Breast cancer in mothers given diethylstilbestrol in pregnancy
1980 Study Abstract
Reports in the popular press have suggested that exposure to diethylstilbestrol (DES) is followed by an abnormally high incidence of breast cancer. The reports were based on a reanalysis of data not considered ominous originally; and both data and analyses are summarized here.
Preliminary data from the Mayo Clinic Center of the National DESAD Project (DESAD = DES plus Adenosis) bearing on the occurrence of breast cancer in women given DES (diethylstilbestrol) during pregnancy are reported. Data from 408 DES-exposed women were collected in a follow-up study. 8 cases of breast cancer were confirmed in the group. This compares with an expected rate of 8.1 for parous women in that county. These preliminary data do not show an excess of observed over expected cases of breast cancer among a DES-exposed population.
A previous case-control study at the Mayo Clinic designed to determine any association between breast cancer and antihypertensive therapy had found a breast cancer rate of 10% in the DES-exposed portion of the group and 12% in the controls, also denying any DES association with breast cancer causation.
It is pointed out that an earlier study at the University of Chicago which did find an association between DES usage and breast cancer had utilized higher doses of DES than the current study at Mayo.
There is a clear need for further research into the association between DES usage and breast cancer, taking into account dosage and duration of therapy. Excess risk, if it does exist, seems to concentrate in the under-50 age group.
Breast cancer in DES-exposed mothers: absence of association, Mayo Clinic proceedings, NCBI PubMed PMID: 7354650, 1980 Feb.
Increased risk of early cancer mortality in DES Mothers
There is striking evidence that there is an increased risk of early cancer mortality in women treated with diethylstilbestrol during pregnancy.
Exposure to the drug is associated with
more than a twofold increase in risk of all cancer,
which increases to 2.89 for breast cancer,
and to 2.73 for endocrine related tumors.
Most published studies on the subject lack the statistical power to reject the hypothesis that there are no significant differences between treated and untreated women, especially in the presence of a 50% increase in risk.
There is a difference in the magnitude of the relative risk between premenopausal and postmenopausal breast cancer, the mortality cases being primarily in premenopausal women. Additional studies on diethylstilbestrol are needed.
Diethylstilbestrol and the risk of cancer, The New England journal of medicine, NCBI PubMed PMID: 759877, 1979.
In the mid 60s, Morris and van Wagenen showed that diethylstilbestrol prevented implantation in rabbits very efficiently
1966 Study Abstract
The observation that estrogens in sufficient dosage given postcoitally may prevent implantation of the ovum have led to studies regarding practical clinical application.
Estrogens that appear effective in humans include stilbestrol and ethinyl estradiol orally and estrone parenterally. Mestranol should also be effective as well as ORF-3858. Any estrongenic substance in sufficient dosage would probably prevent implantation.
Effective period of administration is only between time of fertilization and implantation or 4 to 6 days following coitus.
Test dosages have been 25-50 mg stilbestrol or .5-2 mg esthinyl estradiol daily for 5 days. It is now considered that 2-5 mg ethinyl estradiol would be more effective. In over 100 midcycle exposures there have been no pregnancies. Others have reported failures with inadequate dosage. Injectable estrone, 2-20 mg on alternate days for 3 doses, has also been reported effective.
The process of implantation is discussed. Endometrial biopsies have usually revealed a “retarded endometrium,” a possible mode of action. Side effects have been those usually associated with estrogens: nausea, vomiting, breast soreness, prolonged menses.
Breast cancer in mothers given diethylstilbestrol in pregnancy
1984 Study Abstract
We compared the incidence of breast cancer in 3033 women who had taken diethylstilbestrol (DES) in pregnancy during the period from 1940 to 1960 with the incidence in a comparable group of unexposed parous women. We ascertained vital status in 95 per cent of the exposed women and in 93 per cent of the unexposed women and received completed questionnaires for 88 and 85 per cent, respectively.
With over 85,000 woman-years of follow-up in each group, the incidence of breast cancer per 100,000 woman-years was 134 in the exposed group and 93 in the unexposed group, yielding a crude relative risk of 1.4 (95 per cent confidence interval, 1.1 to 1.9). The elevated incidence did not appear to be due to bias or to confounding by other risk factors measured in the study.
Breast-cancer mortality was slightly higher in the exposed women (relative risk, 1.1) but not significantly so (95 per cent confidence interval, 0.7 to 2.0). We conclude that the incidence of breast cancer is moderately increased in women given DES, but we cannot exclude the possibility that some unrecognized concomitant of DES exposure accounts for this increase.
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The authors compared the incidence of breast cancer in 3033 women who had taken diethylstilbestrol (DES) in pregnancy during the period 1940-60 with the incidence in a comparable group of unexposed parous women. The vital status was ascertained in 95% of the exposed women and in 93% of the unexposed women and completed questionnaires were received for 88 and 85% respectively. With over 85,000 women-years of follow-up in each group, the incidence of breast cancer/100,000 woman-years was 134 in the exposed group and 93 in the unexposed group, yielding a crude relative risk of 1.4 (95% confidence interval, 1.1-1.9). The elevated incidence did not appear to be due to bias or to confounding by other risk factors measured in the study. Breast cancer mortality was slightly higher in the exposed women (relative risk, 1.1) but not significantly so (95% confidence interval, 0.7-2.0). The incidence of breast cancer is moderately increased in women given DES, but the possibility cannot be excluded that some unrecognized concomitant of DES exposure accounts for this increase.
Breast cancer in mothers given diethylstilbestrol in pregnancy, The New England journal of medicine, NCBI PubMed PMID: 6493300, 1984 Nov 29.
The purpose of our study was to evaluate maternal DES exposure in relation to risk of cancer, particularly tumours with a hormonal aetiology. DES exposure status was determined by a review of medical records of the Mothers Study cohort or clinical trial records of the Dieckmann Study. Poisson regression analyses were used to estimate relative risks (RR) and 95% confidence intervals (CI) for the relationship between DES and cancer occurrence.
The study results demonstrated a modest association between DES exposure and breast cancer risk, RR = 1.27 (95% CI = 1.07-1.52). The increased risk was not exacerbated by a family history of breast cancer, or by use of oral contraceptives or hormone replacement therapy. We found no evidence that DES was associated with risk of ovarian, endometrial or other cancer.
Read the full paper (free access) : Long-term cancer risk in women given diethylstilbestrol (DES) during pregnancy, British Journal of Cancer, NCBI PubMed, PMC2363605, 2001.
Design Follow-up continuation through June 1, 1989, of a historical cohort of DES-exposed and unexposed mothers ascertained by review of obstetric records.
Participants Totals of 3029 each of DES-exposed and unexposed mothers who had delivered live babies at four centers in the United States during 1940 through 1960. Questionnaires were returned for 92.6% of the DES-exposed and 88.8% of the unexposed women.
Main Outcome Measures Breast cancer incidence and mortality assessed from returned questionnaires and review of medical records and death certificates.
Main Results The relative rate of breast cancer associated with DES exposure, after adjustment for demographic and reproductive variables, was 1.35 (95% confidence interval, 1.05 to 1.74). For 30 years or more following exposure, the relative rate was not appreciably higher (relative rate, 1.33; 95% confidence interval, 0.95 to 1.87) than that in earlier periods. Surveillance and increased detection seemed unlikely explanations for the increased risk, since DES-exposed women had excesses of both large and small breast cancers and the two cohorts reported similar breast cancer detection practices. A history of miscarriage before first term delivery was not associated with breast cancer occurrence.
Conclusion Exposure to DES during pregnancy is associated with a modest but statistically significant increased risk of breast cancer.Contrary to prior indications, the risk does not appear to increase greatly over time. The findings are sufficient to exclude the possibility of a doubling of risk for the period of 30 or more years following exposure.
Breast cancer in mothers prescribed diethylstilbestrol in pregnancy. Further follow-up, Journal of the American Medical Association, NCBI PubMed, PMID: 8468763, 1993 Apr.
A twenty-five-year follow-up study of women exposed to diethylstilbestrol during pregnancy
1978 Study Abstract
To assess the long-term effects of diethylstilbestrol we conducted a health survey among 693 mothers who had taken the drug during pregnancy and a comparable group of 668 who had not. These women had participated in a study during 1951-52 to evaluate the drug.
There were 32 (4.6 per cent) breast cancers among the 693 exposed and 21 (3.1 per cent) among the 668 unexposed, but the difference was not statistically significant (P = 0.16). No statistically significant differences occurred between the groups in any of the other categories of disease.
The occurrence of breast cancer in both groups was compared to the Connecticut State Tumor Registry for 1963-65. Compared to the registry data, a significantly (P less than 0.01) higher incidence of breast cancer occurred in both the exposed and unexposed groups at ages over 50. The reason for this increase is not known, but effects linked to the selection of mothers participating in the original clinical study cannot be excluded.
A twenty-five-year follow-up study of women exposed to diethylstilbestrol during pregnancy, The New England journal of medicine, NCBI PubMed, PMID: 628409, 1978 Apr.
This follow-up study presents the effects of DES on the genital tract of male and female offspring of mothers who were part of a double-blind, placebo-controlled investigation during 1951 and 1952 aimed at determining the effect of DES on pregnancy
1977 Study Abstract
Epididymal cysts, hypotrophic testes, and capsular induration were the more common genital lesions found in 25% of 163 DES-exposed males as compared to 6% in 168 control males. Semen analysis data on 39 subjects of the DES-exposed group and 25 subjects of the control group showed that 26% of the DES-exposed group produced an ejaculate volume under 1.5 ml; no such cases were observed in the control group. The average values for sperm density ant total motile spermatozoa per ejaculate, although in the normal range, were more than two times lower in the DES-exposed group as compared to the controls. A quality score of greater than 10 (“severely pathologic semen”) was found in 28% of the DES-exposed group as compared to 0 in the control group. An association of pathologic semen quality with physical abnormalities was found only in the DES-exposed group. Two cases of azoospermia, one without genital abnormalities on physical examination and one with bilateral hypotrophic testes were observed so far in the DES-exposed group.
Eighteen percent of 229 DES-exposed female patients had irregular menstrual cycles (oligomenorrhea) as compared to 10% of 136 controls. The history of pregnancy revealed a lower incidence of pregnancy in the DES-exposed group (18%) than in the control group (33%). Circumferential ridges of the vagina and cervix were seen in 40% of 229 DES-exposed females but in none of 136 controls. Colposcopic findings in the vagina revealed adenosis in 66.8% of the DES-exposed females and in 3.6% of the control group. Dysplastic lesions were more prevalent in the vagina and cervix of the DES-exposed subjects.
No cases of cancer were observed in either the male or female offspring.
Follow-up study of male and female offspring of DES-exposed mothers, Obstetrics and gynecology, NCBI PubMed, PMID: 318736, 1977 Jan.
A University of Chicago follow-up study indicated that women who had used DES had more breast and gynecological cancers than a control group, although the results were statistically insignificant.
DES daughters have a higher occurrence of a rare malignant vaginal cancer, clear cell adenocarcinoma,
and DES-exposed males showed a history of cryptorchidism, hypoplastic testes, epididymal cysts, and low sperm counts.
A DES Task Force formed by the Office of the Assistant Secretary for Health in 1978 recommends that all persons exposed to DES be informed of health risks and that DES daughters be carefully monitored by using Pap smears, iodine staining, and colposcopy when necessary.
In addition, the Task Force recommends
that DES women not use estrogens,
that postmenopausal replacement estrogens be prescribed prudently,
that DES not be given to suppress lactation,
and that women given DES for postcoital contraception be informed of the possible health risks.
Health effects: pregnancy use of diethylstilbestrol, The Journal of the Indiana State Medical Association, NCBI PubMed, PMID: 458172, 1979 May.