Tag: DES-exposed

Animal models of prenatal exposure to diethylstilboestrol

The multigeneration effect of DES provides a model to test the mechanism of transmission of cancer risk from one generation to the next

1989 Study Abstract

Animals of several species exposed perinatally to diethylstilboestrol (DES) have been evaluated for anomalies and tumours.

In male offspring, anomalies of the testis and epididymis have been reported, but evidence for tumours has been very limited.

Many anomalies and tumours have been recorded in female offspring, and some of these duplicate the anomalies and tumours reported in DES-exposed women, whereas others either have not yet been discovered or else do not occur in the human species..

Animal models of prenatal exposure to diethylstilboestrol, US National Library of Medicine National Institutes of Health, IARC scientific publications, NCBI PubMed PMID: 2680952, 1989.

A variety of abnormal physiological responses has been identified in animals exposed perinatally to DES.

There were altered levels of hormones and receptors; responses to postnatal injection of hormones were often modified; and an increased susceptibility to other carcinogens has been established.

Several mechanisms have been postulated to explain tumour production later in life after perinatal exposure to DES:

  1. Deficiencies in immune function indicate a mechanism of impaired immune surveillance.
  2. The presence of DES and its metabolites in the fetus and neonate raise the issue of somatic mutation. Evidence for sister chromatid exchange, cell transformation in tissue culture and other toxic effects on chromosomes support the somatic mutation hypothesis.
  3. A third hypothesis is involvement of abnormal differentiation of the hypothalamus. Structural, hormonal and behavioural changes support this idea.

Possible additional problems in humans after exposure to DES, on the basis of animal model studies, are increased tumour frequency with ageing and transmission of cancer risk to the third generation.

The multigeneration effect of DES provides a model to test the mechanism of transmission of cancer risk from one generation to the next.

The outcome of such experiments could have considerable impact on the understanding of the association between DES and cancer specifically and transplacental cancer generally.

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Environmental factors, epigenetics, and developmental origin of reproductive disorders

US National Library of Medicine National Institutes of Health, Reproductive toxicology, 2016

Highlights

  • Epidemiological and model system studies support an early origin of reproductive dysfunction.
  • Estrogenic/anti-androgenic chemicals as endocrine disrupting chemicals (EDCs) have vast developmental influences on adult reproductive outcomes.
  • Gestational, perinatal, neonatal, and pubertal periods are “windows of susceptibility” for epigenetic programming.
  • EDCs induce exposure-specific epigenetic modifications in regulatory genes in organs of the reproductive system.
  • Germline epigenetic disruption is a mechanism underlying transgenerational inheritance of reproductive disorders.

2017 Study Abstract

Environmental factors, epigenetics, and developmental origin of reproductive disorders, US National Library of Medicine National Institutes of Health, Reproductive toxicology (Elmsford, N.Y.), NCBI PubMed PMID: 27421580, 2016 Jul.

Image credit Daniel Friedman.

Sex-specific differentiation, development, and function of the reproductive system are largely dependent on steroid hormones.

For this reason, developmental exposure to estrogenic and anti-androgenic endocrine disrupting chemicals (EDCs) is associated with reproductive dysfunction in adulthood.

Human data in support of “Developmental Origins of Health and Disease” (DOHaD) comes from multigenerational studies on offspring of diethylstilbestrol-exposed mothers/grandmothers.

Animal data indicate that ovarian reserve, female cycling, adult uterine abnormalities, sperm quality, prostate disease, and mating behavior are susceptible to DOHaD effects induced by EDCs such as bisphenol A, genistein, diethylstilbestrol, p,p’-dichlorodiphenyl-dichloroethylene, phthalates, and polyaromatic hydrocarbons.

Mechanisms underlying these EDC effects include direct mimicry of sex steroids or morphogens and interference with epigenomic sculpting during cell and tissue differentiation.

Exposure to EDCs is associated with abnormal DNA methylation and other epigenetic modifications, as well as altered expression of genes important for development and function of reproductive tissues.

Here we review the literature exploring the connections between developmental exposure to EDCs and adult reproductive dysfunction, and the mechanisms underlying these effects.

DES DiEthylStilbestrol Resources

The Diethylstilbestrol Legacy

A Powerful Case Against Intervention in Uncomplicated Pregnancy

2016 Report Abstract

Although the basic tenet of medicine is “First, do no harm,” history is filled with good intentions that were at best unhelpful and at worst harmful. Because medicine seeks to cure afflictions, there is an overwhelming desire on the part of health providers and patients to administer treatment. In certain settings, treatment can be reasonable despite a risk of adverse consequences: for example, if the disease is cured or its morbidity abated and the treatment consequences are less disabling than the disease itself.

In the absence of overt disease, the question of whether to apply an intervention is far more challenging. The safety of interventions must be weighed against the population’s level of risk, the morbidity and/or mortality associated with the disease, and the intervention’s efficacy (eg, BRCA1 mutation, mastectomy, reduced breast cancer risk). Interventions must meet an especially high standard of safety and efficacy when administered in low-risk populations or in settings in which the morbidity associated with the disease is minor. In the worst-case scenario, an intervention may be both ineffective for its primary purpose and cause iatrogenic illness.

The Diethylstilbestrol Legacy: A Powerful Case Against Intervention in Uncomplicated Pregnancy,
Pediatrics, November 2016, VOLUME 138 / ISSUE Supplement 1, Supplement_1/S42.abstract, November 2016.

Interventions in pregnancy are especially problematic because of the complex physiology of the condition and the possibility of causing short- and long-term adverse consequences in both the mother and her offspring. The continuing story of diethylstilbestrol (DES), a synthetic estrogen, shows the importance of caution when evaluating the merits of interventions involving pregnant women. With regard to DES, investigators believed that pregnancy loss was caused in part by a decrease in estrogen and that administering DES to pregnant women would help maintain a healthy pregnancy. Moreover, because endogenous estrogen concentrations increase dramatically during a healthy pregnancy, supplementation with DES was deemed harmless. During its early years of use, DES was administered to women with threatened pregnancy loss or a history of pregnancy loss. Eventually, DES was advertised to the medical community for “routine prophylaxis in ALL pregnancies” and administered to women with otherwise healthy pregnancies.

By the time DES was formally evaluated, it was standard of care in high-risk obstetrics practices. The first clinical trial to determine the efficacy of DES, reported in 1953, showed that DES did not improve pregnancy outcome. (Indeed, a subsequent reanalysis of the data revealed that DES increased the risk of spontaneous abortion, preterm birth, and neonatal death) Despite lack of evidence supporting a benefit, DES continued to be prescribed during pregnancy until 1971, when a small study showed a stunning 40-fold increase in the risk of clear cell adenocarcinoma (CCA) of the vagina and cervix in girls and young women who were prenatally exposed to DES. Several months later, the Food and Drug Administration issued a bulletin indicating that the use of DES was contraindicated in pregnancy. By then, however, millions of women, along with their sons and daughters, had been needlessly exposed.

In addition to the increased risk of CCA of the vagina and cervix, daughters exposed in utero to DES also suffered from an increased occurrence of reproductive tract abnormalities, infertility, and pregnancy complications; earlier menopause; twice the incidence of cervical dysplasia; and a possible elevated risk of breast cancer and continued increased risk of CCA in middle age. Recent preliminary data indicate the possibility of an increased risk of cardiovascular disease and diabetes in the prenatally exposed women. Mothers administered DES during pregnancy have an increased risk of breast cancer incidence and mortality. Sons who were exposed in utero have an increased risk of genitourinary defects and a possible increase in testicular cancer. The possibility of epigenetic transmission with consequent adverse outcomes in the offspring of prenatally exposed women is under investigation. Preliminary findings showed increased menstrual irregularity and a possible excess of ovarian cancer in very young women.

The link between prenatal DES exposure and subsequent adverse health outcomes, most of which are fairly common, may easily have escaped detection. The investigation of DES outcomes was initiated solely because a rare tumor occurred in a cluster of cases at an unusually young age, decades before the usual age of presentation. This historical example underscores the necessity of carefully weighing the risks and benefits of interventions in pregnancy and long-term monitoring of the health outcomes in mothers and offspring.

Whether and/or when to use pharmaceutical intervention in pregnancy continues to pose special challenges. At the present time, progesterone used to prevent pregnancy loss appears to be effective, although more data are needed. Thus far, there is little evidence of short-term adverse consequences for the offspring, but continued monitoring of mothers and offspring is warranted to identify any short- or long-term adverse effects. The use of progestins for luteal phase and early pregnancy support after in vitro fertilization is routine, and there are even fewer data on potential short- and long-term risks of this therapy. The tragic legacy of DES supports a cautious approach to the use of pregnancy interventions and assiduous appraisal of their effects.

Rebecca Troisi, Elizabeth E. Hatch, Linda Titus,
Reviewed by Dr Robert Hoover,

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Cancer Risk in Women Exposed to Diethylstilbestrol in Utero

Significant increase of breast cancer in DES Daughters

2015 Study Abstract

OBJECTIVE
To evaluate the overall cancer risk, primarily breast cancer, for women exposed to diethylstilbestrol (DES) in utero in France.

METHODS
A cohort of 3 436 prenatally DES exposed women and a comparable cohort of 3256 unexposed women were recruited retrospectively from voluntary responses to questionnaires, and cases were ascertained by medical history at the time of recruitment.

Cancer Risk in Women Exposed to Diethylstilbestrol in Utero, US National Library of Medicine National Institutes of Health, Therapie, NCBI PubMed PMID: 26071143, 2015 Sep-Oct.

Image credit Amy the Nurse.

RESULTS
One hundred ninety-five cancers were observed in exposed women (136 breast cancers, and 59 in other sites) and 141 cancers in unexposed women (90 breast cancers, and 51 others). A significant increase of breast cancers was found in exposed women, with a multivariate incidence rate ratio of 2.10 (95% CI 1.60-2.76) when compared with unexposed women. When exposed women were compared with the general population in France, the standardized incidence ratio was 2.33 (95% CI 1.93-2.72).

CONCLUSION
Our results suggest a significant increase of breast cancer in prenatally DES exposed women when compared with unexposed women and with the general population. For other cancers, except clear cell carcinoma of the cervix or vagina, there was a global non-significant increase.

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Impact of prenatal exposure to diethylstilbestrol (DES) on psychological outcome

A national survey of DES daughters and unexposed controls

2017 Study Abstract

To explore whether prenatal exposure to diethylstilbestrol (DES) is associated with increased risk of poor psychological outcome independently of the occurrence of major somatic complications related to DES exposure.

Data on health outcome were collected in women prenatally exposed to DES (n = 2566) and unexposed women (n = 2967) recruited in a French national survey.

Women prenatally exposed to DES were 1.7 times more likely to have consulted a mental health specialist compared to unexposed women (adjusted odds ratio = 1.69, 95% confidence interval 1.47-1.96), independently of demographic characteristics, poor gynecological or obstetrical outcome, or history of cancer.

Impact of prenatal exposure to diethylstilbestrol (DES) on psychological outcome: a national survey of DES daughters and unexposed controls, US National Library of Medicine National Institutes of Health, Archives of women’s mental health, NCBI PubMed PMID: 28064340, 2017 Jan 7.

Image credit Alessandra.

Frequency of consultation with a mental health specialist in persons with a history of gynecological complications or cancer was comparable in women prenatally exposed to DES and unexposed women.

Findings regarding psychological outcome obtained in the high-risk group of women prenatally exposed to DES may contribute to improving identification of psychological needs of all women presenting with gynecological abnormalities.

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14 Filles Distilbène, telles qu’elles sont…

3’35 pour “parler” autrement du DES…

Vidéo publiée le 13 janvier 2017 par la chaine Association Réseau DES FRANCE DISTILBENE.

Une série de portraits de femmes touchées, traversées, abîmées par le Distilbène DES.

“Je veux que chaque femme touchée par le DES dans le monde puisse s’y retrouver : française, américaine, australienne, hollandaise, africaine, allemande… Je veux que ce témoignage muet soit entendu dans toutes les langues par toutes les cultures. Je souhaite qu’il permette aux femmes qui y participeront de déposer quelque chose derrière la caméra et de repartir plus légères et fières du courage qu’elles ont eu à le faire. Je veux que la gravité et la beauté de ces visages sans mots résonnent puissamment aux oreilles des lobby, dans les couloirs de la commission européenne, dans l’antichambre des tribunaux où se rejoue David contre Goliath à chaque procès de ‘fille DES’ “

Laetitia Dormoy, créatrice du projet.
Sources : la chronique de Marie Darrieussecq.

Le Distilbène DES, en savoir plus

Risk of cervical intra-epithelial neoplasia and invasive cancer of the cervix in DES daughters

US National Library of Medicine National Institutes of Health, Gynecologic oncology, 2016

Abstract

OBJECTIVE
Women exposed to diethylstilbestrol in utero (DES) have an increased risk of clear cell adenocarcinoma (CCA) of the vagina and cervix, while their risk of non-CCA invasive cervical cancer is still unclear.

METHODS
We studied the risk of pre-cancerous (CIN) lesions and non-CCA invasive cervical cancer in a prospective cohort of 12,182 women with self-reported DES exposure followed from 2000 till 2008. We took screening behavior carefully into account. Incidence was obtained through linkage with the Netherlands Nationwide Pathology database (PALGA). General population data were also derived from PALGA.

Risk of cervical intra-epithelial neoplasia and invasive cancer of the cervix in DES daughters, US National Library of Medicine National Institutes of Health, Gynecologic oncology, NCBI PubMed PMID: 27939984, 2016 Dec 7.

RESULTS
The incidence of CIN1 was increased (Standardized Incidence Ratio (SIR)=2.8, 95% Confidence Interval (CI)=2.3 to 3.4), but no increased risk was observed for CIN2+ (CIN2, CIN3 or invasive cancer) compared to the screened general population (SIR=1.1, 95% CI=0.95 to1.4). Women with DES-related malformations had increased risks of both CIN1 and CIN2+ (SIR=4.1, 95%CI=3.0 to 5.3 and SIR=1.5, 95%CI=1.1 to 2.0, respectively). For CIN2+, this risk increase was largely restricted to women with malformations who were more intensively screened.

CONCLUSIONS
An increased risk of CIN1 among DES daughters was observed, especially in women with DES-related malformations, probably mainly due to screening. The risk of CIN2+ (including cancer) was not increased. However, among DES daughters with DES-related malformations a true small risk increase for non-CCA cervical cancer cannot be excluded.

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Perinatal carcinogenesis: growing a node for epidemiology, risk management

Childhood Cancers, Toxicology and Applied Pharmacology, 2004

Abstract

Perinatal carcinogenesis as a cross-disciplinary concern is the subject of this special issue of Toxicology and Applied Pharmacology, which consists of a total of eight reviews or commentaries in the areas of epidemiology, risk assessment, and animal models. Some of the conclusions from these articles, and the Questions and Answers section that follows most of them, are summarized here.

There is adequate reason to suspect that perinatal exposures contribute to human cancer risk, both childhood cancers, and those appearing later in life. The latter type of risk may actually be quantitatively the more important, and involve a wide range of types of effects, but has received only limited attention.

Introduction and overview. Perinatal carcinogenesis: growing a node for epidemiology, risk management, and animal studies, Toxicology and applied pharmacology, NCBI PubMed PMID: 15313581, 2004 Sep.

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With regard to childhood cancers, fetal irradiation and diethylstilbestrol exposure are known etiological agents, and it is likely, but not yet certain, there are additional external causes of a portion of these. Some current focal points of interest here include nitroso compounds, DNA topoisomerase inhibitors, viruses, anti-AIDS drugs, and endocrine disruptors.

Regulatory agencies must rely heavily on animal data for estimation of human risk due to perinatal exposures to chemicals, and the quantity and quality of these data presently available for this purpose are greatly limiting. Correctly designed conventional animal studies with suspect chemicals are still needed. Furthermore, genetically engineered mouse models for childhood cancers, especially medulloblastoma, have become available, and could be used for screening of candidate causative agents for this cancer type, and for better understanding of gene-environment interactions.

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Critical windows of exposure for children’s health and agents related to childhood cancer

The carcinogenic effects of both ionizing radiation and DES may be mediated via teratogenesis

Abstract

In humans, cancer may be caused by genetics and environmental exposures; however, in the majority of instances the identification of the critical time window of exposure is problematic. The evidence for exposures occurring during the preconceptional period that have an association with childhood or adulthood cancers is equivocal.

Agents definitely related to cancer in children, and adulthood if exposure occurs in utero, include: maternal exposure to ionizing radiation during pregnancy and childhood leukemia and certain other cancers, and maternal use of diethylstilbestrol during pregnancy and clear-cell adenocarcinoma of the vagina of their daughters. The list of environmental exposures that occur during the perinatal/postnatal period with potential to increase the risk of cancer is lengthening, but evidence available to date is inconsistent and inconclusive.

Critical windows of exposure for children’s health: cancer in human epidemiological studies and neoplasms in experimental animal models, Environ Health Perspectives, NCBI PubMed PMID: 10852857, 2000 Jun.

Image via alexsarmy.

In animal models, preconceptional carcinogenesis has been demonstrated for a variety of types of radiation and chemicals, with demonstrated sensitivity for all stages from fetal gonocytes to postmeiotic germ cells. Transplacental and neonatal carcinogenesis show marked ontogenetic stage specificity in some cases. Mechanistic factors include the number of cells at risk, the rate of cell division, the development of differentiated characteristics including the ability to activate and detoxify carcinogens, the presence of stem cells, and possibly others. Usefulness for human risk estimation would be strengthened by the study of these factors in more than one species, and by a focus on specific human risk issues.

DIETHYLSTILBESTROL EXPOSURE

Unlike the situation for preconceptional exposures, there is good evidence that exposure of the human fetus to certain potentially harmful agents can increase the risk of cancer during childhood and possibly during early adulthood. Nonetheless, although numerous potentially harmful agents are suspected including infections, drugs, and maternal lifestyle characteristics the only two generally accepted carcinogenic in utero exposures are ionizing radiation and DES: the former acting directly on the fetus and the latter acting via the placenta.

The strong associations for DES have led researchers to postulate in utero effects for other endogenous and exogenous hormones, particularly for cancers with a suspected hormonal component to their etiology such as breast and testicular cancers. Further, since the birth of the first test-tube baby in 1978 there has been concern about the health of offspring resulting from assisted reproductive technology (ART). Multiple pregnancies often result from ART, which is one of the main determinants of the health of the child at birth. The importance of follow-up studies of these children to assess adverse health outcomes diagnosed after birth, even in adulthood, has been recognized, but few comprehensive and powerful epidemiological studies have been done. Two case reports have highlighted possible increases in cancer incidence in children born as a result of in vitro fertilization, raising concerns about the role of prenatal exposure (before and after conception) to high levels of estrogen and related compounds used for ovarian stimulation. To date, there are limited epidemiological data on this topic; a study of U.K. births after ART failed to find an excess incidence of childhood cancer, but, as noted by the authors, the study was too small to be able to detect a reasonable excess, even if it existed.

With respect to mechanisms and the timing of exposure, it is thought that the carcinogenic effects of both ionizing radiation and DES may be mediated via teratogenesis. This has been documented for DES, which causes various genital tract abnormalities in males as well as in females. In addition, it has been suggested that the exposure of pregnant women to substances that inhibit the function of the topoisomerase II enzymes could be related to the development of acute leukemia in their offspring.

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Diethylstilbestrol Exposure and Leukemia, Brain Tumors, Wilms’ tumor

Childhood cancer: overview of incidence trends and environmental carcinogens

Abstract

An estimated 8000 children 0 to 14 years of age are diagnosed annually with cancer in the United States. Leukemia and brain tumors are the most common childhood malignancies, accounting for 30 and 20% of newly diagnosed cases, respectively.

From 1975 to 1978 to 1987 to 1990, cancer among white children increased slightly from 12.8 to 14.1/100,000. Increases are suggested for leukemia, gliomas, and, to a much lesser extent, Wilms’ tumor.

There are a few well-established environmental causes of childhood cancer such as radiation, chemotherapeutic agents, and diethylstilbestrol.

Childhood cancer: overview of incidence trends and environmental carcinogens, Environ Health Perspectives, NCBI PubMed PMID: 8549470, 1995 Sep.

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Many other agents such as electromagnetic fields, pesticides, and some parental occupational exposures are suspected of playing roles, but the evidence is not conclusive at this time.

Some childhood exposures such as secondhand cigarette smoke may contribute to cancers that develop many years after childhood.

For some exposures such as radiation and pesticides data suggest that children may be more susceptible to the carcinogenic effects than similarly exposed adults.

Diethylstilbestrol exposure and Medications

Transplacental carcinogenesis was established by the discovery in 1971 of vaginal adenocarcinoma in the daughters of women who took the hormone diethylstilbestrol (DES) during pregnancy to avoid miscarriages. This very rare cancer has been detected in girls as young as 7 years old, with most affected between 15 and 22 years of age. There are concerns that at older ages the exposed daughters may also have increased risk of squamous carcinomas of the vagina and cervix and cancers of the breast and that exposed sons may have excess testicular and prostate cancer . Continued followup of the DES-exposed daughters and sons is ongoing at the National Cancer Institute and may provide further information on the late effects of DES and on transplacental carcinogenesis in general.

Suspected, but less well-established, of being a transplacental carcinogen is phenytoin, an antiepileptic drug. There are reports of neuroblastoma and soft tissue sarcoma in children exposed in utero to phenytoin.

There have also been reports of excess brain tumors, neuroblastomas, leukemia, and retinoblastomas in children of women who used antinausea medications (e.g., Bendectin) during pregnancy. This issue had received considerable publicity, however, which may have affected recall of use by study subjects. One study used medical records, not subject recall, to assess exposure and did not show any associations.

There is one report of excess Wilms’ tumor among Swedish children whose mothers were exposed to penthrane (methoxyflurane) anesthesia during delivery. The excess risk was higher in females and increased with age at diagnosis.

Some medical treatments received during childhood also play a role in the development of childhood cancer. Chemotherapy and radiation therapy received for an initial childhood cancer can dramatically increase the risk for second cancers. For example, in one study children treated with alkylating agents for cancer have a 5-fold risk of subsequently developing leukemia. At high doses, the risk was increased as much as 25 times the expected rate of leukemia. Bone sarcomas were also elevated in children treated with radiation and chemotherapy.

The potent antibiotic chloramphenicol, given to treat life-threatening infectious conditions, has been linked to excess acute lymphocytic leukemia and acute nonlymphocytic leukemia in children in Shanghai. This association with leukemia is consistent with a report of bone marrow depression following use of chloramphenicol.

Parental use of illegal drugs has been linked to childhood cancer in a few reports. Marijuana use was associated with rhabdomyosarcoma, leukemia, and brain tumors. Cocaine use was also associated with rhabdomyosarcoma.

These exposures are difficult to study accurately and need further research, but prevention efforts clearly must continue for noncancer-related reasons even in the absence of convincing data on childhood cancer.

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