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Hormone Therapy After the WHI: Thinking Outside the Box

Low-dose estrogen was well tolerated and preserved and built bone in these older postmenopausal women.

Given the risks that have been explicated by data from the Women's Health Initiative (Journal Watch Women's Health Aug 7 2002), is there any role left for hormone therapy? To evaluate the effects on bone and the safety profile of low-dose estrogen in older women, investigators randomized 167 women (age, >65; mean, 74) to receive placebo or one fourth of the standard dosage of 17ß-estradiol (0.25 mg/day) for 3 years. Women with uteri also received micronized progesterone (100 mg/day) for 2 weeks twice yearly. BMD, biochemical markers of bone turnover, and sex-hormone levels were measured regularly.

Compared with placebo recipients, estrogen recipients had significantly increased BMD at all sites (mean increases of 1.2%-3.6%) and significantly decreased markers of bone turnover. Mean estrone and estradiol levels increased significantly with estrogen treatment. Adverse-effect profiles were similar in the 2 groups; 1 woman in each group had endometrial hyperplasia on biopsy. Five estrogen recipients reported bleeding.

Comment: At a very low dosage in women who have long passed menopause, estrogen appears to be well tolerated and to preserve and build some bone. Who would have thought that we might come nearly full circle and return to prescribing essentially unopposed estrogen -- but just at a minuscule dosage! Many researchers are searching for a selective estrogen-receptor modulator (SERM) to be the perfect estrogen, but perhaps we should instead be looking for an estrogen that acts as the perfect SERM. And perhaps that perfect estrogen is just a very low dosage of the estrogens we currently prescribe!

As in most preliminary trials, many questions remain, including: How many patients will not respond to low-dose estrogen? Will the risks identified by the WHI investigators be minimized or eliminated? And, will patients respond well immediately after menopause (i.e., at a time of high bone loss)?

— Ann J. Davis, MD

Published in Journal Watch Women's Health October 22, 2003

Citation(s):

Prestwood KM et al. Ultralow-dose micronized 17ß-estradiol and bone density and bone metabolism in older women: A randomized controlled trial. JAMA 2003 Aug 27; 290:1042-8.

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