Do Harmful Chemicals in Health and Beauty Products Make Uterine Fibroids Grow ?

Phthalates exposure and uterine fibroid burden among women undergoing surgical treatment for fibroids: a preliminary study

A pilot study published in the journal Fertility and Sterility suggests that exposure to certain harmful chemicals called phthalates may lead to an increased burden of fibroids, uterine tumors that can cause heavy bleeding, pain, infertility, and other serious reproductive problems.

2019 Study Abstract

Objectives
To examine the association between phthalate exposure and two measures of uterine fibroid burden: diameter of largest fibroid and uterine volume.

Design
Pilot, cross-sectional study.

Setting
Academic medical center.

Patient(s)
Fifty-seven premenopausal women undergoing either hysterectomy or myomectomy for fibroids.

Intervention(s)
None.

Main Outcome Measure(s)
The diameter of the largest fibroid and uterine dimensions were abstracted from medical records. Spot urine samples were analyzed for 14 phthalate biomarkers using mass spectrometry. We estimated associations between fibroid outcomes and individual phthalate metabolites, sum of di(2-ethylhexyl) phthalate metabolites (∑DEHP), and a weighted sum of anti-androgenic phthalate metabolites (∑AA Phthalates) using linear regression, adjusting for age, race/ethnicity, and body mass index. Fibroid outcomes were also examined dichotomously (divided at the median) using logistic regression.

Results
Most women were of black ethnicity, overweight or obese, and college educated. In multivariable models, higher levels of mono-hydroxyisobutyl phthalate, monocarboxyoctyl phthalate, monocarboxynonyl phthalate, mono(2-ethylhexyl) phthalate, mono(2-ethyl-5-hydroxyhexyl phthalate) (MEHHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), ∑DEHP, and ∑AA Phthalates were positively associated with uterine volume. Associations were most pronounced for individual DEHP metabolites (MEHHP, MEOHP, MECPP), ∑DEHP, and ∑AA Phthalates. For example, a doubling in ∑DEHP and ∑AA Phthalates was associated with 33.2% (95% confidence interval 6.6–66.5) and 26.8% (95% confidence interval 2.2–57.4) increase in uterine volume, respectively. There were few associations between phthalate biomarkers and fibroid size.

Conclusions
Exposure to some phthalate biomarkers was positively associated with uterine volume, which further supports the hypothesis that phthalate exposures may be associated with fibroid outcomes. Additional studies are needed to confirm these relationships.

The George Washington University press release.

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.

“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

EDCs ability to alter reproductive function and health in females

Endocrine disrupting chemicals and disease susceptibility

The ability of EDCs to alter reproductive function and health in females has been clearly demonstrated by the consequences of DES use in pregnant women. The daughters of women given DES while pregnant were shown to have rare cervicovaginal cancers, decreased fertility and increases in rates of ectopic pregnancy , and early menopause. Many of these disorders have been replicated in laboratory animals treated with DES during gestation. As Newbold points out, the lessons learned from 40 years of DES research in humans and animals are that the female fetus is susceptible to environmentally induced reproductive abnormalities,that gonadal organogenesis is sensitive to synthetic hormones and hormone mimics during critical exposure windows, and that reproductive disease may not appear until decades after exposures.

Endocrine disrupting chemicals and disease susceptibility, Journal of Steroid Biochemistry & Molecular Biology,
doi:10.1016/j.jsbmb.2011.08.007, 6 August 2011.

Proper development of ovarian follicles in the fetus is dependent on estrogen exposure during critical periods of development. For instance, mice treated with DES on postnatal day 1–5 develop multioocytic follicles as adults. Therefore,maintaining a homeostatic balance of local and systemic hormones during follicle development is necessary for normal follicle development and germ cell quality. Perturbations in hormone signaling resulting from chemical exposures during developmental periods could contribute to ovarian disorders and declining conception rates in human populations.And while the mechanisms by which EDCs alter follicle development are not fully understood, there is evidence that these chemicals are contributing to increased rates of aneuploidy, polycyctic ovary syndrome (PCOS), premature ovarian failure (POF), and altered cyclicity and fecundity. For example, studies have shown that prenatal exposure to BPA causes irregular cycles in mice, which is likely due to hypothalamic alterations in the circuitry that controls luteinizing hormone (LH) secretion and ovulation. In humans, altered cyclicity has been reported in individuals exposed to organochlorine pesticides. Indeed, cycle irregularities have been noted in women whose mothers were exposed in utero to DES.

Uterine fibroids (leiomyomas) are the most common tumor of the female reproductive system, occurring in 25–50% of all women. The risk of the development of uterine fibroids increases with age during premenopausal years, but tumors typically regress with the onset of menopause. Obesity, age at menarche and unopposed estrogen signaling have been shown to increase the risks for fibroids. The best characterized animal model for the study of uterine fibroids is the Eker rat. A mutation of the tuberous sclerosis complex 2 (Tsc2) tumor suppressor gene causes females to develop spontaneous uterine fibroids at a high frequency. Studies using this model have shown that exposure to EDCs increases the incidence of fibroids in these animals. Developmental exposure to DES causes rats that are genetically predisposed to uterine tumors to develop even more tumors of a larger size, but fails to induce tumors in wild-type rats. Importantly, DES exposure imparts a hormonal imprint on the developing uterus that causes an increase in estrogen-responsive gene expression. The potential for DES to cause uterine fibroids in humans is less clear. Two studies on DES daughters came to different conclusions. In a study of 2570 women born during the period DES was prescribed, no association was found between prenatal exposure and uterine fibroids. Another study of 1188 women found a significant relationship between DES exposure and uterine fibroids. On analysis of these studies, Baird and Newbold concluded that there was a definitive increase in uterine fibroids in DES daughters and the discrepancies between the studies was due to the differences and sensitivities of the methods used to detect the tumors.

In summary, both animal and human studies suggest a role of EDCs in altering female reproductive development. Data from animal experiments show that EDC exposure during critical periods of development, both prenatal and neonatal, can induces functional changes that appear later in life. There are data gaps in understanding the mechanisms by which EDCs carry out their action, but it is clear that to reduce the risk of reproductive disorders we must take action to reduce exposure to these chemicals.

More DES DiEthylStilbestrol Resources

Chemical Exposure linked to 1.4 Billion Euros in Women’s Health Care Costs

Endocrine-disrupting chemicals may raise risk of developing endometriosis, uterine fibroids

Washington, DC – Endocrine-disrupting chemicals may contribute to reproductive health problems experienced by hundreds of thousands of women, costing European Union an estimated €1.4 billion ($1.5 billion) a year in health care expenditures and lost earning potential, according to a new study published in the Endocrine Society’s Journal of Clinical Endocrinology & Metabolism, Female Reproductive Disorders, Diseases, and Costs of Exposure to Endocrine Disrupting Chemicals in the European Union.

Chemical Exposure Linked to 1.4 Billion Euros in Women’s Health Care Costs, The Endocrine Society, March 22, 2016.

The study examined rates of uterine fibroids – benign tumors on the uterus that can contribute to infertility and other health problems – and an often painful condition called endometriosis where the tissue that normally lines the uterus develops elsewhere in the body. The two conditions are common, with as many as 70 percent of women affected by at least one of the disorders.

Research has linked the development of uterine fibroids and endometriosis to chemicals found in pesticides, cosmetics, toys and food containers. Past studies suggest a byproduct of the pesticide DDT, a chemical known as DDE, can raise the risk of developing uterine fibroids. Another group of chemicals called phthalates, which are found in plastic products and cosmetics, have been tied to growing risk of endometriosis.

DDT and phthalates are known endocrine-disrupting chemicals (EDCs). EDCs can contribute to health problems by mimicking, blocking or otherwise interfering with the body’s hormones – the signaling system the body uses to determine how cells develop and grow. Unborn children are particularly vulnerable because exposure during key points in development can raise the risk of health problems later in life.

“The data shows that protecting women from exposure to endocrine-disrupting chemicals could substantially reduce rates of disease and lower health care and other social costs of these conditions”

said Leonardo Trasande, MD, MPP, Associate Professor of Pediatrics, Environmental Medicine & Population Health at NYU Langone Medical Center.

Female Reproductive Disorders, Diseases, and Costs of Exposure to Endocrine Disrupting Chemicals in the European Union, Endocrine Society, dx.doi.org/10.1210/jc.2015-2873, March 22, 2016.

The study is part of a series of economic analyses that found endocrine-disrupting chemical exposure may be costing the European Union upwards of €157 billion ($173 billion) a year. Prior studies in the series examined the costs associated with infertility and male reproductive dysfunctions, birth defects, obesity, diabetes, cardiovascular disease, and neurobehavioral and learning disorders.

To assess the economic burden of EDC exposure, a group of scientists convened a panel of global EDC experts to adapt existing environmental health cost models, relying on the Institute of Medicine’s 1981 approach of assessing the contribution of environment factors in causing illness. Based on the body of established literature, the researchers evaluated the likelihood that EDCs contributed to various medical conditions and dysfunctions.

Researchers only considered endometriosis and uterine fibroids in the analysis because there is robust data on their incidence and association with endocrine-disrupting chemical exposure. The researchers estimated that 145,000 cases of endometriosis and 56,700 cases of uterine fibroids in Europe could be attributed to exposure to endocrine-disrupting chemicals.

“Although these two gynecological conditions affect millions of women worldwide, we recognize that this analysis only reflects the tip of the iceberg,” “A growing body of evidence suggests EDC exposure is linked to a broader range of female reproductive problems, including polycystic ovary syndrome, infertility and pregnancy complications. These disorders also place a significant cost burden on women, their families and society as a whole.”

Trasande said.

The economic analysis included direct costs of hospital stays, physician services, and other medical costs. The researchers also calculated estimates of indirect costs such as lost worker productivity associated with these often painful disorders.

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

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.

UterineFibroids : Questions to ask your Surgeon before Fibroid Surgery

What should you do if you need to have fibroids removed?

Here are three questions to ask your surgeon that may help you decide:

Many physicians are still using morcellators and may inadvertently spread undiagnosed cancer…
  • What exactly are you going to do?
  • What are the risks?
  • What do my imaging tests reveal?

Read 3 Questions to Ask Before Fibroid Surgery, NewsHealth, 2014/09/23.

Also checkout some related posts.

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.

Uterine Cancers among Women undergoing a Minimally Invasive Hysterectomy using Electric Power Morcellation

Evaluating the Risks of Electric Uterine Morcellation

JAMA Network logo
Presence of uterine cancers at time of hysterectomy studied using morcellation.

Even though minimally invasive surgery has improved outcomes for hysterectomy, the procedure requires removal of the uterus through small incisions. Morcellation, or fragmentation of the uterus into smaller pieces, is one method to remove the uterus. Recently, concern has been raised that morcellation may result in the spread of undetected malignancies.

Despite the commercial availability of electric power morcellators for 2 decades, accurate estimates of the prevalence of malignancy at the time of electric power morcellation (herein referred to as morcellation) are lacking.

Among women undergoing a minimally invasive hysterectomy using electric power morcellation, uterine cancers were present in 27 per 10,000 women at the time of the procedure, according to a new study. There has been concern that this procedure, in which the uterus is fragmented into smaller pieces, may result in the spread of undetected malignancies.

Sources and More Information:

  • Uterine Pathology in Women Undergoing Minimally Invasive Hysterectomy Using Morcellation, JAMA, articleid=1890400,  doi:10.1001/jama.2014.9005, July 22, 2014.
  • Presence of uterine cancers at time of hysterectomy studied using morcellation, ScienceDaily, 140722164353, July 22, 2014.
  • Patient safety must be a priority in all aspects of care, The Lancet Oncology, Volume 15, Issue 2, Page 123,  doi:10.1016/S1470-2045(14)70042-7, February 2014.
  • Evaluating the Risks of Electric Uterine Morcellation, JAMA. 2014;311(9):905-906. articleid=1828692, doi:10.1001/jama.2014.1093, March 5, 2014.
  • Peritoneal Dissemination Complicating Morcellation of Uterine Mesenchymal Neoplasms, PLOS one, DOI: 10.1371/journal.pone.0050058, November 26, 2012.
  • Risk of occult malignancy in morcellated hysterectomy: a case series, NCBI, PMID: 21804400, 30(5):476-83. doi: 10.1097/PGP.0b013e3182107ecf, 2011 Sep.
  • Robotically Assisted vs Laparoscopic Hysterectomy Among Women With Benign Gynecologic Disease, JAMA, articleid=1653522, 2013;309(7):689-698. doi:10.1001/jama.2013.186, February 20, 2013.
  • The value of re-exploration in patients with inadvertently morcellated uterine sarcoma, GynecologicOncology, Volume 132, Issue 2 , Pages 360-365, article/S0090-8258(13)01351-6, February 2014

Uterine Morcellation Disseminating Unexpected Malignancy with Associated High Increase in Mortality

Peritoneal dissemination complicating morcellation of uterine mesenchymal neoplasms

Abstract

PLoS logo
Uterine morcellation carries a risk of disseminating unexpected malignancy with apparent associated increase in mortality much higher than appreciated currently

Background:
Power morcellation has become a common technique for the minimally invasive resection of uterine leiomyomas. This technique is associated with dissemination of cellular material throughout the peritoneum. When morcellated uterine tumors are unexpectedly found to be leiomyosarcomas or tumors with atypical features (atypical leiomyoma, smooth muscle tumor of uncertain malignant potential), there may be significant clinical consequences. This study was undertaken to determine the frequency and clinical consequence of intraperitoneal dissemination of these neoplasms.

Methodology/Principal Findings:
From 2005-2010, 1091 instances of uterine morcellation were identified at BWH. Unexpected diagnoses of leiomyoma variants or atypical and malignant smooth muscle tumors occurred in 1.2% of cases using power morcellation for uterine masses clinically presumed to be “fibroids” over this period, including one endometrial stromal sarcoma (ESS), one cellular leiomyoma (CL), six atypical leiomyomas (AL), three smooth muscle tumor of uncertain malignant potential (STUMPs), and one leiomyosarcoma (LMS). The rate of unexpected sarcoma after the laparoscopic morcellation procedure was 0.09%, 9-fold higher than the rate currently quoted to patients during pre-procedure briefing, and this rate may increase over time as diagnostically challenging or under-sampled tumors manifest their biological potential. Furthermore, when examining follow-up laparoscopies, both from in-house and consultation cases, disseminated disease occurred in 64.3% of all tumors (zero of one ESS, one of one CL, zero of one AL, four of four STUMPs, and four of seven LMS). Only disseminated leiomyosarcoma, however, was associated with mortality. Procedures are proposed for pathologic evaluation of morcellation specimens and associated follow-up specimens.

Conclusions/Significance:
While additional study is warranted, these data suggest uterine morcellation carries a risk of disseminating unexpected malignancy with apparent associated increase in mortality much higher than appreciated currently.

Sources:
  • Peritoneal dissemination complicating morcellation of uterine mesenchymal neoplasms, NCBI, PMC3506532, doi: 10.1371/journal.pone.0050058, PLoS One. 2012; 7(11): e50058., Epub 2012 Nov 26.