Progesterone Half-Life by Route of Administration
The biological half-life of progesterone varies substantially by route: oral micronized progesterone has a terminal half-life of approximately 16–17 hours, intramuscular progesterone achieves sustained levels for days to weeks depending on formulation, vaginal progesterone demonstrates a terminal half-life of 13–18 hours, and subcutaneous depot formulations are designed for prolonged release over weeks to months.
Oral Micronized Progesterone
- Terminal half-life: approximately 16.4 hours after a single 100 mg dose, with peak serum concentrations (Tmax) occurring at 6.9 hours post-administration 1.
- Oral progesterone undergoes extensive first-pass hepatic metabolism, resulting in bioavailability of less than 10% despite nearly complete gastrointestinal absorption 2.
- Serum progesterone levels rise rapidly to reach luteal-phase values (mean maximum 55.6 nM) within 1–4 hours and remain elevated for at least 12 hours after a single 100 mg oral dose 3.
- The rapid metabolism and relatively short half-life necessitate multiple daily dosing (typically 200 mg at bedtime or divided doses) to maintain therapeutic levels 4, 5.
Intramuscular Progesterone
- Intramuscular administration of 100 mg progesterone produces serum levels two to three times higher than the oral route, with sustained elevation over days 3.
- The 17-alpha-hydroxyprogesterone caproate (17P) formulation used in obstetric practice (250 mg IM weekly) is designed for prolonged release, maintaining therapeutic levels throughout the dosing interval 6.
- Standard oil-based IM progesterone formulations provide sustained release over several days, avoiding the need for daily administration 7, 5.
- IM progesterone achieves serum progesterone values within the physiologic luteal-phase range and results in adequate secretory endometrial transformation 5.
Vaginal Progesterone
- Terminal half-life: 13–18 hours depending on formulation, with vaginal tablets showing a half-life of 16.4 hours and gelatin capsules demonstrating similar kinetics 1.
- Peak serum concentrations (Tmax) occur at 6–7 hours after vaginal administration of 100 mg progesterone 1.
- Vaginal progesterone exhibits a "uterine first-pass effect," delivering higher progesterone concentrations directly to the endometrium while producing lower systemic serum levels than IM administration 1, 5.
- Despite lower serum progesterone levels compared to IM administration, vaginal progesterone achieves adequate secretory endometrial transformation due to preferential uterine uptake 2, 5.
- The vaginal route avoids hepatic first-pass metabolism, resulting in better bioavailability than oral administration while minimizing systemic side effects 1, 5.
Subcutaneous Depot Formulations
- No specific pharmacokinetic data on subcutaneous depot progesterone half-life are provided in the available evidence.
- Depot formulations are designed for prolonged release over weeks to months, similar to the sustained-release profile of IM depot preparations 7.
- The lack of detailed pharmacokinetic studies on subcutaneous depot progesterone in the provided evidence reflects limited clinical use of this route compared to oral, IM, and vaginal administration 7.
Clinical Implications of Route-Specific Pharmacokinetics
- Oral progesterone requires twice-daily or bedtime dosing (typically 200 mg) to maintain therapeutic levels due to its 16-hour half-life and extensive first-pass metabolism 4, 1.
- Intramuscular progesterone (especially 17P) allows weekly dosing in obstetric applications due to sustained release over days 6.
- Vaginal progesterone provides once-daily dosing (100–200 mg) with preferential uterine delivery, making it ideal for endometrial support in assisted reproduction 1, 5.
- The choice of route should prioritize transdermal or vaginal delivery over oral when systemic side effects (drowsiness, mood changes) are problematic, as these routes bypass hepatic metabolism 4, 1.
Common Pitfalls
- Do not assume oral progesterone provides adequate systemic levels—its bioavailability is less than 10% despite complete absorption, necessitating higher doses (200 mg) compared to vaginal (100 mg) for equivalent endometrial effects 2, 5.
- Do not rely solely on serum progesterone levels to assess vaginal progesterone efficacy—the uterine first-pass effect means endometrial concentrations are adequate even when serum levels appear suboptimal 1, 5.
- Avoid using oral progesterone as the sole route for luteal-phase support in assisted reproduction—vaginal and IM routes have proven superior in clinical outcomes 2, 5.