What are the relative bioavailabilities of different testosterone dosage forms?

Relative Bioavailability of Testosterone Dosage Forms

Transdermal testosterone gels demonstrate approximately 9-14% bioavailability, while transdermal patches deliver approximately 20% of applied testosterone, and intramuscular injections provide complete bioavailability but with significant pharmacokinetic fluctuations. 1, 2

Injectable Formulations

Intramuscular testosterone esters (enanthate, cypionate) provide 100% bioavailability but create strongly fluctuating plasma levels that remain outside the physiological range at least 50% of the time with standard every 2-3 week dosing. 3

• Testosterone enanthate and cypionate administered at 100-200 mg every 2 weeks produce supraphysiological peaks followed by subtherapeutic troughs, with plasma estradiol typically reaching supraphysiological levels. 3
• Weekly dosing at 50-100 mg provides more stable testosterone levels compared to biweekly administration, reducing the time spent outside physiological range. 4
• Testosterone undecanoate (750 mg initially, then at 4 weeks, then every 10 weeks) produces normal plasma testosterone levels for 12 weeks with normal DHT and estradiol levels, representing a major pharmacokinetic improvement over shorter-acting esters. 4, 3

Transdermal Gel Formulations

Transdermal testosterone gels achieve 9-14% bioavailability when applied to upper arms, shoulders, and abdomen, with the 1% hydroalcoholic formulation drying within minutes. 1

• Steady-state levels are reached within 48-72 hours of first application, with serum testosterone rising rapidly into the normal adult male range on day 1. 1
• The 50 mg daily gel dose (delivering 5 mg/day) produces average serum testosterone levels approximately 1.4-fold lower than the 100 mg dose. 1
• Serum DHT increases 3.6-fold with 50 mg gel and 4.6-fold with 100 mg gel, resulting in elevated DHT/testosterone ratios compared to patches. 1
• Peak testosterone levels occur approximately 2 hours post-application, with significantly lower levels at 23 hours, demonstrating the importance of timing when monitoring therapy. 5

Transdermal Patch Formulations

Enhanced transdermal patches deliver approximately 20% of patch testosterone content (mean 5.2 mg/day from patches containing ~26 mg), producing physiological testosterone concentrations. 2

• Nonscrotal patches produce normal DHT/testosterone ratios (0.07) and estradiol/testosterone ratios (0.005), unlike scrotal patches which generate supraphysiological DHT levels. 3, 2
• Peak testosterone levels occur 5-6 hours after evening application, with 24-hour profiles approximately mimicking normal circadian variations in healthy men. 2
• Patches cause skin reactions in up to 66% of users, compared to only 5% with gel preparations, significantly impacting tolerability despite favorable pharmacokinetics. 6

Clinical Implications for Formulation Selection

Injectable testosterone carries greater risk of erythrocytosis than transdermal preparations due to supraphysiological peak levels and fluctuating testosterone concentrations. 6, 4

• Erythrocytosis occurred in 43.8% of patients receiving intramuscular injections versus 15.4% with transdermal patches, with higher rates associated with supraphysiological bioavailable testosterone and estradiol levels. 6
• Dose-dependent erythrocytosis risk was demonstrated with 2.8% incidence at 5 mg/day transdermal delivery, increasing to 11.3% at 50 mg gel (5 mg/day delivered) and 17.9% at 100 mg gel (10 mg/day delivered). 6
• Injectable testosterone may carry greater cardiovascular risk compared to transdermal preparations, possibly due to fluctuating testosterone levels rather than absolute bioavailability differences. 4, 7

Monitoring Considerations Based on Bioavailability

For injectable formulations, measure testosterone levels midway between injections at 2-3 months after initiation, targeting mid-normal values (450-600 ng/dL). 4, 7

For transdermal gels, assess both peak (+2 hours) and trough (+23 hours) levels to ensure adequate coverage throughout the day, as only 36.7% of patients with adequate levels at peak maintain therapeutic levels at trough. 5