Women who were exposed before birth to the drug diethylstilbestrol, popularly known as DES, appear to face an increased risk of health problems not just as adolescents and young adults, as was once thought, but throughout life, according to new research presented last week at a National Institutes of Health meeting.

"The word that we really need to get out to every physician is that the DES story is not closed," said Suzanne Haynes, assistant director for science in the U.S. Public Health Service's Office on Women's Health. "There continue to be problems among DES-exposed women and their families."

DES was discontinued as a treatment option for preventing miscarriages in 1971. It had been linked to a variety of problems in daughters of women who took the drug, including a rare vaginal cancer.

Faced with growing public concerns about DES, Congress mandated a national research and education program in 1992 to further explore the effects of the drug and to educate the public and their health providers about the possible dangers of exposure. From that initiative, scientists last week reported on preliminary evidence that points to potential health problems throughout life for those exposed to DES.

No one knows exactly how many people were exposed to DES, but based on prescription records, the National Institutes of Health estimates that about 4.8 million pregnant women took the drug between 1938 and 1971.

In 1971, the FDA directed doctors to stop prescribing DES to expectant mothers after studies showed the vaginal cancer, called clear cell adenocarcinoma, was occurring at unusually high rates in daughters of women who had taken DES. The disease has been detected in DES daughters as young as 10 years old, but most often strikes at between 15 and 27 years of age. About 1 of every 1,000 daughters exposed to DES before birth develop the disease. Robert N. Hoover, director of epidemiology and biostatistics at the National Cancer Institute, which cosponsored last week's conference, said DES daughters are 40 times more likely to develop the disease than are daughters who were not exposed.

Reproductive health problems also disproportionately afflict DES daughters. Miscarriages, ectopic pregnancies, stillbirths and premature births are more common among these women than among those never exposed to the drug.

Other studies have shown a link between autoimmune diseases and DES exposure. One study found that DES daughters are "two times more likely to develop autoimmune diseases, five times more likely to develop [a thyroid condition called] Hashimoto's thyroiditis, and three times more likely to develop both pernicious anemia and rheumatoid arthritis than unexposed women," Hoover said. But other studies have not found this link.

Until recently, however, the scientific evidence suggested that the cancer risk for those exposed to DES waned in the years just after puberty--the time when hormone levels increase. But the latest findings suggest that DES exposure not only may extract a health toll for DES daughters but also for their children.

At the University of Chicago, Arthur L. Herbst and his colleagues are tracking more than 700 women with vaginal clear cell adenocarcinoma, most of whom were exposed to DES before birth. The oldest DES daughter to develop this type of cancer was 48 when she was diagnosed--roughly two decades later than when the disease has been detected in the past.

"This is not just a disease of women in their teens and twenties," Herbst said. "We now know from studies that the cancers continue to occur in women in their forties. The important issue here is that there are a couple of million of these women in the country that need to be followed."

The findings also raise difficult questions about what DES daughters should do about hormone replacement therapy.

The surge of hormones during adolescence plays a key role in the development of vaginal cancer in DES daughters. "The concern is that if you give another jolt of hormone at menopause, what will happen?" said NCI's Hoover. "We don't know."

Mothers who took DES also appear to face a slight increase in breast cancer risk, Hoover told the conference.

DES sons also may face some special health problems. They have an increased risk of genital malformations. Some studies also suggest a link between DES exposure and an increased risk of testicular cancer. But other studies have found no connection.

Now that most of the DES sons are past the peak time for testicular cancer, scientists are looking at the risk for another hormonally related tumor: prostate cancer. "The research on the sons has really fallen behind the research on the daughters," Haynes said. "They are just getting toward the vulnerable time for prostate cancer."

New findings from animal research also suggest that DES may affect future generations. That conclusion comes from two studies in mice, conducted by separate teams of researchers. However, there is disagreement about whether the findings are the result of genetic changes or something called genetic imprinting.

Unlike genetic defects, imprinting does not alter the DNA of cells, but it does change the way the DNA acts. Retha Newbold and her colleagues at the Environmental Toxicology Program at the National Institute of Environmental Health Sciences in Research Triangle Park, N.C., exposed mice to DES, then bred the mice for two generations. Although fertility was unaffected by DES, the study found "an increased susceptibility for tumors was transmitted from the DES 'grandmothers' to subsequent generations," Newbold reported last week.

There is no evidence that genetic imprinting also occurs in humans, "but many of the DES effects that we have observed in humans were found first in mice," Haynes said. "It's one example where the animal studies have pretty much mirrored the human studies."

It also means for the medical community, Haynes said, "that there needs to be a wake-up call to really examine more thoroughly the granddaughters of those original DES mothers."

Resources

More information on DES is available from:

* DES Action USA, 1615 Broadway, #510, Oakland, CA 94612. 1-800-337-9288. www.desaction.org.

* DES Cancer Network, P.O. Box 10185, Rochester, NY 14610. 1-800-337-6384. The organization's Web site address is www.descancer.org.

* DES Sons Network, 104 Sleepy Hollow Place, Cherry Hill, NJ 08003. 609-795-1658. www.desaction.org/sons

DES at a Glance

Use: DES, or diethylstilbestrol, is a prescription female hormone. It was commonly used between 1949 and 1971 to help prevent miscarriages in pregnant women but was discontinued after researchers discovered a link between the drug and vaginal cancers in the daughters of women who took the drug.

Risks for women who took DES: slightly increased risk of breast cancer.

Reproductive system risks for daughters exposed to DES before birth: twice as likely to miscarry as unexposed women; nine times more likely to have an ectopic or tubal pregnancy; five times more likely to have a premature birth.

Cancer risks for daughters exposed to DES before birth: 1 in 1,000 develop vaginal clear cell cancer, 40 times higher risk than unexposed women. The age range at vaginal cancer diagnosis is 7 to 48 years but the most frequent age at vaginal cancer diagnosis is 15 to 27 years.

Risks to men exposed to DES before birth: Undescended testicles, noncancerous lumps on backs of testicles, increased risk of testicular cancer and possible fertility problems.

Sources: National Cancer Institute, National Institutes of Child Health and Human Development, National Institutes of Health