What are the comparisons of bioavailability between testosterone administered via sublingual, topical, oral, and intramuscular (IM) injection routes of administration?

Bioavailability Comparison of Testosterone Routes of Administration

Direct Bioavailability Rankings

Intramuscular (IM) injection provides the highest bioavailability but with significant fluctuations, while transdermal formulations (gel and patches) offer approximately 10% bioavailability with more stable serum levels, making topical routes preferable for minimizing adverse effects despite lower absorption. 1

Route-Specific Bioavailability Data

Intramuscular Injections

• IM testosterone achieves approximately 90% systemic bioavailability with the majority excreted as metabolites in urine, demonstrating near-complete absorption from muscle tissue 1
• IM injections produce supraphysiologic peak levels that contribute to significantly higher rates of erythrocytosis (43.8% vs 15.4% with transdermal patches) 2
• Biweekly dosing of 200 mg IM testosterone cypionate or enanthate fails to maintain therapeutic levels for the full 14-day interval, with concentrations declining substantially before the next injection 3

Transdermal Formulations (Gel)

• Transdermal testosterone gel delivers approximately 10% bioavailability, with the skin serving as a reservoir for sustained 24-hour release into systemic circulation 1
• Gel application to upper arms/shoulders provides 30-40% higher bioavailability compared to abdominal application, making site selection clinically significant 4
• Steady-state testosterone levels with 100 mg gel application average 612 ng/dL, while 50 mg produces 365 ng/dL at day 30 of therapy 1
• Dose-dependent erythrocytosis occurs at rates of 2.8% (5 mg/day delivered), 11.3% (50 mg gel), and 17.9% (100 mg gel), demonstrating safety advantages over IM despite lower bioavailability 2, 5

Transdermal Formulations (Patches)

• Patches demonstrate similar 10% bioavailability as gels but cause skin reactions in up to 66% of users compared to only 5% with gel preparations 5
• Scrotal patches produced erythrocytosis in only 5.5% of patients, the lowest rate among all formulations 2
• Non-scrotal patches resulted in 15.4% erythrocytosis rate, significantly lower than IM injections 2

Subcutaneous Injections

• SC testosterone achieves therapeutic levels equivalent to IM administration with mean steady-state concentrations of 422 ng/dL (50 mg weekly) and 896 ng/dL (100 mg weekly) 6
• SC administration produces stable serum levels between injections (mean 627 ± 206 ng/dL total testosterone) without the supraphysiologic peaks seen with IM 7
• SC route demonstrates dose-proportional pharmacokinetics with less variation than IM formulations 6

Oral and Sublingual Routes

• The provided evidence does not contain specific bioavailability data for oral or sublingual testosterone formulations 8, 9
• Traditional oral testosterone undergoes extensive first-pass hepatic metabolism, historically limiting its clinical utility (general medical knowledge)

Clinical Implications for Route Selection

Safety Profile by Route

• IM injections carry the highest risk of erythrocytosis and potentially greater cardiovascular risk due to fluctuating supraphysiologic testosterone levels 5
• Transdermal preparations minimize erythrocytosis risk through steady-state delivery avoiding peak concentrations 2
• No consistent differences in long-term cardiovascular events, mortality, or prostate cancer were observed between transdermal and IM formulations in observational studies, though most excluded high-risk cardiovascular patients 2

Practical Considerations

• Weekly IM or SC dosing (50-100 mg) provides more stable levels than biweekly administration (100-200 mg), reducing adverse effects 5
• Patient preference studies show 53% chose injectable testosterone over gel primarily due to lower cost, while 71% of gel users preferred it for convenience and ease of use 2
• Transdermal gels require precautions to prevent transfer to partners or children, a risk not present with injectable formulations 1

Monitoring Requirements Across Routes

• Testosterone levels should be measured 2-3 months after initiation or dose changes, with injectable formulations checked midway between injections targeting mid-normal values (450-600 ng/dL) 5
• Hematocrit monitoring is essential across all routes, with more frequent monitoring needed for IM formulations given the 43.8% erythrocytosis rate 2