New evidence indicates that a drug prescribed in hopes of averting miscarriages in an estimated 2 million women sharply increased their risk of developing often fatal cancer.
The new findings come 6 1/2 years after the discovery that sometimes-fatal vaginal and cervical cancer occurred in about 200 daughters of women who had taken the drug DES, as long as a quarter-century earlier.
In a further report two years ago, scientists said that low sperm counts and other birth defects in the reproductive tract were showing up in thousands of sons of DES mothers.
In the new data, one key finding is a breast-cancer rate 76 per cent higher among women who had taken larges doses of the hormone in 1950-1952 than among controls - otherwise similar women who had taken a dummy drug.
Specifically, 31 of 693 DES mothers developed breast cancer, compared with 17 among 668 controls. The breast-cancer death rate was three times higher among the DES mother: 12 vs 4.
In addition, 16 DES mothers developed other so-called endocrine-related cancers - of the cervix, lining of the uterus, ovaries and colon, compared with 10 controls. In the DES women, six of the cases were fatal; in the controls, two.
Dr. John C. Bailar, editor of the Journal of the National Cancer Institute, told a reporter that the cancers occuring in DES mothers appear to be "killers," meaning that the frequency with which they are fatal, rather than being treatable with mastectomies, is high.
Dr. Sidney M. Wolfe, director of the Health Research Group, which is financed by Ralph Nader's Public Citizen, Inc., disclosed the evidence - which he termed "preliminary" - yesterday in a letter to Joseph A. Califano Jr., secretary of Health, Education and Welfare.
He urged Califano to arrange an alert of all DES mothers to the need for periodic examinations, and to direct the National Institutes of Health to coordinate follows-ups at all medical centers that dispensed DES, with the bills to be paid by drug companies that "profited from DES sales."
Wolfe also requested Califano to ask all physicians to search their files for women to whom they gave DES. Some described it as a "precaution" whenever a woman patient became pregnant, even if there was no sign of an impending miscarriage.
In addition, Wolfe asked the secretary to try to expedite the slow-moving effort to the Food and Drug Administration to bar DES from cattle feed, where it is used as a growth stimulant, and to try to limit use of DES as a "morning after" contraceptive pill to cases of rape and incest.
After reviewing the new DES data, Dr. Bailar said. "It does look like a very bad situation, and it's likely to stay that way."
He termed the evidence of cause and effect "very suggestive" but "not conclusive." Conceivably someone will come up with an explanation other than DES, but, Bailar said, "I don't know what it would be."
Wolfe derived the evidence from ainterim report by University of Chicago scientists on a follow-up of women who were given DES in a carefully controlled experiment at the university's Chicago Lying-In Hospital over a 20-month period ended in November, 1952.
The scientists dated the report Aug. 31 but didn't file it - with the National Institute of Child Health and Human Development, which is financing the study - until Oct. 28. Four contract consultants are to meet late next month to discuss the report.
At Wolfe's request, the Public Citizen litigation Group got a copy of the report under the Freedom of Information Act for him to analyze. He urged Califano to try to speed government handling of such reports hereafter.
The results of the 1950s experiment undermined claims that the hormone prevented miscarriages.To this day, the FDA says, there is no substantial evidence of effectiveness in this usage.
Physicians continued heavy prescribing of DES as late as 1971, almost 20 years after evidence of ineffectiveness had been published. In 1974, the number of prescriptions fell to a low of 11,000. Since then the number of prescriptions written for des to avert spontaneous abortions has been negligible.
The university scientists began to look at the incidence of cancer in DES mothers in the experiment after a nurse participating in the follow-up of their children mentioned that she thought many of the women have died of breast cancer.
DES is an estrogen. The cancer-causing potential of estrogens has been known for decades. Two years ago, scientists reported that the approximately 5 million women talking estrogens over a long period to ease postmenopausal symptoms had a rate of cancer of the lining of the uterus at least five times normal.
Six months later, Dr. Robert N. Hover, head of the Cancer Institute's Environmental Studies Section, co-authored a report suggesting that sustained use of post-menopausal estrogens also could cause breast cancer. Yesterday, he said in a phone interview that the new DES data "look worrisome to me."
The institute's Bailar described prescribing of estrogens for sustained use by post-menopausal women as "a stupid, stupid thing to do. I think it's just insane."
He was asked if there is possible relevance of the new DES findings to combine contraceptives, most of which combine an estrogen with another hormone called a progestogen. Currently, an estimated 10 million American women take them.
"I would be almost as strong about the oral contraceptives," Bailar said. "No woman who takes those really understands what they may do to her in the future, and the same goes for doctors who prescribe them."
The university scientists, in apreliminary check on DEC mothers, found that of 430, nine had reported breast cancer and six had died. Among 320 controls there was one case, and it was fatal. In a proposal for federal financing of a study of the women, the scientists termed the finding "alarming" and follow-ups of "paramount importance."
The much larger group studied as of Aug. 31 - 693 DES mothers, 668 controls - is about 83 per cent of the total involved in the 1950s experiment.
In the letter to Califano, Wolfe wrote that, in addition to excess cases of breast cancer, two other findings implicate DES: the higher speed at which the disease developed in DES mothers as opposed to controls, and the larger proportion of under-50 victims who had taken DES.
As to speed, by January, 1963, for example, four DES mothers but none of the controls had developed breast cancer.
The average age of DES women and controls during the 1950-'52 experiment was nearly the same: 27.8 vs. 27.6.
Subsequently, 30 women developed breast cancer before age 50. Twenty three were DES mothers. But of 18 over-50 women who developed the disease, 10 were controls.
The cases in under-50 DES women represent a "very substantial excess" that leaves him "very much concerned," Bailar said in a phone interview. Noting that many of the DES mothers are not yet 50, he said it is possible that an abnormal rate of breast cancer in over-50 DES users may yet show up.
Bailar said his "best estimate" is that breast cancer is developing among 9 per cent of the women who received DES. This compares with 7 per cent in the entire lifespan of the female population as a whole. Thus the indicated incidence for DES women thus far is 29 per cent higher.
In April, Assistant Secretary of State Patsy T. Mink and two other women filed a $77 million class action suit against the university and Eli Lilly & Co., a leading DES supplier.