new research on fibroids

Breakthrough in understanding genesis of fibroids

Scientists at the University of Helsinki and Helsinki University Hospital have made a breakthrough in understanding the genesis of uterine leiomyomas, also called fibroids.

Fibroids are extremely common tumors. They are a major burden for women's health worldwide, and the most common cause of hysterectomy. The Finland Myoma Study published in Nature found that the part of the human genome that controls expression of genes, is of major importance in fibroid development.

The findings of the new study represent a significant advance in fibroids research. Without detailed knowledge on the mechanisms of tumorigenesis involved, it would be difficult to develop targeted therapies for this condition affecting hundreds of millions of women.

Genes that are poised to change expression level are important for fibroid development.

The researchers discovered that multiple tumors carried mutations in genes that were involved in trafficking certain type of histones, proteins that are important for the structure and functional properties of the genome. They next found that mutations in these same genes were important in hereditary predisposition to the disease.

The work also documented the many changes in the regulatory genome that these mutations exerted, and finally showed a strong effect on gene expression levels.

"In particular, genes that are poised to frequently turn on and off seem affected in fibroids," says Academy Professor Lauri Aaltonen.

This might explain why this new mechanism of tumorigenesis frequently affects the uterine muscle wall but rarely other tissue types, as the uterus needs to adjust to many changing external cues such as those governing the menstrual cycle and pregnancy.

"Thus, disturbances in genes that need to be poised to change expression level might harm the uterus more easily than other organs," explains Aaltonen.

"Some of the overexpressed genes might provide clues for development of new fibroid treatment options," Aaltonen points out.

Women's Health
Parkinson's Research
Human Biology
Personalized Medicine
Medical Topics
Uterine fibroids
Breech birth
Developmental psychology
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Somatic cell

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Materials provided by University of Helsinki . Note: Content may be edited for style and length.

Journal Reference :

Davide G. Berta, Heli Kuisma, Niko Välimäki, Maritta Räisänen, Maija Jäntti, Annukka Pasanen, Auli Karhu, Jaana Kaukomaa, Aurora Taira, Tatiana Cajuso, Sanna Nieminen, Rosa-Maria Penttinen, Saija Ahonen, Rainer Lehtonen, Miika Mehine, Pia Vahteristo, Jyrki Jalkanen, Biswajyoti Sahu, Janne Ravantti, Netta Mäkinen, Kristiina Rajamäki, Kimmo Palin, Jussi Taipale, Oskari Heikinheimo, Ralf Bützow, Eevi Kaasinen, Lauri A. Aaltonen. Deficient H2A.Z deposition is associated with genesis of uterine leiomyoma . Nature , 2021; DOI: 10.1038/s41586-021-03747-1

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Scientists develop new model for understanding uterine fibroids

by Olivia Dimmer, Northwestern University

Northwestern Medicine scientists have developed a new cellular model of uterine fibroids that stem from common genetic mutations, which will accelerate further research and development of future treatments, according to findings published in Nature Communications .

It's estimated that more than half of all women will develop uterine fibroids—noncancerous muscular tumors that grow in the wall of the uterus—at some point in their lives, according to the American College of Obstetricians and Gynecologists.

It's not clear what causes uterine fibroids to develop, but many scientists believe hormonal and genetic factors play a role.

Nearly 70% of uterine fibroids are linked to a mutation in the MED12 gene, but research has been stymied by a lack of tractable cellular models to study, said Mazhar Adli, Ph.D., associate professor of Obstetrics and Gynecology in the Division of Reproductive Science in Medicine and senior author of the study.

"When cultured in the lab, the mutant cells in the fibroid tumor do not survive and hence the cellular model that mimics fibroid tumors could not be generated," said Adli, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

To address this challenge, his lab used CRISPR-based genome editing technology to precisely engineer cells that have the same mutation in the MED12 gene.

"We found that these engineered mutant cells, like fibroid tumor cells, did not proliferate well in a 2D culture, however when we culture them in 3D conditions, that better mimics the normal in vivo physiology, and they proliferated better," Adli said.

After successfully culturing the mutated fibroid cells in 3D spheres, Adli and his collaborators noticed that the cells produced heightened levels of collagen, a key feature of uterine fibroids, as well as other chromosomal abnormalities commonly seen in uterine fibroids in patients.

"Having an accurate cellular model of uterine fibroid growth will aid in future research around fibroid treatment," Adli said.

"This model opens the door for us to conduct subsequent studies to try to identify drugs that will selectively target these mutant fibroid cells," Adli said. "We could not do these experiments before because we didn't have a model system . Now that we do, we are able to conduct high-throughput CRISPR screenings to identify potential therapeutic targets."

In addition to follow-up studies into potential treatment targets for uterine fibroids , Adli's cell models will be available to other scientists and will hopefully expedite further research into the condition.

"So far, the basic biology of this disease has been lacking," Adli said. "Either there were not enough resources or there was not a good model system really to understand the molecular biology and genomic features of this disease. I think this model system and additional model systems that we are generating will really help us to understand the disease in a much better, more tractable way."

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Promising Trial for a Drug to Ease Uterine Fibroids

About three quarters of women will experience uterine fibroids before they reach the age of 50. With a range of often debilitating symptoms including excessive menstrual bleeding, they are the most common reason women undergo hysterectomies. And there is a lack of effective treatments—most therapies either only mask symptoms or are difficult for patients to tolerate.

Now, researchers have developed a new, more patient-friendly drug that could revolutionize the way clinicians treat some of the most common gynecologic diseases including fibroids and endometriosis. The ObsEva-funded clinical trial published September 17 in the Lancet , which included co-first author Hugh S. Taylor, MD , Anita O’Keeffe Young Professor of Obstetrics, Gynecology & Reproductive Sciences and professor of molecular, cellular, and developmental biology, found that linzagolix (brand name Yselty), an oral drug that hinders estrogen production, is an effective and customizable treatment for fibroids. The treatment not only addresses the symptoms, but also tackles the underlying problem through shrinking the fibroids themselves.

“No treatments to date for fibroid growth are something I would ever want my patients to take for a prolonged period of time, as they did not treat the underlying cause of the problem,” says Taylor. “This is an extremely well tolerated class of drugs that can control fibroid growth. We’ve never had anything like that before.”

Fibroids Can Be Debilitating and Hard to Treat

The impact of uterine fibroids can be devastating. Heavy, prolonged bleeding can significantly disrupt a person’s life—they may need to go through excessive numbers of sanitary pads or tampons, worry about bleeding through and staining clothing, or need to wake up throughout the night to change pads. And profound blood loss may lead to anemia and fatigue. “This can be an impediment to getting a good night’s sleep and being socially active, and it can even affect job performance,” says Taylor.

As fibroids grow larger, they may begin putting pressure on other organs, resulting in a range of unpleasant symptoms including diarrhea or constipation and frequent urination. Fibroids can also lead to difficulty in getting pregnant and increased risk of miscarriage.

Uterine fibroids disproportionately impact Black patients—they are more common and tend to be more aggressive in comparison to white patients.

Most drugs commonly used for uterine fibroids, including birth control pills, fail to treat the fibroids themselves and simply only lighten or stop periods. And more aggressive drugs, although they treat the root of the problem, says Taylor, are “overkill.” For example, leuprolide (brand name Lupron) is an injectable drug that puts patients into a menopausal state by initially overstimulating hormonal receptors, which eventually shuts them down and completely blocks estrogen production. Although the treatment addresses the fibroids, it also can initially exacerbate symptoms and cause harsh side effects. In more extreme cases, patients may choose to undergo a hysterectomy.

Promising Clinical Trial Results

Linzagolix is an oral medication that works similarly to leuprolide by hindering hormone production. However, unlike its predecessor, it works by directly blocking the receptors instead of overstimulating them. The drug is also titratable—clinicians can tailor how much estrogen is blocked in order to best suit an individual patient’s needs without necessarily putting them into a full-blown menopause.

This is an extremely well tolerated class of drugs that can control fibroid growth. We’ve never had anything like that before. Hugh S. Taylor, MD

The new drug may cause menopause symptoms such as hot flashes. Hormonal add-back therapy can be an effective option for mitigating these symptoms. For some patients, however, including patients with obesity, hypertension, or diabetes, this therapy has risks and may not be a suitable option. These conditions also tend to be more prevalent in Black patients. In this group, a lower dose of linzagolix without add-back therapy might be preferable.

To test the effectiveness of the drug, Taylor’s team ran two large prospective, randomized, double-blind, placebo-controlled clinical trials known as PRIMROSE 1 and PRIMROSE 2. The studies enrolled patients suffering from substantial bleeding who were randomly selected to receive a placebo or one of several different doses of the drug—100 mg alone, 100 mg with add-back therapy, 200 mg alone, or 200 mg with add-back therapy. The researchers followed the patients and tracked their symptoms for one year. The researchers considered the therapy successful if the patient’s bleeding was reduced by half and also stayed in what is considered the normal range.

Patients in all four treatment groups experienced a significant reduction in menstrual bleeding. The 200 mg with add-back therapy group worked with “amazing efficacy,” says Taylor—the clinical trials showed a 75.5 percent response rate in PRIMROSE 1 and a 93.9 response rate in PRIMROSE 2. Even the lower dose of the drug still showed promising results. There were greater than 60% response rates in both trials for the 100 mg group with add-back therapy, and the 100 mg group without add-back showed better than 50% response rates.

“What is interesting and unique about our trials, that has not been done with other drugs in this class, is that we used a low dose with or without hormones,” says Taylor. “This is a great option for patients who experience severe menopause symptoms from the high dose or have a medical problem where they can’t tolerate hormonal add-back therapy.”

Revolutionizing Treatment of Gynecologic Diseases

Linzagolix is one of several in this new class of drugs in development for the treatment for common gynecologic diseases. Taylor was also involved in the 2017 clinical trial for elagolix , (brand name Orlissa), a medication designed to suppress endometriosis that has recently become available for patients.

Linzagolix has been approved in Europe, but is not yet available in the United States. Taylor says drugs in this class will radically change how clinicians treat fibroids, and he hopes linzagolix will lead to a reduction in future hysterectomies once it becomes available.

“A good medical therapy is finally here for fibroids, and I predict that what was a very common operation will dramatically decrease within the next few years,” he says. “Reducing the need for hysterectomy is very important for patients who don’t want to undergo a major surgery, especially for younger people who may still want to preserve the potential of having children in the future.”

Featured in this article

Hugh Taylor, MD Anita O'Keeffe Young Professor of Obstetrics, Gynecology, and Reproductive Sciences and Professor of Molecular, Cellular, and Developmental Biology; Chair, Obstetrics, Gynecology & Reproductive Sciences; Chief , Obstetrics and Gynecology, Yale New Haven Hospital

News Center

Study identifies novel cellular mechanisms promoting growth of uterine fibroids .

Investigators have discovered a novel molecular pathway that promotes tumor growth in uterine fibroids that contain a specific genetic mutation, which could inform the development of new targeted therapies, according to a Northwestern Medicine study published in the journal JCI Insight.

Uterine leiomyomas, or fibroids, effect approximately 10 million reproductive-age women and individuals with uteruses in the U.S. each year. It is estimated that up to 80 percent of these individuals will develop at least one fibroid by the age of 50. Additionally, one-third of these individuals will develop severe symptoms, including heavy and irregular uterine bleeding, anemia, pregnancy loss or infertility. Furthermore, symptomatic uterine fibroids disproportionally affect Black women compared to other racial and ethnic populations.

“They [leiomyomas]are probably the most important public health problem of reproductive-age women across the world, and in the U.S., they’re fairly common,” said Serdar Bulun, MD , the chair and John J. Sciarra Professor of Obstetrics and Gynecology and co-senior author of the study. “Black women also develop symptomatic fibroids about 10 years earlier than white women, and the statistics show that fibroids are detected three or four times more commonly in Black women compared with white or non-Black women.”

There are no long-term therapies currently available for uterine fibroids due to a severe lack of research exploring the underlying mechanisms of uterine fibroid tumor growth, according to Bulun.

Work published in the last two decades established that the MED12 gene was mutated in 70 percent of uterine fibroid tumors and when MED12 is mutated, the tumors rely on progesterone to grow. This discovery prompted Bulun’s team to determine how the MED12 mutation catalyzes cell proliferation in uterine leiomyoma cells.

In the current study, the investigators used RNA sequencing to study both normal and mutant- MED12 leiomyoma cells. Using these techniques, they discovered that the TDO2 (tryptophan 2,3-dioxygenase) gene was upregulated in mutant- MED12 leiomyoma cells.

In these cells, TDO2 initiates the conversion of the amino acid tryptophan into an internal hormone called kynurenine, which is attached to and in turn activates a transcription factor called aryl hydrocarbon receptor (AHR). When AHR is activated, it signals leiomyoma cells to grow and proliferate.

To further confirm their findings, the investigators activated this newly discovered TDO2 -kynurenine-AHR pathway in mutant- MED12 leiomyoma cells with tryptophan or kynurenine which, in turn, promoted cell proliferation and inhibited apoptosis, or cell death.

This suggests that activating the TDO2 -kynurenine-AHR pathway could inform the development of new long-term targeted therapies, according to the authors.

“This [TDO2] is a very important enzyme because 70 percent of people who have uterine fibroids have this mutation, and if we can find the compound to inhibit the activity of the enzyme, I believe we’ll be able to decrease the symptoms of fibroids or shrink fibroid size,” said Ping Yin, MD, PhD , research associate professor of Obstetrics and Gynecology in the Division of Reproductive Science in Medicine , who was co-senior author of the study.

The findings also highlight the importance of uterine fibroid research, which can help accelerate new precision medicine treatments for a disease that effects nearly all women, Bulun said.

“This is one of the only programs which brings a lot of investigators in a multidisciplinary fashion to study fibroids and look for molecular targets so that we could help women with this disease,” Bulun said.

Co-authors include Ariel Dotts, a student in the Driskill Graduate Program in Life Sciences ( DGP ), and Debabrata Chakravarti, PhD, the Anna Lapham Professor of Obstetrics and Gynecology and the Vice Chair for Translational Research in the Department of Obstetrics and Gynecology.

Bulun and Chakravarti are members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

B-cells may play role in lung transplant rejection, drug shows promise for starving out cancer cells, understanding cellular transcription responses to oxygen deprivation.

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Two people in labcoats examine a computer screen showing different orientations of cells.

UC examines how painful fibroids grow

Researchers find ways that cells respond differently to strain.

Insights into how uterine tumors grow could give hope to millions of women who deal with painful fibroids.

Nearly 8 in 10 women develop fibroids, noncancerous tumors that develop in the uterus during child-bearing years. They can be extremely painful, cause extensive bleeding and lead to infertility.

Researchers at the University of Cincinnati found different signaling pathways being used by the fibroid cells compared to the uterine cells.

“That’s important for identifying therapeutic targets because we want to target the tumor without affecting the surrounding tissue,” said Stacey Schutte, an assistant professor of biomedical engineering in UC’s College of Engineering and Applied Science.

The study was published in the journal F&S Science .

Assistant Professor Stacey Schutte, left, and Research Associate Andreja Moset Zupan study new avenues to treat fibroids in Schutte's biomedical engineering lab in UC's Bioscience Center. Photo/Andrew Higley/UC Marketing + Brand

Treating fibroids is often invasive and expensive, costing patients and their insurers billions of dollars each year, according to the National Institutes of Health. Treatments can often lead to infertility as well, Schutte said.

“One in nine women will have a hysterectomy in their lifetime. And one-third to one-half of those are [because of] uterine fibroids,” Schutte said.

Schutte has experience in this research field. She was a postdoctoral fellow at the Emory University School of Medicine’s Department of Gynecology and Obstetrics.

“It usually isn’t life-threatening, but the pain can be immense,” she said. “Contractions push the tumors into the muscle tissue.”

During each menstrual cycle, the body releases estrogen and progesterone, which causes the tissue lining inside the uterus to thicken in anticipation of possible pregnancy. These hormones also help fibroids grow.

But Schutte said cells likewise can react to physical strain — like a defense mechanism to protect the cells.

“I came from working in cardiovascular medicine. We studied mechanical strain on blood vessels. Mechanical forces can cause cells to produce a lot of extracellular matrix to increase the size of the tissue,” she said.

I want to find ways to affect fibroids but not the surrounding muscle cells.

Stacey Schutte, UC Assistant Professor of Biomedical Engineering

UC researchers grew fibroid cells and uterine cells on plates with an elastic bottom. Then they used a device to expose the cells to mechanical strain to mimic the environment that fibroids encounter in the uterus.

“We have a flexible tension device. We grew cells on plates with an elastic bottom. Then we used a vacuum to pull and stretch it,” Schutte said. “It stretches cells in a single direction.”

“We found that fibroid cells were more sensitive to strain,” said study lead author Rachel Warwar, MD, in UC’s College of Medicine.

Warwar said they identified differences in the ways the cells held their shape.

Warwar works in UC’s Department of Obstetrics and Gynecology. She said the findings highlight the importance of incorporating not just hormones but mechanical strain into the study of fibroid cells.

“The more we are able to mimic the environment of these cells in the uterus, the more we will understand the pathology of these cells and can then work to target anomalous pathways in fibroid cells,” she said.

Assistant Professor Stacey Schutte's biomedical engineering lab in UC's Bioscience Center collaborates with researchers in the UC College of Medicine. Photo/Andrew Higley/UC Marketing + Brand

Nearly 4 in 5 women have fibroids during their lifetimes. Because they are so common, they represent a major health care cost — as much as $9 billion per year in the United States.

Common noninvasive treatments target hormones responsible for fibroid growth.

“We are looking for nonhormonal treatments for fibroids,” said study coauthor Andreja Moset Zupan, a research associate in Schutte’s biomedical engineering lab.

“It’s another option we could use to preserve the fertility of women who still want to get pregnant,” she said.

Once researchers understand the cell pathology, Warwar said, they can study fibroids using 3D simulations and modeling, which could help them further understand how fibroids develop and the best ways to treat them.

“I want to find ways to affect fibroids but not the surrounding muscle cells,” Schutte said. “There is at least one pathway, if not more, that responds differently.”

Schutte said the next step is to create more complex tissue models to mimic tumor growth to learn ways to inhibit it.

“It makes me really happy to think we can find a target.”

Featured image at top: Assistant Professor Stacey Schutte, right, and Research Associate Andreja Moset Zupan are looking for new treatments for fibroids in Schutte's biomedical engineering lab in UC's Bioscience Center. Photo/Andrew Higley/UC Marketing + Brand

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Review article, understanding the impact of uterine fibroids on human endometrium function.

Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, United States

Uterine fibroids (leiomyomas) are the most common benign gynecological tumors in women of reproductive age worldwide. They cause heavy menstrual bleeding, usually leading to severe anemia, pelvic pain/pressure, infertility, and other debilitating morbidities. Fibroids are believed to be monoclonal tumors arising from the myometrium, and recent studies have demonstrated that fibroids actively influence the endometrium globally. Studies suggest a direct relationship between the number of fibroids removed and fertility problems. In this review, our objective was to provide a complete overview of the origin of uterine fibroids and the molecular pathways and processes implicated in their development and growth, which can directly affect the function of a healthy endometrium. One of the most common characteristics of fibroids is the excessive production of extracellular matrix (ECM) components, which contributes to the stiffness and expansion of fibroids. ECM may serve as a reservoir of profibrotic growth factors such as the transforming growth factor β (TGF-β) and a modulator of their availability and actions. Fibroids also elicit mechanotransduction changes that result in decreased uterine wall contractility and increased myometrium rigidity, which affect normal biological uterine functions such as menstrual bleeding, receptivity, and implantation. Changes in the microRNA (miRNA) expression in fibroids and myometrial cells appear to modulate the TGF-β pathways and the expression of regulators of ECM production. Taken together, these findings demonstrate an interaction among the ECM components, TGF-β family signaling, miRNAs, and the endometrial vascular system. Targeting these components will be fundamental to developing novel pharmacotherapies that not only treat uterine fibroids but also restore normal endometrial function.

Introduction

Uterine fibroids (UFs), also known as leiomyomas, are benign tumors in women of reproductive age. Despite their benign nature, they are able to undergo rapid and significant growth ( Andersen and Barbieri, 1995 ). They cause irregular and heavy menstrual bleeding (HMB), leading to severe anemia, dysmenorrhea, pelvic pressure and pain, urinary incontinence, dyspareunia, infertility, preterm labor, and early and recurrent pregnancy loss ( Stewart, 2001 ; Wallach and Vlahos, 2004 ). UFs are present in more than 70% of women, become symptomatic in approximately 30% of women, and are the most common clinical indication for hysterectomy that prematurely ends a woman’s reproductive life ( Walker and Stewart, 2005 ). African American women are more likely to develop UFs at an early age and to present more severe clinical symptoms compared to Caucasian women ( Kjerulff et al., 1996 ). Other risk factors for UFs include age, obesity, hypovitaminosis D, and endogenous and exogenous hormonal factors ( Pavone et al., 2018 ; Ali et al., 2019 ; Bariani et al., 2020 ). Despite the high prevalence of UFs, there are no approved effective pharmacotherapies, and surgery remains the main option for UF treatment ( Bulun, 2013 ). UF prevalence is a personal and economic burden, within an estimated healthcare cost of United States $34 billion annually in the United States ( Cardozo et al., 2012 ).

UFs cause HMB and poor uterine receptivity and implantation leading to infertility, two major female reproductive disorders affecting millions of women in the United States and globally. Both disorders reflect endometrial dysfunctions caused by the presence of UFs, and the degree of dysfunction appears associated with the location and size of the UFs. There is a significant gap in our understanding of how UFs affect endometrial function. It is generally agreed that the expansion in the endometrial surface area caused by UFs leads to greater menstrual bleeding and transformations in the shape of uterine cells that affect gene expression and function. Yet, recent studies have demonstrated that UFs actively influence not only the adjacent endometrium but also the uterus as a whole ( Rackow and Taylor, 2010 ). We conducted a literature review to highlight new and significant insights into endometrial and UF biology, with the goal of elucidating the effects of UFs on human endometrial function, particularly HMB, infertility, and pregnancy complications.

We used several strategies to identify primary research literature, review articles, and book chapters related to UFs and the negative impacts of UFs on endometrial function, focusing on HMB, infertility, and pregnancy complications. We did not place restrictions on year of publication and included all relevant publications up to November 2020. We performed PubMed and Google Scholar searches to identify relevant articles using the following keywords either alone or in combination with “uterine fibroid(s), uterine leiomyoma, and endometrium,” “heavy menstrual bleeding,” “recurrent pregnancy loss,” “miscarriage,” “early pregnancy loss,” “infertility,” and “subfertility.” We also considered additional pertinent articles included as references in the downloaded articles. With this review, we summarize and expand on what is presently known regarding the influence of UFs on the endometrium and the associated clinical consequences of UFs such as HMB and infertility.

Origin of Uterine Fibroids

UFs are monoclonal tumors ( Holdsworth-Carson et al., 2014 ), and increasing evidence indicates that they arise from a single myometrial stem cell (MMSC) ( Mas et al., 2012 ; Yin et al., 2015 ). MMSCs constitute a small proportion of the total population of cells and express specific surface markers that distinguish them from the bulk of other cells ( Mas et al., 2015 ). The plasticity of MMSCs during development and tissue maintenance permits the acquisition of mutations or aberrant cellular reprogramming via epigenetic mechanisms. Consequently, normal MMSCs can be converted into tumor-initiating stem cells (TICs) that are able to initiate UF development. The most common genetic drivers associated with the development of UFs are somatic mutations present in exons 1 and 2 of the MED12 gene, which encodes a subunit of the mediator complex, a co-activator involved in the transcription of nearly all RNA polymerase II-dependent genes ( Makinen et al., 2011 ). In addition to MED12 mutations, which account for ∼70% of UFs ( Je et al., 2012 ; Kämpjärvi et al., 2014 ), a proportionally smaller fraction of UFs is thought to arise from genetic alterations leading to the overexpression of high-mobility group AT-hook 2 (HMGA2, ∼20%), biallelic inactivation of fumarate hydratase (FH, ∼2%) ( Mehine et al., 2016 ), and disruption of the COL4A6 locus (∼3%).

Factors Implicated in Uterine Fibroid Development and Growth and Their Influence on Endometrial Biology

The exact cellular and molecular mechanisms that direct and control the development and growth of UFs are not clearly elucidated. However, several factors have been implicated in the development and growth of UFs, such as cytokines, chemokines, growth factors, extracellular matrix (ECM) components, factors involved in the DNA damage response and inflammation, vasoactive substances, and microRNAs ( Figure 1 ). The factors expressed and secreted by UFs could affect endometrial cell growth and function and vessel remodeling, thereby contributing to the increased incidence of HMB, irregular menses, and infertility ( Table 1 ). One of the main characteristics of UFs is a remarkably excessive production of ECM components including collagens, fibronectin, proteoglycans, and laminins ( Norian et al., 2009 ).

Figure 1. Factors implicated in uterine fibroid (UF) development and growth may influence the endometrial biology. Extracellular matrix (ECM) components, microRNAs (miRNAs), growth factors, cytokines, and chemokines are involved in UF development. These factors may also affect endometrial cell growth and function and vessel remodeling, thereby contributing to the increased incidence of reproductive complications such as heavy and irregular menses and infertility. In addition, we propose that UFs may impact the endometrial microbiome composition.

Table 1. Differential expressions of the factors involved in uterine fibroid (UF) development and growth and its effect on the endometrium.

Extracellular Matrix Components and UFs

Extracellular Matrix Component accumulation and remodeling are thought to be critical in the transformation of the myometrium into UFs. Pivotal ECM components including collagen, fibronectin, and proteoglycans are upregulated in UFs compared to the adjacent myometrium (reviewed in Islam et al., 2018 ) and may be responsible for the increased tissue stiffness and decreased stretch. Interestingly, cells can sense and respond to mechanical stimuli from the environment, such as stretch or compression, by converting them into biochemical signals ( Leppert et al., 2014 ). Furthermore, the ECM may serve as a reservoir of profibrotic growth factors such as the transforming growth factor-β (TGF-β), thus acting as a modulator of their availability and actions ( Islam et al., 2018 ). Beyond its structural role, the ECM is involved in various cellular processes, including cell proliferation and cell death. The structure, organization, and molecular composition of the endometrial ECM are significantly modified during the menstrual cycle and decidualization ( Tanaka et al., 2009 ; Favaro et al., 2014 ; Okada et al., 2018 ). In this respect, changes in the ECM environment due to the presence of UFs can significantly disturb normal endometrial physiological functions. UFs may elicit mechanotransduction changes that result in a decreased uterine wall contractility and an increased myometrial rigidity, which in turn affect normal biological uterine functions like menstrual bleeding, receptivity, and implantation. Depending on the location and size of the UFs, an increase in stiffness can affect the endometrium locally by significantly altering stretch and stress and affect gene expression globally ( Rogers et al., 2008 ; Norian et al., 2012 ). The physical presence of UFs also affects the function of the endometrium, for example by obstructing the transport of gametes or embryo ( Deligdish and Loewenthal, 1970 ) and hindering implantation by altering the normal patterns of myometrial contractions ( Lyons et al., 1991 ). UFs also impair endometrial decidualization in the mid-luteal window of implantation by altering the endomyometrial junctional (EMJ) zone and significantly reducing the concentrations of both macrophages and uterine natural killer (uNK) cells ( Kitaya and Yasuo, 2010b ) and by altering steroid receptors ( Brosens et al., 2003 ; Tocci et al., 2008 ). Another important contributor to conception and implantation is uterine peristalsis; the physical presence of UFs causes a decrease in the acceleration of myometrial peristalsis in the mid-luteal period ( Kido et al., 2014 ). Conditions related to uterine peristalsis may contribute to the pathogenesis of several disorders and may impair sperm and embryo transport as well as implantation ( Yoshino et al., 2010 ).

MicroRNAs in the Regulation of Uterine Fibroids and Their Effects on the Endometrium

MicroRNAs (miRNAs) are small non-coding RNA molecules of approximately 22 nucleotides that function as posttranscriptional regulators of gene expression, affecting a wide array of physiological and pathological processes. miRNAs not only act inside cells but are also released by cells into the extracellular environment to act as autocrine, paracrine, and/or endocrine modulators in recipient cells. Consequently, miRNAs produced and secreted by UFs may influence the entire endometrium. Ali et al. (2020) summarized that multiple studies have reported differential miRNA expressions in UFs compared with matched healthy myometrium. Specifically, UFs have significantly dysregulated the levels of the let-7 family members, miR-21, miR-29b/c, and miR-200c, among others ( Wang et al., 2007 ; Marsh et al., 2008 ; Chuang et al., 2012a , b ). Importantly, the expressions of let-7 miRNAs are significantly upregulated in UFs compared to the matched myometrium, with higher levels of let-7 miRNAs in small UFs (≤3 cm) compared to large UFs (>10 cm) ( Wang et al., 2007 ). Notably, let-7 family members negatively regulated HMGA2 ( Wang et al., 2007 ) and are associated with endometrial receptivity ( Inyawilert et al., 2015 ; Liu et al., 2016 ). Wang et al. (2007) described miR-21 as the most highly upregulated miRNA in UFs. Interestingly, miR-21 is differentially expressed in endometrial stromal cells and glandular epithelial cells ( Nothnick, 2016 ). Within the miR-29 family, miR-29c expression is downregulated in UFs compared with the myometrium; this miRNA targets the ECM and DNA methylation enzymes ( Chuang and Khorram, 2016 ). Within the endometrium of fertile women, miR-29c is differentially regulated across the fertile menstrual cycle: it is elevated in the mid-secretory, receptive phase compared to the proliferative phase ( Kuokkanen et al., 2010 ). This finding suggests that miR-29c may influence endometrial genes associated with cell cycle progression and apoptotic processes. Furthermore, miR-29c expression is linked to infertility; it is upregulated in the early secretory and mid-secretory phases in the endometrium of infertile women compared to the fertile endometrium in the same phase ( Griffiths et al., 2019 ).

Conversely, miR-200c levels are downregulated in UFs compared to the myometrial tissue, with evidence suggesting a biological role in UF pathophysiology ( Chuang et al., 2012b ). Moreover, aberrant expression of miR-200c varies by ethnicity, with much lower levels in UF samples from African Americans compared with Caucasian samples ( Chuang et al., 2012b ). The expression of miR-200c is significantly upregulated in mid-secretory cycle phase samples, and this miRNA is predicted to target many cell cycle genes ( Kuokkanen et al., 2010 ). A very recent study demonstrated that the long non-coding RNA X-inactive specific (XIST) is expressed at higher levels in UFs compared with normal myometrium and that it acts as a molecular sponge for both miR-29c and miR-200c, downregulating the levels of these miRNAs in UFs ( Chuang et al., 2020 ).

It is important to highlight that miRNAs target genes involved in cell growth (miRNA-21/TGF-β), ECM remodeling (miRNA-29/COL1A1 and COL3A), angiogenesis (miRNA-200c, VEGF), and inflammation (miRNA-93/IL-8), leading to complex regulatory networks in UFs that can affect the endometrium ( Chuang et al., 2012a , b ; Karmon et al., 2014 ; Ciebiera et al., 2020 ). Furthermore, steroid hormone signaling, which is crucial in both UF development and endometrial function, regulates miRNAs and vice versa ( Klinge, 2009 ; Yuan et al., 2015 ; Gilam et al., 2017 ). Consequently, the interaction of multiple active molecules in and around UFs drives the creation of an abnormal endometrial environment leading to adverse menstrual and pregnancy-related outcomes.

DNA Damage and Repair in Uterine Fibroids

DNA damage can give rise to tumor initiation and progression. Diverse types of DNA damage can be repaired by different mechanisms, such as homologous recombination (HR), non-homologous end joining (NHEJ), and mismatch repair (MMR), among others. Impaired DNA damage repair can provoke genomic instability and lead to genetic alterations. Previous studies from our group revealed the downregulation of several DNA damage repair genes in UFs compared with the adjacent myometrium in women with UFs ( Yang et al., 2016 ; Ali et al., 2019 ). Prusinski Fernung et al. (2019) compared DNA repair in Stro-1 + /CD44 + MMSCs isolated from human UFs and the adjacent myometrium, revealing increased DNA damage and altered DNA damage repair gene expression and signaling in UFs.

The Eker rat is a unique model to study UF development and the role of early-life exposure to endocrine-disrupting chemicals in UF etiology. We used this model to reveal the accumulation of DNA damage in MMSCs isolated form 5-month-old Eker rats in response to developmental diethylstilbestrol (DES, an endocrine-disrupting chemical) exposure ( Prusinski Fernung et al., 2018 ; Elkafas et al., 2020 ). In addition, we found that the ability to repair DNA double-strand breaks is impaired in DES-MMSCs compared with vehicle (VEH)-MMSCs.

Endometrial Dysfunction Caused by Uterine Fibroids: Heavy Menstrual Bleeding and Poor Receptivity and Implantation Leading to Infertility

Uterine fibroids and heavy menstrual bleeding.

The knowledge gap that links UFs to HMB has limited the development of non-invasive treatment options. HMB is the most common type of abnormal uterine bleeding in women with UFs, and it is commonly accompanied by dysmenorrhea ( ACOG Practice Bulletin, 2008 ; Zimmermann et al., 2012 ). HMB leads to frequent visits to the emergency room and is the number one indication for hysterectomy ( Côté et al., 2003 ). Women with UF-associated HMB also have a higher risk of developing depression, emotional distress, anxiety, marital strife, and loss of intellectual and work productivity, all of which significantly affect quality of life ( Marsh et al., 2014 ). Menstrual bleeding is a multifaceted combination of interacting processes including angiogenesis, vasodilation, vasoconstriction, coagulation, and inflammation. It is believed that mainly bulky submucosal and intramural UFs affect the normal contractions of the myometrium during menstruation. In normal menstrual cycles, myometrial contractions help to expel uterine menstruation products and reduce loss of blood from endometrial vessels; women with UFs have abnormal myometrial contractions leading to heavy and prolonged menstrual bleeding ( Bulun, 2013 ). The most significant menstrual vasoconstrictors are endothelin-1 (ET1) and prostaglandin F2α (PGFα). ET1 is a strong vasoconstrictor that triggers myometrial contraction and mitogenesis ( Masaki, 1993 ; Maybin and Critchley, 2015 ). It is mainly expressed in the endometrium, where it is involved in spiral arteriole vasoconstriction and blood flow. ET1 works by binding to its receptors: endothelin type A receptor (ETAR) and endothelin type B receptor (ETBR). Interestingly, women with UFs have greater endometrial expression of ETAR and a lower expression of ETBR compared to normal endometrium. The imbalance in the expressions of ETAR and ETBR in women with UFs may alter ET1 signaling, leading to faulty vasoconstriction, abnormal uterine contractions, and excessive and prolonged menstrual blood flow. There is general consensus that women with UFs and HMB exhibit more dilated endometrial stromal venous spaces compared to women without UFs. Abnormal vasoconstriction might be one of the possible mechanisms underlying HMB ( Farrer-Brown et al., 1971 ). The receptors of the vasoconstrictor PGF2α are expressed in the healthy endometrium and control uterine contractions. Women with UFs have higher levels of endometrial PGF2α, which results in abnormal uterine contractions that could further contribute to HMB ( Figure 2 ; Pekonen et al., 1994 ; Miura et al., 2006 ).

Figure 2. The presence of uterine fibroids (UFs) may interfere with the endometrial pathways involved in the menstrual cycle, leading to heavy menstrual bleeding. Balance among hormones, growth factors, cytokines, and other factors regulates the cyclic endometrial growth and bleeding. Transforming growth factor-beta (TGF-β), its receptors (TGF-βR), and downstream SMADs are important for endometrial remodeling during menses, and excessive levels of these factors may suppress the gene expressions of the fibrinolytic and anticoagulant components. Prostaglandin F2α (PGF2α) and endothelin-1 (ET-1) are involved in spiral artery vasoconstriction and myometrial constriction during the menstruation period. Vascular endothelial growth factor (VEGF), the most specific endothelial cell growth factor, and platelet-derived growth factor (PDGF) play a role in endometrial angiogenesis, an essential process of endometrial renewal. Nitric oxide (NO) is produced downstream of ET-1 and VEGF signaling, and it is a potent vasodilator. Tumor necrosis factor-alpha (TNF-α) contributes to the process of menstrual shedding and bleeding through the induction of apoptosis. White arrows within circles indicate uterine changes due to UFs presence, which may dysregulate normal endometrium activity, causing excessive endometrium development and, eventually, heavy menstrual bleeding.

Numerous other factors, including cytokines, chemokines, and inflammatory molecules, play important roles in the endometrium during menstrual bleeding and may contribute to UF biology and pathophysiology. Tumor necrosis factor alpha (TNF-α) ( Ciebiera et al., 2018b ), interleukin 1 (IL-1), IL-11 ( Luo et al., 2005 ), IL-13, IL-15, IL-33 ( Santulli et al., 2013 ), interferon gamma (IFN-γ), and granulocyte–macrophage colony-stimulating factor (G-CSF) ( Chegini et al., 1999 ) are involved in UF pathogenesis. Specifically, TNF-α participates in tissue homeostasis and systemic inflammation, and it is also related to UF-associated HMB ( Ciebiera et al., 2018b ). TNF-α expression levels are higher in UFs compared with the adjacent myometrium ( Kurachi et al., 2001 ). Moreover, Ciebiera et al. (2018a) demonstrated that TNF-α serum levels are elevated in women with clinically symptomatic UFs. TNF-α is elevated in the menstrual effluent of women with HMB ( Malik et al., 2006 ); thus, this molecule may act as an important local signal that contributes to the process of menstrual shedding and bleeding in UFs ( Tabibzadeh, 1996 ).

Chemokines are a family of chemoattractant cytokines that regulate the infiltration of immune cells subsets, such as leukocytes, into tumors ( Nagarsheth et al., 2017 ) as well as into the endometrium during the normal menstrual cycle ( Thiruchelvam et al., 2013 ). IL-8, which chemoattracts neutrophils, is secreted by several cell types and contributes significantly to various disease-associated processes, including tissue injury, fibrosis, and angiogenesis ( Russo et al., 2014 ). Senturk et al. (2001) demonstrated higher levels of IL-8 and its receptor in the myometrium immediately surrounding the UF compared with the UF itself. Within the endometrium, the IL-8 messenger RNA (mRNA) levels fluctuate throughout the menstrual cycle, with significantly higher expression in the late secretory and early to mid-proliferative phases compared to the mid cycle, suggesting that sex hormones may regulate IL-8 gene expression ( Arici et al., 1998a ). Like IL-8, the monocyte chemoattractant protein-1 (MCP-1) mRNA levels in UFs are lower than those in the adjacent myometrium ( Sozen et al., 1998 ). Interestingly, higher MCP-1 levels were reported in the myometrium adjacent to UFs than in the myometrium of healthy control patients ( Sozen et al., 1998 ). In the endometrium, MCP-1 plays a key role in the control of macrophage migration in the endometrium. One study revealed that the highest levels of MCP-1 are detected when the estrogen levels are low, and MCP-1 levels are lowest around the time of ovulation, when the estrogen levels are high ( Arici et al., 1999 ). In this context, it is possible that cytokine and chemokine expressions in the endometrium are affected by the presence of UFs, resulting in changes in the endometrial cellular function.

Several studies have demonstrated that TGF-β ( Norian et al., 2009 ; Ciebiera et al., 2017 ), vascular endothelial growth factor (VEGF) ( Gentry et al., 2001 ; Tal and Segars, 2014 ), platelet-derived growth factor (PDGF) ( Hwu et al., 2008 ; Suo et al., 2009 ), and epidermal growth factor (EGF) ( Harrison-Woolrych et al., 1994 ; Vollenhoven et al., 1995 ; Dixon et al., 2000 ) are differentially expressed in UFs compared to the healthy myometrium. A significantly higher expression of VEGF-A is observed in large and small UFs of younger women, indicating that angiogenesis does not depend on UFs size ( Plewka et al., 2016 ). Estrogens upregulate PDGF expression and downregulate EGF expression in UFs ( Yin et al., 2011 ). TGF-β and its profibrotic effects play a significant role in the pathophysiology of UFs ( Ciebiera et al., 2017 ). At the same time, it is well known that TGF-β is involved in the initiation of menstruation and in the rapid proliferation and remodeling of endometrial tissue during the menstrual cycle and the preparation of the endometrium for implantation ( Jones et al., 2006 ; Omwandho et al., 2010 ). In addition, higher levels of basic fibroblast growth factor receptor 1 (FGFR1) and basic fibroblast growth factor (bFGF) observed in women with UFs may lead to aberrant angiogenesis and HMB ( Anania et al., 1997 ). UFs-secreted TGF-β3 provokes bone morphogenetic protein-2 (BMP2) resistance in the endometrium by downregulation of its receptor BMPR2 and leads to defective endometrial decidualization, as assessed by several decidualization markers after rhBMP2 treatment ( Sinclair et al., 2011 ). TGF-β3 also plays a crucial role in UF-associated HMB, leading to the reduced expressions of thrombomodulin, PAI-1, and ATIII in the endometrium, likely contributing to menorrhagia ( Sinclair et al., 2011 ). BMP7 inhibits the proliferation and decidualization in endometrial stromal cells, and it is significantly upregulated in women with abnormal menstrual bleeding ( Richards et al., 2017 ). The higher levels of TGF-β3 observed in women with UFs inhibit the secretion of coagulation and thrombosis factors including thrombomodulin, antithrombin III, and plasminogen activator inhibitor 1 (PAI1) ( Sinclair et al., 2011 ). Consequently, higher levels of TGF-β3 secreted by UFs dysregulate the expressions of genes associated with anticoagulant and fibrinolytic action, leading to HMB.

Evidence suggests that women with UFs have increased angiogenesis and that angiogenic growth factors such as VEGF and PDGF are involved in the abnormal vasculature formation and other features of UF pathophysiology ( Figure 3 ; Tal and Segars, 2014 ). Although the regulation of EGF expression in UFs compared to the myometrium is not clear, a role of EGF in UF growth is supported by the fact that the selective EGF-R blocker AG1478 inhibits UF cell proliferation ( Shushan, 2004 ). Endometrial angiogenesis involves numerous factors and is a fundamental process for generating new capillary blood vessels during menstrual cycles and early pregnancy. It is well documented that UFs exhibit abnormal vasoconstriction including vasocongestion and dilated venous spaces ( Farrer-Brown et al., 1971 ). A recent clinical trial of women with UFs treated with asoprisnil over the course of a year demonstrated an increase in endometrial thickness and cessation of HMB ( Diamond et al., 2019 ). Several studies have demonstrated that angiogenic factors are differentially upregulated in UFs compared to the adjacent and distant myometrium ( Anania et al., 1997 ). In this regard, increased expressions of angiogenic factors and their receptors in UFs may influence endometrial proliferation, ECM formation, angiogenesis, and vascularization and contribute, at least in part, to UF-associated abnormal bleeding. Taken together, changes in the number of active molecules produce an abnormal endometrial environment in UFs that leads to HMB.

Figure 3. Effect of uterine fibroids (UFs) on heavy menstrual bleeding. The presence of UFs causes alterations in the endometrial vascular architecture and function, contributing to increased and prolonged menstrual bleeding. UFs influence the production of angiogenic factors such as VEGF, VEGFA, ET-1, EGF, and PDGF, among others, which support increased angiogenesis. EGF , epidermal growth factor; ET-1 , endothelin 1; PDGF , platelet-derived growth factor; VEGF , vascular endothelial growth factor; VEGFA , vascular endothelial growth factor A.

The Impact of Uterine Fibroids on Fertility

UFs are symptomatic in approximately 30% of cases, causing HMB, pelvic pain, and infertility ( Stewart, 2001 ; Wallach and Vlahos, 2004 ). The impact of UFs on fertility is complex and remains controversial. UFs are present in up to 27% of patients seeking reproductive assistance and may be the only cause of infertility in 1–3% of infertile patients ( Ezzati et al., 2009 ; Cook et al., 2010 ; Guo and Segars, 2012 ). The most common types of UFs are intramural, submucosal, and subserosal. The clinical symptoms are influenced by UF size and anatomical location, and they are characterized by an excessive production of ECM leading to abnormal uterine contractility and decreased blood supply to the endometrium ( Eldar-Geva et al., 1998 ; Casini et al., 2006 ). UFs situated completely or partially within the endometrial cavity usually cause anatomical distortion of the uterine cavity and are implicated in altering endometrial receptivity, with decreased implantation and pregnancy rates ( Pritts et al., 2009 ).

Classification of UFs and Associated Endometrial Dysfunction

UFs are categorized according to their anatomical location into three main types: subserosal, intramural, and submucosa, with the most recent classification described by FIGO 2011 ( Munro et al., 2011 ). Subserosal UFs are the least common type of UFs, protruding to the outside of the uterus (outer surface of the uterus) with minimum extension into the myometrial muscle layer. Consequently, subserosal UFs do not affect fertility, though they might cause minor alterations in uterine contractility and gamete migration. No differences in the rates of implantation, current pregnancy, and live birth were seen when comparing patients with subserosal UFs and those with no UF ( Casini et al., 2006 ; Pritts et al., 2009 ).

Intramural UFs are the most common type and grow within the muscle layer. Depending on their size, intramural UFs can negatively impact fertility. There is broad agreement that intramural UFs that distort the endometrial cavity lead to decreased implantation and pregnancy rates and increased miscarriage rates. However, evidence on the effect of intramural UFs that do not distort the endometrial cavity on reproductive outcomes remains inconsistent. Most studies concur that non-cavity-distorting intramural UFs affect reproductive outcomes to a lesser degree compared to cavity-distorting intramural UFs. A recent study demonstrated abnormal Akt signaling in infertile women with non-cavity-distorting intramural UFs; these women exhibited higher expressions of Akt1, Akt2, p-Akt, and phospho-PTEN and a lower expression of PTEN mRNA in the endometrium compared to fertile women ( Makker et al., 2018 ). In 1998, several studies demonstrated a reduction in the implantation and pregnancy rates in women with intramural UFs regardless of any cavity distortion ( Eldar-Geva et al., 1998 ; Stovall et al., 1998 ). Recent studies have also shown a negative impact of intramural UFs on the implantation [16.4 vs . 27.7%, odds ratio (OR) = 0.62, 95%CI = 0.48–0.8] and delivery (31.2 vs . 40.9%, OR = 0.60, 95%CI = 0.50–0.950) rates in patients undergoing assisted reproduction when compared with patients with no UF ( Benecke et al., 2005 ; Somigliana et al., 2007 ). Similarly, Pritts et al. (2009) performed a systematic review of in vitro fertilization (IVF) and non-IVF patients in relation to the effects of UFs on fertility. The authors confirmed the negative impact of intramural UFs on the fertility outcomes, with lower clinical pregnancy rates (OR = 0.81, 95%CI = 0.696–0.941), implantation (OR = 0.684, 95%CI = 0.587-0.796), and live birth rates (OR = 0.7, 95%CI = 0.583-0.848), along with increased spontaneous abortion rates (OR = 1.7, 95%CI = 1.226–2.489). Additional studies have reported differences in the ECM components and miRNA expression profiles in UFs with or without endometrial cavity distortion. Kim et al. (2018) reported higher expressions of estrogen receptor, matrix metalloproteinases (MMPs), and tissue inhibitors of MMPs (TIMPs) and lower expressions of miR-29c and miR200c in UFs with compared to UFs without distortion of the endometrial cavity.

Submucosal UFs generally bulge into the uterine cavity and are more likely to affect fertility due to their proximity to the endometrium, distortion of the endometrial cavity, and interference with embryo implantation and placentation ( Figure 4 ). The harmful influence of submucosal and large cavity-distorting UFs on reproductive outcomes is well recognized and guides clinical management ( Pritts et al., 2009 ; Olive and Pritts, 2010 ). Approximately 26% of women have had submucosal UFs by the time they reach their late 40s ( Baird et al., 2003 ). In their meta-analysis, Pritts et al. (2009) revealed that patients with submucosal UFs have reduced clinical pregnancy rates [relative risk (RR) = 0.363, 95%CI = 0.179–0.737], implantation rates (RR = 0.318, 95%CI = 0.123–0.649), and ongoing pregnancy/live birth rates (RR = 0.318, 95%CI = 0.119–0.850) and an increased risk of spontaneous miscarriage (RR = 1.678, 95%CI = 1.373–2.051). Interestingly, a recent retrospective study analyzed the long-term fertility consequences after myomectomy relative to the number of UFs removed. They found a direct relationship between the number of UFs removed and fertility problems. UF patients with more than six UFs removed were less likely to achieve pregnancy or carry a birth to full term, and more likely to need fertility treatment, compared to women with six or fewer UFs removed ( Shue et al., 2018 ). Infertility is a multifaceted disorder, and the precise influence of UFs on pregnancy outcomes is difficult to assess. However, it is well documented that submucosal and intramural UFs that alter the uterine cavity have a negative impact on endometrial receptivity, implantation, and live birth rates ( Bulletti et al., 2004 ; Casini et al., 2006 ).

Figure 4. Effect of uterine fibroids (UFs) on endometrial receptivity and implantation. The presence of UFs impacts endometrial gene expression, contributing to failure in endometrial receptivity. In addition, submucosal UFs can distort the uterine cavity, which interferes with embryo implantation and placentation, likely affecting fertility. ALDH3A2 , aldehyde dehydrogenase 3 family member 2; BMP2 , bone morphogenetic protein 2; HOX10 , homeobox gene 10; IL-11 , interleukin 11; LIF , leukemia inhibitory factor; MCP-1 , monocyte chemoattractant protein-1; TGF- β 3 , transforming growth factor beta 3.

Effect of Uterine Fibroids on Endometrial Receptivity and Implantation

Implantation is a process that involves a highly regulated and synchronous development of the embryo and the endometrium to make it amenable to implantation, a process that occurs between 7 and 10 days after ovulation and is known as the window of implantation (WOI) ( Achache and Revel, 2006 ). Endometrial receptivity allows for implantation of the embryo, and it is a multidimensional process of molecular events influenced by hormones, cytokines, growth factors, and other signaling molecules. Any abnormality can lead to implantation failure, early pregnancy loss, or problems conceiving.

Critical Factors in Endometrial Implantation

The family of homeobox genes comprises 39 HOX transcription factors that are fundamental to the proper development of the female reproductive tract and to endometrial development during the menstrual cycle ( Du and Taylor, 2015 ). HOX genes are also crucial to endometrial receptivity; the most relevant are HOXA10 and HOXA11 , which are expressed in the endometrium throughout the proliferative phase and reach a peak in the mid-secretory phase under the influence of progesterone ( Taylor et al., 1998 , 1999 ). The proteins encoded by these genes affect endometrial receptivity by inhibiting or activating target genes including β 3-integrin and Emx2 ( Figure 3 ; Du and Taylor, 2015 ). HOXA10 and HOXA11 are downregulated in the secretory phase of women with low rates of implantation ( Taylor et al., 1999 ; Bagot et al., 2000 ). HOXA10 expression is also reduced in the endometrium of women with submucosal UFs; the reduction is detected throughout the endometrium, but is significantly reduced in the endometrium covering submucosal UFs ( Rackow and Taylor, 2010 ). Endometrial expressions of HOXA10 and HOXA11 increase after myomectomy of intramural UFs, but not submucosal UFs ( Unlu et al., 2016 ). A study analyzing endometrial HOXA10 and HOXA11 levels during the WOI in infertile women with intramural UFs found significantly decreased levels of HOXA10 and HOXA11 and a slight decrease in E-cadherin compared to healthy fertile women ( Makker et al., 2017 ). HOX genes are regulated by BMP2; consequently, increased endometrial resistance to BMP2 could contribute to the low HOXA10 and HOXA11 levels in the endometrium of women with UFs ( Sinclair et al., 2011 ; Doherty and Taylor, 2015 ). Endometrial HOXA10 and HOXA11 expressions are upregulated by progesterone and 17β-estradiol during the mid-secretory phase and improve endometrial receptivity ( Cermik et al., 2001 ).

Numerous studies have analyzed gene expression in endometrial tissue from women with intramural and/or submucosal UFs and women without UF to investigate correlations with endometrial receptivity. These studies identified several genes that are differentially expressed during the mid-secretory phase. However, the genes reported to be significantly altered vary across studies, and the precise mechanism by which gene alterations affect receptivity remains unclear ( Gómez et al., 2015 ; Aghajanova et al., 2017 ). One study investigated gene expressions during the WOI in women with and without intramural UFs and in those without and with observed alterations in aldehyde dehydrogenase 3 family member 2 (ALDH3A2) and the glycodelin expression in women with intramural UFs of >5 cm ( Horcajadas et al., 2008 ). The findings indicated that larger intramural UFs may have a more significant impact on endometrial gene expressions; more studies are needed to better understand this association. In addition, analyses of gene expressions during WOI revealed endometrial dysregulation of the molecules involved in cell adhesion. One study reported the downregulation of E-cadherin and the increased expressions of integrin and osteopontin in women with non-cavity-distorting intramural UFs, as well as an increased pinopode formation ( Bentin-Ley, 2000 ; Apparao et al., 2001 ; Lessey, 2002 ). Recently, a very well-designed study investigated the association between the expressions of endometrial receptivity genes and essential endometrial functions such as decidualization, proliferation, and apoptosis in women with UFs. Women with UFs demonstrated significantly altered transcriptional patterns throughout the menstrual cycle compared to healthy women, although no significant differences were observed in the expressions of receptivity and decidualization genes ( Aghajanova et al., 2017 ).

A significant number of endometrial events are crucial to boost endometrial receptivity, which requires a complex interchange among paracrine and autocrine factors such as cytokines, chemokines, their receptors, and secondary messengers. The surge in progesterone following ovulation leads to decidualization of the endometrium and is characterized by rising levels of VEGF, prostaglandins, and immune cells (macrophages and natural killer cells) ( Wang et al., 2000 ; Lee et al., 2015 ). During decidualization, there is an increase in endometrial blood vessel permeability and the production of cytokines necessary for implantation, such as leukocyte inhibitory factor (LIF), which is a marker of the WOI. Successful embryo implantation is the result of a bidirectional invasive process that is coordinated by decidual markers including LIF, prolactin, insulin-like growth factor-binding protein 1 (ILGFBP1), and IL-11. LIF and IL-11 are crucial decidual markers for embryo implantation ( Stewart et al., 1992 ; Dimitriadis et al., 2005 ; Hasegawa et al., 2012 ). These factors bind to their respective ligand-specific receptors, LIFR and IL-11R, which share the same signal transduction target, gp130. Murine studies have demonstrated that the gp130 pathway is vital for embryo implantation and that its inactivation leads to failure of implantation ( Ernst et al., 2001 ). LIF is a key player in the endometrium and is required for decidualization; embryos from mice lacking LIF are unable to implant in the endometrium of mice lacking LIF, but are able to implant in the endometrium of wild-type mice ( Stewart et al., 1992 ; Robb et al., 1998 ). In several human studies, the LIF levels were shown to be upregulated in the luteal phase and reach their highest expression levels during WOI; in contrast, women with submucosal UFs show decreased levels of LIF during the luteal phase. Additionally, a recent study demonstrated that LIF is significantly downregulated in the endometrium of women with large (≥3 cm) and non-cavity-distorting intramural UFs ( Pier et al., 2020 ). Once the embryo has attached to the endometrium, IL-11 moderates trophoblast invasion. Reduced levels of IL-11 lead to decreased levels of natural killer (NK) cells in the secretory endometrium and to early pregnancy loss in mice and humans ( Hasegawa et al., 2012 ). The presence of submucosal UFs leading to reduced IL-11 during the WOI may thus cause implantation problems ( Hambartsoumian, 1998 ).

Progesterone is vital for decidualization and the production of immune cells, such as macrophages and NK cells. Macrophages secrete crucial cytokines for implantation, such as LIF, and they are critical during trophoblast invasion and placental development ( Miura et al., 2006 ; Jensen et al., 2012 ; Helige et al., 2014 ). During the WOI, NK cells are the predominant immune cells and are critical regulators of immunotolerance, trophoblast migration and invasion, and angiogenesis. NK cells secrete VEGF and placental growth factor, both of which play a role in trophoblast invasion and maternal uterine vasculature remodeling ( Wang et al., 2000 ; Tayade et al., 2007 ). Murine studies have shown that mice lacking NK cells are able to achieve pregnancy, but they have significant rates of fetal loss, preeclampsia, and intrauterine growth restriction ( King, 2000 ). Human studies of the mid-secretory endometrium of women with and without UFs demonstrated a rise in macrophage production and a reduction in the production of NK cells ( Kitaya and Yasuo, 2010b ). The dysregulated levels of NK cells and macrophages lead to abnormal endometrial function and may contribute to failure in endometrial receptivity and implantation. Moreover, women with UFs have greater expression of MCP-1, which is associated with a higher density of macrophages and PGF2α and an inflammatory effect in the endometrium. Recent studies analyzed the endometrial flushing levels to check for endometrial receptivity markers and found a significant reduction in the IL-2 levels, but no significant differences in PGF 2 α, ανβ 3 integrin, and TNF-α in women with UFs compared to healthy women ( Demir et al., 2017 , 2019 ). The same study found only a slight increase in glycodelin in women with UFs.

Growth factors play crucial roles in decidualization and implantation, and they are dependent on progesterone. Important growth factors include members of the TGF-β family, such as heparin-binding epidermal growth factor (HB-EGF), which stimulates the secretion of BMP2 and its downstream target member WNT4 ( Paria et al., 2001 ; Li et al., 2013 ). The stimulation of BMP2 levels by progesterone seems to be essential for WNT4 activation and, consequently, implantation. Murine studies have demonstrated that mice lacking BMP2 are incapable of achieving endometrial decidual differentiation ( Lee et al., 2007 ; Li et al., 2007 ). Though embryo attachment is achievable, the lack of decidual differentiation leads to faulty implantation and pregnancy loss. Human studies have shown that BMP2 resistance occurs in submucosal UFs, and this resistance adversely affects cell proliferation and differentiation, leading to impaired decidualization and faulty implantation. Most women with submucosal UFs secrete higher levels of TGF-β3, a factor that impairs the signaling of BMP2 in the endometrium and is associated with defective embryo implantation in UFs ( Lee et al., 2007 ). In general, studies have shown a direct correlation of the expression level of TGF-β and UF burden. Significantly, lower levels of BMP2 are associated with decreased endometrial stromal cell expressions of HOXA10 and LIF ( Sinclair et al., 2011 ), a higher rate of spontaneous abortions, and a lower rate of implantation.

In summary, it is critical to understand how UFs affect the normal physiology of the endometrium and lead to two of the most common endometrial dysfunctions: HMB and subfertility. There is a crucial need for non-invasive treatment options and anti-fibroid therapeutics, which disproportionally affect African American women and cause a significant burden on women’s everyday quality of life. In general, it is believed that UFs cause abnormal menstrual bleeding by altering local and distant endometrial gene expressions, which subsequently alters endometrial function. UFs affect the normal endometrium by modifying the vascular architecture, impairing the normal contractility, and altering the production of angiogenic factors ( Figure 2 ; VEGF, VEGFA, and ET-1), cytokines (TNF-α), chemokines, growth factors (TGF-β, bFGF, EGF, PDGF, and PDEF), prostaglandins (PGF2α), and factors involved in coagulation and fibrinolysis (PAI1, tPA, ATIII, and TM). It is of paramount importance to investigate the mechanisms underlying HMB and subfertility secondary to decreased receptivity and implantation in women with UFs and to better understand the processes underlying UF pathophysiology so that new therapeutics can be identified.

Overall, some of the main factors that affect fertility in women with UFs are distortion of the endometrium and uterine cavity, interference with the normal patterns of endocrine function, abnormal uterine vascularization, endometrial inflammation, and dysfunctional uterine contractility ( Rogers et al., 2008 ; Rackow and Taylor, 2010 ; Norian et al., 2012 ). The impact of submucosal and intramural UFs that distort the uterine cavity is well documented, with negative effects on endometrial receptivity, implantation, and pregnancy, increased miscarriage rates, and decreased live birth rates ( Pritts et al., 2009 ). However, the effect of endometrial non-cavity-distorting intramural UFs remains inconsistent, with most studies concurring that they affect reproductive outcomes to some extent, but to a lesser degree. Several mechanisms have been proposed to explain the effects of UFs on fertility, including simple physical impedance by obstructing the transport of gametes or embryos. Other mechanisms delay implantation by altering the normal pattern of myometrial contractions ( Lyons et al., 1991 ), inducing a chronic inflammatory reaction and fibrosis, and impairing endometrial decidualization in the mid-luteal WOI by significantly reducing the concentrations of both macrophages and uNK cells in the EMJ zone ( Kitaya and Yasuo, 2010a ; Kido et al., 2014 ). Physical disruptions of the EMJ and alteration of the steroid receptors, acceleration of myometrial peristalsis in the mid-luteal period, and upregulation of the prolactin and aromatase levels are additional mechanisms by which UFs may affect fertility ( Brosens et al., 2003 ; Tocci et al., 2008 ; Yoshino et al., 2010 ).

The field continues to advance with innovative studies examining the impact of UF-derived exosomes on the human endometrium and the impact of UFs on the endometrial microbiome ( Figure 5 ), and this is an area of active investigation in our lab. Though limited data are available, it is hypothesized that the UF secretome is delivered to the human endometrium via exosomes, which affect critical biological functions including menstrual bleeding, endometrial receptivity, and implantation. Exosomes are vesicles ranging from 30 to 150 nm, derived from the fusion of multivesicular bodies with the plasma membrane and are secreted by a variety of cells. They consist of a lipid bilayer membrane and contain various functionally active proteins, mRNAs, and miRNAs that are delivered to target cells and tissues. Exosomes play crucial physiological roles as mediators of intercellular cell signaling between neighboring cells and distant tissues, acting independently but synergistically with soluble factors and hormones ( Di Pietro, 2016 ). One preliminary study by Brakta et al. (2015) characterized exosomes derived from human UF stem cells. The authors described a significantly higher exosome production and an increased cell proliferation under hypoxic conditions compared to normoxic conditions. There is consensus that the vagina is colonized with bacteria, while the uterus and the rest of the upper reproductive tract are considered sterile. However, recent studies have demonstrated the presence of bacteria continuum throughout the reproductive female tract, challenging the traditional dogma ( Chen et al., 2017 ). The role of the endometrial microbiome under normal physiological conditions and in disease conditions is an area of active investigation, and currently, research in our team is focusing on the impact of an altered microbiome in women with UFs. Most endometrial microbiome studies have focused on pregnancy, leaving a significant gap in our understanding of the role of the microbiome in UFs. The term “estrobolome” was recently coined to describe the secretion of circulating estrogens and their impact on the microbiome. We predict that the estrobolome plays a crucial role in UF pathophysiology, as fibroids are estrogen- and progesterone-dependent, and endometrial microbiome dysbiosis may contribute to modifications in the normal actions of estrogen in women with UFs. In the absence of a well-defined catalog of endometrial microbiota, we postulate that the presence of UFs impacts the composition of the endometrial microbiome ( Figure 5 ). Recently, Dr. El Andaloussi was the first to report a 16S rRNA screen of the microbiome in human UF. His study demonstrated a higher alpha and beta diversity in the endometrium of women with UFs compared to a healthy endometrium ( El Andaloussi et al., 2020 ). Investigating the effect of UFs on the endometrial microbiome may lead to the development of novel non-hormonal, non-invasive treatment options for UFs and its associated endometrial dysfunctions. Overall, there is an urgent need to discover novel therapeutics for the treatment of UFs, a common disease with a huge personal and societal burden globally and in the United States, affecting critical reproductive functions like menstrual bleeding and fertility.

Figure 5. Proposed model of future directions in the uterine fibroid (UF) field. The presence of UFs causes alterations in the healthy endometrial microbiome and changes in the exosome content, leading to increased factors involved in cell proliferation, angiogenesis, and inflammation, among others. This creates a vicious cycle contributing to increased and prolonged heavy menstrual bleeding in women with UFs.

Author Contributions

AN and MVB designed the review, performed the literature search, and wrote the manuscript. QY and AA-H performed revisions and critically discussed and reviewed the complete manuscript. All authors contributed to the article and approved the submitted version.

This work was supported in part by the National Institute of Health grants: R01-HD094378, R01-ES028615, R01-HD094380, and U54-MD007602.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

The figures were created using BioRender.com .

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Keywords : uterine fibroids, endometrium, heavy menstrual bleeding, endometrial receptivity, implantation, subfertility, transforming growth factor beta

Citation: Navarro A, Bariani MV, Yang Q and Al-Hendy A (2021) Understanding the Impact of Uterine Fibroids on Human Endometrium Function. Front. Cell Dev. Biol. 9:633180. doi: 10.3389/fcell.2021.633180

Received: 24 November 2020; Accepted: 13 April 2021; Published: 25 May 2021.

Reviewed by:

Copyright © 2021 Navarro, Bariani, Yang and Al-Hendy. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Ayman Al-Hendy, [email protected]

This article is part of the Research Topic

Hype or Hope: New Frontiers in Endometrial Research

Current Trends in the Evaluation and Management of Uterine Fibroids

Reproductive Endocrinology and Infertility (REI) (R Anchan, Section Editor)
Published: 28 March 2022
Volume 11 , pages 125–132, ( 2022 )

Cite this article

Anna C. Vanderhoff ORCID: orcid.org/0000-0002-5097-4917 1 , 2 ,
Jason Silberman 2 , 3 &
Antonio R. Gargiulo 1 , 2

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Purpose of Review

Evaluation and management of uterine fibroids is an ever evolving area of medicine, impacting a large percentage of the female population. We present contemporary trends in evidence-based practice and research.

Recent Findings

Point of care intraoperative ultrasound may improve surgical ability to detect and remove small myomas, improving surgical success and decreasing the likelihood of fibroid recurrence. Imaging modalities including elastography, augmented reality, and 3D printing are not currently optimized for clinical practice but offer promise as potential avenues through which to better gauge tumor burden. Pregnancies have been reported after uterine artery embolization and radiofrequency ablation for fibroid management, but the rate of pregnancy loss is substantial, and additional information regarding fertility and pregnancy outcomes after non-surgical intervention for treatment of fibroids is needed before these technologies can find safe applicability in women who have not completed childbearing. Robotic myomectomy may have advantages over laparoscopic myomectomy in the hands of skilled operators. Non-cavity distorting intramural fibroids are clearly associated with reduced odds of live birth in an infertile patient population, but additional research is needed to indicate whether removal of these tumors improves fertility and pregnancy outcomes.

The high prevalence of fibroids in the general population results in a high incidence of fibroid-associated morbidity and high frequency of gynecology visits for discussion of fibroid management. MRI remains the gold standard imaging modality for pre-operative evaluation of fibroids. There is data to support the use of both GnRH-agonists and GnRH-antagonists as short-term treatment strategies. These medications can be used to optimize patients prior to surgery. Selective progesterone receptor modulators (SPRMs) are not currently approved in the USA, but nonetheless they remain a promising option for the medical treatment of uterine fibroids in the future. There is a growing body of literature on the role of non-surgical intervention (UAE, radiofrequency ablation, MR-guided ultrasound) for the treatment of fibroids, but there is insufficient data on fertility and pregnancy outcomes to recommend these strategies as first-line treatment to women desiring future fertility. Ultimately, surgery is the most definitive fibroid management option. Minimally invasive myomectomy is associated with improved outcomes when compared to open myomectomy, but choice of surgical management should be guided by fibroid burden as well as patient preference and—ultimately—surgeon experience.

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Treatment Modalities for Fibroids, Indications, Risks, and Benefits

Management of Fibroids

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Vanderhoff, A.C., Silberman, J. & Gargiulo, A.R. Current Trends in the Evaluation and Management of Uterine Fibroids. Curr Obstet Gynecol Rep 11 , 125–132 (2022). https://doi.org/10.1007/s13669-022-00331-w

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New research reveals important discovery for women who have fibroids

Published: 30 July 2020

New research findings will help women and doctors make an informed decision about treatment of uterine fibroids.

The NIHR-funded FEMME trial led by a collaborative group of researchers at the University of Oxford, St George’s Hospital London, and the Universities of Birmingham and Glasgow, compared two competing treatments which allow fertility for symptomatic uterine fibroids, to see which option best reduced symptoms and improved the patient’s quality of life.

The results from the trial, which published in the New England Journal of Medicine , showed that myomectomy, a surgical procedure performed to remove uterine fibroids, resulted in a small but significantly higher quality of life compared with uterine artery embolisation (UAE). UAE is a minimally invasive procedure which shrinks the fibroids by placing tiny beads into the blood vessels which supply them.

A fibroid is a non-cancerous growth of the womb, with 1 in 3 women developing them at some point in their life. They most often occur in women aged 30-50 and develop more frequently in women of African-Caribbean family origin. Approximately half of women with uterine fibroids experience significant symptoms that can include heavy menstrual bleeding, abdominal pain and bloating.

Fibroids may also be associated with infertility and problems during pregnancy, including miscarriage and preterm birth. As more women are having children at a later age, fibroids are becoming more of an issue for them and safe and effective fertility sparing treatments are needed.

Two hundred and fifty-four eligible women, wishing to reduce fibroid symptoms were recruited from over 29 UK hospitals to participate in the trial. Researchers compared the two fertility preserving treatments for uterine fibroids on two patient groups. The first patient group comprised of women with an intention to conceive whilst the second group was made up of black women (who have a particularly high incidence of uterine fibroids).

The women were randomised to receive either a myomectomy or UAE procedure. The trial revealed that contrary to popular belief, rates of conception were shown to be broadly similar between the myomectomy and UAE group. Although too few trial participants were trying to get pregnant to be able to determine with certainty whether there was an impact of either treatment on pregnancy rates, which was higher in the UAE group.

Klim McPherson, Visiting Professor of Public Health Epidemiology at Oxford University and study Chief Investigator, said: “These findings are important and reveal new evidence for our understanding of the best treatment for women with fibroids who wish to avoid a hysterectomy.

“It is worth noting that the myomectomy group reported only marginally higher quality of life score than the Uterine Artery Embolisation group, although on average women in both groups saw improvements. Interestingly, the perceived drawback associated with embolisation, that it might affect the working of the ovaries, was not supported by the evidence in this trial.”

Professor Andy Shennan, Professor of Obstetrics, and Clinical Director NIHR Clinical Research Network South London, said, “This work is a major contribution to knowledge on the management of the most common tumour in women of reproductive age. The researchers found a significant but small advantage for myomectomy in terms of quality of life, while observing slightly more pregnancies in the UAE arm, which provides wider treatment choices for women with symptomatic fibroids.”

The study was funded by the NIHR Health Technology Assessment Programme

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Published: 23 June 2016

Uterine fibroids

Elizabeth A. Stewart 1 ,
Shannon K. Laughlin-Tommaso 1 ,
William H. Catherino 2 ,
Sujata Lalitkumar 3 ,
Devashana Gupta 4 , 5 , 6 &
Beverley Vollenhoven 4 , 5 , 6

Nature Reviews Disease Primers volume 2 , Article number: 16043 ( 2016 ) Cite this article

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Reproductive disorders

Uterine fibroids (also known as leiomyomas or myomas) are common clonal neoplasms of the uterus. Fibroids have both smooth muscle and fibroblast components, in addition to a substantial amount of fibrous extracellular matrix, which all contribute to the pathogenetic process. Fibroids are extremely heterogeneous in their pathophysiology, size, location and clinical symptomatology. They are also a part of a range of disease in which some variants have facets of malignant behaviour but overall are benign. Risk for fibroids is associated with race; black women have a higher risk of developing fibroids earlier in life than their white counterparts and also develop more-severe forms of the disease. Clinically, fibroids account for one-third to half of all hysterectomies and are associated with substantial morbidity and health care costs for women of reproductive age. Indeed, current treatments are primarily surgical and interventional; approximately three-quarters of all fibroid treatments are hysterectomies. However, clinical innovations are emerging in the use of progesterone receptor modulators as a medical therapy. New information is rapidly accumulating about the genetic subgroups that lead to fibroid formation, which might aid further understanding of the clinical heterogeneity of this disease and lead to individualized treatments. This information is a crucial development given the current lack of high-quality evidence on which to base therapeutic decisions.

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Acknowledgements

E.A.S. has received research support from the US NIH (R01HD060503, P50HS023418 and R01HD074711) and from Insightec Inc. The authors acknowledge the technical assistance of D. Littlefield.

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Elizabeth A. Stewart & Shannon K. Laughlin-Tommaso

Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA

William H. Catherino

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Sujata Lalitkumar

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Devashana Gupta & Beverley Vollenhoven

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Introduction (E.A.S.); Epidemiology (S.K.L.-T.); Mechanisms/pathophysiology (E.A.S., B.V. and D.V.); Diagnosis, screening and prevention (W.H.C.); Management (E.A.S. and S.L.); Quality of life (E.A.S. and S.L.); Outlook (E.A.S.); Overview of Primer (E.A.S.).

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Correspondence to Elizabeth A. Stewart .

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Competing interests.

E.A.S. is a consultant for AbbVie, Allergan, Astellas Pharma, Bayer Health Care, Gynesonics and Viteava and has received royalties from UpToDate and the Massachusetts Medical Society. S.K.L.-T. has received research support from InSightec and support for consulting from Truven Health Analytics and for serving on the data monitoring board for ULTRA trail from HALT medical. She is an author for UpToDate. W.H.C. has received research support from Bayer Schering Pharma and Patient-Centered Outcomes Research Institute (PCORI), and is a consultant for AbbVie Pharmaceuticals and Actavis. He is an oral boards examiner for the American Board of Obstetrics and Gynecology and a content Review Committee for the American Society of Reproductive Medicine. S.L., B.V. and D.G. declare no competing interests.

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Stewart, E., Laughlin-Tommaso, S., Catherino, W. et al. Uterine fibroids. Nat Rev Dis Primers 2 , 16043 (2016). https://doi.org/10.1038/nrdp.2016.43

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DOI : https://doi.org/10.1038/nrdp.2016.43

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