Prometrium Metabolism and Energy Expenditure: What the Clinical Evidence Actually Shows

What the label reports about absorption and metabolism

Prometrium 100 mg and 200 mg capsules contain micronized progesterone for oral use [2]. After an oral dose, maximum serum concentrations are reached within 3 hours [1]. After five daily doses in postmenopausal women, 100 mg produced a mean Cmax of 17.3 ng/mL and Tmax of 1.5 hours; 200 mg produced a mean Cmax of 38.1 ng/mL and Tmax of 2.3 hours [1]. Levels appeared linear and dose proportional from 100 to 300 mg per day, with high between-person variability; standard deviations often exceeded the means [1]. The label states that absolute bioavailability is not known [1]. Food increased bioavailability at 200 mg relative to fasting, but the label gives no size estimate [1].

Progesterone is 96% to 99% protein bound, with albumin at 50% to 54% and transcortin at 43% to 48% [1]. The label says it is metabolized primarily in the liver, largely to pregnanediols and pregnanolones, which are conjugated to glucuronide and sulfate metabolites and excreted in bile and urine [1]. The label does not state which enzyme carries out the main metabolism. Ketoconazole inhibited progesterone metabolism by human liver microsomes in vitro with an IC50 below 0.1 micromolar, and the label calls the clinical relevance unknown [1].

What the PEPI trial measured

The PEPI trial was a 3-year, multicenter, randomized, double-blind, placebo-controlled trial in 875 healthy postmenopausal women aged 45 to 64 [3]. The arms were placebo, conjugated equine estrogen 0.625 mg daily, conjugated equine estrogen plus cyclic medroxyprogesterone acetate 10 mg for 12 days a month, conjugated equine estrogen plus continuous medroxyprogesterone acetate 2.5 mg daily, and conjugated equine estrogen plus cyclic micronized progesterone 200 mg for 12 days a month [3]. The placebo group received no hormones, and the estrogen was conjugated equine estrogen, not estradiol [3]. Primary endpoints were HDL-C, systolic blood pressure, serum insulin and fibrinogen [3]. Mean HDL-C changed by -0.03 mmol/L with placebo, +0.14 mmol/L with conjugated equine estrogen alone, +0.11 mmol/L with conjugated equine estrogen plus micronized progesterone, and +0.03 to +0.04 mmol/L with the medroxyprogesterone acetate regimens [3].

Is there clinical evidence that Prometrium raises energy expenditure?

The label's pharmacokinetic sections describe blood levels, protein binding and metabolic fate, and its clinical studies describe endometrial outcomes [1]. PEPI measured cardiovascular risk factors [3]. Neither of these reports a measured resting-energy-expenditure or thermogenesis result.