Uterine Fibroids: Hiding in Plain Sight

Abstract

Uterine fibroids (leiomyomas) are present in >75% of women and can cause serious morbidity. They are by far the leading cause of hysterectomy. Fibroids are a complex mixture of cells that include fibroblasts and smooth muscle cells. Rich in extracellular matrix, they typically arise through somatic mutations, most commonly MED12. Their lack of growth inhibition and their ability to have facets of malignancy yet be histologically and biologically benign provide opportunities to explore basic processes. To date, the mechanisms responsible for growth and development of leiomyomas are an enigma. This review provides an overview of current understanding and future directions for clinical and basic research of fibroids.

Clinical Importance

The prevalence of uterine fibroids (e.g., leiomyomas, myomas) reaches more >75% of women worldwide and thus accounts for much gynecologic care (1–3). However, only 25% of these women have fibroid symptoms, which can include heavy or prolonged menstrual bleeding that frequently results in severe iron-deficiency anemia, pelvic pain, extrinsic compression of bowel or bladder, appearance of pregnancy when it does not exist, and reproductive impairment, including infertility and pregnancy complications (FIGURE 1).

FIGURE 1.

The clinical picture of uterine fibroids Although uterine fibroids can be symptomatic, clinical disease is often impressive. A: sagittal view of a single slice of a T2-weighted magnetic resonance image showing the uterus (outlined in green) with multiple fibroids (outlined in blue) and the endometrial cavity (highlighted in yellow). B: the same uterus at the beginning of the myomectomy. The large posterior fibroid is on right in the image. The origin of the fallopian tubes, and thus the normal part of the uterine cavity, is highlighted by the arrows. The left ovary is highlighted in blue, and the right ovary is hidden by the fibroid. C: fibroids surgically excised. D: the uterus after myomectomy, which is a normal size. Both ovaries are outlined in black, and arrows indicate the origin of the fallopian tube. The same ruler is visualized for comparison in B–D.

In addition, fibroids are the leading cause of hysterectomy, accounting for at least one-third of all hysterectomies; in contrast, all types of gynecologic cancers account for <10% (4). This predominance of hysterectomy for benign disease is important not only for economic reasons but also because long-term health risks are increasingly identified after hysterectomy, even with conservation of both ovaries (5).

Fibroids are clinically important during a woman’s reproductive years. They rarely are seen in teenage girls and have a progressive increase in incidence and severity until menopause, which for most women occurs in their early 50s. Thus, most research has focused on the role of the gonadal steroids estrogen and progesterone in fibroid pathogenesis.

Uterine fibroids are a disease with substantial health disparities that most often affect women of African descent (6, 7). In Black women, fibroids are more common, are more severe, have an earlier age at onset, and have different growth patterns. Prusinski Fernung et al. (9) reported that the myometrial stem cell population is expanded in the uteri of African American women compared with White women and that this increase is correlated with fibroid number and size, thus potentially contributing to the biological understanding of these disparities. Black women also have different priorities in fibroid therapies, prefer different sources of fibroid information, and have more impairment of work and home life because of this disease (10). Although most studies have suggested that Latina and Asian women have a risk of fibroids that is similar to White women, little research has been done in this area.

The annual cost of fibroid treatment was estimated in 2010 dollars to be $34 billion in the United States (11). This cost is likely an underestimate because only direct costs for care and pregnancy complications were considered. Loss of work productivity and long-term sequelae of fibroid therapies, including hysterectomies, have not been included in cost estimates.

Biological Factors

Fibroids are well-circumscribed lesions of the uterine myometrium that can range more than several orders of magnitude in size—from microscopic to larger than a 20-cm diameter. New investigative work is changing the classic conception of fibroids as a clonal smooth muscle cell (SMC) neoplasm (12) to a conception of various SMC types (myometrial and vascular), fibroblasts, immune cells, and stem cells (13–16). Some investigative work has proposed that through an initiating event the clonal cell differentiates into both fibroblast and SMC (17); other work challenges that premise. Using single-cell RNA sequencing, investigators have identified 18 different cell types in leiomyoma tumors, and not all these cells express somatic mutations (13).

Extracellular Matrix

An essential component of fibroids is the abundant extracellular matrix (ECM) caused primarily by overexpression of collagen types I and III (18, 19). ECM proteins were once thought to have only passive roles, serving merely as scaffolding proteins, but apparently the ECM has an active part in regulation of the survival, migration, and proliferation of cells (18, 20, 21). Leiomyoma tissues contain an altered collagen III protein-to-collagen I protein ratio compared with myometrium, and the collagen fibrils are highly disorganized, similar to keloids (18, 22).

Gonadal Steroids

Historically, estrogen was thought to be the driver of fibroid biological processes. Then, the primacy of progesterone was shown in both the basic science of estrogen’s key role in induction of the progesterone receptor (PR) and the clinical success of PR modulators for treatment of fibroids while maintaining physiological levels of estradiol (23, 24). Medical therapy for fibroids still relies on modulation of the hypothalamic-pituitary-ovarian axis. Most recent therapies are oral gonadotropin-releasing hormone (GnRH) antagonists with menopause-range add-back of estrogen and progestins to treat fibroids while limiting hypogonadal adverse effects (5, 25).

Fibrosis

Transforming growth factor-β (TGF-β) signaling has been consistently linked to fibrosis and leiomyoma pathology (18, 21, 26). Compared with adjacent myometrium, leiomyomas show a three- to fivefold greater expression of TGF-β3, a 30% higher level of SMAD3 mRNA, and a markedly increased phosphorylation of TGF-β-RII and Smad3 proteins (18, 19, 21, 27, 28). In addition to aberrant activation of the TGF-β signaling pathways in fibroids (29), dysregulated mechanistic pathways have been identified recently. These include the nuclear receptors NR4A1, A2, and A3, which are markedly suppressed in leiomyomas compared with myometrium (19) and act as negative regulators of profibrotic factors, including TGF-β3, SMAD3, and collagens I and VI (19).

Several para-phenyl-substituted diindolylmethane analogs have been developed that specifically activate the NR4A receptors and can target this pathway for therapeutic purposes. In addition, the activin signaling pathway has been shown to regulate ECM production in leiomyoma cells and myofibroblast transformation in myometrial cells (30) through the p38/mitogen-activated protein kinase (MAPK) (30, 31) and sphingosine-1-phosphate (32) signaling pathways. Small-molecule inhibitors of the activin A receptor-like type 1, such as SB-431542 and A-83-01, are available and merit investigation as potential therapies.

Angiogenesis

Leiomyomas produce and secrete various angiogenic factors, including fibroblast growth factors, heparin-binding growth factor, platelet-derived growth factor, vascular endothelial growth factor, and prolactin (33, 34). This abundant supply of angiogenic factors has an important role in neoangiogenesis during the early development and growth of fibroid tumors and likely is a contributing factor to the abnormal uterine bleeding that is one of the main symptoms of leiomyomas. Interestingly, the larger leiomyoma tumors with abundant collagen deposition are less vascular because of the large areas of ECM.

Genetics

Most fibroids arise from somatic mutations within SMCs, with MED12, the Mediator Complex Subunit 12 gene, accounting for up to one-half of all fibroids in most series (35). The high-mobility group AT-hook2 (HMGA2) and collagen IV α5 (COL4A5) are the other two most frequent somatic driver mutations (36). Chromothripsis, multiple concurrent gene rearrangements, and genomic instability also have apparent roles in fibroid pathogenesis (36, 37).

Mutations in fumarate hydratase (FH) are most often autosomal-dominant germline changes and result in fibroids, papillary renal cell cancer, and cutaneous leiomyomas—the triad of hereditary leiomyomatosis and renal cell cancer syndrome (38). However, because fibroids arise independently within the uterus, and thus multiple genetic subtypes of myomas may be present in that uterus, the signaling pathways of all the groups except the FH group have substantial overlap. Therefore, genotype-based therapies have not been developed (39).

Stem Cells

Fibroid initiation is becoming better understood as studies identify populations of progenitor or stem cells (FIGURE 2) (40–43). The identities of leiomyoma stem cells and myometrial stem cells are not completely clear because several different sets of surface markers have been used to isolate and characterize these stem cell populations. They include CD34/CD49 (41), Stro11/CD44 (44), SUSD2, and CD146/CD140b (45) cell surface markers. The results of these studies indicate that the CD34/CD49 and Stro11/CD44 populations are most likely the same. The myometrial stem cells are thought to have an important part in tissue regeneration and may become leiomyoma tumor-initiating stem cells when undergoing somatic mutations, such as MED12. The leiomyoma stem cells remain as a subpopulation within the tumor cells and retain the ability to initiate tumors in mouse xenograft models (41).

FIGURE 2.

Early pathogenesis of uterine fibroids The initiation of fibroids requires paracrine events among multiple cell types in the uterus. The normal myometrial cells (myocytes pictured in black) contain receptors for the steroids estrogen and progesterone (ER and PR). The uterine stem cells (orange) do not have steroid hormone receptors, but products produced by the myocytes in response to these steroids act on stem cells to promote transformation. Additionally, somatic mutations take place in the stem cells to create the phenotype of intermediate cells (blue). Of note, multiple somatic mutations can take place in a uterus, so that, as shown, the uterus commonly can have 2 fibroids with MED12 mutations and 1 with HMGA2 mutation. Fibroid cells (red) represent the transformed cell type and have increased extracellular matrix (ECM). RANKL, receptor activator of NF-κB; Wnt, wingless related integration site.

Several reports have provided crucial insights regarding the interaction between stem cell populations and other cells to initiate and promote growth of a clinical fibroid. Somatic mutations including MED12 are expressed in the stem cell population and in the SMCs within leiomyoma tumors but not in the associated cells (15, 44). Several studies (46–48) have determined that the receptor activator of NF-κB (RANKL)-RANK, wingless related integration site (Wnt), and IGF2–insulin receptor A (IR-A) signaling pathways are important regulators of proliferation in the leiomyoma stem cell population. RANKL is produced by the differentiated SMCs within the tumor and acts to increase proliferation of the stem cell population. Studies have also determined that leiomyoma stem cells exhibit a more inflammatory phenotype with increased expression of cytokines associated with the T-helper type II pathway (49). Finally, the stem cells undergo increased DNA damage with altered expression of DNA repair genes (9) and dysregulated DNA methylation with hypermethylation of important myometrial genes (50).

MicroRNAs

MicroRNAs (miRNAs) are short, noncoding, single-stranded RNAs that regulate gene expression at the transcriptional and translational levels (51). Alterations in miRNA levels were first described as regulators of malignant tumors but have also been associated with various reproductive diseases, including endometriosis (52). Many miRNAs have been identified in leiomyomas with expression profiles that differ from autologous myometrium (53, 54). Several appear to regulate important aspects of leiomyoma function and phenotype (55).

miR-21 is one of the key overexpressed miRNAs in leiomyomas. It has been shown to promote tumor fibrosis by blocking the inhibitory effects of the Smad7 protein. Thus, it stimulates the TGF-β signaling pathway, increases the expression of TGF-β receptor type 2 (56), increases expression of TGF-β3 in uterine leiomyoma and myometrial cells, and increases collagen, fibronectin, and cell proliferation (57). Fitzgerald et al. (58) also reported that miR-21 levels were higher in leiomyomas and that knockdown of miR-21 in these cells led to increased apoptosis.

Another important leiomyoma miRNA is miR-29. miR-29 is downregulated in fibroids and is a negative regulator of ECM genes, including collagens I, II, and III (8, 59). Moreover, overexpression of miR-29 in leiomyoma cells reduced collagen and fibronectin production, whereas knockdown of this miRNA in myometrial cells led to upregulation of several ECM proteins and a more fibroidlike phenotype (8, 59–61). Finally, let-7 miRNA is downregulated in leiomyomas, which gives investigators insight into the pathogenesis of the HMGA2 subgroup. Exogenous let-7 miRNAs directly repress HMGA2, and the levels of miR-let-7 are negatively correlated with HMGA2 expression (62, 63).

Limitation of Current In Vitro Systems

Studies focusing on leiomyoma molecular mechanisms have relied heavily on the use of primary cultures of human leiomyoma and myometrial cells from surgical tissue specimens. It has become apparent that traditional cell culture systems are not ideal for studying the biology of these cells, particularly if the cells must be passaged in culture, because primary and passaged leiomyoma cell cultures begin to lose expression of important genes, including estrogen receptor (ER) and PR, after only a few days (16, 64). Traditional two-dimensional culture of leiomyoma cells also leads to altered expression of specific genetic mutations and chromosomal rearrangements.

The HMGA2 gene is expressed in uterine leiomyomas with the (12,14)(q15;q24) chromosomal rearrangement but not in autologous myometrium or in karyotypically normal leiomyomas. However, HMGA2 expression was present in primary cultures of karyotypically normal leiomyoma cells and myometrial cells (65). Studies focusing on the MED12 mutation have shown that even during the early phases of in vitro culture, MED12-mutated cells are lost (43, 66).

Establishment of cells as primary two-dimensional cell cultures from fibroids results in a mixed population of cells. Analysis of differential gene expression in the three different cell subtypes within leiomyoma and myometrial cultures showed that genes including TGFβ2, PR, and cellular retinoic acid-binding protein 2 were differentially expressed in the SMCs of leiomyomas but not in the fibroblast cells in these cultures (17). A more recent study (15) identified a substantial proportion of tumor-associated fibroblasts within MED12-mutant leiomyomas. The MED12 mutation was not present in the tumor-associated fibroblasts but only in the SMCs. MED12-mutant leiomyomas also contained more collagen than the HMGA2-overexpressing leiomyomas, likely due to the fibroblasts. These findings suggest that the loss of MED12-expressing cells in culture may be due to preferential growth of fibroblasts in primary cultures and in subsequent passages. Future studies are needed to better understand how the heterogeneity of cell populations within leiomyomas contributes to the phenotype of those tumors.

Because of these limitations, interest has been substantial in the potential use of three-dimensional culture systems. The systems allow for a more physiological tissue structure, recapitulating the interactions between ECM and the heterogeneous cell populations present within leiomyomas. Initial studies used immortalized leiomyoma and myometrial SMCs cultured in collagen gels (67). These SMCs maintained their normal morphological characteristics and differential expression of several profibrotic genes, including TGFβ-3, collagen, fibronectin, and dermatopontin. Subsequently, investigators developed in vitro three-dimensional leiomyoma spheroid culture systems, in which primary cells from leiomyomas or myometrium were cultured on low-attachment plates in mesenchymal stem cell medium. These spheroid cultures can be maintained for up to 7 days and, importantly, maintain expression of ER and PR and differential expression and secretion of collagen (68, 69). Leiomyoma spheroids also have shown low proliferation, increased levels of phosphorylated AKT (protein kinase B), and increased oxidative stress, similar to in vivo tissue (61). The spheroid culture system has been used to study the role of specific circular RNAs and long noncoding RNAs that are expressed differentially between leiomyoma and autologous myometrium (70, 71).

Clinical and Environmental Influences

Lifestyle factors appear to influence clinically important uterine fibroids. Through studies such as the Nurses’ Health Study (72), the Black Women’s Health Study (73), and the Study of Environment, Lifestyle and Fibroids (74), the medical community knows that race/ethnicity, diet, exercise, and contraceptive use influence fibroid risk. However, unlike studies conducted after the Framingham Heart Study, evidence is not currently available about whether modifying risk results in decreased fibroid risk or progression. One currently exciting possibility is that vitamin D deficiency may be associated with fibroid risk, because that outcome would also explain the increased risk of fibroids in women with darker skin. However, modification of risk with vitamin D supplementation would need to be demonstrated.

Hypertension and fibroids have been linked through multiple epidemiological studies, and the fact that they both are diseases of SMC proliferation raises the possibility of a shared pathogenesis (75). One recent study suggested that the angiotensin-converting enzyme (ACE) pathway may be the link, where a large database study showed fibroid risk lessened with clinical ACE inhibitors (76). Similarly, statin use has been linked to decreased fibroid risk (77).

Environmental Toxicants

Endocrine-disrupting chemicals are environmental toxicants that can cause adverse effects on the endocrine system because of their structural similarity to endogenous hormones (78–80). As hormone-dependent neoplasms, fibroids may be targets for the endocrine-disrupting chemicals. Various studies are now accumulating evidence on a role for endocrine-disrupting chemicals in the pathogenesis of uterine leiomyomas (78, 81, 82).

Diethylstilbestrol (DES) is a pharmacological estrogen widely used between the 1940s and 1970s to prevent miscarriages in pregnant women. The National Institute of Environmental Health Sciences Fibroid Study Group (83) reported that women who were born in the era when DES was prescribed and who self-reported prenatal DES exposure had a greater incidence of uterine leiomyomas and had a tendency to develop larger fibroids. Studies performed in rat ELT-3 cells showed that treatment with DES increased cell proliferation in a dose-dependent manner. Coumestrol and naringenin, two phytoestrogens, have also been reported to induce proliferation of ELT-3 cells (84). Early-life exposure to environmental estrogens such as DES or genistein also led to increased tumor incidence and tumor size in Eker rats (85).

There appears to be a link between exposure to endocrine-disrupting chemicals, such as bisphenol A (BPA) and phthalates, and increased risk of leiomyomas. Shen et al. (86) evaluated the amounts of BPA, nonylphenol, and octylphenol in samples of blood and urine from Han Chinese women. The investigators observed that urinary BPA, nonylphenol, and octylphenol concentrations were greater in women who had leiomyomas than in control women. Zhou et al. (137) also quantified the levels of BPA, nonylphenol, and octylphenol in the urine of women with leiomyomas versus control women and found similar results. Zota et al (88) reported a positive association between the urinary levels of the di(2-ethylhexyl) phthalate (DEHP) metabolites MEHHP, MEOHP, and MECPP and the fibroid volume in a patient cohort undergoing hysterectomy. Further epidemiological and mechanistic studies are warranted to validate the associations observed in these studies.

The effects of BPA, nonylphenol, and octylphenol on leiomyoma cells were examined with primary cultures of human leiomyoma cells. Shen et al. (87) treated human leiomyoma cells with estrogen, BPA, nonylphenol, or octylphenol and saw increased proliferation rates compared with untreated cells, along with downregulation of the TGF-β-Smad signaling pathway. They further reported that BPA also increased proliferation of human leiomyoma cells by increasing the expression of ER, IGF-1, and vascular epithelial growth factor. He et al (89) isolated mesenchymal stem cells from uterine leiomyomas and determined that BPA induced cyclooxygenase-2 (COX-2) expression and stimulated both proliferation and migration of leiomyoma stem cells. Kim et al (90) tested the effects of DEHP on human leiomyoma cells in vitro and observed that DEHP-treated cells had greater viability, less apoptosis, and increased expression of COX-2.

The mechanisms by which endocrine-disrupting chemicals affect the development and growth of uterine leiomyomas involves epigenetic effects and DNA damage. Prusinski Fernung et al. (91) analyzed DNA repair capacity and function in myometrial stem cells isolated from adult Eker rats exposed during uterine development to DES. Their results showed that exposure to DES resulted in higher levels of DNA damage and a reduced ability to repair DNA double-strand breaks compared with stem cells from unexposed control rats. In a subsequent study, Elkafas et al (92) investigated whether vitamin D₃ could ameliorate the DNA damage response defects in rat myometrial stem cells due to early-life exposure to DES and whether this was a mechanism leading to reduced incidence of uterine fibroids later in life. Their results confirmed that treatment of rats with DES led to significantly reduced expression of key DNA repair proteins in isolated myometrial stem cells and that treatment of these myometrial stem cells with vitamin D₃ restored the DNA damage repair signaling network.

Taken together, the results of these studies confirm that endocrine-disrupting chemicals can have direct effects on uterine leiomyoma cells, including stem cells, through epigenetic mechanisms that may promote tumorigenesis. Additional investigations are needed to clarify the molecular pathways involved and to identify potential therapeutic approaches to ameliorate these effects.

Parallels in Physiology

Leiomyomas and Pregnant Myometrium Share Several Characteristics

In an interesting and relatively unexplored characteristic of leiomyomas, leiomyoma SMCs have a differentiated phenotype that is more similar to myometrial SMCs of pregnancy than of nongravid myometrium. Both myometrium of pregnancy and leiomyomas are characterized by increased responsiveness or hypersensitivity to gonadal steroids, particularly estrogen, due to increased expression of steroid hormone receptors. This hypersensitivity leads to increased cell proliferation; increased extracellular matrix production, particularly fibrillar collagens; increased expression of connexin-43; and decreased apoptosis (93–96).

More recent studies have identified additional similarities between leiomyoma SMCs and myometrium of pregnancy, including increased expression of the IGF ligands and signaling (97, 98) and of COX-2 (40, 99) compared with SMCs of nongravid myometrium. Expression of COX-2 was linked to the proliferative capacity of leiomyoma SMCs. Jaffer et al (100) reported that the mammalian target of rapamycin (mTOR) pathway is activated in association with increased proliferation of myometrium during pregnancy. Leiomyomas show a similar activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway (101). Why leiomyoma SMCs maintain the pregnancy phenotype requires further investigation.

Bypassing the Gonads

Most fibroid pathogenesis is tied to the gonadal steroids, yet direct actions of pituitary hormones may occur (102). Studies have linked both the anterior pituitary (luteinizing hormone) and posterior pituitary (prolactin) to uterine disease through fibroids and the related disorder adenomyosis (83, 103, 104). This evidence is most developed for prolactin, where work has shown that the receptor is present in myometrium and the ligand serves as an SMC mitogen (104)

Unique Features of Leiomyomas

Lack of Growth Inhibition

Unlike most neoplasms, which range in size from millimeters to a few centimeters, fibroids can commonly exceed 20 cm, suggestive that they lack growth inhibition (105). Their location within the peritoneal cavity indicates that growth may escape detection in a way that a thyroid or breast lesion might not. However, the same should be true for lesions of the gastrointestinal tract, which does have leiomyomas but typically not large ones. Likewise, animal models of leiomyomas typically have small nodules and not the large lesions seen in women (106–110) (Table 1). In most cases, the leiomyomas become apparent only in older animals, most likely because of the slow growth and smaller size of the tumor.

Table 1.

Animal models for uterine leiomyomas

Species	Incidence	Reference
Gray seals	65%; occur in older seals ages 22–41 yr	(106)
Miniature pigs	75%; incidence linked to older age (mean 9.7 yr)	(107)
Dogs	Linked to age; most common uterine tumor in dogs	(110)
Nonhuman primates	Oviductal and uterine leiomyomas; incidence increases with age	(108)
Poultry	Oviductal; incidence increases to 75% in aging hens	(109)

Some Facets of Malignancy, Yet a Benign Disease

A group of lesions typically referred to as leiomyoma variants occupy the interstices of cancer and benign lesions (111). Benign metastasizing leiomyomas are lesions where clonal lesions arising from a uterine source are found in distant sites, with the lung being the most frequent site (112). Intravenous leiomyomatosis occurs when a fibroid spreads through the venous system from the pelvis to the heart, often presenting as dyspnea or an atrial mass; it can occur long after hysterectomy (113). Finally, disseminated peritoneal leiomyomatosis, or leiomyomatosis peritonealis disseminata, clinically resembles ovarian cancer, with nodules throughout the pelvis that are histologically benign and share some of the karyotypic changes found in conventional fibroids (114).

Additional diseases have less clear relationships to fibroids. SMC tumors of undetermined malignant potential and even uterine sarcomas also present as a myometrial mass on imaging but are histologically different (115).

Lymphangioleiomyomatosis (LAM) presents with histologically benign but much more morbid disease in the lung. It is linked to fibroids through mutations in the tuberous sclerosis gene in LAM and the early Eker rat model (116, 117).

Paradox of Growth

Finally, the mechanics of growth in leiomyomas are unclear. By definition, fibroids have a low mitotic index, yet image-based studies showed a median volume growth of 9% over 6 mo and a maximal growth rate of 138% over the same interval (118). Approximately 7% of the fibroids in that study shrunk at least 20%; however, the shrinkage was mainly in the smaller fibroids. Because leiomyomas are rich in ECM, expansion of the matrix component can occur, but studies have suggested that this is not the primary mechanism of their growth.

Future Directions

Surgery and Hormonal Therapies

Fibroid therapy currently is rooted in the nineteenth century model of surgical excision, analogous to the Halstead paradigm of breast cancer. This model has limitations beyond the morbidity of surgery. Although fibroids can be surgically removed or destroyed with various therapies (e.g., radiofrequency ablation, embolization, focused ultrasound), the risk of new fibroids forming is high (119). Nonetheless, both myomectomy (surgical removal of fibroids alone) and uterine artery embolization are highly effective at reducing symptoms and likely are underused (120, 121).

Hysterectomy continues to be a mainstay of therapy because it removes the risk of new disease formation. Yet, increasingly, research has shown substantial downstream risk of hysterectomy even when both ovaries are conserved, including increased cardiovascular risk, mood disorders, and urinary dysfunction (4, 122). Moreover, since long-term risks appear higher in women who have hysterectomy at a younger age, improvement in uterine-sparing therapies is critical (122).

Contraceptive steroids are used to treat early-stage symptoms and especially heavy menstrual bleeding (HMB). They neither treat the symptoms attributable to fibroid size nor allow for pregnancy. Despite their widespread off-label use, little evidence supports use of oral contraceptives for fibroid-related HMB; instead, evidence favors use of localized progestin action in the form of a progestin-releasing intrauterine device (123, 124). Newer therapies still focus on modulation of gonadal steroids.

PR modulators have been widely used outside the United States and have shown great efficacy. In the United States, concerns about rare but sometimes fatal liver toxicity have restricted their use. PR modulators are unlikely to receive approval from the US Food and Drug Administration (125). A new therapeutic possibility is the use of oral GnRH antagonists. The goal of this therapy is to suppress endogenous gonadal steroid hormone production coupled with estrogen and progestin to recreate the steroidal milieu of the early follicular phase and thereby to abrogate fibroid symptoms but not provoke hypogonadal symptoms (5, 25).

Given the near ubiquity of subclinical disease, especially for women of color, prevention of growth may be more successful than targeting clinical lesions (2). However, tools to accurately predict future growth do not exist. Data demonstrate that fibroids can regress, so targeting the regression pathway is another unexplored treatment route (118).

Dietary intervention as a therapeutic approach to leiomyoma treatments has only recently begun to be considered (40, 126). Several different plant-based compounds have been investigated. Studies carried out in quail have tested dietary lycopene, an antioxidant, to slow the growth of leiomyomas and have shown both reduced size and a 40–50% decrease in the incidence of oviductal leiomyomas (127, 128).

Curcumin, a curcuminoid found in turmeric that has strong anti-inflammatory and antioxidant properties, has also been studied. Malik et al (129) found that curcumin treatment of human leiomyoma cells in culture inhibited proliferation, increased apoptosis, and decreased expression of fibronectin production in a dose-dependent manner. In addition, Tsuiji et al (130) confirmed the effects of curcumin on proliferation and apoptosis of cultured ELT-3 leiomyoma cells. These effects of curcumin occurred through activation of peroxisome proliferator-activated receptor-gamma.

Clinical pilot studies and studies in animal models are needed to determine the mechanisms by which such plant-based anti-inflammatory compounds affect the growth of uterine leiomyomas.

Interest is strong in the use of vitamin D₃ supplementation as a dietary treatment of leiomyomas. Several studies have reported that serum vitamin D₃ levels are inversely correlated with leiomyoma tumor size, and African American women often have vitamin D₃ deficiency (131, 132). Vitamin D₃ is recognized not only as an antifibrotic agent (103, 133) but also for its anti-inflammatory effects (40). Recent studies by Halder, Al-Hendy, and colleagues (44, 132, 134, 135) have focused on 1,25-hydroxyvitamin D₃ supplementation as a dietary intervention for leiomyomas. The investigators reported that 1) the vitamin D receptor activator paricalcitol inhibited leiomyoma tumor formation in Eker rats and 2) vitamin D₃ inhibited proliferation and collagen production in cultured human leiomyoma cells (44, 134). Using a mouse xenograft model in which rat ELT-3 cells were injected into mice, these investigators also demonstrated that treatment with oral paricalcitol caused significant size reduction in the leiomyoma tumors that formed (135). Vitamin D₃ supplementation of cultured leiomyoma cells also decreased DNA damage by increasing the expression of DNA repair genes (136). Taken together, these studies support that vitamin D₃ has strong potential as a dietary intervention therapy for uterine leiomyomas. However, additional in vivo studies and clinical trials are needed.

Summary

Uterine fibroids are a major disease of women, yet the science of the disease has been limited by an overreliance on hysterectomy as treatment. Important strides have been made in understanding the genesis of these tumors and the mechanisms regulating their growth (FIGURE 3). Exploration of facets other than steroid responsiveness should lead to better treatments and prevention strategies. Moreover, distinct lesions such as leiomyoma variants may provide model systems for investigating such fundamental disease processes as malignancy.

FIGURE 3.

The genetic and environmental factors contributing to initiation and growth of uterine leiomyoma tumors Somatic mutations of the stem cell population are thought to have a major role in initiation of tumors while the subsequent phenotype, and progression is influenced by environmental and epigenetic factors. miRNA, microRNA; RANKL, receptor activator of NF-κB; TGFβ, transforming growth factor β; Wnt, wingless related integration site.