Petites-filles DES : malformations utérines, fertilité, reproduction

Professeur Michel Tournaire, Réseau DES France, Forum d’Infertilité 2017

Vidéos en français: Distilbène DES : 60 vidéos à visionner sur YouTube.

Le troisième génération de victimes du médicament Distilbène® arrive aujourd’hui en âge de procréer.

Qu’en est-il au niveau de leur fertilité et risques supplémentaires en cas de grossesse ?

Le Professeur Michel Tournaire, membre du Conseil Scientifique de Réseau DES France, présente de nouveaux résultats de l’étude Distilbène 3 générations :

  • petites filles DES : malformations utérines.
  • petites filles DES : fertilité et reproduction.

Enregistrement provenant de la 4ème Journée Nationale de l’Infertilité, un forum d’information et d’aide aux personnes infertiles organisé cet automne 2017, Paris 12.

Le Distilbène DES, en savoir plus

Mécanismes épigénétique des perturbateurs endocriniens

Dr Anne Wautier, Réseau DES France, Forum d’Infertilité 2017

Vidéos en français: Distilbène DES : 60 vidéos à visionner sur YouTube.

Image credit @magicmaman_com.

Le Dr Anne Wautier, gynécologue médicale, aborde de façon très claire (et avec des exemples aidant à la compréhension) des notions complexes telles que : épigénétique, perturbateurs endocriniens, effets transgénérationnels du distilbene DES.

Enregistrement provenant de la 4ème Journée Nationale de l’Infertilité, un forum d’information et d’aide aux personnes infertiles organisé cet automne 2017, Paris 12.

Le Distilbène DES, en savoir plus

Forum d’Infertilité 2017

Avec les Dr Anne Wautier et Pr Michel Tournaire, Réseau DES France

Vidéos en français: Distilbène DES : 60 vidéos à visionner sur YouTube.

Lors de la 4ème Journée Nationale de l’Infertilité, un forum d’information et d’aide aux personnes infertiles organisé cet automne, deux personnalités de l’association Réseau DES France ont partagé leur expertise.

  • le Dr Anne Wautier (45:40) a abordé des notions telles que effets distilbène, épigénétique, perturbateurs endocriniens, effets transgénérationnels.
  • le Pr Michel Tournaire (51:45) a présenté de nouveaux résultats de l’étude Distilbène 3 générations : fertilité et grossesses des “petites-filles DES“.
Le Distilbène DES, en savoir plus

Perturbateurs Endocriniens : du Poison pour Nos Enfants

Nos enfants sont- ils condamnés ?

RTBF Auvio, Questions à la une, 16.11.2017.

Ecoutez Tifenn, de l’association Réseau DES France, nous parler de la 3ème génération de victimes exposées au médicament distilbène, modèle de perturbateurs endocriniens.

Avec l’avènement de la chimie, les perturbateurs endocriniens ont envahi notre environnement. Ils sont partout : dans le plastique de nos cuisines, au coeur de nos ordinateurs, dans le moteur et la peinture de nos voitures, dans nos assiettes, et même dans l’air que nous respirons. Impossible d’y échapper !

Mais ces substances parasitent notre système hormonal et dérèglent notre organisme. Les scientifiques tirent la sonette d’alarme. Infertilité, obésité, trouble de l’attention, perte de mémoire et même cancer… Les pathologies qu’on attribue aux perturbateurs endocriniens explosent.

Le Distilbène DES, en savoir plus

Trajectoires clinique des enfants distilbène

Vivre la maladie : expériences et identités contemporaines

  • Comment n’a-t-on rien appris du distilbène ?
  • Comment personne n’est-il au courant ?
  • Comment les médecins ne savent-ils rien et ne font-ils rien ?
  • Comment les personnes exposées se retrouvent-elles dans des états divers et variés ; le plus souvent de méconnaissance
    • soit de leur statut ?
    • soit des effets de cet éventuel statut ?

Il y a trois facteurs importants limitant la diffusion des connaissances :

  1. L’absence d’identification des problêmes de santé publique et des populations exposées.
  2. Les limites imposées à la production et à la diffusion des connaissances.
  3. Une généralisation tardive ; le distilbène a longtemps été considéré comme un dossier à part

Vidéo publiée le 3 février 2015 par la chaine Paris Diderot.

Suite à leur enquête – Distilbène : quelles leçons sociologiques – menée de 2010 à 2013, Emmanuelle Fillion (EHESP) et Didier Torny (INRA), sociologues, poursuivent leurs travaux et interviennent dans différents colloques.

Emmanuelle Fillion et Didier Torny

Le Distilbène DES, en savoir plus

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.

More DES DiEthylStilbestrol Resources

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,

Click to download the full paper.

More DES DiEthylStilbestrol Resources

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.

More DES DiEthylStilbestrol Resources

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.

More DES DiEthylStilbestrol Resources