Exposure to Synthetic Estrogens at different Times during the Life and their Side Effects on Health

Synthetic Estrogens exposures induce epigenetic modifications for multiple generations

2013 Study Abstract:

Exposures to Synthetic Estrogens at Different Times During the Life, and Their Effect on Breast Cancer Risk
Synthetic Estrogens exposures induce epigenetic modifications for multiple generations

Women are using estrogens for many purposes, such as to prevent pregnancy or miscarriage, or to treat menopausal symptoms. Estrogens also have been used to treat breast cancer which seems puzzling, since there is convincing evidence to support a link between high lifetime estrogen exposure and increased breast cancer risk. In this review, we discuss the findings that maternal exposure to the synthetic estrogen diethylstilbestrol during pregnancy increases breast cancer risk in both exposed mothers and their daughters. In addition, we review data regarding the use of estrogens in oral contraceptives and as postmenopausal hormone therapy and discuss the opposing effects on breast cancer risk based upon timing of exposure. We place particular emphasis on studies investigating how maternal estrogenic exposures during pregnancy increase breast cancer risk among daughters. New data suggest that these exposures induce epigenetic modifications in the mammary gland and germ cells, thereby causing an inheritable increase in breast cancer risk for multiple generations.

2013 Study Conclusion:

Women use estrogens for many purposes. During pregnancy, synthetic strogen DES was used to prevent miscarriage and promote healthy pregnancy, although it turned out to cause the opposite. During the reproductive years when a woman’s own estrogen levels are high, women use synthetic estrogens as contraceptives. Since estrogens play an important role in normal physiological functions in women, some menopausal and postmenopausal women use estrogen supplementation to regain the benefits of natural estrogens.

The effects of estrogens on breast cancer risk differ depending upon when during a woman’s life time they are used. Maternal exposure to DES during pregnancy increases breast cancer risk in mothers and their daughters. The adverse effects of synthetic estrogen exposure during pregnancy may not be limited to mothers and their daughters. Our preclinical study in rodents showed that maternal exposure to EE2 increases breast cancer risk in daughters, granddaughters, and great granddaughters. The first generation of OCs increased breast cancer risk at the time women were taking them, but the increase in risk was not permanent. The current, third generation contraceptives do not increase breast cancer risk. Menopausal and postmenopausal HT, if it contains both estrogens and progestin, increases a woman’s breast cancer risk, and recent data suggest that tumors developing during therapy are more aggressive than those in women not using HT. Estrogen-only HT does not increase breast cancer risk, and might even reduce it. However, due to other adverse effects of estrogen-only HT, it is not recommended beyond using it to control the most severe menopausal symptoms.

We are beginning to understand how the increase in breast cancer risk following in utero exposures to synthetic estrogens occurs. It most likely involves long-term epigenetic changes in genes that are important in determining the risk for breast cancer development, such as tumor suppressor genes, PcTGs and oncogenes. Briefly, an exposure to synthetic estrogens during the fetal period induces modifications in the epigenetic reprogramming of the genome, leading to changes in mammary gland morphology, and gene and protein expression. Some of these changes are transient, such as an increase in the number of TEBs in rodents, and some persist, such as an altered gene and protein expression involving tumor suppressor genes and oncogenes. Together, epigenetically induced modifications in the mammary gland morphology and gene expression increase the likelihood that environmental carcinogens and radiation induce malignant transformation, and evetually breast cancer. The next challenge is to determine whether the increase in risk can be reversed by reversing epigenetic changes that occur as a consequence of early life exposure to synthetic estrogens.

Additional Information : Exposures to Synthetic Estrogens at Different Times During the Life, and Their Effect on Breast Cancer Risk, Springer, Journal of Mammary Gland Biology and Neoplasia, Volume 18, Issue 1, March 2013, Special Issue: Environmental Risk Factors. Full text on NCBI PMC3635108.

More DES DiEthylStilbestrol Resources

U.S. PSTF advise to use Hormone Replacement Therapy for only short periods of Time

U.S. Panel Warns Hormone Replacement Therapy Is Too Risky

Postmenopausal Hormone Replacement Therapy for Primary Prevention of Chronic Conditions: Recommendations and Rationale
Alexandra Sifferlin is a reporter for TIME Health and Family

In their November 2002 recommendations, the U.S. Preventive Services Task Force confirmed that the risk of HRT outweigh its potential benefits.

The USPSTF recommends against the routine use of estrogen and progestin for the prevention of chronic conditions in postmenopausal women ; advising women to use HRT to treat symptoms of menopause for only short periods of time.

Read U.S. Panel Warns Hormone Replacement Therapy Is Too Risky
by Alexandra Sifferlin, 23 Oct 2012

Read Panel Advises Against Hormones to Prevent Disease
by Brenda Goodman, WebMD Health News, 22 Oct 2012.

Sources: Postmenopausal Hormone Replacement Therapy for Primary Prevention of Chronic Conditions: Recommendations and Rationale
U.S. Preventive Services Task Force, 19 Nov 2002.

All our posts about EstrogenHRTMenopause.

Promotional Tone in Reviews of HRT after the Women’s Health Initiative

Does author relationships with industry affect articles published on hormone therapy?

Promotional Tone in Reviews of Menopausal Hormone Therapy After the Women's Health Initiative: An Analysis of Published Articles
Some articles promoting HRT have authors with conflicts of interest

Background:
Even after the Women’s Health Initiative (WHI) found that the risks of menopausal hormone therapy (hormone therapy) outweighed benefit for asymptomatic women, about half of gynecologists in the United States continued to believe that hormones benefited women’s health. The pharmaceutical industry has supported publication of articles in medical journals for marketing purposes. It is unknown whether author relationships with industry affect promotional tone in articles on hormone therapy. The goal of this study was to determine whether promotional tone could be identified in narrative review articles regarding menopausal hormone therapy and whether articles identified as promotional were more likely to have been authored by those with conflicts of interest with manufacturers of menopausal hormone therapy.

Methods and Findings:
We analyzed tone in opinion pieces on hormone therapy published in the four years after the estrogen-progestin arm of the WHI was stopped. First, we identified the ten authors with four or more MEDLINE-indexed reviews, editorials, comments, or letters on hormone replacement therapy or menopausal hormone therapy published between July 2002 and June 2006. Next, we conducted an additional search using the names of these authors to identify other relevant articles. Finally, after author names and affiliations were removed, 50 articles were evaluated by three readers for scientific accuracy and for tone. Scientific accuracy was assessed based on whether or not the findings of the WHI were accurately reported using two criteria: (1) Acknowledgment or lack of denial of the risk of breast cancer diagnosis associated with hormone therapy, and (2) acknowledgment that hormone therapy did not benefit cardiovascular disease endpoints. Determination of promotional tone was based on the assessment by each reader of whether the article appeared to promote hormone therapy. Analysis of inter-rater consistency found moderate agreement for scientific accuracy (κ = 0.57) and substantial agreement for promotional tone (κ = 0.65). After discussion, readers found 86% of the articles to be scientifically accurate and 64% to be promotional in tone. Themes that were common in articles considered promotional included attacks on the methodology of the WHI, arguments that clinical trial results should not guide treatment for individuals, and arguments that observational studies are as good as or better than randomized clinical trials for guiding clinical decisions. The promotional articles we identified also implied that the risks associated with hormone therapy have been exaggerated and that the benefits of hormone therapy have been or will be proven. Of the ten authors studied, eight were found to have declared payment for speaking or consulting on behalf of menopausal hormone manufacturers or for research support (seven of these eight were speakers or consultants). Thirty of 32 articles (90%) evaluated as promoting hormone therapy were authored by those with potential financial conflicts of interest, compared to 11 of 18 articles (61%) by those without such conflicts (p = 0.0025). Articles promoting the use of menopausal hormone therapy were 2.41 times (95% confidence interval 1.49–4.93) as likely to have been authored by authors with conflicts of interest as by authors without conflicts of interest. In articles from three authors with conflicts of interest some of the same text was repeated word-for-word in different articles.

Conclusion:
There may be a connection between receiving industry funding for speaking, consulting, or research and the publication of promotional opinion pieces on menopausal hormone therapy.

Read Promotional Tone in Reviews of Menopausal Hormone Therapy After the Women’s Health Initiative: An Analysis of Published Articles
PLoS Med. March 2011 – full PDF

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Hot Flash Havoc Trailer

Entertaining, at times Laugh-out-loud funny take on Menopause

Watch the trailer of Hot Flash Havoc, a film of “Menopausal Proportions”…

Hormone Therapy may pose higher Breast Cancer Risk in some Women

The increase in risk varies depending on a woman’s race, body mass index and breast density

Hormone Therapy May Pose Higher Cancer Risk in Some Women
Hormone Therapy may pose higher Breast Cancer Risk in some Women

Taking hormones to treat the symptoms of menopause is thought to increase women’s risk of breast cancer, but this risk doesn’t rise equally in all women, a new study finds.

The researchers looked at nearly 1.65 million postmenopausal women ages 45 and older, and found that leaner women, as well as women with denser breasts, were more likely to see the detrimental effects of hormone replacement therapy (HRT) on their breast cancer risk.

Read Hormone Therapy May Pose Higher Cancer Risk in Some Women
by Bahar Gholipour, LiveScience, 03 Sept 2013.

Related post: HRT-use associated with an increased Risk of Breast Cancer, Research suggests.

HRT-use associated with an increased Risk of Breast Cancer

Estrogen Plus Progestin and Breast Cancer Incidence and Mortality in the Women’s Health Initiative Observational Study

WHI: Combo HRT, Breast Cancer Risk LinkedThe use of combined estrogen plus progestin among postmenopausal women was associated with an increased risk of breast cancer, a longer-term analysis of data from the observational Women’s Health Initiative (WHI) suggested.

Read WHI: Combo HRT, Breast Cancer Risk Linked and Estrogen Plus Progestin and Breast Cancer Incidence and Mortality in the Women’s Health Initiative Observational Study.

DES Action USA commented:
Most DES Daughters go cautiously when considering HRT-use to avoid additional hormonal exposures. Another study now bolsters the concern. While not specifically about DES it’s a good reminder for all to use the lowest dose for shortest period of time – if absolutely needed. ”

Abstract

Background
In the Women’s Health Initiative (WHI) randomized trial, estrogen plus progestin increased both breast cancer incidence and mortality. In contrast, most observational studies associate estrogen plus progestin with favorable prognosis breast cancers. To address differences, a cohort of WHI observational study participants with characteristics similar to the WHI clinical trial was studied.

Methods
We identified 41 449 postmenopausal women with no prior hysterectomy and mammogram negative within 2 years who were either not hormone users (n = 25 328) or estrogen and progestin users (n = 16 121). Multivariable-adjusted Cox proportional hazard regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CI). All statistical tests were two-sided.

Results
After a mean of 11.3 (SD = 3.1) years, with 2236 breast cancers, incidence was higher in estrogen plus progestin users than in nonusers (0.60% vs 0.42%, annualized rate, respectively; HR = 1.55, 95% CI = 1.41 to 1.70, P < .001). Women initiating hormone therapy closer to menopause had higher breast cancer risk with linear diminishing influence as time from menopause increased (P < .001). Survival after breast cancer, measured from diagnosis, was similar in combined hormone therapy users and nonusers (HR = 1.03, 95% CI = 0.79 to 1.35). On a population basis, there were somewhat more deaths from breast cancer, measured from cohort entry (HR = 1.32, 95% CI = 0.90 to 1.93, P = .15), and more all-cause deaths after breast cancer (HR = 1.65, 95% CI = 1.29 to 2.12, P < .001) in estrogen plus progestin users than in nonusers.

Conclusions
Consistent with WHI randomized trial findings, estrogen plus progestin use is associated with increased breast cancer incidence. Because prognosis after diagnosis on combined hormone therapy is similar to that of nonusers, increased breast cancer mortality can be expected.

Menopausal Hormone Therapy and Risk of Cholecystectomy

Prospective study based on the French E3N cohort

Menopausal hormone therapy and risk of cholecystectomy: a prospective study based on the French E3N cohortAmong menopausal women taking hormone replacement therapy (HRT), the risk of cholecystectomy was increased among those using oral estrogen therapy, especially oral regimens without a progestagen.

This is the finding of a prospective cohort study that assessed the use of different regimens of HRT among more than 70 000 menopausal women. Complicated gallstone disease should be added to the list of potential adverse events to be considered when balancing the benefits and risks associated with HRT, say the authors.

Read Menopausal hormone therapy and risk of cholecystectomy: a prospective study based on the French E3N cohort, March 18, 2013.

Hormone Replacement Therapy: The Wonder Drug for the ’90s?

The Advantages and the Disadvantages of HRT

HRT The Wonder Drug for the ’90s
Proceed with extra caution if you have been exposed to DES

What are your views about HRT?

Do you think the benefits of Hormone Replacement Therapy during menopause are worth the risks, known and unknown?
Is the treatment safe for DES-exposed women?

Read HRT The Wonder Drug for the ’90s
by Isabelle Trépanier and Marie Cocking, DES Action Canada

All our posts about Estrogen – HRT – Menopause.

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