DES used as an emergency contraception, Hungary, 1978
It is almost impossible at this point to make an estimate of the possible delayed adverse effects of the hormonal contraceptives presently marketed. The consequences of the administration of DES were revealed years later as it affected the children of the women who had been taking it.
The author discusses the word “catastrophy” in connection with this kind of consequences. He asks the question whether the mortality due to illegal abortion and even to legal abortion in the 1st years following its legalization should not also be considered as a catastrophy. The author refers in his argument to a paper published in the journal Orvosi Hetilap by Professor Csaba in 1977.
Another question doctors ask themselves concerns the relativity of a side-effect’s seriousness. Should one consider the damage done to the individual, or the number of subjects affected? There is no doubt that the presently used hormonal contraceptives contain a number of possible side effects, which however may be kept under control to a certain extent by doctors who carefully respect their indications and contraindications before prescribing them. But it is at this point extremely difficult to predict which delayed effects they might have. The medical schools in Hungary are doing a lot of research on the subject, but what can be done about the women who have been taking oral contraceptives for 10 years already? The possible delayed effects have not even started to show in these patients.
The author underlines the fact that medical schools should insist more than they do on the ethical aspects of medicine.
Diethylstilbestrol: Potential health risks for women exposed in utero and their offspring
2017 Study Abstract
An increased risk of breast cancer has been well documented for women who took DES during pregnancy, and is estimated to be 30% greater than in unexposed women.
Long-term US studies of women exposed in utero reveal an increased risk of breast cancer in women age 40 years and older, with a hazard ratio of 1.82 (95% CI, 1.04-3.18) when compared with unexposed women. European follow-up studies do not support the finding of an increased breast cancer risk in women exposed to DES in utero. However, this may be due to the fact that the European cohort of women studied were 10 years younger than the American cohort and thus, at the time, included many women under age 40 years.
Animal studies suggest a transgenerational risk specifically for breast cancer in female offspring of women exposed to DES in utero, but this has not been supported by current patient data from United States or European follow-up studies.
Diethylstilbestrol: Potential health risks for women exposed in utero and their offspring, Journal of the American Academy of Physician Assistants DOI: 10.1097/01.JAA.0000511800.91372.34, 2017 Feb.
DES used as an emergency contraception, Czechoslovakia, 1977
55 women were administered a series of postcoital contraceptives, 35 of whom received only a single application and 20 received the preparations for more than 1 cycle (more than 2 but less than 13).
34 women of the 1st group (48 hours after unprotected coitus) and 7 women from the 2nd group were administered diethylstilbestrol (DES) for 5 days for a total of 250 mg.
The remaining subjects were given norethisterone Spofa for 3 days at 30 mg/day.
Results from this administration in the sense of a general contraceptive were not considered favorable, primarily due to contraindications in regard to physiological side effects, particularly with DES. DES proved to be the most successful in preventing pregnancy.
Exposure to diethylstilbestrol during sensitive life stages: a legacy of heritable health effects
The legacy of the adverse effects that stem from DES administration to pregnant women in the 1950s to 1970s has not completely formed. The male and female offspring of those women have reported significant fertility, cancer, and birth-related outcomes, but the cancer outcomes are not completely understood, with few exceptions (CCA and breast cancer in women over 40 yr old).
Information on DES mothers and daughters, in addition to substantial animal data, earned DES a place in the First Annual Report on Carcinogens, a critical review of carcinogenic compounds produced by the National Toxicology Program, in 1980 and was noted by the International Agency for Research on Cancer in their Monographs (IARC 1974). As the male and female offspring of those women age, the overall effect of DES on reproductive cancers will be better understood. Even more important to understand is the potential effect of this endocrine disruptor and carcinogen on the 3rd generation offspring who were not directly exposed, but may be affected in a heritable way through estrogen reprogramming and DNA modification.
Further research is needed to indicate the mechanisms of action on the target tissues, so that future pharmaceuticals/environmental estrogen mimics will avoid these pathways, leading to healthier future generations. Future studies should focus on common target tissue pathways affected and the health of the DES grandchildren.
Walker and Haven (1997) predicted that “if the high intensity of DES multigenerational carcinogenicity seen in mice is applicable to the human population, this is a health problem of major proportions.” They go on to say that it “could take over 50 years” to detect the effects in future generations, due to the length of time required for diseases such as cancer to manifest. It is predicted that cross-generational responses to DES exposure are possible due to epigenetic changes in the DNA and that the “germ cell pool could have become massively contaminated”. For example, early exposure to EDCs, like DES, is thought to reprogram mouse female reproductive tract development and affect how the reproductive tract responds to endogenous estrogens later in life (Ma 2009; Hilakivi-Clarke et al., 2013). They (Walker and Haven 1997) suggest that “environmental estrogens may be more potent than previously suspected, due to synergistic action from concurrent exposures.”
The studies on the cohort of men (grandsons) and women (granddaughters) whose mothers were exposed prenatally to DES (grandchildren had no direct exposure) are limited as they are just beginning to reach the age when relevant health problems can be studied (CDC 2012). Studies that have been performed contain preliminary data, as the power is low. Therefore, the main sources of information for third generation effects are rodent studies. In general, multi-generational mouse studies have shown an increased susceptibility to tumor formation in the third generation which suggests that DES grandchildren are also at an increased risk for cancer
Full study (free access) : Exposure to Diethylstilbestrol during Sensitive Life Stages: A legacy of heritable health effects, Birth Defects Res C Embryo Today, NCBI PubMed PMC3817964, 2013 Nov 5.
The usual dosage is 25 mg twice a day for 5 days. If given soon after intercourse, the medication is found to be almost universally effective in the prevention of pregnancy.
However, at the same time DES was being approved as a contraceptive, its teratogenic effect on the unborn fetus was beginning to be realized. The association between DES exposure and the late development of clear cell adenocarcinoma of the vagina and cervix is now well known. Although DES is still approved as a postcoital contraceptive, the FDA does require that the recipient be warned of the possible effects on the fetus should pregnancy occur.
Its role in the development of vaginal adenocarcinoma and cervical dysplasia is known and screening codified.
Recent cohort studies show that exposure to DES in utero increases breast cancer risk especially after 40 years.
This article reports the observation of a breast cancer of exceptional gravity in a patient exposed to DES in utero. It details the risk of breast cancer for “DES daughters” and support possible screening modalities.
Prenatal diethylstilbestrol exposure and breast cancer, Gynécologie, obstétrique & fertilité, NCBI PubMed PMID: 23102737, 2012 Dec.
“Breast cancer following diethylstilbestrol exposure in utero: insights from a tragedy” author reply to Dr. Bluming, who has been compensated on an hourly basis for testimony as an expert witness on behalf of defendant, Pfizer Pharmaceuticals, in DES litigation.
We thank Dr. Tournaire and his colleagues for sharing data on diethylstilbestrol (DES) doses prescribed in France. This information supports the notion that DES was prescribed in lower doses and for shorter periods during pregnancy in Europe than in the US. It would be particularly interesting to know whether any women in the French cohort developed vaginal epithelial changes as a marker of high-dose exposure. And it is unfortunate that the small size of the French cohort (110 women) does not allow an informative analysis of breast cancer risk.
Although we realize that our opinion may not be appreciated in some quarters, Dr. Bluming’s denial of the indicated statistical significance in the NCI cohort is strange. We can only encourage readers to scrutinize the two most informative studies and develop their own opinion. Exclusion of one component cohort in the most recent study, due to lack of information on vaginal epithelial changes as a marker of high exposure, reduces statistical power but does not compromise the validity of the study. Although we are fortunate to have one high quality, competently analyzed prospective study, causal inference is challenging as discussed in our Commentary.
Definition of a tragedy is obviously a subjective process. We doubt, however, that the millions of women who were prescribed a useless drug with several harmful effects would disagree with our judgment.
Dr. Adami, consultant in litigation on behalf of DES daughters claiming breast cancer injury due to DES exposure.
Breast cancer following diethylstilbestrol exposure in utero: a tragedy?, NCBI PubMed, European journal of epidemiology PMID: 22860252, 2012 Apr.
Diethylstilbestrol exposure: evaluation of the doses received in France, 2012
In an analysis of two prospective studies on the relationship between DES exposure in utero and breast cancer, Adami et al. oppose a dose dependent excess risk after the age of 40 years and the absence of evidence of such an excess risk. Indeed, the American study suggested an excess risk of breast cancer for women exposed in utero aged 40 years or more. The Incidence Rate Ratio (IRR) was 1.91 (95 % CI 1.09–3.33) relative to unexposed cohorts. Nevertheless, IRR was significant for high dose exposure (IRR = 2.16, 95 % CI, 1.18–3.96) but not for low-dose exposure (IRR = 1.63, 95 % CI, 0.87–3.08) relative to unexposed cohort. The Dutch study by contrast revealed no increase of breast cancer for DES-exposed daughters.
One hypothesis that may explain these discordant results, besides possible differences in age of the cohorts and methods, concerns the differences in doses of DES given in the United States and in the Netherlands. This could stimulate a renewed interest in prescribed doses of DES, especially in Europe. Adami et al. observed that additional informative studies seem unfeasible since the use of DES ended four decades ago. However, we would like to focus on information obtained 2 or 3 decades ago on the DES doses used in France since our results seem relevant.