Diethylstilbestrol usage was questioned by WJ Dieckmann in 1953
- American Journal of Obstetrics and Gynecology, Volume 66, Issue 5 Pages 1062–1081, November 1953.
- Featured image sciencedirect.
Diethylstilbestrol usage was questioned by WJ Dieckmann in 1953
Thesis, Walter-Kull Agnès, June 2002
Le diéthylstilbestrol (Distilbène®) était le premier oestrogène de synthèse nonstéroïdien à apparaître sur le marché français en 1950. Son utilisation s’imposait d’abord aux USA à la suite des travaux menés par Smith dans le cadre de la prévention de certaines complications de la grossesse.
Après 25 ans d’utilisation, Herbst découvrait que le diéthylstilbestrol était responsable d’adénocarcinomes vaginaux à cellules claires chez les filles exposées in utero.
Après avoir retracé les principales étapes de « l’affaire Distilbène® » et rappelé les principales propriétés pharmacologiques de la molécule, l’ensemble des effets secondaires lié à l’utilisation du diéthylstilbestrol est abordé. Un cas clinique vient illustrer ces propos en exposant une malformation utérine (utérus en T) chez une jeune femme consultant pour stérilité secondaire et ayant été exposée au diéthylstilbestrol in utero. Une augmentation du risque de cancer du sein chez les mères traitées pendant leur grossesse est en outre rapporté ainsi qu’un nombre accru de malformations uro-génitales chez les garçons exposés in utero.
L’ensemble de ces données a amené le corps médical et paramédical à préconiser une prise en charge gynécologique, obstétricale et médico-psychologique de la population exposée. En 2002, soit 25 ans après l’interdiction de son utilisation chez la femme enceinte, de nouvelles données apparaissent et on parle pour la première fois d’une transmission transgénérationnelle des effets secondaires du médicament.
The psychological impact of DES exposure in women : a comparison of short-term and long-term effects in several generations of DES-exposed
Les aspects psychologiques liés à la prise du DES n’ont jusqu’ici que rarement fait l’objet d’études spécifiques. Ce sont principalement les équipes américaines qui ont fait des recherches dans ce domaine. Les auteurs se sont préoccupés essentiellement du vécu des femmes exposées in utero, de leurs réactions à l’annonce de cette exposition, et des conséquences qui en résultent : effets neurologiques, endocriniens qui peuvent entraîner des conséquences au développement intellectuel, psychique et sexuel de ces femmes ayant reçu du DES.
Ils concluent qu’il n’y a aucun effet du DES sur le plan cognitif. En revanche, il semblerait que sur le plan du comportement sexuel les femmes ayant reçu du DES in utero ont plus de difficultés dans leur vie sexuelle – “Psychosexual milestones in women prenatally exposed to diethylstilbestrol” – “Sexual activity level and sexual functioning in women prenatally exposed to diethylstilbestrol” – que les femmes du groupe témoin. De même, ils trouvent que ces femmes sont plus dépressives et montrent plus de difficultés psychologiques. Ils concluent que cette vulnérabilité psychologique est due à l’inquiétude consécutive aux problèmes gynécologiques et obstétricaux qu’elles rencontrent.
Par ailleurs, une équipe s’est plus particulièrement attachée à la recherche des effets psychiatriques sur le comportement humain des individus ayant reçu du distilbène in utero. Trois sur quatre jeunes adultes masculins psychotiques présentaient un électroencéphalogramme (EEG) perturbé. Tous les quatre avaient reçu du DES in utero. Les auteurs pensent que cette prérecherche est suffisamment significative pour qu’elle soit poursuivie. D’autres cliniciens se sont attachés à repérer quelle pourrait être la détresse des mères qui ont pris ce médicament. Ils ont rencontré des femmes qu’ils décrivent comme anxieuses, craintives et à la fois très mécontentes vis-à-vis du DES. Les plus âgées sont les plus atteintes.
Long-term distress subsequent to pregnancy drug administration: women with in utero diethylstilbestrol (DES) exposed daughters
Diethylstilbestrol (DES) is linked to cancer and reproductive loss in females exposed in utero. To examine levels of distress among mothers with in utero DES exposed daughters, we conducted interviews with 60 DES mothers. DES related distress was measured by a scale of 19 items and included such facets of emotional response as worry, fear, anger, and guilt. We also assessed levels of demoralization, a measure of generalized psychological symptomatology. In addition, information was gathered on age, education, psychological treatment history, DES health effects to daughter, certainty of drug exposure and knowledge regarding the efficacy and safety of DES.
We found worry, concern, fear, and anxiety to be the strongest type of response at both discovery and the current time. Likewise, anger was a prominent emotion at both time periods while guilt was not as focal a response as had been suggested by a previous study. We collapsed our multiple DES distress items into two reliable scales and found a highly significant decline from distress levels at discovery to the current time. We compared the extent to which variables explaining levels of current DES distress also explain demoralization levels. As would be expected, DES distress at discovery was the strongest predictor of current DES distress. Significant effects were also found for age and DES knowledge, as well as a trend for DES health effects to daughter to exacerbate levels of DES distress. Psychological treatment history had no significant effect. In contrast, present demoralization was best explained by past psychological treatment, while all other factors, including DES situational factors, were not significant predictors.
We conclude that there is no direct relationship between current DES distress and psychological problems but that the controversial record regarding the safety and efficacy of DES did contribute to greater distress.
Proceedings of the Summit on Environmental Challenges to Reproductive Health and Fertility: Executive Summary
The 2007 Summit on “Environmental Challenges to Reproductive Health and Fertility” convened scientists, health care professionals, community groups, political representatives and the media to hear presentations on the impact of environmental contaminants on reproductive health and fertility and to discuss opportunities to improve health through research, education, communication and policy. Environmental reproductive health focuses on exposures to environmental contaminants, particularly during critical periods of development, and their potential effects on future reproductive health, including conception, fertility, pregnancy, adolescent development and adult health. Approximately 87,000 chemical substances are registered for use in commerce in the US, with ubiquitous human exposures to environmental contaminants in air, water, food and consumer products. Exposures during critical windows of susceptibility may result in adverse effects with lifelong and even intergenerational health impacts. Effects can include impaired development and function of the reproductive tract and permanently altered gene expression, leading to metabolic and hormonal disorders, reduced fertility and fecundity and illnesses such as testicular, prostate, uterine and cervical cancers later in life. This executive summary reviews effects of pre- and post-natal exposures on male and female reproductive health and provides a series of recommendations for advancing the field in the areas of research, policy, health care and community action.
Prenatal exposure to diethylstilbestrol (DES), a synthetic estrogen and thus EDC, provides an unfortunate example of developmental programming. DES was given to U.S. pregnant women between 1938 and 1971 under the erroneous assumption that it would prevent pregnancy complications. In fact, in utero exposure to DES alters the normal programming of gene families, such as Hox and Wnt, that play important roles in reproductive tract differentiation. As a result, female offspring exposed to DES in utero are at increased risk of clear cell adenocarcinoma of the vagina and cervix, structural reproductive tract anomalies, infertility and poor pregnancy outcomes, while male offspring have an increased incidence of genital abnormalities and a possibly increased risk of prostate and testicular cancer. These observed human effects have been confirmed in numerous animal models which have also provided information on the toxic mechanisms of DES. Animal experiments have also predicted changes later found in DES-exposed humans, such as oviductal malformations, increased incidence of uterine fibroids and second-generational effects such as increased menstrual irregularities and possibly ovarian cancer in DES-granddaughters and increased hypospadias in DES-grandsons.
DES is but one example of how exposure to EDCs can disrupt developing organ systems and cause abnormalities, many of which only appear much later in life or in the subsequent generation, such as endometriosis, fibroids and breast, cervical and uterine cancer in women; poor sperm quality and increased incidence of cryptorchidism and hypospadias in men; and subfertility and infertility in men and women.
Women exposed to DES in utero during critical periods of reproductive tract development developed several types of reproductive tract abnormalities, as well as an increased incidence of cervical-vaginal cancer later in life. Animal studies that simulate the human DES experience have since shown that exposure of the developing reproductive tract of CD-1 mice to DES imparts a permanent estrogen imprint that alters reproductive tract morphology, induces persistent expression of the lactoferrin and c-fos genes and induces a high incidence of uterine adenocarcinoma. Experiments in rats have shown exposure to DES during the critical window of uterine development leaves a hormonal imprint on the developing uterine myometrium in rats that were genetically predisposed to uterine leiomyoma, increasing the risk for adult uterine leiomyoma from 65% to greater than 90% and increasing tumor multiplicity and size. DES-induced developmental programming appears to require the estrogen receptor α, suggesting that signaling through this receptor is crucial for establishing developmental programming.
Some epigenetic alterations that influence cancer risk are inherited through the germline from the DES-exposed to offspring and are observed in multiple DES generations of victims
Epigenetic alterations of the genome such as DNA promoter methylation and chromatin remodeling play an important role in tumorigenesis. These modifications take place throughout development with subsequent events occurring later in adulthood. Recent studies, however, suggest that some epigenetic alterations that influence cancer risk are inherited through the germline from parent to child and are observed in multiple generations. Epigenetic changes may be inherited as Mendelian, non-Mendelian, or environmentally induced traits. Here, we will discuss Mendelian, non-Mendelian, and environmentally induced patterns of multigenerational epigenetic alterations as well as some possible mechanisms for how these events may be occurring.
One example of multiple generations in families showing effects of an environmental agent are daughters of mothers who were exposed to diethylstilbestrol (DES) during the first trimester.
The daughters show developmental abnormalities and an increased risk of developing a rare type of clear-cell adenocarcinoma. DES daughters also show a 2.5-fold increase in breast cancer risk after 40 years of age. To prove that this indeed is an inherited transgenerational effect, granddaughters and great granddaughters of the exposed mothers will need to show a DES phenotype. This analysis has not yet been completed.
Mouse studies have shown that the F2 generation from a DES-exposed pregnant female had strikingly similar effects as the F1 generation, including abnormal uterine development and uterine cancer. The proposed mechanism of action of DES is aberrant CpG methylation of key uterine cancer genes. The changes in CpG methylation may be stable throughout gametogenesis, providing insight into the transgenerational effects of DES.
Proposed model to explain an increase in breast cancer risk in daughters, and possibly granddaughters and great granddaughters, of mothers who took diethylstilbestrol during pregnancy
Gene expression can be altered as a consequence of mutations or epigenetic changes. In contrast to gene mutations within the DNA, epigenetic changes involve post-transcriptional modifications; that is, methylation of gene promoter regions, histone modifications, deposition of certain histone variants along specific gene sequences and microRNA (miRNA) expression. Although both changes are heritable, an important distinction between the two is that mutations are not reversible, but epigenetic modifications generally are.
Probably the most common mechanism of epigenetic gene silencing is methylation, and it might also be the most important. DNA methyltransferases (DNMTs) catalyze the methylation of genomic DNA by adding a methyl group (CH3) onto the 5-carbon of the cytosine ring within CpG dinucleotides. Histone modifications are complex, as they involve not just histone methylation but also acetylation, deacetylation and other post-translational changes. These modifications occur in the amino-terminal tails of histones and affect the ‘openness’ of the chromatin, which determines whether a gene is expressed or silenced (for example, acetylation allows transcription, while deacetylation represses transcription). Trimethylation of histone H3 at lysine K27 is catalyzed by the Polycomb group (PcG) protein enhancer of Zeste-2 (EZH2) and results in gene silencing. PcG/H3K27me3 interact with DNMTs, and together they establish and maintain silencing of PcG target genes. Over 2,000 different PcG target genes have been identified and they include some tumor suppressor genes. Many of the PcG target genes regulate cell fate, including apoptosis, proliferation and stem cell differentiation. As discussed in more detail below, methylation of PcG target genes is linked to increased breast cancer risk.
DNMTs may be key players in regulating histones and the entire epigenomic machinery, since DNA methylation events often precede histone modifications. Upregulation of DNMTs increases the expression of EZH2 and other polycombs; this may happen by DNMTs inducing methylation of non-coding miRNAs that target the polycombs.
We and others have observed that the expression of DNMTs is persistently altered in estrogen-regulated tissues following estrogenic exposures during early life. In utero exposure to DES is reported to increase the expression of DNMT1 in the epididymis and uterus . We found that DNMT1 expression is increased in the mammary glands of adult rat offspring of dams exposed to ethinyl estradiol during pregnancy. These changes provide a key regulatory layer to influence gene expression in the mammary gland and perhaps breast tumors of individuals exposed to DES or other estrogenic compounds in utero.
In utero DES exposure alters methylation patterns of several genes in estrogen’s target tissues, including Hox genes, c-fox, and Nsbp1, but it has not been studied whether changes in methylation patterns occur in the mammary gland. We have explored changes in methylation in the mammary glands of adult rats exposed in utero to the synthetic estrogen ethinyl estradiol using global sequencing approaches. Among the genes that exhibited increased promoter methylation were several PcG target genes, suggesting that a maternal exposure to synthetic estrogens during pregnancy causes long-lasting changes in the methylation of genes that regulate cell fate, including stem cell differentiation.
As an increase in EZH2 expression in the mammary glands of mice exposed to DES in utero has been reported, histone modifications also seem to be influenced by maternal exposure to synthetic estrogens during pregnancy. Jefferson and colleagues recently investigated whether upregulation of lactoferrin and sine oculis homeobox 1 (Six1) in the uterus of adult mice exposed to DES neonatally is caused by histone modifications. Their data indicate that neonatal DES exposure induces changes during the early postnatal period in the expression of multiple chromatin-modifying proteins but these changes do not last to adulthood. However, alterations in epigenetic marks at the Six1 locus in the uterus were persistent. Similarly, changes in the methylation of Nsbp1 and expression of DNMTs in the uterus of DES-exposed offspring are different in the early postnatal period compared to adulthood. This suggests that some epigenetic alterations are further influenced by factors operating during postnatal development, such as a surge of estrogens and progesterone from the ovaries at puberty onset.
Maternal exposures during pregnancy have been found to induce persistent changes in miRNA expression in the offspring. miRNAs are short non-coding single-stranded RNAs composed of approximately 21 to 22 nucleotides that regulate gene expression by sequence-specific base-pairing with the 3’ untranslated region of target mRNAs. miRNA binding induces post-transcriptional repression of target genes, either by inducing inhibition of protein translation or by inducing mRNA degradation. Expression of many miRNAs is suppressed by estrogens. Although the effects of maternal DES exposure during pregnancy on miRNA expression in the offspring have not been investigated, it is known that many other manipulations, such as maternal low protein diet, alter miRNA patterns among the offspring. We recently found that in utero exposure to ethinyl estradiol lowers the expression of many of the same miRNAs in the adult mammary gland as are downregulated by E2 in MCF-7 human breast cancer cells. Since miRNAs can be silenced by methylation or as a result of increased PcG expression, and they target DNMTs, histone deacetylases and polycomb genes, the observed increase in DNMT expression, histone marks and EZH2 in the in utero DES-exposed offspring may be a result of epigenetic silencing of miRNAs that target them.
In summary, women exposed to DES in utero are destined to be at an increased risk of developing breast cancer, and this risk may extend to their daughters and granddaughters as well. It is of critical importance to determine if the increased risk is driven by epigenetic alterations in genes that increase susceptibility to breast cancer and if these alterations are reversible.
Exposure to DES may reveal pre-existing difficulties from generation to generation
The psychological consequences resulting from the exposure to diethylstilbestrol (DES), a non-steroidal oestrogen, on the mother-daughter relationship are studied using semi-directive interviews with 43 daughters and 7 mothers treated with DES during their pregnancies.
Prenatal exposure to diethylstilbestrol and the mother-daughter relationship, US National Library of Medicine, European journal of obstetrics, gynecology, and reproductive biology, NCBI PubMed PMID: 8730622, 1996 Apr.
These women referred to gynaecological consultation for DES-related problems.
The daughters, exposed to DES during their foetal life, learned about DES after a pregnancy mishap (35% of the cases), or by accident (65% of the cases).
All of them were shocked when the existence of DES and its side effects were revealed to them.
Consequences on the mother-daughter relationship were
Five percent of the women showed hostility towards the medical practice, but 65% were not suspicious of the drugs administered to them during their pregnancies. For 64% of them, administration of DES to their mother had been kept secret. In 7 out of 50 cases, parents alone came for medical assistance in order to manage the secret.
Exposure to DES may reveal pre-existing difficulties not only between the mother and the daughter, but sometimes beyond from generation to generation.
Physical and psychological problems associated with exposure to DES
The synthetic hormone diethylstilbestrol (DES) was widely prescribed between 1943 and 1971 to minimize pregnancy complications.
It has caused serious physical and psychological damage to the women who took it and to their offspring. DES-exposed mothers may suffer a higher incidence of breast cancer, their exposed daughters are at risk for reproductive tract cancers and infertility, and their exposed sons are more likely to have genital abnormalities and reproductive dysfunction.
Depression and diethylstilbestrol exposure in women, US National Library of Medicine, Hospital & community psychiatry, NCBI PubMed PMID: 3276594, 1988 Jan.
Image credit pedro veneroso.
Psychiatric disorders among DES-exposed persons are reportedly twice as common as for nonexposed persons, with anger, anxiety, low self-worth, identity confusion, and guilt the most frequent symptoms. The author describes therapeutic interventions designed to alleviate these problems.
Vulnerability to stress among women with in utero diethylstilbestrol (DES) exposed children
In utero exposure to diethylstilbestrol (DES) was initially linked to vaginal-cervical cancer and subsequently to reproductive difficulties. These unanticipated and ongoing health risks to female offspring may constitute a chronic source of stress for DES mothers.
Vulnerability to stress among women with in utero diethylstilbestrol (DES) exposed daughters, US National Library of Medicine, Journal of human stress, NCBI PubMed PMID: 3855173, 1985.
Image credit michaelclesle.
We interviewed 60 mothers of exposed daughters and 30 acquaintance controls. Two hypotheses were tested in regard to DES mothers: DES discovery and its aftermath have a direct, long-term, negative effect on psychological health and the DES experience intensifies the negative psychological effects of other adverse life circumstances.
To operationalize psychological health, we measured symptoms of “demoralization” and positive health practices–the latter as a behavioral indicator of mastery and personal control. We also measured adversities that may mediate the threat posed by DES, including stressful events, medical problems, and chronic burdens. We found DES history to be associated with poorer psychological health only when mothers encountered other losses and threats to themselves and their families.
We concluded that DES mothers may manifest increased vulnerability to subsequent stresses in their lives.