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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Toxic Bodies: the history of endocrine disrupting chemicals

LIVING ON EARTH with Jeff Young and Nancy Langston

Endocrine disrupting chemicals like bisphenol A have been making news lately, with several states passing regulations limiting or banning their use. The trajectory of BPA is similar to another chemical, commonly known as DES, once prescribed for pregnant and menopausal women. Host Jeff Young talks with Professor Nancy Langston about the history of endocrine disrupting chemicals and how this history can inform future chemical regulation. Her book is called, “Toxic Bodies: Hormone Disruptors and the Legacy of DES.” (published March 19, 2010).

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Sources and more information

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Environmental Estrogens and Obesity, Body Weight following DES Exposure

Environmental Estrogens and Obesity

Control-and-DES-treated-Mice image
Representative photograph of control and DES-treated mouse at ~ 6months of age. Image via NCBI.  Complex events including exposure to environmental chemicals during development may be contributing to the obesity epidemic.

2010 Study Abstract

Many chemicals in the environment, in particular those with estrogenic activity, can disrupt the programming of endocrine signaling pathways that are established during development and result in adverse consequences that may not be apparent until much later in life. Most recently, obesity and diabetes join the growing list of adverse consequences that have been associated with developmental exposure to environmental estrogens during critical stages of differentiation. These diseases are quickly becoming significant public health issues and are fast reaching epidemic proportions worldwide.

In this review, we summarize the literature from experimental animal studies documenting an association of environmental estrogens and the development of obesity, and further describe an animal model of exposure to diethylstilbestrol (DES) that has proven useful in studying mechanisms involved in abnormal programming of various differentiating estrogen- target tissues.  Other examples of environmental estrogens including the phytoestrogen genistein and the environmental contaminant Bisphenol A (BPA) are also discussed. Together, these data suggest new targets (i.e., adipocyte differentiation and molecular mechanisms involved in weight homeostasis) for abnormal programming by estrogenic chemicals, and provide evidence that support the scientific hypothesis termed “the developmental origins of adult disease”.

The proposal of an association of environmental estrogens with obesity and diabetes expands the focus on the diseases from intervention/treatment to include prevention/avoidance of chemical modifiers especially during critical windows of development.

Summary and Conclusions

The data included in this review supports the idea that brief exposure, early in development to environmental chemicals with estrogenic activity, increases body weight gain with age and alters markers predictive of obesity in experimental animals. Epidemiology studies support the findings in experimental animals and show a link between exposure to environmental chemicals (such as PCBs, DDE, and persistent organic pollutants) and the development of obesity. Furthermore, the use of soy-based infant formula containing the estrogenic component genistein has been positively associated with obesity later in life.

Using the DES animal model as an important research tool to study “obesogens”, the mechanisms involved in altered weight homeostasis (direct and /or endocrine feedback loops, i.e., ghrelin, leptin, etc.) by environmental estrogens can be elucidated. In addition, hopefully this animal model may shed light on areas of prevention. Public health risks can no longer be based on the assumption than overweight and obesity are just personal choices involving the quantity and kind of foods we eat combined with inactivity, but rather that complex events including exposure to environmental chemicals during development may be contributing to the obesity epidemic.

Sources
  • Environmental Estrogens and Obesity, Retha R. Newbold, Elizabeth Padilla-Banks, and Wendy N. Jefferson, NCBI PMCID: PMC2682588, 2010 May 25.
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Mediator 150 mg – Combien de morts?

Interview d’Irène Frachon 2010 (Mediator 150 mg, sous-titre censuré)

Rencontre avec Irène Frachon, qui a publié son récit Mediator 150 mg, sous-titre censuré, chez editions-dialogues, où elle raconte comment elle a fait interdire ce médicament à la vente en France. Réalisation : Ronan Loup.

En savoir plus

Long-term risk of cancer in women exposed to Diethylstilbestrol in utero

Cancer risk in DES Daughters, 2010 cohort study

woman-on-a-bench
In this 2010 cohort study, most DES daughters are still relatively young (44 years), Image by Nicholas Erwin.

2010 Study Abstract

OBJECTIVE:
We examined long-term risk of cancer in women exposed to diethylstilbestrol (DES) in utero.

METHODS:
A total of 12,091 DES-exposed women in the Netherlands were followed prospectively from December 1992 till June 2008. Cancer incidence was assessed through linkage with the Dutch pathology database (PALGA) and the Netherlands Cancer Registry and compared with the Dutch female population.

RESULTS:
A total of 348 medically verified cancers occurred; median age at end of follow-up was 44.0 years. No overall increased risk of cancer was found (standardized incidence ratio [SIR] = 1.01; 95% confidence interval [CI] = 0.91, 1.13). The risk of clear cell adenocarcinoma of the vagina and cervix (CCA) was statistically significantly increased (SIR = 24.23; 95% CI = 8.89, 52.74); the elevated risk persisted above 40 years of age. The risk of melanoma diagnosed before age 40 was increased (SIR = 1.59; 95% CI = 1.08, 2.26). No excess risks were found for other sites, including breast cancer.

CONCLUSIONS:
The results of our study are generally reassuring except for CCA, with a risk increase persisting at older ages. The slightly elevated risk of melanoma before age 40 is remarkable, but needs to be confirmed by other studies. We did not confirm the increased risk of breast cancer at older ages, as suggested in the NCI DES Follow-up study. Since most DES daughters in our cohort are still relatively young (44.0 years), longer follow-up is warranted to examine cancer risks at ages when cancer occurs more frequently.

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U.S. Senator Scott Brown and DES activists, 2010

Watch @DES_Journal diaporama and DES Info album on Flickr.

Senator-Brown-and-DES-activists image
WONDER DRUG screenwriter Caitlin McCarthy; US Senator Scott Brown; and Andrea Goldstein (former President of DES Action USA) at the Senator’s 2010 Christmas Party, taken by event photographer Katie Kaizer at the Senator’s Christmas Party at the Boston Park Plaza Hotel.

On February 22, 2011, US Senator John Kerry and US Senator Scott Brown received a 3-page response from the FDA, per their joint letter about a DES apology. The FDA’s letter did not contain an official apology from the federal government for the DES drug disaster. However, it acknowledged the devastating health consequences of DES, explained FDA initiatives to prevent future drug disasters, and talked about DES as a “tragedy“.

The FDA closed the letter by writing, “We hope that our new tools for identifying, monitoring and mitigating drug risks will prevent other tragedies like those brought out by the widespread use of DES. We are committed to providing the public with timely and accurate drug safety information and we recognize the critical responsibility that the FDA has to protect the safety of the public’s health“.

More information

  • Image source: DES (Diethylstilbestrol) Info DES News on Facebook, 26 July 2012.
  • FDA Response on DES Letter, WONDER DRUG Facebook album, 22 February 2011.
  • The DES (Diethylstilbestrol) Drug Disaster, 40 Years Later: The Tragedy Is Far From Over, desinfo411, April 22, 2011.
  • FDA Acknowledges, But Doesn’t Apologize For, DES Drug Disaster, desinfo411, April 19, 2011.
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Physiological effects and mechanisms of action of endocrine disrupting chemicals that alter estrogen signaling

Four distinct EDCs that alter estrogen signaling

violet-salve image
Lavender oil and tea tree oil are essential oils frequently used in over-the-counter health and beauty products, including topically applied lotions, gels, and creams, to impart pleasant aromas and for a variety of purported health benefits. Consequently, topical exposure to essential oils is widespread; however, little is known regarding the acute and long-term effects of such exposure in humans. Clinical evidence suggests that lavender oil and tea tree oil may possess endocrine disrupting activity. Image by Jacqueline Boissonneau.

2010 Study Introduction

A large number of natural and synthetic chemicals have been identified that are reported to disrupt the normal functioning of the endocrine system and produce untoward effects in hormone-responsive target tissues and organs in both humans and animals. These chemicals are broadly referred to as endocrine disrupting chemicals (EDCs) and consist of numerous physically and chemically distinct compounds. The physicochemical differences among EDCs are paralleled by unique biological effects and mechanisms of action within this class of compounds.

The purpose of this review is to provide an overview of the physiological effects and unique mechanisms of action of four distinct EDCs that alter estrogen signaling.

  • Two of these compounds, diethylstilbestrol (DES), and genistein (GEN), have been extensively studied and serve as classic examples of EDCs,
  • while the other two compounds, methoxyacetic acid (MAA) and the essential oils of lavender and tea tree, have only recently been described as EDCs.

2010 Study Conclusions

In this review we have provided examples of the activity and actions of several different EDC type compounds of varying chemical structure, properties, and sources. Findings from in vitro cell based assays and/or experimental animal studies have provided evidence of their hormonal biological actions involving receptor mediated activities as a mechanism for their toxicities. Additionally, an example is given of a unique EDC clinical observation regarding the properties of some essential oils. As expected, further observations of other types of toxicities and development of additional experimental models and systems will be required for the evaluation of the mechanisms involved. Finally, the impact that these exposures may have on the human population will require appreciation of potential chemical effects from certain exposure as well as broader epidemiological assessments in support of the experimental findings.

Sources and Full Study
  • Physiological effects and mechanisms of action of endocrine disrupting chemicals that alter estrogen signaling, HORMONES 2010, 9(3):191-205, 691, 2010, PDF.
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Diethylstilbestrol Exposure in Utero and Depression in Women

Understanding the relation between in utero DES exposure and depression will provide insight to the potential adverse effects of BPA

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The 2010 study found that women who were exposed to DES in utero had a higher risk of depressive symptoms and use of antidepressants, and that this increase in risk extended into their middle age. Image via Hartwig HKD.

2010 Study Abstract

Diethylstilbestrol (DES) is an estrogenic endocrine disruptor with long-term health effects, possibly including depression, following exposure in utero. Understanding the relation between in utero DES exposure and depression will provide insight to the potential adverse effects of bisphenol A , a functionally similar and ubiquitous endocrine disruptor. The association between in utero DES exposure and depression was assessed among participants in the Nurses’ Health Study II who first reported their history of antidepressant use in 1993 and lifetime history of depressive symptoms in 2001. DES exposure was reported by 1,612 (2.2%) women. A history of depression at baseline was higher among women exposed to DES in utero compared with those not exposed (age-adjusted odds ratio (OR) = 1.47, 95% confidence interval (CI): 1.26, 1.72) (P < 0.001). Incident depression (first use of antidepressants among women who also reported depressive symptoms) during follow-up (1995–2005) was reported by 19.7% of women exposed to DES and 15.9% unexposed (age-adjusted OR = 1.41, 95% CI: 1.22, 1.63) (P < 0.001). Adjustment for risk factors of depression and correlates of DES exposure moderately attenuated the association (multivariable-adjusted OR = 1.30, 95% CI: 1.13, 1.51) (P = 0.0004). These results suggest that the neurophysiologic effects of in utero exposure to DES could lead to an increased risk of depression in adult life. Further research should assess whether in utero exposure to bisphenol A has similar adverse effects..

Conclusion

In summary, we found that women who were exposed to DES in utero had a higher risk of depressive symptoms and use of antidepressants, and that this increase in risk extended into their middle age. Although the possibility that some women became depressed because of awareness of their exposure status cannot be ruled out, these results are consistent with the hypothesis that the physiologic effects of in utero exposure to DES lead to higher rates of depression during adult life. It remains to be established whether prenatal exposures to ubiquitous environmental chemicals that are structurally similar to DES and have similar estrogenic effects also increase the risk of depression.

Sources and Full Study
  • Diethylstilbestrol Exposure in Utero and Depression in Women, Am. J. Epidemiol. (2010) 171 (8): 876-882. doi: 10.1093/aje/kwq023, March 23, 2010.
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Autoimmune Disease Incidence among Women prenatally exposed to Diethylstilbestrol

This 2010 study provides little support for an association between prenatal DES exposure and development of autoimmune disease

DES Follow-up Study Summary

National Cancer Inst logo image
This 2010 study provides little support for an association between prenatal DES exposure and development of autoimmune disease.

Data shows no difference between rates of autoimmune diseases among the DES exposed and unexposed women.

Autoimmune disease is a class of diseases where antibodies usually meant to recognize foreign organisms instead react to a person’s own cells and tissues. We studied four specific types of autoimmune disease to investigate whether prenatal Diethylstilbestrol (DES) exposure affects the occurrence of these diseases. Systemic Lupus Erythematosus, or lupus, is an inflammatory disease resulting from an antibody attack on tissues and organs resulting in skin rashes, arthritis (chronic joint swelling), renal failure, or nervous system disorders. Rheumatoid arthritis (RA), not to be confused with commonly occurring osteoarthritis, is a disorder resulting from an immune response to an individual’s own connective tissue. The disease results in joint swelling and stiffness. Optic neuritis (ON) is a swelling of the optic nerve due to immune response resulting in vision loss in one eye, painful eye movement, and loss of color vision. Idiopathic Thrombocytopenia Purpura (ITP) is an unexplained decrease in the amount of platelets, cells designed to aid in blood clotting.

The rates of these diseases were compared among women who were and were not prenatally exposed to DES. Women who reported a diagnosis of any of these four diseases on the questionnaires sent in 1994, 1998, or 2001 were asked for permission to contact their doctors to verify the diagnosis. Considering all verified reports, there was no difference between the combined rates of these autoimmune diseases among the DES-exposed and unexposed women. Individually, there was also no difference in the rates of lupus and ON in these two groups. While there was no overall difference in RA between the two groups, there did appear to be a higher rate of RA among exposed women under the age of 45 compared to unexposed women of the same age. This difference however was based on a small number of cases (17 DES-exposed and 2 unexposed) and as a result there is some uncertainty as to the magnitude of this increase. Also there was no increase in RA among DES-exposed women 45 years and older compared with unexposed women of the same age. There were too few ITP cases to conclude whether or not there was a difference in the rate of this disease in the two groups.

Research has suggested that early life characteristics, such as size at birth and age at menarche, may be associated with health conditions later in life. For example, some studies have suggested that low birth weight babies tend to have a higher risk of cardiovascular disease later in life. Other studies have shown that women who begin having periods at a young age have a slightly higher risk of breast cancer than those who begin menstruation later.

2010 Study Abstract

OBJECTIVE:
Animal studies have suggested that prenatal diethylstilbestrol (DES) exposure may alter immune system development and function including antigen self-recognition. A cohort study was conducted to investigate whether prenatal DES exposure might influence the incidence of at least some specific autoimmune diseases in women.

METHODS:
A group of women who were and were not prenatally exposed to DES have been followed for more than 25 years for numerous health outcomes including autoimmune disease. To verify diagnoses, medical records or physician abstracts were requested for all women who reported a diagnosis of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), optic neuritis (ON), and idiopathic thrombocytopenic purpura (ITP). Incidence rates of these autoimmune diseases were compared between women who were and who were not prenatally DES-exposed.

RESULTS:
Overall, there was no increase in verified autoimmune disease among DES-exposed women relative to those who were not exposed (RR 1.2; 95% CI 0.7, 2.1). There was, however, a positive association between prenatal DES exposure and RA among women younger than 45 years (RR 4.9; 95% CI 1.1, 21.6) and an inverse association among women who were 45 years and older (RR 0.1; 95% CI 0.01, 0.7).

CONCLUSION:
Overall, these data provide little support for an association between prenatal DES exposure and development of autoimmune disease. The implication that such exposure may be related to RA in an unusual age-related manner is based on small numbers of cases and warrants further study.

Sources

  • Autoimmune disease incidence among women prenatally exposed to diethylstilbestrol,NCBI, PMID: 20634240, 2010 Oct;37(10):2167-73. doi: 10.3899/jrheum.091092. Epub 2010 Jul 15. Full text link.
  • NCI, DES Follow-up Study Published Papers.
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The Phenomenon of Overdiagnosis in Cancer

Overdiagnosis triggers overtreatment, and all of our treatments carry some harm

Abstract
JNCI
This article summarizes the phenomenon of cancer overdiagnosis—the diagnosis of a “cancer” that would otherwise not go on to cause symptoms or death. Archives JNCI 2010.

This article summarizes the phenomenon of cancer overdiagnosis—the diagnosis of a “cancer” that would otherwise not go on to cause symptoms or death. We describe the two prerequisites for cancer overdiagnosis to occur: the existence of a silent disease reservoir and activities leading to its detection (particularly cancer screening). We estimated the magnitude of overdiagnosis from randomized trials: about 25% of mammographically detected breast cancers, 50% of chest x-ray and/or sputum-detected lung cancers, and 60% of prostate-specific antigen–detected prostate cancers. We also review data from observational studies and population-based cancer statistics suggesting overdiagnosis in computed tomography–detected lung cancer, neuroblastoma, thyroid cancer, melanoma, and kidney cancer. To address the problem, patients must be adequately informed of the nature and the magnitude of the trade-off involved with early cancer detection. Equally important, researchers need to work to develop better estimates of the magnitude of overdiagnosis and develop clinical strategies to help minimize it.

Early detection has forced clinicians and researchers to contemplate a more expansive and, to many, counterintuitive definition of the word “cancer.” What most of us were taught in medical school is captured by the terse definition contained in the medical dictionary—“a neoplastic disease the natural course of which is fatal”. It was a simple definition that was largely accurate in an era when patients were diagnosed with cancer because they had signs and symptoms of the disease.

But that all changed after we became technologically able to advance the time of diagnosis and detect cancer early—before it produces signs and symptoms. Now it has become evident that the word “cancer” encompasses cellular abnormalities with widely variable natural courses: Some grow extremely rapidly, others do so more slowly, others stop growing completely, and some even regress. Clinicians are left with the realization that the word “cancer” is less a prediction about disease dynamics and more a pathological description made at a single point in time. Continued adherence to the dictionary definition of cancer, however, can lead to harm—including overuse of anticancer therapies.

Although not yet contained in medical dictionaries, recently, a new word has appeared in the medical literature to describe a side effect of our technological progress: “overdiagnosis.” This article is intended to summarize the phenomenon.

Read Overdiagnosis in Cancer, Oxford JournalsMedicine & Health JNCI,
J Natl Cancer Inst Volume 102, Issue 9Pp. 605-613, March 5, 2010.
Full PDF.