testosterone gels and patches provide the most physiologic testosterone delivery with minimal fluctuations:

• Gels maintain stable testosterone levels within the normal range throughout the day with only 5% experiencing skin reactions, compared to 66% with patches 1
• A 36-month placebo-controlled study demonstrated no significant fluctuations in testosterone levels with transdermal preparations 1
• Transdermal delivery produces normal DHT and estradiol levels, unlike injections which elevate estradiol 2
• Dosing flexibility allows titration from 20.25-120 mg/day depending on the preparation to achieve mid-normal range levels (450-600 ng/dL) 1, 3

Second-Line: Long-Acting Testosterone Undecanoate

For patients who cannot tolerate or prefer not to use daily transdermal therapy, testosterone undecanoate (Aveed) provides stable levels:

• 750 mg injections every 10 weeks maintain average testosterone concentrations of 495 ng/dL (within physiologic range) 4
• 94% of patients maintained levels between 300-1000 ng/dL at steady state 4
• Only 7.7% experienced Cmax >1500 ng/dL, and no patient exceeded 1800 ng/dL 4
• Steady-state is achieved by the third injection at 14 weeks, providing consistent levels for 10-week intervals 4
• This formulation produces normal DHT and estradiol levels unlike shorter-acting injections 4

Modified Injection Protocol for Traditional Esters

If transdermal or long-acting preparations are not options, reduce fluctuations with more frequent dosing:

• Administer testosterone enanthate/cypionate 50-100 mg weekly instead of 200 mg every 2 weeks to minimize peaks and troughs 1
• Weekly dosing reduces time spent in supraphysiologic and subtherapeutic ranges 1
• Monitor testosterone levels at different time points relative to injection (peak at 2-5 days, trough at 10-14 days) to assess the degree of fluctuation 1

Monitoring Strategy to Confirm Physiologic Levels

Target testosterone levels in the mid-to-upper normal range (450-600 ng/dL) to optimize clinical response while minimizing adverse effects: 1, 3

• First follow-up at 1-2 months to assess efficacy and adjust dosing if needed 1
• Subsequent visits every 3-6 months for the first year, then yearly 1
• For injection therapy, time blood draws appropriately: measure at peak (2-5 days) and trough (10-14 days) to assess fluctuation magnitude 1
• For transdermal therapy, measure testosterone levels 2-8 hours after application when levels are most representative 1

Critical Safety Considerations Related to Fluctuations

The non-physiologic peaks with injection therapy carry specific risks:

• Erythrocytosis occurs in 43.8% of patients on intramuscular injections versus only 15.4% with transdermal patches, associated with supraphysiologic testosterone peaks 1
• Monitor hematocrit at each visit; if >52%, consider dose reduction, temporary discontinuation, or therapeutic phlebotomy 1
• Safety concerns regarding cardiovascular events may be related to increased time in both supratherapeutic and subtherapeutic ranges with injections 1
• Avoid testosterone therapy for 3-6 months following cardiovascular events 3

Body Weight Impact on Achieving Physiologic Levels

Heavier patients require dose adjustments to maintain physiologic levels:

• Patients weighing ≥100 kg achieve lower average testosterone concentrations (426 ng/dL) compared to those 65-100 kg (568 ng/dL) with standard dosing 4
• BMI >30 kg/m² results in lower testosterone levels (445 ng/dL) versus BMI <26 kg/m² (579 ng/dL) 4
• Consider higher doses or more frequent administration in obese patients to achieve target physiologic range 4

Algorithm for Formulation Selection

1. Start with transdermal gel (first-line for physiologic stability) 1, 2
2. If skin reactions occur or patient preference dictates, switch to testosterone undecanoate injections every 10 weeks 4
3. If cost or access limits these options, use weekly injections of enanthate/cypionate (50-100 mg) rather than biweekly 1
4. Avoid oral testosterone undecanoate due to short half-life requiring multiple daily doses and elevated DHT 2
5. Never use 17-alpha-alkylated androgens (methyltestosterone) due to hepatotoxicity and adverse lipid effects 3