Subcutaneous vs Intramuscular Progesterone: Serum Levels
Subcutaneous progesterone will result in lower serum progesterone levels compared to intramuscular progesterone, but this does not necessarily reflect reduced clinical efficacy due to route-specific pharmacokinetic differences.
Pharmacokinetic Differences Between Routes
The route of progesterone administration significantly affects both serum levels and tissue bioavailability:
Subcutaneous progesterone achieves lower systemic exposure (AUC) but higher peak concentrations (Cmax) compared to intramuscular administration. In a comparative bioavailability study, SC progesterone 25 mg twice daily showed 92.4% of the AUC and 138.0% of the Cmax compared to IM progesterone 50 mg daily 1.
Intramuscular progesterone produces higher sustained serum levels. After IM administration of 10 mg progesterone in oil, maximum plasma concentrations (geometric mean 7 ng/mL) are reached within approximately 8 hours, with levels remaining above baseline for about 24 hours 2. IM progesterone achieves serum progesterone values within the range of the natural luteal phase 3.
Subcutaneous progesterone is absorbed more rapidly but with shorter duration. A novel aqueous SC formulation achieved peak serum levels at 1 hour versus 7 hours for IM reference products 4.
Clinical Context: Route Matters for Indication
The clinical guidelines do not support interchangeability between routes for preterm birth prevention:
For women with prior spontaneous preterm birth, 17-hydroxyprogesterone caproate (17P) 250 mg IM weekly from 16-20 weeks until 36 weeks is the recommended formulation. This is based on stronger evidence of effectiveness compared to other progesterone preparations 5, 6.
Vaginal progesterone should not be substituted for IM 17P in women with prior preterm birth, as direct comparison trials show IM 17P is superior 6.
For women without prior preterm birth but with short cervical length ≤20 mm, vaginal progesterone (90 mg gel or 200 mg suppository) daily is recommended, not IM progesterone 5, 7, 6.
Important Caveats About Serum Levels vs Clinical Efficacy
Lower serum progesterone levels do not necessarily indicate inadequate clinical effect:
Vaginal progesterone demonstrates a "first uterine pass effect" where adequate endometrial transformation occurs despite lower serum levels compared to IM administration. This indicates better bioavailability of progesterone in the uterus with minimal systemic effects 3.
Sublingual progesterone produces significantly lower mean serum levels than IM (30.5 vs 41.6 ng/mL at embryo transfer) but achieves equivalent pregnancy outcomes in frozen embryo transfer cycles 8.
Clinical Bottom Line
If you are monitoring serum progesterone levels in a patient receiving subcutaneous progesterone, expect lower values compared to intramuscular administration—this is a pharmacokinetic difference, not necessarily a therapeutic failure. However, subcutaneous progesterone is not currently part of standard clinical guidelines for preterm birth prevention, where IM 17P remains the evidence-based standard for women with prior spontaneous preterm birth 5, 6.
The relative bioavailability of SC to IM progesterone is approximately 92% for total exposure, meaning SC administration delivers slightly less systemic progesterone overall 1. Laboratory values should be interpreted in the context of the specific route, dose, and timing of administration rather than using universal reference ranges.