Designer Estrogens

Science News, Oct 16, 1999 by Damaris Christensen

"Different shapes [of the receptor-estrogen complex] attract different regulatory molecules" that themselves activate different genes, he says. "This may also help explain why the same hormone affects different people differently. People have slightly different proportions of coactivators and corepressors."

One question that has perplexed researchers is, Why are estrogen receptors so flexible about the compounds they bind? The observation that estrogen does not exist in just one natural form, but several, may provide an answer. Scientists have long known about the natural variants but believed that they all have the same effect. New research suggests that each of these naturally occurring estrogens has a subtly different effect.

In a study of 30 postmenopausal women, one natural variant of estrogen, called dehydroestrone sulfate, was effective in preventing hot flashes. It did not, however, seem to lower the amounts of fatty acids in the women's blood, suggesting that this estrogen doesn't benefit the heart.

These findings indicate that naturally occurring estrogens work selectively, says Andres Negro-Vilar of Ligand Pharmaceuticals in San Diego. He and his colleagues reported their results in the June JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM.

"These data suggest that there are naturally occurring estrogens which can act as bona fide SERMs," says McDonnell. However, it will take a great deal of research to tease out their different activities, he says.

The more that basic research illuminates the natural function of the estrogen receptor, the better insight drug developers will have for creating new designer estrogens, he says.

Despite the progress scientists have made in understanding actions of designer estrogens, their long-term use is fraught with complications. "We're very excited about the potential of SERMs, but there is still a lot of work to do, especially on the long-term safety," cautions Franks. "To give a drug to a basically healthy person with the intention of preventing disease, you need to be very sure the benefits outweigh the risks."

Even the well-accepted benefits can be hard to weigh precisely. Despite many reports that estrogen therapy reduces heart disease, a U.S. study of almost 3,000 postmenopausal women who had already had a heart attack found that those given hormone-replacement therapy were just as likely to die of heart disease as were women given a placebo, Stephen B. Hulley of the University of California, San Francisco and his colleagues reported in 1998.

"Overall, we don't know for sure whether raloxifene--or even estrogen--reduces heart disease," says Manson, although she suspects that both do. "It's going to be decades until we have a clear picture of all the benefits and risks of different SERMs."

One could make the case that until long-term trials are completed, physicians shouldn't prescribe any designer estrogen for extended use, she says. However, Manson also points out that few of the current drugs for preventing heart disease and osteoporosis have undergone long-term trials.