I have written several articles on the coronavirus and on masks and healthcare issues. A series of links have been provided at the bottom of this article for your convenience. This article will, however address a different aspect of the virus or on healthcare issues in general.
I am writing this article because Fibroid Tumors have just recently come into my life. Yes my wife has a fibroid tumor, thatshe will be having emoved this winter. According to the OBGYN it is benign and need only be removed if it is affecting her adversely. Well it is so it is coming out. Now this brings me to the reason for this article. Are fibroid tumor strickly a homo sapien maifestation or are they common in other species as well? If they are strictly found in humans, then why? Is it a recent occurance and if so is it environmentally affected? These are all questions I would like answered. We all know how chemicals can affect our health, so why couldn’t they be caused by chemicals in our nvironment or diet? I will do my best to find the answers. I will start by discussing what they are and then go from there.
I’m Dr. Michelle Louie, a minimally invasive gynecologic surgeon at Mayo Clinic. In this video, we’ll cover the basics of uterine fibroids. What is it? Who gets it? The symptoms, diagnosis, and treatment. Whether you’re looking for answers for yourself or someone you love. We’re here to give you the best information available. Uterine fibroids, also called leiomyomas or myomas, are growths that appear in the uterus. They’re made of uterine muscle. They’re noncancerous and extremely common. In fact, 75 to 80% of people with a uterus will be diagnosed with fibroids at some point in their lives. These growths often show up during the reproductive years, most commonly in your 20s to 30s. They can range in quantity, size and growth rate. So each case is a bit different.Who gets it?
We believe uterine fibroids occur when one cell of muscle divides repeatedly to create a firm, rubbery mass of tissue. Scientists are not yet sure exactly what sparks this behavior, but we’re looking into specific genes. We do know a couple of risk factors that may make someone more likely to get fibroids. First, race. For reasons that are unclear, fibroids are more prevalent and more severe among black patients compared to other racial groups. Second, family history. If your mother or sister had fibroids, you’re at increased risk for developing them, too. And more studies look into other risk factors like obesity, lifestyle choices, and diet.What are the symptoms?
Most people with fibroids don’t have symptoms at all. That’s why they’re often found unintentionally during a routine checkup. If a patient does have symptoms, heavy, prolonged, or painful menstrual bleeding is a common problem. Periods that lasts more than one week or cause soaking through pads or tampons every hour or large blood clots are also considered abnormal. If fibroids get very large, they can cause your belly to bulge like a pregnancy or press on nearby organs causing constant pelvic pressure, frequent urination, or difficulty passing bowel movements. In some cases, fibroids can make it harder to get pregnant or cause problems during pregnancy or childbirth. If you’re experiencing any of these symptoms, talk to your doctor.How is it diagnosed?
Fibroids are often found during a routine pelvic exam. If your doctor feels an irregularity in the shape of the uterus or if you come in with symptoms, they’ll probably order a diagnostic test like an ultrasound. Beyond that, your doctor may need more information, especially if you’re trying to get pregnant or at risk for uterine cancer. They might order blood tests or imaging studies like an MRI. Sometimes other unique imaging studies that use water to see inside the uterus or dye to check the fallopian tubes are needed if you’re trying to get pregnant. Even hysteroscopy, in which a small camera is guided through the vagina, is sometimes used to see inside the uterus where some fibroids can be located. All these tests are done in service of getting a better, clearer picture of what’s going on or to check for other problems.How is it treated?
There are many ways in which we treat uterine fibroids. If you have no or only mild symptoms, as many women do, the best treatment may be no treatment at all. We call this watchful waiting where we keep a careful eye on your fibroids until further action is needed. Medication or birth control is another option which can relieve symptoms like heavy, irregular or painful periods. For some more severe cases, surgery may be needed. The kind of surgery we recommend depends on the size, number, and location of fibroids, as well as your personal goals, feelings about pregnancy and surgery, and general health. A hysterectomy is where the uterus and the fibroids are removed together. And it is a great option for those who have no desire for pregnancy as it guarantees no more period bleeding and the fibroids cannot return in the future. A myomectomy is a surgery in which we remove the fibroids through the vagina or the abdominal wall. Uterine fibroid embolization is a more minor procedure in which we blocked the blood supply to the fibroids, causing them to shrink but not go away completely. A radiofrequency fibroid ablation is where a probe is inserted into the fibroid and heats the tissue, so it shrinks. Magnetic resonance-guided focused ultrasound passes energy through the abdomen to destroy the fibroid. Lastly, an endometrial ablation is a procedure in which a device is inserted through the vagina to treat the uterine lining, and stop heavy period bleeding due to fibroids. But this does not treat the fibroids themselves.What now?
Fibroids are common, noncancerous and often don’t need treatment. Whether or not you do end up needing treatment, know that there are many options that can address your concerns and give you a great quality of life. Talk to your doctor or get a referral to a fibroid specialist to ensure that you are offered all the treatment options. If you’d like to learn more about fibroids, watch our other related videos, or visit mayoclinic.org. We wish you well.Fibroid locationsOpen pop-up dialog box
Uterine fibroids are noncancerous growths of the uterus that often appear during childbearing years. Also called leiomyomas (lie-o-my-O-muhs) or myomas, uterine fibroids aren’t associated with an increased risk of uterine cancer and almost never develop into cancer.
Fibroids range in size from seedlings, undetectable by the human eye, to bulky masses that can distort and enlarge the uterus. You can have a single fibroid or multiple ones. In extreme cases, multiple fibroids can expand the uterus so much that it reaches the rib cage and can add weight.
Many women have uterine fibroids sometime during their lives. But you might not know you have uterine fibroids because they often cause no symptoms. Your doctor may discover fibroids incidentally during a pelvic exam or prenatal ultrasound.
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Many women who have fibroids don’t have any symptoms. In those that do, symptoms can be influenced by the location, size and number of fibroids.
In women who have symptoms, the most common signs and symptoms of uterine fibroids include:
- Heavy menstrual bleeding
- Menstrual periods lasting more than a week
- Pelvic pressure or pain
- Frequent urination
- Difficulty emptying the bladder
- Backache or leg pains
Rarely, a fibroid can cause acute pain when it outgrows its blood supply, and begins to die.
Fibroids are generally classified by their location. Intramural fibroids grow within the muscular uterine wall. Submucosal fibroids bulge into the uterine cavity. Subserosal fibroids project to the outside of the uterus.
When to see a doctor
See your doctor if you have:
- Pelvic pain that doesn’t go away
- Overly heavy, prolonged or painful periods
- Spotting or bleeding between periods
- Difficulty emptying your bladder
- Unexplained low red blood cell count (anemia)
Seek prompt medical care if you have severe vaginal bleeding or sharp pelvic pain that comes on suddenly.
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Doctors don’t know the cause of uterine fibroids, but research and clinical experience point to these factors:
- Genetic changes. Many fibroids contain changes in genes that differ from those in typical uterine muscle cells.
- Hormones. Estrogen and progesterone, two hormones that stimulate development of the uterine lining during each menstrual cycle in preparation for pregnancy, appear to promote the growth of fibroids.Fibroids contain more estrogen and progesterone receptors than typical uterine muscle cells do. Fibroids tend to shrink after menopause due to a decrease in hormone production.
- Other growth factors. Substances that help the body maintain tissues, such as insulin-like growth factor, may affect fibroid growth.
- Extracellular matrix (ECM). ECM is the material that makes cells stick together, like mortar between bricks. ECM is increased in fibroids and makes them fibrous. ECM also stores growth factors and causes biologic changes in the cells themselves.
Doctors believe that uterine fibroids develop from a stem cell in the smooth muscular tissue of the uterus (myometrium). A single cell divides repeatedly, eventually creating a firm, rubbery mass distinct from nearby tissue.
The growth patterns of uterine fibroids vary — they may grow slowly or rapidly, or they may remain the same size. Some fibroids go through growth spurts, and some may shrink on their own.
Many fibroids that have been present during pregnancy shrink or disappear after pregnancy, as the uterus goes back to its usual size.
There are few known risk factors for uterine fibroids, other than being a woman of reproductive age. Factors that can have an impact on fibroid development include:
- Race. Although all women of reproductive age could develop fibroids, black women are more likely to have fibroids than are women of other racial groups. In addition, black women have fibroids at younger ages, and they’re also likely to have more or larger fibroids, along with more-severe symptoms.
- Heredity. If your mother or sister had fibroids, you’re at increased risk of developing them.
- Other factors. Starting your period at an early age; obesity; a vitamin D deficiency; having a diet higher in red meat and lower in green vegetables, fruit and dairy; and drinking alcohol, including beer, appear to increase your risk of developing fibroids.
Although uterine fibroids usually aren’t dangerous, they can cause discomfort and may lead to complications such as a drop in red blood cells (anemia), which causes fatigue, from heavy blood loss. Rarely, a transfusion is needed due to blood loss.
Pregnancy and fibroids
Fibroids usually don’t interfere with getting pregnant. However, it’s possible that fibroids — especially submucosal fibroids — could cause infertility or pregnancy loss.
Fibroids may also raise the risk of certain pregnancy complications, such as placental abruption, fetal growth restriction and preterm delivery.
Although researchers continue to study the causes of fibroid tumors, little scientific evidence is available on how to prevent them. Preventing uterine fibroids may not be possible, but only a small percentage of these tumors require treatment.
But, by making healthy lifestyle choices, such as maintaining a healthy weight and eating fruits and vegetables, you may be able to decrease your fibroid risk.
Also, some research suggests that using hormonal contraceptives may be associated with a lower risk of fibroids.
Fibroids: What You Need to Know
- Uterine fibroids are an extremely common condition in which solid tumors develop in the uterus.
- Fibroids are not cancerous and do not increase the risk for uterine cancer.
- It is not known what causes fibroids, but studies suggest genetics and prolonged exposure to estrogen may increase your risk of developing fibroids.
- Symptoms can include heavy and prolonged periods, bleeding between periods, pressure in the abdomen and pelvic pain.
- Fibroids are most often found during a routine pelvic exam or incidentally noted on imaging. If treatment is needed, it may include medications or surgery.
What are fibroids?
Fibroids are growths made of smooth muscle cells and fibrous connective tissue. These growths develop in the uterus and appear alone or in groups. They range in size, from as small as a grain of rice to as big as a melon. In some cases, fibroids can grow into the uterine cavity or outward from the uterus on stalks.
An estimated 20% to 50% of women of reproductive age currently have fibroids, and up to 77% of women will develop fibroids sometime during their childbearing years. Only about one-third of these fibroids are large enough to be detected by a health care provider during a physical exam, so they are often undiagnosed.
In more than 99% of fibroid cases, the tumors are not cancerous and do not increase the risk for uterine cancer.
What causes fibroids?
The cause of fibroids is not known. Research suggests each tumor develops from an abnormal muscle cell in the uterus and multiplies rapidly when encountering the estrogen hormone, which promotes the tumor’s growth.
Who is at risk for fibroids?
Women in their reproductive age are most likely to be affected by fibroids.
Other risk factors may include:
- Family history of fibroids
- Diet high in red meat
- High blood pressure
Black women are more likely to develop fibroids than other women, they are diagnosed at younger ages and they more often require treatment. It is not clearly understood why fibroids disproportionately affect Black women.
It is common that women who have fibroids do not experience any noticeable symptoms. Other women with fibroids experience severe symptoms that interfere with their daily lives. Common fibroid symptoms include:
- Heavy or prolonged periods
- Bleeding between periods
- Abdominal discomfort and/or fullness
- Pelvic pain
- Lower back pain
- Bladder symptoms, such as frequent urination or difficulty emptying the bladder
- Bowel symptoms, such as constipation or excessive straining with bowel movements
Women with fibroids can also experience:
- Complications during pregnancy
- Pain during intercourse
Emergency Fibroid Symptoms
In rare cases, women with fibroids need emergency treatment. You should seek emergency care if you have sharp, sudden pain in the abdomen that is unrelieved with pain medication, or severe vaginal bleeding with signs of anemia such as lightheadedness, extreme fatigue and weakness.
How are fibroids diagnosed?
Fibroids are most often found during a routine pelvic exam. During this exam, your health care provider will press on your abdomen and may feel a firm, irregular mass that might indicate a fibroid.
To diagnose uterine fibroids, your doctor may order one of the following tests:
- Pelvic Ultrasound. A procedure during which a small instrument, called a transducer, is either inserted into the vagina or pressed over the abdomen to produce pictures of the internal organs using sound waves. The doctor can see the size, shape and texture of the uterus and evaluate any growths.
- Magnetic resonance imaging (MRI). This is a form of advanced imaging technology that provides highly detailed images of internal organs. These images help your provider determine the exact location and characteristics of fibroids and, if needed, plan minimally invasive treatments.
- Hysterosalpingography. This is a type of X-ray exam of the uterus and fallopian tubes. Your doctor will use a special dye to more easily visualize these organs and determine if the fibroids have blocked your fallopian tubes.
- Hysteroscopy. This is a visual exam of the canal of the cervix and the interior of the uterus using a viewing instrument (hysteroscope) inserted through the vagina.
How are fibroids treated?
Since the growth of most fibroids slows as you approach menopause, your health care provider may simply suggest “watchful waiting” if your symptoms are tolerable. With this approach, the health care provider closely monitors your symptoms with frequent follow-up visits and ultrasounds to make sure there are no significant changes in your condition.
Treatment may be necessary if your fibroids cause significant symptoms. Treatment options include medicinal and surgical approaches. Your doctor will recommend treatment based on your symptoms, location and size of the fibroids, your age and medical history, and your health goals such as a desire for pregnancy.
In some cases, women also require treatment for iron-deficiency anemia due to heavy or prolonged periods, or because of abnormal bleeding between periods.
Medicinal Treatment Options
Anti-inflammatory painkillers such as ibuprofen or naproxen may reduce menstrual bleeding caused by fibroids and provide pain relief. This is the most conservative treatment method and is recommended for women with occasional pelvic pain or discomfort due to fibroids.
Hormonal treatment can include:
- Gonadotropin-releasing hormone agonists (GnRH agonists). This treatment lowers your estrogen level and triggers a temporary “medical menopause.” GnRH agonists are used to shrink the fibroid(s). They are also used to stop your period in preparation for surgery or to improve your blood count. Doctors will not typically administer this medication for longer than a year — and the medication’s effects are reversed once it leaves your system.
- Oral contraceptive pills (or a patch or vaginal ring) can help reduce bleeding associated with fibroids.
- Progesterone-containing agents — pills, implant, injection or intrauterine device (IUD) — may also control bleeding.
Procedural Treatment Options
Conservative surgical therapy. Myomectomy is a procedure during which the fibroids are removed but the uterus stays intact. This approach is recommended for women who want to preserve their fertility. There are three primary myomectomy methods:
- Traditional open myomectomy. The procedure is performed via an abdominal incision and carries some risks, including bleeding and scar tissue formation at the incision site and a longer recovery. This approach may be necessary depending on the size and number of fibroids.
- Laparoscopic or robotic myomectomy. This outpatient procedure uses small “keyhole” abdominal incisions and a laparoscope. This minimally invasive approach often results in less bleeding and a faster recovery, but it is not suited for all patients. Most patients go home the day of surgery and recover within a few weeks. Your doctor will determine if you are a good candidate for this procedure.
- Hysteroscopic myomectomy. During this outpatient procedure, your doctor uses a camera inserted through the vagina to shave off visible portions of the fibroid tumors. This method only treats fibroids that have formed inside the uterine cavity.
Uterine artery embolization (UAE), also called uterine fibroid embolization, is a newer technique. This minimally invasive procedure shrinks fibroids by cutting off their blood flow. An interventional radiologist performs UAE, using X-rays for guidance. Health care providers are looking at this procedure’s long-term implications regarding fertility and regrowth of the fibroid tissue.
Magnetic resonance guided focused ultrasound, also a newer technique, focuses sound waves on fibroids that are at the front of the uterus. The potential effects on fertility are not yet understood.
Radiofrequency ablation of fibroids is another newer technique, during which — under laparoscopic and ultrasound guidance — heat is applied into the fibroids to make them smaller and softer. The potential effects on fertility are not currently well understood.
Hysterectomy for Fibroids
During a hysterectomy, the entire uterus is removed. Fibroids are the #1 reason for hysterectomies in the U.S.
The procedure can be performed vaginally or abdominally via a large incision, laparoscopically or robotically, depending on the size of your uterus, location of the fibroids and your medical history.
Because a hysterectomy is a major surgery, it is only recommended to treat fibroid cases for women who are not interested in preserving their fertility. It is the most effective method of fibroid treatment because it eliminates the possibility of recurrence.
Fibroids and Pregnancy
Uterine fibroids can affect fertility in a variety of ways. If fibroids grow and block the uterus or fallopian tubes, they may make it harder to become pregnant. They may also have other negative effects on pregnancy including:
- Increased risk of miscarriage and preterm labor
- Abnormal attachment of the placenta
- Increased likelihood of delivery by cesarean section
- Postpartum hemorrhage
If you have fibroids and are experiencing infertility, consult a reproductive endocrinologist who specializes in treatment of women with fibroids. A fertility specialist can develop a treatment plan that maximizes your chances of a successful pregnancy. If surgery to treat fibroids is needed before pursuing fertility treatment, myomectomy is likely your best option.
Fibroids After Menopause
Typically, once a woman goes through menopause, fibroids will stop growing or will shrink down. So, postmenopausal women with fibroids do not often experience symptoms related to their fibroids. In some cases, however, surgery may be necessary if the woman has significant symptoms including post-menopausal bleeding, pressure related symptoms or pain. If a fibroid grows during menopause, it might indicate an unexpected cancer such as leiomyosarcoma— additional testing is needed to determine the cause of the fibroid growth and to develop a treatment plan.
Early Life Adverse Environmental Exposures Increase the Risk of Uterine Fibroid Development: Role of Epigenetic Regulation
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. 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.
Exposure to environmental toxicants and toxins causes epigenetic changes that play a role in the development of disease (Cook et al., 2005; Walker and Ho, 2012; Yang et al., 2015b). Identifying changes in epigenomic marks (e.g., DNA methylation, histone modifications, non-coding RNAs) in affected tissues/cells is not always feasible in humans. Herein lies one of the challenges in making a direct connection between exposure-induced epigenetic changes and health outcomes in human populations. UFs, also known as uterine leiomyomas, are the most common pelvic tumors, occurring in nearly 70% of all reproductive-aged women (Al-Hendy and Salama, 2006; Bulun, 2013). It is the leading indication for hysterectomy with a conservative economic burden of about $34.4 billion/year in the US alone (Cardozo et al., 2012). These UFs cause severe symptoms such as heavy, irregular, and prolonged menstrual bleeding, anemia, pelvic pain, bowel and bladder dysfunction, infertility, recurrent abortion, and many obstetric complications such as preterm labor, obstructed labor necessitating cesarean section, fetal malpresentation, and fetal anomalies, as well as postpartum hemorrhaging (Sabry and Al-Hendy, 2012). These morbidities exert a tremendous toll on an individual’s overall health and well-being, impacting the quality of life of women of all ethnicities. Understanding mechanisms which regulate normal and aberrant myometrial cell function is paramount in the management of UFs. Therefore, development of effective, safe and inexpensive approach for the management of UFs is highly needed to improve the quality of life among those affected by UFs, but also in consideration of the significant impact UFs have in the context of public health (Sabry and Al-Hendy, 2012).
The Role of Estrogen in Non-Genomic and Genomic Signaling of UFs
A striking feature of UFs is their dependency on the ovarian steroids estrogen and progesterone (Bulun, 2013). A number of experimental data suggests that estrogen stimulates the growth of UFs through ER α. The primary roles of estrogen and its’ receptor α in UFs growth are permissive in that they enable tissue to respond to progesterone by inducing expression of the progesterone receptor (Ishikawa et al., 2010).
The biological effects of 17β-estradiol are mediated by two isoforms of the ERs (ERα and ERβ). Hormone-activated ERs form dimers. Since the two forms are coexpressed in many cell types, the receptors may form ERα (αα) or ERβ (ββ) homodimers or ERαβ (αβ) heterodimers. Although ERs are widely expressed in different tissues types, some notable differences in their expression patterns occur. For instance, the ERα is found in endometrium, ovarian stromal cells, and breast cancer cells. ERs mediate the effects of 17β-estradiol under physiologic and pathologic conditions. ERs trigger 17β-estradiol-sensitive gene transcription by binding to specific estrogen response elements (i.e., genomic mechanism) (Hewitt et al., 2003; Gielen et al., 2007; Winuthayanon et al., 2014). In the absence of the estrogen hormone, ERs are largely located in the cytosol. The estrogen binds to the receptor, triggering a cascade of events, starting with the migration of the receptor from the cytosol into the nucleus; dimerization of the receptor; and subsequent binding of the receptor dimer to specific sequences of DNA known as estrogen response elements. The DNA/receptor complex then recruits other proteins that are responsible for transcriptional activation, which eventually alters target gene expression. ERs are also found within the cell nucleus, and both ER subtypes have a DNA-binding domain and can function as transcription factors to regulate gene expression (Burns and Korach, 2012).
Some ERs can be rapidly activated to downstream kinase cascades by exposure of the cells to estrogen (i.e., non-genomic mechanism; Bjornstrom and Sjoberg, 2002, 2005; Wong et al., 2002; Hofmeister et al., 2012). These so-called “non-genomic” effects are independent of gene transcription or protein synthesis and involve steroid-induced modulation of cytoplasmic or cell membrane-bound regulatory proteins. Estrogen can modulate regulatory cascades, such as MAPK, PI3K, and tyrosine kinases through non-transcriptional mechanisms. Furthermore, steroid hormone receptor modulation of cell membrane-associated molecules, such as ion channels and G-protein-coupled receptors, e.g., GPR30 has been shown in diverse tissues (Kelly et al., 2003; Prossnitz and Arterburn, 2015).
Both ER-evoked genomic and non-genomic effects originate from a unique signaling network (Bjornstrom and Sjoberg, 2005). A growing amount of evidence suggests that non-transcriptional signaling plays a pivotal role in the estrogen effect, which has clinical relevance, particularly in the development of UFs. Fibroids are common estrogen-dependent uterine tumors that cause significant morbidity for women and inflict a substantial economic impact on the US health delivery system (Al-Hendy and Salama, 2006). Our in vivo data in a mouse model demonstrates the ability of an adenovirus-expressing dominant-negative ER to arrest fibroid growth (Hassan et al., 2010). Taken together, cellular activities of estrogen and EDCs are the result of a combination of non-genomic and genomic actions via membrane and nuclear ERs-mediated signaling pathways.
Epigenetic Modifications: PcG Proteins and TrxG Proteins
Epigenetic regulation is a dynamic process, which integrates environmental changes and enables cellular plasticity. As a result, it is involved in various pathologies related to environmental exposure to toxins. Proteins that carry out these epigenetic modifications are classified as “writers”, “readers”, and “erasers” (Figure 1). Epigenetic writers catalyze the addition of chemical groups onto either histone tails or onto the DNA itself (Cosgrove, 2012). These modifications are known as epigenetic marks (Vermeulen et al., 2010; Yun et al., 2011). Among them, PcG and TrxG proteins function as crucial epigenetic “writers” that regulate developmental gene expression in a variety of tissues and organs (Figure 2; Ringrose and Paro, 2007; Schuettengruber et al., 2007).
FIGURE 1. Histone modification, DNA methylation, and non-coding RNA alter gene expression pattern. Epigenetic writers catalyze the chemical modifications of amino acids on histones or the cytosine of DNA. Epigenetic erasers catalyze the removal of these modifications and epigenetic readers recognize the modifications and recruit large macromolecular complexes to the chromatin template. Ac, Acetyl; M, Metyl; C, protein complex.
FIGURE 2. Transcriptional regulation by PRC1, PRC2, and TrxG chromatin complex. (A) Transcriptional regulation by PRC1 and PRC2 complex. PRC1 ubiquitinate H2A at lysine 119 (H2AK119ub). PRC2 trimethylates lysine 27 on histone 3 (H3K27me3). Experimental study suggests that H3K27me3 generated by PRC2 facilitates compaction of chromatin leading to the repression of gene expression. The CBX subunit of the PRC1 recognizes H3K27me3, and subsequently RING1A/1B subunits of the PRC1 ubiquitinate H2AK119 to facilitate the maintenance of the repressed state. H3K27 demethylases JMJD3 and UTX demethylate methylated H3K27. (B) Transcriptional regulation by TrxG complex. TrxG trimethylates histone 3 lysine (H3K4me3) leading to activate gene expression.
Polycomb group proteins form multimeric complexes that exert their functions by modifying chromatin structure and by regulating the deposition and recognition of multiple post-translational histone modifications (Morey and Helin, 2010). Two major PcG protein complexes have been described. The first complex, named polycomb repressive complex 1 (PRC1) is composed of four submits as shown in Figure 2. The second complex PRC2 consists primarily of EZH2, which is the catalytic core protein, EED, and SUZ12 (Figure 2). PRC2 methylates H3K27 via its EZH2 subunit. This modification, in turn, provides a binding site for the chromodomain-containing Pc subunit of PRC1, which subsequently leads to ubiquitination of H2AK119 via its Ring1a/1b subunit (Wang et al., 2004; Lehmann et al., 2012; Figure 2). In recent years, these proteins have raised considerable interest, due to their regulatory mechanisms and for the variety of key roles they play in normal cellular and disease processes (Villa et al., 2007; Pasini et al., 2010; Ntziachristos et al., 2012; Mozzetta et al., 2014; Serresi et al., 2016). For instance, EZH2 regulates chromatin structure and chromosome architecture at their target loci (Table 1) through canonical and non-canonical activity (Figure 3).
TABLE 1. List of EZH2-regulated genes.
FIGURE 3. Role of EZH2 in genomic signaling through canonical and non-canonical activity. EZH2 confers long-term, heritable memory by sustaining silent gene expression states. In addition to its role as epigenetic modifier, EZH2 also works as transcriptional co-activators through non-canonical signaling pathway.
Trithorax group proteins also function in multi-subunit complexes (Figure 2), confer heritable memory by sustaining active gene expression states, but they antagonize the function of the PcG (Schuettengruber et al., 2007, 2011; Steffen and Ringrose, 2014). For example, H3K4 trimethylation inhibits PRC2-mediated H3K27 trimethylation (Schmitges et al., 2011).
Epigenetic Targets in Response to Environmental Factors in Some Tissues
The process of developmental programming exhibits a high degree of epigenetic plasticity, which is modifiable by intrinsic and extrinsic factors (Walker and Ho, 2012). However, when the in utero environment is suboptimal, permanent developmental reprogramming of the epigenetic targets could take place. Adverse environmental exposures during development can alter susceptibility later in life to adult diseases, including UFs (Cook et al., 2005, 2007; Greathouse et al., 2012). Increasing evidence suggests that early exposure to EDCs induces epigenetic changes in context to epigenetic regulated target genes in some tissues (Cook et al., 2005; Wong et al., 2015). For instance, neonatal exposure of CD-1 mice to EDCs such as DES (Walker and Ho, 2012; Gibson and Saunders, 2014), induces uterine adenocarcinoma in aging animals, concomitantly inducing hypomethylation of nucleosome binding protein1 (Nsbp1) promoter CpG Island (CGI) in the uteri which leads to persistent overexpression throughout life. Since the Nsbp1 encodes a nuclear protein similar to the HMG 14, this protein may alter the gene expression pattern in utero, in response to early life EDC exposure leading to an increased risk of uterine cancer in adulthood (Tang et al., 2008). In rat mammary gland, prenatal exposure to BPA, another EDC, alters the epigenome and increases the propensity to neoplastic development. Accordingly, BPA exposure led to higher levels of MLL mediated epigenetic mark H3K4 trimethylation at the transcriptional initiation site of the alpha-lactalbumin gene, concurrently enhancing mRNA expression of this gene (Dhimolea et al., 2014). The protein encoded by this gene plays an important role in galactose metabolism. In addition, using a rat model for developmental reprogramming of susceptibility to prostate carcinogenesis (Yean Wong et al., 2015), neonatal exposure to BPA significantly upregulated (>100-fold) the expression of Scgb2a1 in the prostate of adult rats via H3 lysine 9 acetylation. Importantly, Secretoglobin, Family 2A, Member 1 (Scgb2a1) encodes a component of prostatein, a major androgen-binding protein secreted by rat prostate, and hence suggests potential implications for cancer risk and response to chemotherapeutics associated with prostatein binding (Wong et al., 2015).
Animal Model for Developmental Reprogramming of Susceptibility to UF Pathogenesis
Although there are several UF developmental models available (Hassan et al., 2009; Friel et al., 2010; Prizant et al., 2013; Mas et al., 2015), the best experimental animal model for studying UFs in response to early life adverse environmental exposure is the Eker rat model (Cook et al., 2005; Walker and Ho, 2012). Eker rats carry a germ-line mutation in the tuberous sclerosis complex-2 (Tsc2) tumor suppressor gene (Cook and Walker, 2004). In this Eker rodent model, the high spontaneous incidence of smooth muscle tumors of the uterus provides a unique opportunity to study the molecular mechanisms underlying the development of these clinically important neoplasms (Everitt et al., 1995). Using this model, Dr. Walker’s group demonstrated that early life exposure to EDCs including DES or genistein, a natural isoflavone phytoestrogen found in soybeans, increased tumor penetrance (from 65% to >90%), tumor multiplicity and overall size (Cook et al., 2005; Greathouse et al., 2012). This increased penetrance induced by early life environmental exposure to EDCs is associated with the reprogramming of estrogen-responsive genes, which become hyper-responsive to the estrogen hormone and promote the development of hormone-dependent UFs (Greathouse et al., 2008; Walker and Ho, 2012).
Role of Epigenetic “Writers” in UF Development
Estrogen triggering genomic signaling in context to epigenetic “writers” has recently been identified. Bhan et al. (2014) demonstrate that EZH2 is transcriptionally induced by estradiol in cultured breast cancer cells and in the mammary glands of ovariectomized rats. Similar to estradiol, DES-induced EZH2 expression is coordinated by ERs, MLLs and CBP/P300. These studies suggest that EZH2 is potentially dysregulated upon exposure to EDCs, and provides a direct link between EDC-induced nuclear hormone receptor signaling and modulation of the epigenetic machinery (Bhan et al., 2014).
Until recently, little information has been available about the role of PcG/TrxG proteins in the development UFs. However, Dr. Walker’s group reported that DES is capable of binding to membrane-associated ER to activate non-genomic ER signaling, activating PI3K signaling and the kinase AKT. Subsequently Phosphorylation of serine 21 of EZH2 by AKT inactivates EZH2 leading to reduced levels of the repressive trimethylation of H3K27 in the developing uterus (Bredfeldt et al., 2010). A further study indicated that yet another environmental estrogen, genistein, also induced PI3K/AKT non-genomic ER signaling to the histone EZH2 (Greathouse et al., 2012). These studies demonstrate the importance of the interplay between non-genomic signaling and epigenetic mechanisms in response to early life environmental exposure to estrogen that may contribute to an increased risk of UF development.
DNA Damage Repair in Stem Cells
Accumulating evidence demonstrates that environmental chemicals or their reactive intermediates can react with DNA to modify DNA bases leading to DNA damage (Linder, 2012; Moller et al., 2013). Exposures can act through an epigenetic mechanism by which DNA damage repair is altered (Langie et al., 2013). Currently, Med12 somatic mutation is the most widely detected DNA mutation in human fibroid lesions. We and others have detected a single nucleotide Med12 mutations in up to 85% of sporadic fibroid lesions (Makinen et al., 2011a,b; Markowski et al., 2012; McGuire et al., 2012; Halder et al., 2014). Interestingly, distinct Med12 mutations are detected in different fibroid lesions in the same uterus (Makinen et al., 2011b). This strongly suggests that the emergence of each Med12 mutation is an independent event in an altered myometrial stem cells. It is possible that some risk factors attenuate key DNA damage repair gene function leading to reduced myometrial DNA repair capacity. This reduction in the DNA repair capacity may eventually cause the emergence of mutations such as Med12 in myometrial stem cells converting them into fibroid tumor-forming stem cells; and thereby, leading to the development of UFs (Figure 4). In a mouse model that conditionally expresses a Med12 missense variant (c. 131G > A), it has been demonstrated that this alteration alone promotes fibroid formation and drives genomic instability (Mittal et al., 2015).
FIGURE 4. Early life adverse environmental exposure compromises DNA damage repair system in myometrial stem cells through epigenetic regulation eventually leading DNA instability and mutations and subsequent formation of UFs.
A comparative analysis of dysfunctional DNA repair capacity in stem cells from fibroid tissues or at-risk myometrium with fibroid versus stem cells from normal myometrium has not yet been conducted. However, Chang et al. (2011) reported that BTICs exhibited increased EZH2 expression which was linked to decreased expression of key DNA repair gene RAD51. Therefore, accumulation of recurrent Raf-1 proto-oncogene, serine/threonine Kinase (RAF1) gene amplification in BTICs occurred, which activates p-ERK-β-catenin signaling to promote BTIC expansion (Chang et al., 2011). It has been shown that both human myometrial and UF tissues contain side population (SP) cells with progenitor/stem cell properties (Ono et al., 2007, 2012, 2013; Mas et al., 2012). We recently isolated human surface marker-specific myometrial and fibroid stem cells. Using Stro-1/CD44 surface markers, we were able to isolate stem cells from adjacent myometrium and human fibroid tissues using the magnetic beads approach (Mas et al., 2015). In vitro Stro-1+/CD44+ myometrial cells exhibit the ability to differentiate into adipocytes, osteocytes, and chondrocytes with the functional capacity to form fibroid-like lesions in a xenotransplantation mouse model. In the future, we will compare the DNA repair capacity of Stro-1+/CD44+ myometrial stem cells from normal human myometrium versus at-risk myometrium tissues or fibroids.
Cell-Derived Exosomes: Roles in Tumor Development and Progression
Emerging evidence consistently demonstrates that exosomal miRNAs can be reprogrammed by environmental factors (Goustard-Langelier et al., 2013; Shah et al., 2016). Exosome are cell-derived small sized vesicles (40–150 nm), present in many biological fluids (Pan et al., 1985; Simons and Raposo, 2009). Exosomes are either released from the cells when multivesicular bodies fuse with plasma membrane or released directly from the plasma membrane. Emerging evidence indicates that exosomes contain a range of biological molecules, including mRNA, microRNA, long non-coding RNAs, proteins, lipids, molecular chaperones, and signaling molecules (Skog et al., 2008), as well as involvement in many biological events including cancer progression (Kogure et al., 2011; Luga et al., 2012). Importantly, the molecular signatures of exosomes are specific to each tissue type, providing an alternative option for clinical applications (Nawaz et al., 2014).
Exosomes exhibit fundamental paracrine mechanisms that mediate cell-to-cell communication and play a role in the transfer of messages from one cell to another (Simons and Raposo, 2009; O’Brien et al., 2013). Exosomes are important players in the regulation of physiological as well as pathological processes in our body – depending on their content, they can induce activation, proliferation, differentiation, or apoptosis of the recipient cells (Roma-Rodrigues et al., 2014; Ung et al., 2014). In cancer, this cell-to-cell communication leads to increased proliferation, motility, induction of invasive properties of the recipient cells, as well as conferring drug resistance (Kahlert and Kalluri, 2013).
Although the role of exosomes in tumor development is not well understood, some studies have highlighted a possible role in tumor development and progression. Exosomes with a specific surface protein (glypican-1) were found to be detected in the serum of patients with pancreatic cancer, distinguishing healthy subjects from those with benign pancreatic disease (Melo et al., 2015). Melanome exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype via MET, and exosome-mediated transfer of the oncoprotein. MET functions as a key regulator of bone marrow education, mobilization, and metastatic progression (Peinado et al., 2012). The exosomes from normal and abnormal cells differ in their cargo content, and potentially in their functions. For instance, breast cancer exosomes perform cell-independent miRNA biogenesis and alter the transcriptome of receipt cells in a Dicer-dependent manner (Melo et al., 2014).
Uterine Fibroids are thought to be monoclonal tumors arising from the myometrium, and tumor stem cells are considered to play pivotal roles in the tumorigenesis of UFs. It is possible that cell-to-cell interaction between myometrial stem cells and differentiation cells is involved in the development of UFs. Although the role of myometrial stem cell-derived exosomes is unknown, increasing, studies have suggested that stem cell-derived exosomes containing important effectors of Wnt (Luga et al., 2012), Hedgehog (Gradilla et al., 2014), and β-catenin (Chairoungdua et al., 2010), may play a potential role in maintaining stem cell characteristics. Cancer stem cell-derived exosomes contain distinct biomolecules as compared to exosomes derived from normal stem cells indicating the important role of exosomal miRNA content from cancer stem cells in cancer progression and development. For instance, gastric cancer tissue-derived mesenchymal stem cells favor gastric cancer progression by transferring exosomal miRNAs to gastric cancer cells and promote their proliferation and migration (Wang et al., 2014). Similarly, glioma-associated stem cells produce substantial amounts of exosomes which leads to sustained malignant properties of both glioma cells and glioma stem cells. Moreover, a recent study has shown that exosomes from bone marrow-derived mesenchymal stem cells transport tumor regulatory miRNAs, anti-apoptotic proteins, and metabolites that promote breast tumor growth (Vallabhaneni et al., 2015). These studies suggest that stem cell-derived exosomes contain important molecules that promote tumor progression.
The importance of stem cell-derived miRNAs in response to environmental factors has recently been identified (Goustard-Langelier et al., 2013; Shah et al., 2016). Shah et al. (2016) determined the effects of the chemoprotective fish oil/pectin diet on miRNAs in colonic stem cells obtained from Lgr5-EGFP-IRES-creER knock-in mice. They demonstrated that 26 miRNAs were differentially expressed in Lgr5 (high) stem cells as compared to Lgr5 (negative) differentiated cells. Fish oil/pectin treatment up-regulated miR-19b, miR-26b and miR-203 expression as compared to corn oil plus cellulose (CCA) specifically in Lgr5 (high) cells. They further demonstrated that only miR-19b and its indirect target PTK2B were modulated by the fish oil/pectin diet in Lgr5 (negative) cells. In addition, rat neural stem cells/neural progenitors (NSC) proliferation and differentiation were dually altered by the in utero polyunsaturated fatty acid supply, along with marked alterations in miRNA expression (Goustard-Langelier et al., 2013). Although the role of exosomes in the pathogenesis of UFs is unknown, we recently isolated myometrium stem cells from adult uteri early life exposed to DES. These cells will serve as a tool in determining how early life environmental exposure alters stem cell derived exosomal cargo and thereby leads to an increased risk of UF pathogenesis.
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. Accordingly, in response to EDC administration, no single PcG or TrxG-target genes have been discovered in myometrium tissues as well as in myometrial stem cells (Yang et al., 2015a). In addition to EZH2 “writer”, many other epigenetic proteins that play a role in UF development, need to be investigated. High throughput epigenetic analysis such as ChIP-seq are needed to determine locus specific and/or genome-wide epigenetic modifications in myometrial stem cells and tissues. A better understanding of these changes in myometrial stem cells will lead to the mechanistic plausibility as to the role of epigenetic regulation in mediating risk and tumorigenesis and the development of new stem cell-directed therapies for patients with UFs.
Battling uterine fibroids
Uterine leiomyomas, also known as fibroids, are the leading cause of hysterectomies in the United States and account for up to an estimated $34 billion annually in costs.
On Oct. 10, Erica Marsh, M.D., a renowned uterine fibroid expert, addressed NIEHS scientists in her seminar, “‘There Will be Blood’: A Patient-centered View of Uterine Leiomyomas.” Marsh’s talk was hosted by NIEHS researcher Janet Hall, M.D.
According to Marsh, 65-70 percent of women have uterine fibroids by the age of 50, yet the origin of uterine fibroids remains unknown. She suggested that research and clinical experience have implicated several factors in fibroid development and growth, including race, obesity, genetics, and hormones such as estrogen and progesterone.
Marsh said that women often suffer for years before seeking medical treatment to relieve their symptoms. She advocated for greater attention by researchers and more public health outreach. “There is a lot of work to be done, and I hope some of you will engage in it,” she told the packed room.
The impact of a fibroid diagnosis
Marsh, an assistant professor at Northwestern University Feinberg School of Medicine, and her team have qualitatively assessed the burden of uterine fibroids on women’s emotional health. Of the 60 women with symptomatic uterine fibroids recruited for her study, including African-Americans, Caucasians, Hispanics, and Asians, the majority exhibited a significant emotional response, including fear, anxiety, anger, and depression.
Many women also felt helpless and believed that they had no control over their fibroids. More importantly, some women felt they lacked adequate support in handling these serious issues. The title of her talk came from a comment by one patient who, discussing the variability of symptoms, said, “I know one thing — there will be blood.”
Ultrasound studies have demonstrated that African-American women exhibit a higher fibroid incidence than Caucasian women. This prevalence is driven by an earlier age of initiation and a longer growth window. Moreover, said Marsh, African-American women are more likely to be deficient in vitamin D than Caucasian women.
She cited several studies by Donna Baird, Ph.D., lead researcher in the NIEHS Epidemiology Branch. For instance, Baird’s work has provided evidence that sufficient vitamin D may be associated with a reduced risk of uterine fibroids.
Racial disparities and health inequities
The remainder of Marsh’s presentation focused on racial disparities and health inequities, including the fact that women are more likely to face health inequities because their biological makeup demands more care and attention. “We need to do better for women,” Marsh emphasized.
She and her team have found that African-American women often exhibit larger fibroids, which entails different treatment options and risks. Disparities in prevalence and treatment may lead not only to an altered perception of what is normal, but also to different recovery scenarios and greater dissatisfaction with care and treatment. “If all of your sisters have this experience, and your mother and aunts have this experience, you start to think this is normal,” Marsh said.
A diagnosis of uterine fibroids is not something women should accept without diligent examination of lifestyle and options, she stressed. There are many approaches to treating uterine fibroids, including medications, hysterectomy, myomectomy, uterine artery embolization, and MRI-guided focused ultrasound surgery.
The patient and doctor must choose a treatment based on preferences, reproductive plans, and other medical considerations. Perhaps more importantly, new and effective therapies for this chronic condition must be developed. “I hope that I have convinced at least some of you to drop what you’re doing immediately and look at uterine fibroids,” she said. “We’re talking about a serious public health issue.”
The effects of exposure to air pollution on the development of uterine fibroids
Air pollution may cause specific genetic or epigenetic abnormalities and lead to the development of uterine fibroids (UFs). However, there have been limited studies evaluating the relationship between air pollutant exposure and the development of UFs.
We conducted a 10-year cohort-based case-control study in Taiwan from 2001 to 2010 using National Health Institute Research Database (NHIRD) to assess the association between air pollution and the UFs development among Taiwanese women. The case group consisted of 11,028 women newly diagnosed with UFs during the study period and the control group was 44,112 women aged 25–45 years using density sampling with a 1:4 matching on the date of birth from 224,675 women in 2001–2010. The average age of onset was 36 ± 4.37 years old. Daily concentrations of PM2.5 were estimated by linear mixed-effects model integrating aerosol optical depth (AOD) and meteorological variables; daily concentrations of O3, CO, NO2 and SO2 were calculated by the Inverse Distance Weighting (IDW). The annual cumulative exposure to air pollutants during the study period was calculated corresponding to residential zip codes.
Uterine fibroids (UFs), the benign tumors and generally known as uterine leiomyoma, are the most frequently occurring tumors and neoplasms of the reproductive tract in women in Taiwan. Marino et al. (2004) examined the association of menstrual cycle characteristics with UFs in women and reported that UFs commonly occurred in reproductive-aged women with the incidence approximately up to 60%. Chao et al. (2005) examined the rate of inappropriate hysterectomy and found that UFs (46.2%) was the major indication for hysterectomy, following by cancer or premalignant conditions (22.2%), pelvic relaxation (12.6%) and endometriosis (9.9%) in Taiwan. UFs accounted for the largest percentage of hysterectomy not only in Taiwan (46.2%), but also in the U.S. (40.7%), Italy (41%), South Africa (23%), and India (27.9%) (Ho et al., 2015).
Air pollution may play an important role in environmental problems around the world. Mounting epidemiologic studies showed significant associations between air pollution and numerous women’s health problems. Hooper et al. (2018) conducted a cohort study of women in the U.S. and investigated the relationship between long-term exposure to air pollutants (NO2 and PM) and chronic bronchitis. They found that PM exposure was associated with the prevalence of chronic bronchitis, particularly for the women who smoke. Merklinger-Gruchala et al. (2017) attempted to examine if air pollutants such as PM10, SO2, CO and NOX were related to the women’s reproductive health and even influenced the length or phases of menstrual cycle. PM10, SO2, and CO per 1 g/m3 increase resulted in a decrease of the length of the luteal phase −0.02 day in PM10 (p = 0.03), 0.1 day in SO2 (p = 0.02) and 0.52 day in CO (p = 0.06). They finally indicated that air pollution might cause female fertility problems. Coogan et al. (2012) evaluated the risk of incident hypertension with the exposure to fine particulate matter (PM2.5) in Los Angeles. They concluded that the risk of hypertension (HTN) was associated with traffic-related pollutants. Boynton-Jarrett et al. (2005) further reported a positive relationship between elevated blood pressure and the risk of UFs. Not only HTN, but also PM2.5 plays a critical role in contributing to global cardiovascular (CV) disability and mortality. Weichenthal et al. (2014) investigated the association between PM2.5 and CV mortality in the United States. They reported that CV mortality may increase by a relative 10% (per 10 μg/m3) during long-term exposure to PM2.5. Similar results were also found in the nationwide study in Canada. An increase of ischemic heart disease deaths was significantly associated with an interquartile increase of PM2.5 (6.2μg/m3). And the exposure level was lower (mean = 8.7 μg/m3) than that found in previous studies (Crouse et al., 2012).
To the best of our knowledge, there was only one study investigating the association between air pollution and the development of UFs. Mahalingaiah et al. (2014) conducted a prospective cohort study of 85,251 female nurses aged 25–42 years in the United States. They found that cumulative average concentrations of PM2.5 were associated with an increased risk of UFs. The cumulative average concentrations of PM2.5 were 15.2 μg/m3, much lower than those in Taiwan (33.93 μg/m3). Therefore, we conducted a 10-year cohort-based case-control study at the area with high PM2.5 concentrations (approximately three times higher than the criteria recommended by the WHO) to assess the effects of long-term exposure to PM2.5, O3, CO, NO2 and SO2 on the development of UFs among Taiwanese women.
We utilized the Longitudinal Health Insurance Database 2000 (LHID 2000), which includes 1,000,000 beneficiaries randomly sampled from the National Health Institute Research Database (NHIRD). NHIRD, a single-payer National Health Insurance program, covers 99.9% of the 23 million residents in Taiwan. This nationally representative sample was provided by the National Health Research Institutes (NHRI) authorized by the Ministry of Health and Welfare of Taiwan. All personal identification numbers
Characteristics of study population
The final study population consisted of 11,028 cases and 44,112 controls. Table 1 presents demographic characteristics of the study population. The odds ratios (ORs) of UFs were higher in groups with highest social economic status (OR = 1.62; 95% CI: 1.52–1.72), COPD (OR = 1.40; 95% CI: 1.30–1.51), and HTN (OR = 1.46; 95% CI: 1.30–1.64). In contrast, parity was negatively associated with UFs. The risk of UFs for the parous women was 0.87 (95% CI: 0.83, 0.91) lower than the nulliparae. With
In the present study, we found associations between exposure to air pollutants and the risk of UFs. In the average exposure over 2-year and 4-year periods before the onset of UFs, our results showed that exposure to PM2.5 or O3 was significantly associated with an increased odds ratio of the development of UFs. Mahalingaiah et al. (2014) found a modest risk of exposure to PM2.5 in the cumulative exposure period, yielding adjusted odd ratio of 1.11 (95% CI: 1.03, 1.19), but not for the average
In the conditional logistic regression adjusting for confounders, the adjusted odds ratio (aOR) for UFs per 10 μg/m3 increase in PM2.5 was 1.105 (95% confidence interval: 1.069, 1.141), per 10 ppb increase in O3 was 1.075 (95% confidence interval: 1.039, 1.113), respectively.
Our study suggests that women aged 25–45 years with higher long-term exposure to PM2.5 and/or O3 have an increased chance of developing UFs. However, further studies are still needed to confirm or repeat our novel findings.
Endocrine-disrupting Chemicals and Uterine
As defined by the U.S. National Institute of Environmental
Health Sciences (NIEHS), endocrine-disrupting chemicals
(EDCs) are ‘‘chemicals that interfere with the body’s endocrine
system and produce adverse developmental, reproductive,
neurological and immune effects.’’ The endocrine system is
composed of glands that are distributed throughout the
body that synthesize the hormones that are released in the
circulatory system to regulate development, physiologic
processes, and homeostatic functions. These glands include, but
are not limited to, the hypothalamus, pituitary, thyroid, and
reproductive organs. Endocrine-disrupting chemicals can be
natural or man-made, such as pharmaceuticals, plasticizers,
dioxins, polychlorinated biphenyls (PCBs), organochlorines,
polyfluoroalkyls (PFOAs), phthalates, and pesticides.
Although the route of exposure depends on the individual
EDC, common routes of exposure in humans are ingestion,
inhalation, and dermal absorption. Importantly, EDCs can
exhibit non-monotonic dose–response curves, and low doses
of EDCs can produce a pathophysiologic effect.
Numerous EDCs have been shown to interact with nuclear
receptors to exert their actions in target tissues.
The binding of EDCs to nuclear receptors can alter hormone functions
by mimicking naturally occurring hormones in the body,
blocking the endogenous hormone from binding or interfering
with the production or regulation of hormones and/
or their receptors. An individual EDC may interact with
more than one receptor, and multiple EDCs can interact
with the same receptor, highlighting the complexity of the
response of animals and humans to environmental EDC
exposures. For example, the xenoestrogen bisphenol A (BPA) has
been shown to bind and activate estrogen receptor (ER),
estrogen-related receptor g, and pregnane X receptor.
In addition to BPA, a variety of other EDCs, such as
diethylstilbestrol (DES), polychlorinated biphenyls (PCBs),
polyfluoroalkyl (PFOA), and phthalates, can also bind to
Liganded nuclear hormone receptors that function as
transcription factors interact with DNA, producing what
are termed ‘‘genomic’’ effects that regulate gene transcription,
but they are also capable of action outside the nucleus
via what is termed ‘‘nongenomic signaling’’.
Endocrine-disrupting chemicals are also capable of inducing
both genomic and nongenomic signaling: both BPA and
DES, for example, have been shown to activate nongenomic
signaling pathways through the ER. Regardless of
the mode of action, EDCs have been linked to several
adverse health outcomes including diabetes, obesity,
cardiovascular disease, reproductive tract disorders, and
Causes and Risk Factors of Uterine Fibroids
With insights into the effect on Black women
The causes of uterine fibroids are unknown, but there is evidence that multiple factors–such as race, age, family history, the number of micronutrients, and stress—play a role in their growth.
Black women are especially burdened by fibroids. Not only are Black women more likely to get fibroids and experience severe symptoms, but they often get treatment later or may get inappropriate treatment due to systemic racism and implicit bias in the U.S. healthcare system.
This leads to earlier deterioration of health and quality of life. The cumulative impact of economic, psychosocial, and environmental stresses and the role it plays in the deterioration of a Black woman’s overall health must be discussed when we think about fibroids and Black health.
This article discusses the causes of uterine fibroids, with insights into the effects on Black women.
Researchers have come up with a number of theories to explain the cause of uterine fibroids, but they have yet to arrive at a definitive answer.
Fibroid growth varies in pregnancy, but if they do grow this is more likely to happen in the first trimester. They may also stop growing or shrink once a woman reaches menopause, although this occurs less frequently in Black women for unknown reasons.
While the definitive cause of uterine fibroids is unknown, most medical professionals believe that there are many different factors at play. Some potential causes include:
- Hormones: Unopposed estrogen levels have been shown to promote fibroid development. High progesterone levels have also been associated with increases in fibroid growth.
- Genetics: Genetic mutations in the MED12, HMGA2, COL4A5/COL4A6, or FH genes have all been implicated in the development and growth of uterine fibroids.
- Family history: Having a family member with fibroids increases your risk of developing fibroids in your lifetime. In fact, if your mother had fibroids, you are three times more likely to have fibroids compared with a woman with no family history of fibroids, highlighting the strong genetic component of this condition. More research needs to be done to elucidate the genetic factors that contribute to this condition.
- Growth hormones: Hormones such as insulin-like growth factors, epidermal growth factors, and transforming growth factors may also play a role in fibroid development.
- The number of micronutrients in your blood: The amount of certain micronutrients, such as low iron and/or vitamin D levels, may contribute to the growth of fibroids
- Major stress: Some studies have cited stressful life events and possibly childhood abuse as possible triggers of uterine fibroid development.
Black Women and Uterine Fibroids
Black women are hit hardest by uterine fibroids, and healthcare providers don’t know why:
- They are four times more likely to have fibroids between the ages of 18 and 30, compared with White women.
- Over a woman’s entire life, it is estimated that 80% of Black women will go on to develop some form of benign pelvic tumor condition versus 70% of White women.
The reasons for the disparities are unclear, although research offers some clues. Fibroids have been associated with the following risk factors:
- African ancestry: Black women are two to three times more likely to develop fibroids than White women, but healthcare providers don’t know why. Several studies have hypothesized that obesity and non-modifiable risk factors such as race or genetic ancestry may interact to jointly influence uterine fibroid growth, but most existing studies have not evaluated their interaction.
- Age: Development of fibroids increases with age, but symptoms tend to diminish since tumors regress after menopause.
- Obesity: A large meta-analysis found that women who are obese were 17% to 26% more likely to have uterine fibroids, although the cause-and-effect link between the two is unknown. Other studies have found that the risk of women who are obese developing fibroids is two to three times greater than that of women who are of average weight. This is especially the case with those who have central obesity, or higher amounts of belly fat. Fibroid growth is triggered by estrogen, which can be overproduced by excess abdominal fat.
- Family history of uterine fibroids
- High blood pressure
- No history of pregnancy: Women who have never been pregnant or have been pregnant two or fewer times are more likely to develop symptomatic fibroids.
- High stress levels
- Vitamin D deficiency: Women with darker-pigmented skin tones are more likely to experience vitamin D deficiency, which some studies have associated with an increased risk of uterine fibroid development.
Definitively, there are factors that have been shown to lower the risk of fibroids, such as:
- Pregnancy (the risk decreases with an increasing number of pregnancies)
- Long-term use of oral or injectable contraceptives
Uterine fibroids are the most common pelvic tumor in women of childbearing age, but their cause remains a mystery. Fortunately, some recent genetic studies have led to some hope for answers.
Cytogenetic studies—which study DNA—have found that up to 40% of uterine fibroids bear some chromosomal abnormalities.
Uterine fibroids arise from an uncontrolled overgrowth of smooth muscle and connective tissue in the uterus. The two components that contribute to this overgrowth are a transformation of normal smooth muscle cells, also known as myocytes, to abnormal smooth muscle cells and their growth into clinically apparent tumors.
The identity of the factors and molecular mechanisms involved in the cellular transformation of myometrial cells into uterine fibroids is unknown, but our knowledge of tumor formation in cancer cells is a strong foundation to build off of.
The development of uterine fibroids involves a complex interaction among genes and environment, but the degree to which this plays a role in disease severity is unknown—leaving many women, especially Black women, searching for answers.
Family History and Fibroids
Women with a first-degree relative with fibroids are three times more likely to develop fibroids compared with women with no family history of fibroids.
Research studying affected women and their first-degree relatives who also have uterine fibroids is essential to deciphering the genetic components of uterine fibroids.
This research also needs to be inclusive, with robust and equal representation among women of different races and ethnicities. The availability and examination of such individuals not only hastens cytogenetic and molecular studies but also serves as a crucial component in dissecting and defining the genetic loci that contribute to the development of uterine fibroids.
It is the hope of the scientific community that by understanding and uncovering the genetic and environmental mechanisms responsible for uterine fibroids, future gene therapies may be designed.
Diversity in Studies
Studies that focus on racial differences in disease development and treatment are essential, given the health disparities that persist even when differences in socioeconomic status are accounted for.
The following modifiable lifestyle factors have been shown to change your risk for having uterine fibroids:9
- Stress: Some preliminary research has linked high stress levels and fibroid symptomatology. Relaxation techniques like yoga, massage, tai chi, and acupuncture have been reported as effective means of not only managing stress but relieving pain as well.
- Obesity: Maintaining a healthy weight, exercising, and avoiding foods high in sugar, sodium, or calories has been shown to halt the growth of current fibroids and stop the development of new ones.
- High blood pressure: Studies suggest that the presence of uterine fibroids is associated with increased blood pressure levels, and the prevalence of hypertension in women with uterine fibroids has been shown to be as high as 40%.
- Red meat intake: High red meat intake has been associated with higher fibroid prevalence, but the causal link between the two is unknown. Still, health professionals suggest limiting red meat consumption for its overall health benefits.
- Food additive consumption: Avoiding processed foods, especially those high in sugar, sodium, or calories, has been shown to help stop the growth of current and new fibroids. Some even encourage eating a special fibroid diet high in natural fruits and vegetables.
- Use of soybean milk: High soybean consumption is associated with a high risk of uterine fibroids because soybeans contain phytoestrogen, which can raise estrogen levels.
Effect on Black Women
The disproportionate impact of fibroids on Black women is no secret, and the lack of consensus on its causes and treatment puts Black women at an even greater disadvantage.
Younger Black Women
Black women are diagnosed more frequently and at younger ages—between 29 and 39—than any other group of women, which underscores the long period of time they deal with their symptoms.
Lower socioeconomic status, higher obesity rates, less access to care, and medical mistrust are just a few of the obstacles further standing in the way.
The propagation of untrue myths about Black pain and neglecting the concerns of Black women have also led some women to normalize their pain. As a result, some Black women are reluctant to engage with the U.S. healthcare system.
Unsurprisingly, these obstacles increase the likelihood of Black women showing up to a clinic with:
- More severe symptoms
- Poorer overall health
- Greater need for more invasive treatment
Of note, while Black women are most affected by fibroids, they are often one of the least represented groups in research studies.
A review of 106 studies cited in the Agency for Healthcare Research and Quality (AHRQ) report on uterine fibroids found that nearly one in four studies on uterine fibroids did not include data on the patients’ ethnicity or race. In the studies that did, Black women made up only 15% of study participants.
Frequently Asked Questions
What causes Black women to develop uterine fibroids?
The main causes of uterine fibroids in Black women are unknown, but it is likely a combination of many factors, such as genetic, environmental, and lifestyle factors. Vitamin D deficiency and hereditary factors have been spotlighted due to the race-based differences that exist in disease prevalence.
What makes fibroids flare up?
Fibroids can flare up for a number of reasons, including:
- During sexual intercourse
- Bowel movements
- Your period
The symptoms can be so painful that they wake you up at night or impact your ability to complete normal daily activities.
Do fibroids cause miscarriages?
The size and type of fibroid determine how likely your fibroid is to impact your fertility:2
- If a fibroid is closer to the middle of the uterus, where a fertilized egg is more likely to implant, it is more likely to cause a miscarriage.
- If a fibroid is very large, it can impinge your fallopian tube, which may increase your risk of miscarriage and affect your fertility in general.
Fibroid Tumors in other Species and Classes of Vertebrates
Of Elephants and Other Mammals: A Comparative Review of
Uterine Leiomyoma as a Case Study to Understand Potential Reproductive
Consequences of Tumors in Veterinary Patients
Leiomyomas have been reported to occur in a wide range of species: human, bongo,
rhinoceros, felids, canids, primates, and elephants, among others . The literature on neoplasia often does not include the unaffected population, making it difficult to
estimate prevalence, but studies that do report these benign lesions show a wide variation
in leiomyoma prevalence across mammalian species. These species-specific
differences in prevalence suggest a genetic component to these benign lesions, where some
species may have evolved better defenses against uterine leiomyomas than others. Similar
to observations in other species, uterine leiomyomas in elephants can negatively affect
reproduction without causing death. While reported prevalences vary among humans
and great apes, comparisons are hampered by differences in methods of data collection
across studies. Accurately assessing incidence and prevalence of leiomyomas in women is
challenging, because unlike animals cared for in American Zoological Association (AZA)
accredited institutions, most women are not examined for tumors at death. A systematic
review of published studies reporting uterine leiomyoma prevalence in women between
1995 and 2015 found that prevalences ranged from 4.5% to 68.6%. This broad range
results from differences in study populations and methodologies. Because differences in
study methodologies also exist between human and animal studies, comparing prevalence
across primates or between humans and other primates is challenging. In addition, the
presence and prevalence of these leiomyomas in the free-ranging counterparts of many of
Animals, 5 of 18 these non-human species is unknown since necropsies of free-ranging populations are rare, and often, sample quality is inadequate due to autolysis, and a thorough examination for uterine pathologies may not be performed. However, prevalence across non-human animals can be compared with more consistent study protocols, and differences in prevalence are seen at higher taxonomic levels, felids are more prone to leiomyomas
than canids and suids more so than tayassuidae. Some ungulates, such as the bongo, seem
to be particularly prone to developing leiomyomas. Risk factors for uterine leiomyomas are not completely elucidated, and this is an active field of investigation in both human and veterinary medicine. Both genetic and life factors likely contribute to leiomyoma risk, as, even within the same species, differences in disease prevalence are observed between populations. Reproductive history is a shared risk factor associated with leiomyoma development across species. For example, nulliparity is an established risk factor across many species. Exposure
to endogenous hormones without pregnancy, specifically estrogen, is positively correlated
with the risk of uterine leiomyomas in humans. Known human risk factors, such as
high gonadotropin levels, should be explored in veterinary patients for their influence on
uterine leiomyoma development across species.
Among humans, multiple studies report genetic factors associated with the development of uterine leiomyoma, suggesting that genetic predisposition plays a role.
Animals likely also have some unidentified genetic predispositions that contribute to
disease risks, as genetic differences between species and within species can influence
risk. Within similarly managed populations, marked differences can be observed between
related species; for example, a very high prevalence of leiomyomas in Asian elephants
(30–100%) versus a very low prevalence in African elephants (0%). In addition to
genetic factors, indirect factors may be associated with this difference, such as the higher
percentage of acyclic African elephant females compared to Asian elephants in managed
populations, and where acyclicity may reduce leiomyoma growth. Leiomyomas
are also commonly reported in chimpanzees, and differences in prevalence between laboratory (53.6%) and sanctuary (8.8%) chimpanzees have been observed. These differences
may be due to differences in reproductive management (separating the sexes and/or use of
contraceptives) of females, how often they are pregnant (as opposed to constant hormone
cyclicity when not pregnant), or due to differences in tumor diagnosis approach (necropsy
The Exotic Species Cancer Research Alliance (ESCRA) is a neoplasia database established to collect and record neoplasia cases in non-domestic species across facilities,
including those not reported in the literature. Cases of neoplasia and corresponding
treatments are collected from multiple zoological and aquatic institutions, as well as veterinary teaching hospitals and private practices. These cases are continually collected to
determine which species develop neoplasia, if and how they are treated, and their outcomes
(survival and adverse effects). This supplements typical reports in the literature, which
often consist of interesting case reports, case series, or cases from a single institution or
laboratory evaluating prevalence only. This list includes a leiomyoma in an
African lion that was surgically removed by ovariohysterectomy, and a leiomyoma in a
chimpanzee that was inoperable due to its location within the pelvic canal (T.M. Harrison,
unpublished data). Both cases (chimpanzee and lion) were diagnosed when the animals
were near the end of their reproductive lifespan and reproductive outcomes prior to diagnosis were not documented. Therefore, the impact on their reproduction cannot be
evaluated. Similar to cases in the literature, most of the cases documented in ESCRA were
either diagnosed at the time of death or not treated. Uterine leiomyomas can be identified in living animals by ultrasound, but these examinations are only performed when
medically necessary. Limited diagnosis in living animals means that most animals do not
receive treatment for these lesions. However, examples of fertility preserving treatments in
domestic animals do exist. Surgery was performed to remove a uterine leiomyoma in a
Animals 6 of 18 Holstein cow, and post-surgery, the animal successfully became pregnant and gave birth. In another example, a horse with a leiomyoma in the right uterine horn underwent
a partial ovariohysterectomy and reproductive potential was maintained. Although
both of these cases were diagnosed and treated successfully, early diagnosis and successful
treatment of tumors is uncommon in non-domestic animals. While fertility preservation
treatments are rarely attempted in non-domestic animals diagnosed with tumors, gamete
rescue has been performed in other situations. Successful birth of live animals using this
approach varies between species.
In addition to elucidating the risk factors that contribute to the development of leiomyomas and potential treatment approaches, it is necessary to investigate the repercussions
of these benign tumors. Uterine leiomyomas have the potential to hamper pregnancy, but
a lack of pregnancy is a risk factor for leiomyomas. Therefore, it is difficult to determine
which issue (lack of pregnancy or leiomyoma) develops first without regular reproductive
exams early in life, before leiomyomas develop.
Reports of negative impacts of these tumors in non-domestic animals exist.
For example, in the endangered greater one-horned rhinoceros (Rhinoceros unicornis) reproductive tract tumors grew large enough to cause infertility by the age of 18, out of a typical
reproductive lifespan of 28 years, and overall lifespan of 40 years. These animals were
diagnosed and evaluated through ultrasound examination, and 100% of screened rhinos
over 12 years of age had presumed leiomyomas present in the cervix, vagina and uterus,
and 72.2% of rhinoceros with reproductive tract tumors were not successful breeders. Furthermore, 33% of these animals were presumed to be infertile due to the size or number of
these tumors. The presence of tumors and reduced fertility was more common in animals
bred later in life compared to those bred successfully earlier in their life. This example
highlights the need to establish preventative and treatment approaches to decrease the
impact of uterine leiomyomas in affected species.
Auburn scientists use laying hens to study fibroid tumors
Using the laying hen as an experimental model, he and Haruka Wada, an Auburn biological sciences assistant professor specializing in the short- and long-term effects of pre- and postnatal developmental stress in birds and other animals, are investigating their theory that overnutrition during infancy and childhood and early onset of puberty increase a woman’s chances of developing uterine fibroids.
Berry’s expertise is in the reproductive physiology of poultry, and in extensive research over the past decade, he has established the egg-type chicken—the hormonal cycle and ovarian surface cells of which are remarkably similar to humans’—as a scientifically valid animal model for studying human reproductive-tract disorders, including ovarian cancer and uterine fibroids. Through the years, he also observed that, among hens 2 years of age and older, the rate of oviductal fibroid tumors is extremely high. Most recently, work in his lab yielded evidence that molecular markers in hen oviduct fibroids are identical to those in human uterine fibroids.
“Uterine fibroids are a huge quality of life issue for a large segment of the population, but little progress has been made in determining what causes the disease or recommendations for prevention, in part due to a lack of experimental models for study of it,” Berry said. “Dr. Wada has formulated the hypothesis for our study, which is among the first to examine how the developmental environment, such as childhood diet, impacts a woman’s risk for the disease.”
Fibroids are most common in women in their 30s and 40s. Depending on a tumor’s size and location in the uterus, it can cause symptoms including abdominal pain and pressure, bloating, heavy or prolonged menstrual bleeding, backache and, in rare cases, infertility.
Although a few new experimental treatment procedures have become available in recent years, fibroids still are a major cause of hysterectomies in the U.S., accounting for a third of the 600,000 performed each year. The annual cost of hospitalizations, surgeries, lost work hours and pregnancy complications due to uterine fibroids is estimated at $34.4 billion.
Past research has shown that developmental nutrition affects both childhood body composition and age at puberty by altering the programming of the insulin-like growth factor system, which plays a significant role in tissue growth and development. Scientists have found, too, that the younger a female is when she reaches puberty, the greater her chances of developing uterine fibroids later in life.
“Our question is, what is the relationship among all those parameters?” Berry said. “Our theory is that a high or even excessive level of postnatal nutrition contributing to early onset of sexual maturity increases the risks of uterine fibroids, and they do that by altering IGF regulation and cell proliferation signals.”
To investigate the causal relationship between developmental nutrition and fibroid tumors, the scientists have developed experimental diets they will feed to six groups of test hens from 1 day of age and regularly monitor serum IGF levels in the birds. They also will use the hens as models to explore fibroid development in relation to early or late sexual maturity.
“This is another reason why hens are an excellent model species: it’s easy to either speed up or delay the onset of sexual maturity by manipulating the diet and lighting conditions in their houses,” Berry said. “Hens kept on short days of eight hours of light a day lay their first egg 13 days later than those on long days of 14 hours of light a day.”
A $40,000 Alabama Agricultural Experiment Station grant is funding the fibroid study. Berry said he and Wada will use data they collect from the project to apply for a substantially larger grant from a National Institutes of Health/U.S. Department of Agriculture funding program specifically for projects that use agriculturally important domestic animal species to improve human health through the advancement of basic and translational research that is highly relevant to both agricultural and biomedical research.
“We also will use our data to help establish recommendations for nutrition during infancy and the prepubertal period that could help prevent and lessen the severity of uterine fibroid tumors,” Berry said.
Uterine Smooth Muscle Tumors in Potbellied Pigs (Sus scrofa) Resemble
Human Fibroids: A Potential Animal Model
Obviously since men do not get fibroid tumors the cause of these has to be related to hormones. In fact progesterone and estrogen production have been linked to their presence. The higher the concentration in the woman the greater the prevalence. Poor nutrition, and obesity have also been loosely linked to their presence. Soy increases the production of female hormones, so if you are at a higher rish for the fibroid tumors, you should avoid using these food products. The Asian ppulation has a greater amount of soy in their diet and as you would expect the female population does have a higher incidience of fibroid tumors. Approximately 50% of women of African descent will have a fibroid visualized on the pelvic ultrasound, with Asian Women very close behind. Approximately 30% of all Caucasian women will be found to have a fibroid tumor by the time they turn 30.
It turns out that the female population of other vertebrate species also get these tumors, even different classes. Our avian friends have these tumors as well, chickens in particular. Female pot bellied pigs also have them. When I heard tat these two species get them , I said to myself that it could still be environmental, since they do share close quarters in many cases to humans. However when I found out that female elephants also get them, I had to conclude that the cause is more hormonal than environmental. So as much as I would like to point fingers at big pharma and the petro chemical companies, there is just not enough evidence out there to substantiate these claims.
mayoclinic.org, “Uterine Fibroids.”; hopkinsmedicine.org, ” Fibroids.”; animals MDPI, “Of Elephants and Other Mammals: A Comparative Review of Reproductive Tumors and Potential Impact on Conservation.” By Lisa M. Abegglen, Tara M. Harrison, Anneke Moresco, Jared S. Fowles, Brigid V. Troan, Wendy K. Kiso, Dennis Schmitt, Amy M. Boddy and Joshua D. Schiffman; agriculture.auburn.edu, “Auburn scientists use laying hens to study fibroid tumors.” by Josh Woods; frontiersin.org, “Early Life Adverse Environmental Exposures Increase the Risk of Uterine Fibroid Development: Role of Epigenetic Regulation.” By Qiwei Yang, Michael P. Diamond and Ayman Al-Hendy; factor.niehs.nih.gov, “Battling uterine fibroids.” By Tara Ann Cartwright;sciencedirect.com, “The effects of exposure to air pollution on the development of uterine fibroids.” By Chia-YingLin, Chi-MinWang, Mei-LingChen and Bing-FangHwang; fertstert.org, “Endocrine-disrupting chemicals and uterine fibroids.” By Tiffany A. Katz, Ph.D., Qiwei Yang, Ph.D.,b Lindsey S. Trevino, Ph.D., Cheryl Lyn Walker, Ph.D., and Ayman Al-Hendy, M.D., Ph.D; verywellhealth.com, “Causes and Risk Factors of Uterine Fibroids: With insights into the effect on Black women.” By Shamard Charles, MD, MPH; journals.sagepub.com, “Uterine Smooth Muscle Tumors in Potbellied Pigs (Sus scrofa) Resemble: Human Fibroids: A Potential Animal Model.” By KRISTIE MOZZACHIO, KEITH LINDER AND DARLENE DIXON; fertilitypartnership.com, “FIBROIDS: FACTS, FICTION, AND FERTILITY.” by Dr. Elan Simckes;
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