What Are the Benefits of Prometrium in Hormone Replacement Therapy?

Stephen Nunn, PA-C


February 13, 2002


Prometrium is becoming more widely used for hormone replacement therapy (HRT). What are the benefits of Prometrium versus a progesterone-like therapy (Provera), and why is it only taken during days 12-28?

Francis Jenkins, PA-C

Response from Stephen Nunn, PA-C

The answers to this timely question are derived primarily from the findings of the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial,[1] the Heart and Estrogen/Progestin Replacement Study (HERS),[2] and the Women's Health Initiative.[3]

The PEPI trial was a 3-year randomized, controlled, double-blinded study of 875 women.[1] Three of the 5 different treatment regimens showed a reduction in cardiovascular disease (CVD) risk. The use of combined equine estrogens (CEE) alone showed a 31% CVD risk reduction; CEE plus micronized progestin showed a 27% risk reduction; and CEE plus medroxyprogesterone acetate (MPA) resulted in a 21% risk reduction. The micronized progestin used was identical to Prometrium, while the MPA is equivalent to Provera. The difference in the risk reduction between micronized progestin and MPA is statistically significant. This may be due to the finding that micronized progestin had a significantly less negative effect on the estrogen-associated increase in HDL cholesterol levels compared with MPA. Based on this study, it was suggested that clinicians should consider greater use of micronized progestin over MPA in prescribing HRT.

HERS[2] was an 8-year randomized, controlled, double-blinded study of 2763 women. Of these, 1383 were randomized to the placebo group and 1380 were randomized to 0.625 mg CEE plus 2.5 mg daily. Similar to the PEPI Trial, CEE and MPA were used. However, the women studied had preexisting cardiovascular risk as evidenced by a previous myocardial infarction, coronary artery bypass graft surgery, percutaneous coronary revascularization, or angiographic evidence of at least a 50% occlusion of 1 or more major coronary arteries. In the first year, 57 patients in the treatment group had adverse cardiovascular events compared with 38 in the placebo group. By the fourth year this trend had reversed to 33 vs 44. The study was terminated after the fifth year because of the finding of no overall cardiac benefit and the increased risk in this population in the early years of the study.

MPA is a known vasoconstrictor, and it is postulated that this may account for the statistically significant incidence of adverse cardiovascular events in the first year. For subsequent years the cardioprotective effects of CEE appear to increase such that the CVD risk may be reduced or disappear over time.

The Women's Health Initiative is a 15-year disease-prevention study of over 160,000 postmenopausal women that began in 1993.[3] Evaluation of the initial 2-year data suggested a slight increase of thromboembolic disease in the first year of HRT use. The compounds being studied are CEE and MPA. Again, the risk appears to decrease or disappear over time.

The question of why Prometrium is taken from days 12-28 may be based on a misunderstanding. Prometrium, for prevention of endometrial hyperplasia, is recommended to be taken at a dosage of 200 mg for 12 sequential days of every 28-day cycle. This, in part, has to do with the wording required by the Food and Drug Administration in the product-information pamphlet. There is no pharmacologic reason for why Prometrium could not be used in a continuous dosing regimen. However, if used for HRT as continuous or cyclic continuous therapy, the 100-mg formulation would be used.

Important caveat: Prometrium contains peanut oil. Do not prescribe it for patients with peanut or peanut oil allergies.

Related Resource

Estrogen Replacement Therapy and Heart Disease: A Discussion of the PEPI Trial
http://www.ama-assn.org/special/womh/library/ scan/vol_1/no_1/jcr.htm