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Banned Hormone's Effects Last Three Generations

Grandsons of women who took DES more prone to genital defect

THURSDAY, March 28, 2002 (HealthDayNews) -- Boys whose grandmothers took a long-banned hormone treatment for troubled pregnancies appear to be at increased risk of a rare genital malformation.

A new study by Dutch scientists has found that the grandsons of women who took DES to stabilize pregnancy may be roughly 20 times more likely than other children to develop hypospadias, a rare birth defect in which the location of the urethra opening on the penis is askew.

The condition, which occurs in between two and six baby boys per 1,000, isn't life-threatening. But it often requires multiple surgeries to repair and can leave significant scars on a man's sexual confidence.

DES, or diethylstilbestrol, was a synthetic form of estrogen prescribed to 4 million pregnant women worldwide during the 1950s and 1960s on the shaky notion that it prevented miscarriages and preterm delivery.

The drug was banned in this country in 1971 (but was available in Europe for another seven years), after reports that it caused vaginal and cervical cancers, as well as fertility trouble, in the daughters of women who used it. Men whose mothers took DES were also at risk of urinary and genital defects, including various testicle problems.

Data in mice have shown that the drug's effects may extend into the third generation. But the new study, which appears this week in The Lancet, is the first to find such a legacy in humans.

Flora van Leeuwen, a cancer epidemiologist at the Netherlands Cancer Institute in Amsterdam, led the study. She and her colleagues compared the rate of hypospadias in 205 boys whose mothers were exposed to DES in the womb and 8,729 whose mothers weren't exposed to the drug.

Four of the 205 boys whose grandmothers had taken DES had hypospadias, compared with eight in the other group. In other words, van Leeuwen and her colleagues said, the odds of developing the defect were about 21 times higher than normal for the boys whose mothers had been exposed to DES as fetuses.

How DES might act at such a distance is unclear, van Leeuwen said. Yet at least three possibilities exist, each of which is speculative.

The first, she said, is that DES scrambled genes in the boys' mothers' egg cells. Women took the drug during the first three months of pregnancy, which is when female fetuses form their eggs, or oocytes. "It is possible in principle that there has been a genetic alteration in utero in the oocyte from which later on the DES son was formed," van Leeuwen said.

Another explanation: DES disturbed hormones in the daughters of the women who took it. When these women went on to have their own children, their developing sons weren't exposed to enough testosterone in the womb to form a fully proper penis.

Similarly, van Leeuwen said, it's possible that women whose mothers used DES were prone to abnormal placentas, which addled the hormones that help shape their babies.

At least one expert cautioned that the findings may somewhat overstate the link.

Dr. Sonia Hernandez-Diaz, a Boston University epidemiologist, said the defect may be more common in the male offspring of women who inherited reproductive problems from their mothers, confounding the effects of DES. Similarly, women vulnerable to effects of DES may have been more likely to have affected grandchildren, and thus the results might not apply to all women exposed to the drug.

Still, Hernandez-Diaz said, these factors can't account for the entire 21-fold increased risk of urethra defects seen in the grandsons of women who took DES during pregnancy. And while the number of cases in the study was quite low, "it's an interesting result that needs confirmation to really be sure," she said.

Although DES was an estrogen product, Hernandez-Diaz said women who take other forms of the hormone, such as oral contraceptives, needn't worry about the risk of hypospadias. For starters, they shouldn't be using the pill while pregnant. And, more importantly, DES had a much higher concentration of hormone than birth control tablets.

What To Do: To find out more about the toxic history of DES, try DES Action. You can also learn more at Discovery.com.

SOURCES: Flora E van Leeuwen, Ph.D., professor of cancer epidemiology, The Netherlands Cancer Institute, Amsterdam; Sonia Hernandez-Diaz, M.D., Ph.D., assistant professor, Boston University School of Public Health; March 30, 2002 The Lancet
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