Women's Health Initiative Hormone Replacement Study

Aeron LifeCycles Clinical Laboratory Position Statement

In May of 2002, the Women’s Health Initiative (WHI) stopped part of a large study designed to assess the benefits and risks of Hormone Replacement Therapy (HRT) using a combination of conjugated estrogens (0.625 mg/day) and medroxyprogesterone acetate (MPA at 2.5 mg/day) in a fixed single tablet. The study was arrested before conclusion due to an increased risk of breast cancer and heart disease for the 16,000 women (with intact uterus) aged 50-79.

After an average of 5.2 years of follow-up, the data showed increases in the risk of breast cancer, heart disease, and stroke, but decreased risk of colon and rectal cancer, uterine cancer, hip fracture, and death from other causes. Comparable increased risks were not seen in the conjugated estrogen–only portion of the WHI study, which is still ongoing.

The results show that among 10,000 women taking the combination drug for a year, there will be 7 more women experiencing coronary heart disease events. That is 37 women taking the hormones would have heart attacks compared to 30 women taking the placebo.

There are several limitations in this trial. The trial results are only applicable to a single drug and dose regimen – conjugated estrogens at 0.625mg/day and MPA at 2.5 mg/day in an oral tablet. It is clear with the recent proliferation of lower dose formulations from pharmaceutical companies that this 0.625 dose may be excessive for many women. It has also been thought that MPA may be the cause of the increased risks since the conjugated estrogen-only arm of the study has not shown any oF the above increased risks after 5.2 years of follow-up (results of this study arm are due in 2005). In an earlier study entitled, "Postmenopausal Estrogen/Progestin Intervention" (PEPI), both MPA and Progesterone were studied in conjunction with conjugated estrogens. In the PEPI study both the conjugated estrogen alone arm as well as the conjugated estrogen + Progesterone arm showed significant benefit to cardiovascular lipid profiles. The arm of the study with conjugated estrogen plus MPA did not maintain the cardiovascular lipid profile benefit.

AERON POSITION: There is ample evidence that the risks associated with estrogen use rise with increasing dose and length of time used. Hormone levels should always be tested before beginning replacement therapy to ensure the correct hormones are being used. Monitoring hormone levels annually for hormone level changes associated with supplementation allow dose titration to ensure the lowest amount of hormones possible to attain the desired effect. The WHI study corroborates previous information as to risk and side effects of estrogen use. What it does not show is a decrease in cardiovascular risk to outweigh the other side effects that might have been expected based on previous observational studies. Although it is tempting to generalize this information, little can be extrapolated to other forms of HRT (bio-identical with 17- beta estradiol and progesterone) or other non-oral modes of delivery (transdermal) where the risk benefit ratio might be more favorable. It is clear from both the WHI and PEPI data that progesterone and MPA act differently.