Designer Estrogens

Science News, Oct 16, 1999 by Damaris Christensen

A 3-year follow-up to the major study proving that raloxifene blocks bone loss provided encouraging evidence that, like tamoxifen, it can prevent breast cancer. Among more than 7,700 postmenopausal women with low bone density, those taking raloxifene were only one-fourth as likely to develop breast cancer within 3 years as those taking a placebo (SN: 6/19/99, p. 388).

The benefits and side effects of these drugs and newer variations on estrogen are still being described. Two large studies that may answer important questions within 5 years are now under way. In one, which will include about 22,000 women, researchers are testing raloxifene and tamoxifen head-to-head to see which one prevents breast cancer more effectively and with fewer side effects. The second study is looking at 10,000 women to determine whether raloxifene benefits the cardiovascular system.

Definitions of the perfect designer estrogen may vary depending on the patient. None of the estrogen variants now available treats hot flashes and other symptoms of menopause, Manson says. Raloxifene, in fact, worsens hot flashes.

Furthermore, basic research doesn't always predict clinical effects. "Some of these designer estrogens will have effects on tissues that were not anticipated," predicts Manson. Large-scale clinical trials of a designer estrogen known as idoxifene were recently canceled after several years because, like estrogen and tamoxifen, the compound seemed to boost a woman's chance of developing endometrial cancer.

Nonetheless, doctors who treat breast cancer and osteoporosis are excited by current progress, says Adele L. Franks of the Prudential Center for Health Care Research in Atlanta. Raloxifene's apparent ability to prevent breast cancer provides "solid encouragement" that the first designer estrogens will live up to their promise, Franks says.

Tamoxifen and raloxifene were both originally developed to treat cancer, not to selectively block or mimic estrogen's effects. A growing knowledge of how designer estrogens work "intensifies the anticipation of finding something even better than raloxifene," Franks says. "We bumble upon something interesting--like the tamoxifen paradox--and very profound things happen in the process of trying to figure it out."

When the tamoxifen paradox first came to light, researchers knew of only one cellular receptor for estrogen. For tamoxifen or other designer estrogens to have differing effects in various organs, several kinds of estrogen receptors might be involved, scientists speculated. Each type of tissue might have a different combination of receptors.

Evidence for this scenario appeared in 1996, when researchers discovered a second estrogen receptor in rat prostate glands and ovaries. Others soon found that the original estrogen receptor, now dubbed ER-alpha, and the new find, ER-beta, are unevenly distributed in the body. Cells of the pituitary gland, uterus, testis, kidney, and adrenal glands harbor only ER-alpha receptors. Cells in the ovary, testis, prostate, and thymus have only ER-beta receptors. Both estrogen receptors are present in bone, breast, and brain.