Experimental study on relationship between exogenous estrogen and breast cancer risk
1997 Study Abstract
OBJECTIVE To investigate the relationship between exogenous estrogen and breast cancer risk.
METHODS Female rats were randomly divided into three groups, namely diethylstilbestrol (DES), norethindrone compositae (CoNET) and control group. The histological structure and ultrastructural changes of mammae were observed. The levels of sexual hormones in serum were determined and the AgNOR counts, DNA contents and steroid receptor contents in mammary epithelium were also detected.
RESULTS In DES group, the level of progesterone (10.38 ng/ml) was obviously lower than that in the control group (13.37 ng/ml); the incidence of hyperplasia of mammary gland (73.33%) was significantly higher than that in the control group (7.69%); and the degree of hyperplasia was obviously more serious than that in the control group. Moreover, there were 13.33% of rats with atypical hyperplasia in DES group. The DNA contents, AgNOR counts and estrogen receptor (ER) positive rate were markedly higher in DES group (95.60, 2.43 and 71.71% respectively) than in the control group (83.07, 1.88 and 40% respectively). However, in CoNET group, there were no obvious influences on ER, AgNOR and DNA in mammary epithelium.
CONCLUSIONS Exogenous estrogen (DES) could affect the levels of sexual hormones in serum, accelerate the DNA duplication, increase the AgNOR counts and ER contents, and induce atypical hyperplasia and ultrastructural changes of mammary gland, hence becoming a latent risk factor of breast cancer. However, the results failed to suggest that the contraceptive, CoNET, could increase the risk of breast cancer.
Experimental study on relationship between exogenous estrogen and breast cancer risk, Chinese medical journal, NCBI PubMed PMID: 9594309, 1997 May.
Diethylstilbestrol and risk of fatal breast cancer in a prospective cohort of US women
1996 Study Abstract
The authors examined the association between the use of diethylstilbestrol during pregnancy and the risk of subsequent fatal breast cancer in a large prospective study of US adults.
After 9 years of follow-up, 1,574 cases of fatal breast cancer were observed among 501,536 gravid women who reported no prior history of cancer in 1982.
Results from Cox proportional hazards models showed a positive association between a history of diethylstilbestrol exposure (reported by 3.9% of all women) and fatal breast cancer (adjusted rate ratio = 1.34, 95% confidence interval 1.06-1.69). This excess risk did not increase over time; women who were exposed more than 35 years ago (rate ratio = 1.35, 95% confidence interval 0.97-1.87) were not at greater risk than women who were exposed within the past 35 years (rate ratio = 1.39, 95% confidence interval 1.01-1.93). The positive association was not observed in women who used diethylstilbestrol before age 25 years but was seen at all other ages. The age of study participants did not modify the association between exposure and breast cancer, and there were no significant interactions between ever use of diethylstilbestrol and any of the other potential risk factors included in the analysis.
These findings are consistent with those of several other studies of diethylstilbestrol exposure and breast cancer.
Diethylstilbestrol and risk of fatal breast cancer in a prospective cohort of US women, American journal of epidemiology, NCBI PubMed PMID: 8823060, 1996 Oct 1.
The most common cancer in US women and the 2nd leading cause of cancer death is breast cancer.
Between 1980-1987 in the US. age-adjusted incidence rates of breast cancer rose rapidly. They are also rising rapidly in several Asian countries (e.g., in Japan) which have the lowest incidence rates. These rapid increases may mean that environmental factors are responsible.
Incidence rates rise greatly with age until the late 40s. US women at highest risk of breast cancer are Jewish women, urban women, single women, and women living in the northern US. Women at lowest risk include Mormon and Seventh-Day Adventist women, Hispanic and Asian women, rural women, women living in the southern US, and married women.
Factors that have a relative risk greater than 2 are
mother and sister with history of breast cancer, especially if diagnoses at an early age;
atypical epithelial cells in nipple aspirate fluid;
nodular densities on the mammogram;
history of cancer in 1 breast;
mother or sister with history of breast cancer;
biopsy-confirmed benign proliferative breast disease;
hyperplastic epithelial cells without atypia in nipple aspirate fluid;
and radiation to chest in moderate to high doses.
Ovarian hormones appear to stimulate cell division in the breast, thus elevated levels may be risk factors.
Exogenous hormones may also increase the risk. Women are exposed to these exogenous hormones through
Postmenopausal obesity increases the risk while premenopausal obesity decreases the risk. A high fat diet in childhood and adolescence may increase the risk. Alcohol drinking may also increase the risk.
Older, white, and nulliparous women are more likely to have estrogen receptor-positive cancers.
Breast cancer in males tends to share the same risk factors as well as its own unique factors.
Prevention of postmenopausal obesity is the only established primary prevention effort. Screening is the only secondary prevention means.
Breast cancer epidemiology: summary and future directions, Epidemiologic reviews, NCBI PubMed PMID: 8405209, 1993.
European journal of cancer (Oxford, England : 1990)
Diethylstilboestrol is still used as an adjunct palliative treatment in certain patients with breast and prostate cancer. Its pharmacological, toxicological and carcinogenic properties are reviewed.
In addition to the usual untoward effects following subacute or chronic administration of oestrogens, treatment with diethylstilboestrol has been associated with serious cardiovascular sequelae.
Most characteristic are, however, the carcinogenic properties of this drug.
Many epidemiological data provide evidence that prenatal exposure to diethylstilboestrol is causally associated with vaginal and cervical clear-cell adenocarcinomas, a very rare type of cancer in the unexposed female population.
The intrauterine exposure of males leads to an increased risk of testicular cancer, although the data are less conclusive in this respect.
There is some evidence that administration of diethylstilboestrol in large doses to adult women during pregnancy increases the risk of subsequent breast cancer
and it probably increases the incidence of endometrial carcinoma, as has been shown with other similar oestrogens given chronically for menopausal symptoms.
Diethylstilboestrol: I, Pharmacology, Toxicology and carcinogenicity in humans, European journal of cancer, NCBI PubMed PMID: 1627392, 1992.
Long-term follow-up of mothers who received high doses of stilboestrol and ethisterone in pregnancy
1980 Study Abstract
The report by Dr Valerie Beral and Linda Colwell linking oestrogen therapy during pregnancy with later appearance (after 18-22 years) of breast cancer prompted us to review studies on oral contraceptives. …
… The data in the table indicate an increased risk of breast cancer among women with a positive history of oral contraceptive use but only after they have passed into their fifth or sixth decade. Breast cancer is common in women in their later years; a small increase in risk would therefore mean a large increase in the absolute number of cases. Most oral contraceptive users have not yet reached the critical age. Future studies should address this potential problem.
Full text (free access) : Long-term follow-up of mothers who received high doses of stilboestrol and ethisterone in pregnancy, British medical journal, NCBI PubMed PMC1715108, 1980 Dec.
Randomised trial of high doses of stilboestrol and ethisterone in pregnancy: long-term follow-up of mothers
1980 Study Abstract
In 1950 a trial was set up to evaluate the effects of large doses of stilboestrol and ethisterone on rates of fetal loss in pregnant diabetic women. Eighty women were allocated at random to receive the hormonal treatment and 76 to receive inactive tablets of identical appearance.
At follow-up 27 years later, information was obtained about 97% of the women, all but four being traced. All respondents were unaware of who had received hormones.
The overall mortality was 4.5 times that of women of comparable age in England and Wales, most deaths being from complications of diabetes.
More tumours, mainly benign, of the reproductive tract were reported in the hormone-exposed than the non-exposed group (14 (18%) and two (3%) respectively).
Four cases of malignant breast disease were reported in the hormone-exposed women and none in the non-exposed.
These findings support other evidence linking oestrogen treatment and breast cancer and suggesting that the latent period before the tumour becomes clinically apparent may be 15 years or longer.
Full text (free access) : Randomised trial of high doses of stilboestrol and ethisterone in pregnancy: long-term follow-up of mothers, British medical journal, NCBI PubMed PMC1714571, 1980 Oct.
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.