Upper genital tract changes associated with exposure in utero to diethylstilbestrol

American journal of obstetrics and gynecology, 1977

woman-in-the-dark
1977 study : in none of the control subjects were defects noted which could be considered comparable with those seen in the DES-exposed patient.

1977 Study Abstract

Hysterosalpingograms of 60 young women exposed in utero to diethystilbestrol were obtained.

In 46 instances, documentation of this exposure was obtained from the mother’s chart review or confirmed by the attending physician. In 14 instances, the patients’ mothers were sure they had received stilbestrol, but documentation could not be specifically confirmed.

  • In 40 women exposed to stilbestrol, changes in the uterus which differed significantly from those seen in the past in nonexposed individuals were noted. These changes consisted of:
    • a ‘T-shaped appearance of the uterus,
    • ‘ constricting bands in the uterine cavity,
    • a hypoplastic uterus,
    • and less frequently, intrauterine polypoid defects,
    • synechiae,
    • and in one instance a unicornuate uterus.
  • In 36 of the 40 women gross defects were also noted in the cervix.

Hysterosalpingograms of 23 women being investigated for infertility during the same period that the current study was conducted were also reviewed.

  • By comparison, in none of the control subjects were defects noted which could be considered comparable with those seen in the DES-exposed patient.
Sources and more information

Upper genital tract changes associated with exposure in utero to diethylstilbestrol, American journal of obstetrics and gynecology, NCBI PMID: 851159, 1977 May 1.

More DES DiEthylStilbestrol Resources

EU court hearing puts spotlight on Commission delay over hormone disrupting chemicals

HEAL’s Lisette van Vliet attended a crucial court hearing against the EU Commission

This post content was published by HEALa leading alliance of health and environment groups working at EU level for better health, through a healthy environment.

image of European Union Court of Justice in Luxembourg
HEAL’s Lisette van Vliet attended a crucial court hearing against the EU Commission. The EU Court of Justice in Luxembourg heard Sweden’s case against the Commission for failing to fulfil its legal obligations regarding endocrine disrupting chemicals (EDCs)

Reminder: The European Commission failed to adopt scientific criteria by 13 December 2013 for the identification of hormone disrupting chemicals under the Biocides Products Regulation. That law, adopted in 2012, requires biocide substances to be examined for endocrine disrupting properties, and if found, to be taken off the EU market except under certain circumstances. A similar even stricter law exists for pesticides. The European Commission Environment Directorate General had made good progress on draft criteria by spring 2013, but after immense lobbying by the chemical manufacturers and pesticide companies, the European Commission Secretary General decided an impact assessment on the criteria and further regulatory adjustments was necessary and under the new Commission President Juncker, the work on biocides criteria was transferred to the Health Directorate General.

Brussels, Luxembourg 18 November 2015 – A crucial court hearing against the European Commission took place yesterday. The European Union Court of Justice in Luxembourg heard Sweden’s case against the Commission for failing to fulfil its legal obligations regarding hormone disrupting chemicals, also known as endocrine disrupting chemicals (EDCs).

Sweden’s anger erupted after the European Commission missed its legal deadline to put forward criteria to identify EDCs by the end of 2013. The case is supported by the EU Council of governments, which is considered to be the highest political body of the European Union. The European Parliament and three governments are individually backing Sweden. They are Denmark, France and the Netherlands.

Lisette van Vliet, Senior Policy Adviser, Health and Environment Alliance (HEAL), who attended the hearing, says:

When all EU governments and the European Parliament join together to prosecute the European Commission, it is clear that the Commission is getting it wrong. These delays are keeping Europeans exposed to chemicals that contribute to breast and prostate cancer, diabetes and obesity, infertility and learning disorders. We look to the European Court to make the Commission abide by deadlines set in European law to protect the health of Europeans.”

EDCs interfere with the body’s highly sensitive hormone system. Studies point to EDCs causing obesity, diabetes and cancer. Even tiny amounts of EDCs pose particular risks to unborn children and infants. Policies are urgently needed to reduce human exposure. (3) Costs attributable to exposure to a selected sample of endocrine-disrupting chemicals (with only the highest probability of causation) were recently estimated at €157 billion per year in the European Union.

The EU Commission is currently conducting an impact assessment partly prompted by intensive lobbying by the chemicals and pesticide industry. This is expected to delay the setting EU criteria for defining EDCs until 2017 at the earliest.

For Press releases, Media coverage, Notes for journalists and Contacts, visit HEAL’s paper.

Plus ne veut pas nécessairement dire mieux…

Est-ce que plus de tests de dépistage mènent à une meilleure santé?

La campagne Choisir avec soin vise à encourager un dialogue entre le médecin et son patient afin de choisir les examens et les traitements les plus appropriés pour assurer des soins de qualité..

En savoir plus

Age at menarche among diethylstilbestrol granddaughters

Age at menarche for DES granddaughters seemed to be unaffected by mother’s prenatal DES exposure

girl-ocean-sskennel-text
In this 1995 study, age at menarche for DES granddaughters seemed to be unaffected by mother’s prenatal diethylstilbestrol exposure. However the 2011 study showed DES-exposed girls were somewhat more likely to have begun menstruating at age 10 or younger.

1995 Study Abstract

American journal of obstetrics and gynecology, NCBI PMID: 7573253, 1995 Sep.

We interviewed 542 women whose mothers were in a randomized trial of diethylstilbestrol. Effects of diethylstilbestrol on the third generation were explored by ascertaining age at menarche for the women’s daughters. A total of 123 daughters were > or = 10 years old (52 exposed and 71 unexposed). Age at menarche was unaffected by mother’s prenatal diethylstilbestrol exposure.

Sources and more information
More DES DiEthylStilbestrol Resources

Hormone-disrupting activity of fracking chemicals worse than initially found

Fracking Chemicals Can Cause Endocrine Disruption and Illness

This post content was published by The Endocrine Society, Hormone Science to Health.

fracking-Operation image
There is mounting data to suggest that hydraulic fracturing (fracking) can have adverse affects on the environment. A new study, however, suggests that populations living close to fracking sites also have a higher incidence of health complications.

Chicago, IL – Many chemicals used in hydraulic fracturing, or fracking, can disrupt not only the human body’s reproductive hormones but also the glucocorticoid and thyroid hormone receptors, which are necessary to maintain good health, a new study finds. The results were presented Monday at the joint meeting of the International Society of Endocrinology and the Endocrine Society: ICE/ENDO 2014 in Chicago.

Among the chemicals that the fracking industry has reported using most often, all 24 that we have tested block the activity of one or more important hormone receptors,” said the study’s presenting author, Christopher Kassotis, a PhD student at the University of Missouri, Columbia. “The high levels of hormone disruption by endocrine-disrupting chemicals (EDCs) that we measured, have been associated with many poor health outcomes, such as infertility, cancer and birth defects.”

Hydraulic fracturing is the process of injecting numerous chemicals and millions of gallons of water deep underground under high pressure to fracture hard rock and release trapped natural gas and oil. Kassotis said spills of wastewater could contaminate surface and ground water.

In earlier research, this group found that water samples collected from sites with documented fracking spills in Garfield County, Colorado, had moderate to high levels of EDC activity that mimicked or blocked the effects of the female hormones (estrogens) and the male hormones (androgens) in human cells. However, water in areas away from these gas-drilling sites showed little EDC activity on these two reproductive hormones.

The new study extended the analysis to learn whether high-use fracking chemicals changed other key hormone receptors besides the estrogen and androgen receptors. (Receptors are proteins in cells that the hormone binds to in order to perform its function.) Specifically, the researchers also looked at the receptor for a female reproductive hormone, progesterone, as well as those for glucocorticoid—a hormone important to the immune system, which also plays a role in reproduction and fertility—and for thyroid hormone. The latter hormone helps control metabolism, normal brain development and other functions needed for good health.

Among 24 common fracking chemicals that Kassotis and his colleagues repeatedly tested for EDC activity in human cells, 20 blocked the estrogen receptor, preventing estrogen from binding to the receptor and being able to have its natural biological response, he reported. In addition, 17 chemicals inhibited the androgen receptor, 10 hindered the progesterone receptor, 10 blocked the glucocorticoid receptor and 7 inhibited the thyroid hormone receptor.

Kassotis cautioned that they have not measured these chemicals in local water samples, and it is likely that the high chemical concentrations tested would not show up in drinking water near drilling. However, he said mixtures of these chemicals act together to make their hormone-disrupting effects worse than any one chemical alone, and tested drinking water normally contains mixtures of EDCs.

We don’t know what the adverse health consequences might be in humans and animals exposed to these chemicals,” Kassotis said, “but infants and children would be most vulnerable because they are smaller, and infants lack the ability to break down these chemicals.”

His study received funding from the Passport Foundation Science Innovation Fund, the University of Missouri, and from the Environmental Protection Agency, through a STAR predoctoral fellowship awarded to Kassotis.

More information

  • Endocrine-Disrupting Chemicals and Oil and Natural Gas Operations: Potential Environmental Contamination and Recommendations to Assess Complex Environmental Mixtures, ehp, 27 August 2015.
  • Fracking Chemicals Can Cause Endocrine Disruption and Illness, Says Study, triplepundit, Sep 21st, 2015.

Femmes, gynécologues, et maltraitance gynécologique

La maltraitance gynécologique, variante du viol

Lors d’une consultation, d’un accouchement, d’une IVG… le corps de la femme ne lui appartient plus. Quand elle survient la maltraitance médicale est une réalité que les femmes taisent, car elle reste perçue comme inhérente à la condition féminine.

Tout au long de leur vie, les femmes livrent leur corps à des gynécologues pas toujours respectueux et parfois méprisants. En gynécologie et obstétrique la maltraitance médicale est une réalité que les femmes taisent, car elle reste perçue comme inhérente à la condition féminine. Mais depuis quelques temps sur internet et dans la presse les femmes se sont mises à parler.

Quelques mois après la révélation sur les réseaux sociaux de la pratique des touchers vaginaux réalisés à l’insu de patientes endormies au bloc opératoire, France Culture diffuse un documentaire réalisé par Mélanie Déchalotte et François Teste sur la maltraitance gynécologique.

En savoir plus

  • Collection Témoignages : Maltraitance gynécologique, franceculture, 28.09.2015.
  • Pour en finir avec la maltraitance gynécologique, metronews, 29 septembre 2015.
  • La maltraitance gynécologique, variante du viol, c-pour-dire, 28 sep­tembre 2015.

Diethylstilbestrol effects on the female reproductive system

Epigenetic effects of endocrine-disrupting chemicals on female reproduction : an ovarian perspective

image of Depressed-and-lonely
The link between in utero and neonatal exposure to environmental toxicants, such as endocrine-disrupting chemicals (EDCs) and adult female reproductive disorders is well established in both epidemiological and animal studies. Recent studies examining the epigenetic mechanisms involved in mediating the effects of EDCs on female reproduction are gathering momentum. In this review, we describe the developmental processes that are susceptible to EDC exposures in female reproductive system, with a special emphasis on the ovary. We discuss studies with select EDCs that have been shown to have physiological and correlated epigenetic effects in the ovary, neuroendocrine system, and uterus. Importantly, EDCs that can directly target the ovary can alter epigenetic mechanisms in the oocyte, leading to transgenerational epigenetic effects. The potential mechanisms involved in such effects are also discussed. Depressed and lonely.

2010 Study Abstract

DES is a nonsteroidal synthetic estrogen that was prescribed to pregnant women at doses of 5–150 mg/day to prevent miscarriages from 1940s to 1970s. Even though early on DES was shown to be an ineffective drug, it was continued in use till the 1970s. Numerous abnormalities in the reproductive, cardiovascular, and immune systems have since been reported in both male and female offspring of women treated with DES, and validated in animal models. There are limited reports that these effects are being observed in the granddaughters of DES-treated women as well. While DES caused vaginal clear cell adenocarcinoma in only 0.1% of the female offspring, over 95 % reported reproductive tract dysfunction and poor pregnancy outcomes. Since there is evidence of multi-generational effects, epigenetic mechanisms could play an important role and were therefore investigated.

Mice injected with a single dose of 10 μg/kg DES on E15 and examined at 7 months of age had no CL and numerous atretic follicles. They were also found to have vacuolated interstitial tissue with lipid droplet inclusions. Other studies with varying doses of DES (5 μg/kg to 100 μg/kg) administered either in utero (E9-E16), or neonatally (PND1-PND5), demonstrated that adult DES ovaries developed similar hypertrophy and vacuolation of interstitial tissue, hemorrhagic cysts and lack of corpora lutea. These animals also had high levels of testosterone. There was a dose-dependent reduction in the number of the litters as well as the number of oocytes ovulated after stimulation with exogenous gonadotropins. The oocytes derived from such treated ovaries and used in IVF showed lower levels of fertilizability, suggesting reduced oocyte quality. However, 5 µg/day DES-treated ovaries transplanted into untreated ovariectomized host mice were able to give rise to normal female offspring that in turn gave birth to normal size litters and had normal uterine morphology, suggesting that the DES treatment effects were not mediated via germ cells. However, the age at which these animals were sacrificed was 8–12 weeks, and other studies have shown that DES-treated animals do develop epithelial cancers of the uterus by 18 months of age.

DES can bind to both ERs with many fold higher affinity than estradiol. Multiple studies from Iguchi and colleagues showed that in utero (E15–18) and neonatally (PND1-5) DES-treated mice had ovaries containing excessive number of MOFs by adulthood. MOFs were also observed in ovaries that were treated in vitroat PND1-5, following their transplantation to untreated mice, suggesting a direct effect of DES in the ovary. Recent studies showed that neonatal exposure to 3 μg/kg DES induced MOFs, a process mediated by ERβ and not ERα. DES exposure was shown to reduce oocyte apoptosis (potentially suppressing oocyte nest breakdown) via ERβ signaling mechanisms. Furthermore, it was hypothesized that such alterations in the germ cell and somatic cell populations may affect the invasion of pregranulosa cells and basement membrane remodeling during primordial follicle formation. Interestingly, the incidence of MOFs has been reported with other EDC exposures as well.

The effects of DES on the sexual dimorphism of the brain have been documented. In utero and postnatal exposures increased the size of SDN-POA in females thereby defeminizing the region. It was also found that PND1-10 treatment led to a significant reduction in the levels of LH secreted although a similar effect was not found when the exposure was prenatal (E16-20), highlighting the importance of DES actions on the neuroendocrine circuits.

It is well known that DES caused T-shaped uteri and clear cell adenocarcinoma of the uterus, cervix, and vagina in women whose mothers were exposed to DES during pregnancy. There are numerous animal studies validating these human reports. For example, progeny of DES-treated mice have shown malformations of the uterus, squamous metaplasia of the luminar and glandular epithelium, endometrial hyperplasia and leiomyomas, and oviductal proliferative lesions. Ovariectomized animals when supplemented with estradiol are able to respond by a transient increase in gene expression and concomitant uterine proliferation and growth. When such a stimulus is removed, the uterus returns to its unstimulated state. However, when DES or estradiol is administered during neonatal development, expression of immediate early genes such as lactoferrin,EGF, and proto-oncogenes such as c-fos, c-jun, and c-myc is upregulated even into adulthood. Inversely, expression of genes that are necessary for uterine development, such as the Abdominal B (AbdB) Hoxgene, Hoxa-10, (known to be controlled by estradiol and progesterone, Wnt7a as well as Msx2 are repressed leading to structural abnormalities of the reproductive tract. Numerous studies have been conducted to assess the methylation patterns of promoters of several of these estrogen-responsive genes associated with uterine development.

Neonatal DES exposure in mice caused nearly 90% incidence of epithelial cancers of the uterus by 18 months of age. In mice similarly treated with DES, the promoter region of the lactoferrin gene was found to be hypomethylated in the adult uterus. However, if the animals were exposed for the same length of time during adulthood, no such methylation or expression defects were observed. Subsequently, it was also found thatexon 4 of the c-fos gene was extensively hypomethylated while the promoter region and intron 1 was unaffected, thereby potentially allowing for the upregulation of c-fos expression. QPCR studies performed by Sato and colleagues examining the expression of Dnmts in neonatally DES exposed C57BL/6 mice, revealed that expression of Dnmt1 and Dnmt3b was decreased at PND5 in DES-treated mice, and the pattern continued until PND14. Interestingly, it was found that human leiomyoma samples had alterations in the levels of Dnmts as well, with concomitant global hypomethylation.

As mentioned above, DES down-regulates Hoxa gene expression. These effects are akin to those associated with uterine abnormalities found in Hoxa KO mice. The predominant phenotype is the loss of boundary between the oviduct and uterus. It has been shown that the anterior to posterior specific pattern of Hoxa-9 is essential for the normal development and function of the uterus and that DES causes a posterior shift of Hoxa-9 and Hoxa-10expression and homeotic anterior transformations. A recent report by Bromer and colleagues has shown that after in utero (E9-16) exposure to 10 μg/kg DES, there is hyper-methylation in the promoter and intron 1 regions ofHoxa-10 gene, in the caudal part of the uterus with a concomitant increase in the Hoxa-10 expression in the same region. While these data are interesting from the point of epigenetic regulation of the regionalization of the uterus, the authors suggest that the apparently conflicting data i.e., increased methylation vs increased gene expression might be due to differential binding to transcriptional repressors. Since previous studies have shown that no epigenetic changes were detected in the promoters of Hoxa-10 and Hoxa-11 genes, continuation of these studies is warranted.

Alworth and colleagues showed that in utero exposure (E12-18) of CD-1 mice to DES doses of 0.1–100 μg/kg followed by estradiol administration at 7–8 months of age caused opposite responses between low and high doses. The lower dose enhanced the response to exogenous estrogens, resulting in an increase in uterine weight, while the high dose dampened the response resulting in lighter uteri. A global methylation assay was conducted employing DMH, which was suitable to detect hypermethylation events. Over 300 CpG island loci were examined and five candidates were identified in 18S rDNA and 45S pre-rDNA methylation, suggesting a role for ribosomal assembly and protein synthesis in the mediation of DES effects.

Couse and colleagues have shown that ERα is essential for the mediation of DES effects in the uterus: αERKO female mice exhibited a complete resistance to the effects of DES while βERKO mice did not. Additionally, as mentioned earlier, ERα induction is necessary for activation of estrogen responsive gene expression including that of the lactoferrin and c-fos genes. Since these genes are all downstream of ERα signaling, it is imperative to thoroughly examine the potential role of epigenetic mechanisms in the regulation of ERα expression after EDC exposure. Interesting new studies by Bredfeldt and colleagues have now provided a link between ER signaling and regulation of histone modifications. It was found that rapid PI3K/Akt signaling downstream of membrane-associated ER, in response to estradiol as well as DES, caused reduction in trimethylation of H3K27 (see Section 2.1.2). More interestingly, activation of this non-genomic signaling caused reprogramming of the uterine gene expression profile. Whether such altered epigenetic mechanisms are transgenerational would be of great interest to the field.

Sources and more information
  • Epigenetic effects of endocrine-disrupting chemicals on female reproduction: an ovarian perspective, Frontiers in neuroendocrinology, NCBI PMID: 20609371, 2010 Oct.
  • Full study National Institutes of Health, NIHMSID: NIHMS230454 PMCID: PMC3009556, 2010 Jul 4.
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Stop Glyphosate

No more weed killer in our bodies

Stop-Glyphosate
Did you know your food is likely being sprayed with a weed killer that is classified as probably causing cancer by the World Health Organisation? This toxic chemical called glyphosate is found in nearly every second person’s urine. And it was found in breast milk too. It might well already be present in your body.
SIGN THE PETITION NOW to stop it!

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No more weed killer in our bodies. Decline the renewal of glyphosate, a poison commonly used in pesticides like Monsanto’s Roundup. Independent experts of the WHO classified it as a probable cause of cancer. We do not want this poisonous chemical anywhere near our parks, our homes, or our food.

We don’t want our neighbourhoods sprayed with cancer-inducing poison. We don’t want our fruits and vegetables to come from farmers who use glyphosate-based weed-killer.

Our national Governments and the European Commission needs to know we won’t stand by. Please share this action with friends and family.

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Diethylstilbestrol Research – National Cancer Institute

NIH Research on the Health Effects of DES, 2011

DES-Research-2011-NIH-1 cover image
Click image above to download PDF (218 kb).

NIH Research on the Health Effects of Diethylstilbestrol
The Office of Research on Women’s Health, August 2011

The effects of diethylstilbestrol (DES) on the health of men and women and their offspring have long been a research focus at the National Institutes of Health (NIH). This 2011 report is an overview of NIH research related to DES that is primarily conducted or supported by the National Cancer Institute (NCI) and the National Institute of Environmental Health Sciences (NIEHS).

Summaries of DES research funded by NCI and NIEHS for FY2010 are included in this report, which will be posted on the ORWH website.

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Colposcopic evaluation of DES-exposed progeny at two large medical centers: the squamous neoplasia problem

The squamous neoplasia problem, Southern medical journal, 1978

Colposcopy-Unit
Cases of vaginal adenosis in young women should be investigated and screened appropriately, and preferably referred to centres where colposcopic expertise is available.

1978 Study Abstract

Two hundred eight patients with confirmed or suspected diethylstilbestrol exposure were examined colposcopically at two separate medical centers.

  • Cervicovaginal ridges were present in 90 (43.3%)
  • and ectopy was found in 188 (90.4%) of the patients.
  • Evidence of vaginal adenosis was present in 122 (58.6%) of the cases.

Seventy-four percent of the patients had abnormal colposcopic findings:

  • 15.4% having columnar epithelium on the surface of the vagina
  • and 66% having abnormal transformation zones (white epithelium, punctation, mosaic).
  • Twenty patients (9.6%) were initially identified histologically as having squamous dysplasia. Subsequent review of the histologic material in these cases could document only two cases of significant squamous dysplasia, both severe, the remainder having immature, atypical metaplasia or possibly very mild dysplasia.

This finding emphasizes the problems encountered in histologically differentiating squamous neoplasia from the peculiar metaplasia found in these patients, thereby making it difficult to establish whether these patients are at increased risk for the development of squamous neoplasia..

Sources and more information
  • Colposcopic evaluation of DES-exposed progeny at two large medical centers: the squamous neoplasia problem, Southern medical journal, NCBI PMID: 663728, 1978 Jul.
More DES DiEthylStilbestrol Resources