Prometrium Liver Function Impact: What the Clinical Evidence Shows

What the Prometrium label says about the liver

Known liver dysfunction or disease is the sixth of the label's six contraindications [1]. The label states that the effect of hepatic impairment on the pharmacokinetics of Prometrium has not been studied [3].

Progesterone is metabolized primarily in the liver, largely to pregnanediols and pregnanolones, which are conjugated to glucuronide and sulfate and excreted in bile and urine [3]. The label does not name the enzyme responsible for that main metabolism [3].

The hepatic reactions listed after approval

The label's postmarketing section lists cholestasis, cholestatic hepatitis, hepatic failure, hepatic necrosis, hepatitis, increased liver function tests (including ALT, AST and GGT) and jaundice among reported reactions [1]. The label says these voluntary reports came from a population of uncertain size, so their frequency cannot be reliably estimated and a causal relationship cannot be established [1].

What the big trial actually measured

The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial was a 3-year, multicenter, randomized, double-blind, placebo-controlled study of 875 healthy postmenopausal women aged 45 to 64 [4]. Its four primary endpoints were HDL cholesterol, systolic blood pressure, serum insulin and fibrinogen [4]. Because liver enzymes were not among those primary endpoints, the reported primary results do not show whether Prometrium changes ALT or AST [4]. The estrogen in every active arm was conjugated equine estrogen, not estradiol, and the placebo group received no hormones [4].

The study that measured hepatic enzymes

In a 1985 study, Maxson and Hargrove gave a single 200 mg oral dose of micronized progesterone to nine healthy postmenopausal women and one male volunteer, then sampled blood over 24 hours [2]. The authors reported no significant change in estradiol, FSH, LH, cortisol, aldosterone, lipids or hepatic enzymes during that interval [2]. That is one dose and one day, so it cannot show the effect of repeated dosing.

The estrogen half of the pair

Prometrium is labeled for preventing endometrial hyperplasia in postmenopausal women with a uterus who are taking conjugated estrogens tablets [1]. A review of drug-induced cholestasis lists estrogens among agents known to cause cholestasis [5].

Ketoconazole and progesterone metabolism

The label reports that the metabolism of progesterone by human liver microsomes was inhibited by ketoconazole, with an IC50 of less than 0.1 micromolar. Ketoconazole is a known CYP3A4 inhibitor, and the label says the clinical relevance of the in-vitro findings is unknown [3].