Sign Out: Is it time to eliminate the progestin from hormone therapy?

The Women's Health Initiative (WHI) has dramatically changed hormone therapy (HT) in the United States. Because of its perceived risk, women and their health-care providers have dramatically curtailed its use, with the result that millions of women suffer from vasomotor symptoms, declining bone density, and vaginal atrophy.

Reducing the breast Ca risk, improving cardiovascular status

A similar discrepancy exists regarding cardiovascular disease. The estrogen plus progestin arm showed no significant benefit in cardiovascular outcomes.³ For the 50- to 59-year-old women in the estrogen alone arm, for all cardiovascular outcomes, there was actually a statistically significant reduction in cardiovascular adverse outcomes.⁴

How can we eliminate the risk of breast cancer and perhaps even provide a cardiovascular benefit with the use of HT? One of the simplest ways of doing this is to use cyclic hormone regimens. These regimens are readily available and decrease by more than half the number of days of progestin treatment.

Currently, there is a trend toward using lower estrogen doses. These lower doses are often effective in relieving hot flushes, while maintaining bone density and favorable lipid profiles and reversing vaginal atrophy. Is it possible to use even less frequent progestin withdrawal with these regimens? In the prospective randomized HOPE trial, women were treated for 2 years with unopposed estrogen at varying doses.⁵ With 0.625 mg of conjugated equine estrogens (CEE), endometrial hyperplasia occurred in 27% of patients after 2 years, compared to no endometrial hyperplasia in women receiving placebo. In women using 0.45 mg of CEE, the inci-dence of endometrial hyperplasia was only 6.6% at 1 year, and 14.9% by 2 years. So lower estrogen doses cause less hyper-plasia. Those using 0.3 mg of CEE showed no hyper-plasia at 1 year and a nonsignificant 3% by year 2. While any increase in endometrial hyperplasia is cause for concern, I suspect that this low risk could be eliminated with less frequent progestin withdrawal. As there were no cases of endometrial hyperplasia after a year, could progestin withdrawal occur yearly and still prevent the development of hyperplasia?

Finding better ways to ward off endometrial hyperplasia

Another alternative combines oral estrogen with a progestin-releasing IUD, providing endometrial protec-tion while offering the systemic effects of unopposed estrogen. This regimen is popular in Europe, where data suggest that it is highly effective. The Europeans have available a smaller IUD that is more easily placed in the postmenopausal uterus.

Finally, there are alternatives to progestins to counteract the uterine effects of estrogen. Selective estrogen receptor modulators (SERMs) act similarly to estrogens in some tissues, and may act as antiestrogens in others. Unfortunately, most SERMs appear to have similar effects on the uterus and on the central nervous system; those that do not promote endometrial proliferation do not control hot flushes. However, the right combination of estrogens and a SERM may provide a more optimal regimen. Estrogen in combination with the SERM bazedoxifene has been shown to alleviate hot flushes, while counteracting the effect of estrogen on endometrial proliferation. Products containing combinations of estrogen and SERMs are currently completing clinical trials and should enter the marketplace within the next 2 years.