Endocrine disrupting chemicals and uterine fibroids

Endocrine disruptors and reproductive disorders

Abstract

Uterine fibroids are the most frequent gynecologic tumor, affecting 70% to 80% of women over their lifetime.

Although these tumors are benign, they can cause significant morbidity and may require invasive treatments such as myomectomy and hysterectomy.

Many risk factors for these tumors have been identified, including environmental exposures to endocrine-disrupting chemicals (EDCs) such as genistein and diethylstilbestrol.

Endocrine disrupting chemicals and uterine fibroids, Fertility and Sterility, Volume 106, Issue 4, Pages Pages 967–977, September 15, 2016. Full paper PDF.

“Feeling ill” image Maria Morri.

Uterine development may be a particularly sensitive window to environmental exposures, as some perinatal EDC exposures have been shown to increase tumorigenesis in both rodent models and human epidemiologic studies.

The mechanisms by which EDC exposures may increase tumorigenesis are still being elucidated, but epigenetic reprogramming of the developing uterus is an emerging hypothesis.

Given the remarkably high incidence of uterine fibroids and their significant impact on women’s health, understanding more about how prenatal exposures to EDCs (and other environmental agents) may increase fibroid risk could be key to developing prevention and treatment strategies in the future.

DES DiEthylStilbestrol Resources

Ovary Removal tied to Colon Cancer Risk

Hysterectomy and health risks: if given a choice, keep your ovaries

Ovary Removal Tied to Colon Cancer Risk, NY Times, MAY 4, 2016

Removal of the ovaries — a procedure known as oophorectomy — may increase the risk for colorectal cancer, a new study concludes.

Abstract

Population‐based analysis of colorectal cancer risk after oophorectomy, bjs, Apr 26, 2016.

Background
The development of colorectal cancer is influenced by hormonal factors. Oophorectomy alters endogenous levels of sex hormones, but the effect on colorectal cancer risk is unclear. The aim of this cohort study was to examine colorectal cancer risk after oophorectomy for benign indications.

Methods
Women who had undergone oophorectomy between 1965 and 2011 were identified from the Swedish Patient Registry. Standard incidence ratios (SIRs) and 95 per cent confidence intervals for colorectal cancer risk were calculated compared with those in the general population. Stratification was carried out for unilateral and bilateral oophorectomy, and hysterectomy without specification of whether the ovaries were removed or not. Associations between the three oophorectomy options and colorectal cancer risk in different locations were assessed by means of hazard ratios (HRs) and 95 per cent confidence intervals calculated by Cox proportional hazards regression modelling.

Results
Of 195 973 women who had undergone oophorectomy, 3150 (1·6 per cent) were diagnosed with colorectal cancer at a later date (median follow‐up 18 years). Colorectal cancer risk was increased after oophorectomy compared with that in the general population (SIR 1·30, 95 per cent c.i. 1·26 to 1·35). The risk was lower for younger age at oophorectomy (15–39 years: SIR 1·10, 0·97 to 1·23; 40–49 years: SIR 1·26, 1·19 to 1·33; P for trend < 0·001). The risk was highest 1–4 years after oophorectomy (SIR 1·66, 1·51 to 1·81; P < 0·001). In the multivariable analysis, women who underwent bilateral oophorectomy had a higher risk of rectal cancer than those who had only unilateral oophorectomy (HR 2·28, 95 per cent c.i. 1·33 to 3·91).

Conclusion
Colorectal cancer risk is increased after oophorectomy for benign indications.

Early Life Adverse Environmental Exposures Increase the Risk of Uterine Fibroid Development

The mechanistic role epigenetic regulation of stem cells plays in mediating risk and tumorigenesis

Abstract

Currently, there is a remarkable lack of knowledge regarding the involvement of chromatin assembly in the process by which adverse environmental exposures increase the overall risk of UF development. The precise mechanism underlying EDC-dependent effects on myometrial cell physiology are not adequately understood.

Uterine Fibroids [UF(s), AKA: leiomyoma] are the most important benign neoplastic threat to women’s health. They are the most common cause of hysterectomy imposing untold personal consequences and 100s of billions of healthcare dollars, worldwide. Currently, there is no long term effective FDA-approved medical treatment available, and surgery is the mainstay.

The etiology of UFs is not fully understood. In this regard, we and others have recently reported that somatic mutations in the gene encoding the transcriptional mediator subunit Med12 are found to occur at a high frequency (∼85%) in UFs. UFs likely originate when a Med12 mutation occurs in a myometrial stem cell converting it into a tumor-forming stem cell leading to a clonal fibroid lesion.

Although the molecular attributes underlying the mechanistic formation of UFs is largely unknown, a growing body of literature implicates unfavorable early life environmental exposures as potentially important contributors. Early life exposure to EDCs during sensitive windows of development can reprogram normal physiological responses and alter disease susceptibility later in life. Neonatal exposure to the EDCs such as diethylstilbestrol (DES) and genistein during reproductive tract development has been shown to increase the incidence, multiplicity and overall size of UFs in the Eker rat model, concomitantly reprogramming estrogen-responsive gene expression. Importantly, EDC exposure represses enhancer of zeste 2 (EZH2) and reduces levels of histone 3 lysine 27 trimethylation (H3K27me3) repressive mark through Estrogen receptor/Phosphatidylinositide 3-kinases/Protein kinase B non-genomic signaling in the developing uterus. Considering the fact that distinct Mediator Complex Subunit 12 (Med12) mutations are detected in different fibroid lesions in the same uterus, the emergence of each Med12 mutation is likely an independent event in an altered myometrial stem cell. It is therefore possible that a chronic reduction in DNA repair capacity eventually causes the emergence of mutations such as Med12 in myometrial stem cells converting them into fibroid tumor-forming stem cells, and thereby leads to the development of UFs.

Early Life Adverse Environmental Exposures Increase the Risk of Uterine Fibroid Development: Role of Epigenetic Regulation, Frontiers in pharmacology, dx.doi.org/10.3389/fphar.2016.00040, 01 March 2016.

Advancing our understanding of the mechanistic role epigenetic regulation of stem cells plays in mediating risk and tumorigenesis will help in pointing the way toward the development of novel therapeutic options.

More DES DiEthylStilbestrol Resources

Atypical vaginal adenosis and cervical ectropion, Association with CCAC in DES-exposed offspring

Atypical vaginal adenosis and atypical cervical ectropion of the tuboendometrial type are precursors of clear cell adenocarcinoma

Cervical-Ectropion-Analysis image
The frequency with which atypical tuboendometrial glands in the vagina and cervix were associated with the carcinomas and the proximity of the former to the latter provide strong evidence that atypical vaginal adenosis and atypical cervical ectropion of the tuboendometrial type are precursors of clear cell adenocarcinoma.

1984 Study Abstract

Knowledge of the evolution of clear cell adenocarcinomas of the vagina and cervix in diethylstilbestrol-exposed progeny has remained elusive despite the known topographical association of these tumors with the tuboendometrial form of vaginal adenosis and cervical ectropion.

Twenty radical hysterectomy or radical hysterectomy and vaginectomy specimens of clear cell adenocarcinoma of the vagina or cervix were serially blocked in toto;

  • tuboendometrial epithelium was found in the vagina in 19 (95%) of the cases, usually in greatest concentration at the margin of the tumor, particularly inferiorly.
  • Foci of atypical tuboendometrial epithelium were identified in 16 (80%) of the cases, almost always immediately adjacent to the tumor.

Twenty-five of a second group of 47 specimens in which only substantial portions of the vagina or cervix adjacent to a clear cell adenocarcinoma were available for examination also had foci of atypical tuboendometrial epithelium.

The frequency with which atypical tuboendometrial glands in the vagina and cervix were associated with the carcinomas and the proximity of the former to the latter provide strong evidence that atypical vaginal adenosis and atypical cervical ectropion of the tuboendometrial type are precursors of clear cell adenocarcinoma.

Sources and more information
  • Atypical vaginal adenosis and cervical ectropion. Association with clear cell adenocarcinoma in diethylstilbestrol-exposed offspring, Cancer. 1984, Sep 1, ;54(5):869-75. Robboy SJ, Young RH, Welch WR, Truslow GY, Prat J, Herbst AL, Scully RE, NCBI PMID: 6537153.
  • Full paper: Cancer Volume 54, Issue 5, Article first published online: 29 JUN 2006, PDF.
More DES DiEthylStilbestrol Resources

Power Morcellation: a hazardous Practice

Cardiothoracic surgeon Hooman Noorchashm waged a national campaign to put an end to the practice of power morcellation

On Oct. 17, 2013, a surgical instrument called a power morcellator tore into the uterus of Amy Reed, an anesthesiologist at Beth Israel Deaconess Medical Center, pulverizing what were believed to be benign fibroids

More information
  • Reed’s “minimally invasivehysterectomy, a routine procedure, was performed at the Brigham and Women’s Hospital, a teaching hospital of Harvard Medical School.  Alas, Reed’s uterus contained an occult sarcoma, which the morcellator proceeded to spread through her abdominal pelvic cavity.  Over ensuing months, as Reed battled to stay alive, her husband, Hooman Noorchashm, a cardiothoracic surgeon and, at the time, a lecturer at Harvard, waged a national campaign to put an end to the practice of power morcellation.
  • Video published on 3 July 2014 by TheCancerLetter.
    Read the full story on The Cancer Letter, Jul 3, 2014.
Dr. Noorchashm campaign against hysterectomy using electric power morcellation
  • Public testimony gets heated at FDA panel meeting on morcellation, OBGYNNews,video, JULY 11, 2014.
  • Health Alert: Many Women Have Died Because Deadly Cancers of the Uterus Are Being Spread by Gynecologists. Stop Morcellation of the Uterus in Minimally Invasive Surgery,
    Change, SIGN the Petition by Hooman Noorchashm.

1 in 5 women undergoing hysterectomy in the U.S. may not need the procedure

Use of other treatments before hysterectomy for benign conditions in a statewide hospital collaborative

woman-who-undergo-hysterecteroctomy image
This study provides evidence that alternatives to hysterectomy are underutilized in women undergoing hysterectomy for abnormal uterine bleeding, uterine fibroids, endometriosis, or pelvic pain.

It is estimated that one in three women in the United States will have had a hysterectomy by the age of 60.

Although the numbers of hysterectomies are decreasing, a University of Michigan-led study of nearly 3,400 women in Michigan who underwent hysterectomy for benign indications reveals that alternatives to hysterectomy are being underused and that treatment guidelines are often not followed.

Post-surgical pathology showed that nearly one in five (18%) of hysterectomies that were done for benign indications were unnecessary, and that nearly two in five (37.8%) of women under 40 had unsupportive pathology.

Sources and more information

  • Use of other treatments before hysterectomy for benign conditions in a statewide hospital collaborative, ajog, doi.org/10.1016/j.ajog.2014.11.031, March 2015.
  • Nearly 1 in 5 women who undergo hysterectomy may not need the procedure, University of Michigan, JANUARY 06, 2015.
  • Almost 1 in 5 hysterectomies are ‘unnecessary,’ study finds, medicalnewstoday, 11 January 2015.
  • Nearly One in Five Women Who Undergo Hysterectomy May Not Need the Procedure, elsevier, January 6, 2015.

Cervical Cancer – Michelle Whitlock’s Journey

Michelle Whitlock amazing journey included the need for a radical hysterectomy, the birth of a daughter by a surrogate, and the writing of a book chronicling her experiences with cervical cancer

As a young woman, Michelle L. Whitlock was diagnosed with cervical cancer.
Her amazing journey included the need for a radical hysterectomy, the birth of a daughter by a surrogate, and the writing of a book chronicling her experiences with this deadly cancer.

Michelle Whitlock’s book reviews
More information

Rates of Cervical Cancer in the U.S. underestimated

A May 2014 study says the cervical cancer rates in black women and women in their 60s are understated because they include those who have had hysterectomies

Rates of cervical cancer are higher than previously reported, according to a May 2014 study, specifically among older women and black women.

Abstract:

TIMEHealth logo
A May 2014 study says the cervical cancer rates in black women and women in their 60s are understated because they include those who have had hysterectomies.

BACKGROUND:
Invasive cervical cancer is thought to decline in women over 65 years old, the age at which cessation of routine cervical cancer screening is recommended. However, national cervical cancer incidence rates do not account for the high prevalence of hysterectomy in the United States.

METHODS:
Using estimates of hysterectomy prevalence from the Behavioral Risk Factor Surveillance System (BRFSS), hysterectomy-corrected age-standardized and age-specific incidence rates of cervical cancer were calculated from the Surveillance, Epidemiology, and End Results (SEER) 18 registry in the United States from 2000 to 2009. Trends in corrected cervical cancer incidence across age were analyzed using Joinpoint regression.

RESULTS:
Unlike the relative decline in uncorrected rates, corrected rates continue to increase after age 35-39 (APC(CORRECTED) = 10.43) but at a slower rate than in 20-34 years (APC(CORRECTED) = 161.29). The highest corrected incidence was among 65- to 69-year-old women, with a rate of 27.4 cases per 100,000 women as opposed to the highest uncorrected rate of 15.6 cases per 100,000 aged 40 to 44 years. Correction for hysterectomy had the largest impact on older, black women given their high prevalence of hysterectomy.

CONCLUSIONS:
Correction for hysterectomy resulted in higher age-specific cervical cancer incidence rates, a shift in the peak incidence to older women, and an increase in the disparity in cervical cancer incidence between black and white women. Given the high and nondeclining rate of cervical cancer in women over the age of 60 to 65 years, when women are eligible to exit screening, risk and screening guidelines for cervical cancer in older women may need to be reconsidered.

Sources and more information:
  • Rates of Cervical Cancer Are Underestimated, Study Says,
    Time, May 12, 2014.
  • Increased age and race-specific incidence of cervical cancer after correction for hysterectomy prevalence in the United States from 2000 to 2009, NCBI PMID: 24821088, 2014 Jul 1;120(13):2032-8. doi: 10.1002/cncr.28548. Epub 2014 May 12.
    Full study on ReadCube.

Deadly Medicine: Laparoscopic Power Morcellation

A Common Surgery for Women and the Cancer it Leaves Behind

Deadly Medicine ebook cover image
Download this free WSJ ebook.

Since the 1990s, thousands of women have undertaken a surgical procedure that may have risked their lives.

After Dr. Amy Reed had surgery to remove uterine fibroids, involving a procedure known as power morcellation, she learned that it had worsened her prognosis by spreading a cancer she and her doctors didn’t know she had.

Dr. Reed became a vocal critic of power morcellators and the doctors who used them, dividing the medical community. Now doctors and companies are waiting for more-permanent guidance from the FDA.

This story, drawn from ongoing coverage in The Wall Street Journal, is a gripping human-interest account of public trust and the fallibility of modern medicine. ”

Dr. Noorchashm campaign against hysterectomy using electric power morcellation
  • Public testimony gets heated at FDA panel meeting on morcellation, OBGYNNews, video, JULY 11, 2014.
  • Health Alert: Many Women Have Died Because Deadly Cancers of the Uterus Are Being Spread by Gynecologists. Stop Morcellation of the Uterus in Minimally Invasive Surgery,
    Change, SIGN the Petition by Hooman Noorchashm.

Hysterectomy, the second-most Popular Surgery in American Women

An astounding 40% of American women have had a hysterectomy by age 45…

image of MARGARET ARANDA, MD
An astounding 40% of American women have had a hysterectomy by age 45 says Dr. Margaret Aranda

After Cesarean Section, hysterectomy is the second-most popular surgery in American women, providing 600,000 procedures per year, and 20 million procedures to date (Keshavarz, 2012), with 55% having both ovaries removed.

In her post, Dr. Margaret Aranda mentions:

  • Gynecologists and Hysterectomy
  • Did I Consent to this?
  • Hysterectomy Second Opinion
  • In the Operating Room
  • Who will be Performing the Hysterectomy and How?
  • The Morecellator Problem
  • What about the Ovaries?
  • Making the Hysterectomy Decision

Read HYSTERECTOMY IN AMERICA, Hormones Matter, 22 July 2014.