Designer Estrogens

Science News, Oct 16, 1999 by Damaris Christensen

Getting all the benefits, few of the risks

It's the dream of every doctor and patient: a potent treatment with no unwanted side effects. Such selectivity is easier to imagine than to develop, especially for compounds that have multiple effects in the body.

It's not an impossible dream, however. Scientists in 1992 made a surprising finding about a substance developed to treat breast cancer by blocking the effects of the female sex hormone estrogen. The drug turned out to counter estrogen's action in some tissues, but it acted like estrogen in others. This synthetic hormone may lead the way to other compounds, in the group known as designer estrogens, that will be even more selective.

"The ultimate goal is to have all the beneficial effects of estrogen but not the adverse effects," says JoAnn E. Manson of Harvard Medical School in Boston.

Such a drug might be able to induce the advantages of estrogen treatment in women after menopause: boosts in bone density, improvements in heart function, and perhaps delays in the onset of Alzheimer's disease. It would, at the same time, block estrogen's undesirable effects. Taking hormone-replacement therapy for more than 5 years raises a woman's risk of developing breast cancer, endometrial cancer, potentially life-threatening blood clots, and cataracts.

No novel drug is yet able to improve upon postmenopausal estrogen-replacement therapy. Two designer estrogens are currently on the market, however, one to treat breast cancer and one to prevent bone loss that can lead to the brittle-bone disease osteoporosis. The first works by blocking estrogen's effect in the breast; the second, by mimicking it in bone. Several other designer estrogens are being developed in the lab, and a few are in early human trials.

"This is an enormously exciting class of compounds," says Felicia Cosman of the Helen Hayes Hospital in West Haverstraw, N.Y.

"Although not everyone buys into the concept of using pharmacologic agents to prevent disease, for those who do, these drugs will be used to help prevent diseases related to aging and estrogen deficiency," she predicts.

The excitement over designer estrogens began with what is known as the tamoxifen paradox. Scientists at Zeneca Pharmaceuticals of Wilmington, Del., had synthesized tamoxifen, a variation on the estrogen molecule, in hopes of creating a compound that would prevent natural estrogen from stimulating breast cancer.

The drug was effective and, since its introduction almost 20 years ago, has become one of the most widely prescribed breast-cancer treatments. But physicians were concerned that tamoxifen would also prevent natural estrogen from blocking bone loss--meaning that women who survived breast cancer would be especially susceptible to osteoporosis.

This, however, was not the case. A nationwide, 2-year study reported in the March 26, 1992 NEW ENGLAND JOURNAL OF MEDICINE showed that women on tamoxifen had higher bone-mineral density than women not taking the anticancer drug. The unexpected finding sent researchers scurrying to the lab and the clinic.

Part of the research effort focused on the basic science of estrogen and the molecules known as estrogen receptors. When estrogen molecules bind to their receptors inside a cell, some genes turn on and others turn off.

Scientists have developed variations on the estrogen molecule that still bind to the estrogen receptor. If the cell could not distinguish the variant from natural estrogen, the compound would mimic the hormone in all its effects. Other variants would be so different from estrogen that they would not trigger further effects, and by occupying the receptor, they would prevent estrogen from playing its normal role. Researchers had not expected any variations on estrogen to block some of estrogen's effects but not all of them.

While some scientists were examining the molecular actions of designer estrogens, others were exploring the effects of these drugs on patients. According to a study of 6,600 women sponsored by the National Cancer Institute, tamoxifen can not only treat breast cancer but also prevent its development among high-risk, yet healthy women (SN: 4/11/98, p. 228).

Unfortunately, tamoxifen, like estrogen, also raises the risk of endometrial cancer, blood clots, and cataracts. Because of these serious, well-established side effects, tamoxifen is unlikely to be prescribed for routine postmenopausal treatment.

Once tamoxifen's promising effect on bone loss had been demonstrated, scientists at Eli Lilly and Co. in Indianapolis took a new look at an estrogen variant that had proved a disappointing alternative to tamoxifen for treating breast cancer in earlier tests. They discovered that this drug, like tamoxifen, prevents bone loss. In 1997, the Food and Drug Administration approved the drug, now called raloxifene, to prevent osteoporosis.

Raloxifene shares some but not all of tamoxifen's drawbacks. It increases the risk of blood clots but not of endometrial cancer. It may also share some of tamoxifen's benefits.