This article is based on presentations at the conference on Women's Health and the Environment: The Next Century--Advances in Uterine Leiomyoma Research held 7-8 October 1999 in Research Triangle Park, North Carolina, USA.
Address correspondence to D. Dixon, NIEHS, PO Box 12233, 111 Alexander Dr., Bldg. 101, Research Triangle Park, NC 27709 USA. Telephone: (919) 541-3814. Fax: (919) 541-2260. E-mail: dixon@neihs.nih.gov
The authors thank C. Swartz and G. Flake for their critical review of this manuscript.
Received 8 August 2000; accepted 14 August 2000.
Uterine leiomyomas (fibroids, myomas) are the most common solid tumors found in the genital tract of women during their reproductive years (
1). These tumors have been estimated to affect at least 25% of the American female population (
1); however, Cramer and Patel (
2) have reported an incidence of 77% in women after thorough pathologic examination of their uteri. Although uterine leiomyomas are benign smooth-muscle tumors that rarely progress to malignancy (
1), they are often associated with a number of reproductive and gynecologic problems such as infertility, lost pregnancy, pelvic pain, and menorrhagia (
3). Not only are uterine leiomyomas a health concern for American women, but they have also been associated with clinical disease with some frequency in European (
4), Japanese (
5), and African (
6) women. In the United States, alone, uterine leiomyomas are responsible for nearly 200,000 hysterectomies annually in women (
7).
Many studies have shown the ovarian steroid hormone dependency of these tumors, and their regression after menopause (3). Because of their hormonal dependency, these tumors may be targeted by environmental chemicals whose biological effects are mediated through the estrogen and/or progesterone receptors. Nonetheless, little is known of the etiology, genetic or molecular biology, or the influence of the environment on the formation and development of these tumors. This article is an overview of emerging advances in the areas of cell biology, histopathology, molecular biology, experimental model systems, genetics, and current approaches to clinical management of uterine leiomyomas as presented by scientists and clinicians at the conference on Women's Health and the Environment: The Next Century--Advances in Uterine Leiomyoma Research. A conference summary and future research recommendations are also presented.
Although uterine leiomyomas are one of the most common gynecologic tumors in women, little information is available in regard to their etiology. Their dependence on steroid hormones, however, suggests that altered responsiveness to these hormones, especially estrogens, plays an important role in the development and progression of these tumors. In particular, exposure to excessive estrogenic substances during critical stages of reproductive tract differentiation may be a contributory factor in the subsequent development of leiomyomas.
It is of interest, therefore, that chemicals in the environment possessing estrogenic- and/or endocrine-disrupting activity may contribute to an increased incidence of various diseases in hormone-responsive target tissues (8-10). It has been hypothesized that endocrine-active compounds, especially those that bioaccumulate, are related to increases in breast cancer, endometriosis, endometrial cancer, ovarian cancer, autoimmune disease, and uterine leiomyomas (9). Although it remains to be determined if exposure to these chemicals at environmentally relevant levels is related to human disease, this is a matter of utmost concern and importance.
Clearly, ample evidence exists in both humans and experimental animals to link developmental exposure to pharmacological levels of estrogenic compounds such as diethylstilbestrol (DES) with poor reproductive outcome and tumors later in life (11,12). For many years research has focused on studying the effects of DES and other estrogens on differentiating reproductive tract tissues. Using the CD-1 outbred mouse, it has been shown that benign and malignant changes in the developing DES-exposed murine genital tract closely parallel those seen in humans (13-17). Although most of these studies have focused on the characterization of epithelial alterations, including vaginal and uterine adenocarcinoma (18), perinatal exposure to DES is also associated with a high incidence of smooth-muscle changes in the uterus, and a low but significant increased incidence in smooth-muscle tumors (approximately 5%) (13). It is interesting to note that high doses of DES (100 µg/kg maternal body weight) resulted in disorganization and atrophy of the smooth-muscle compartment of the developing fetal reproductive tract and, in some cases, functional alterations and structural malformations (13); exposure to lower doses, however, resulted in hypertrophy and increased smooth-muscle tumors (13). Although most of these tumors had histomorphological characteristics of typical benign smooth-muscle tumors, some were malignant lesions (13). All the benign DES-induced tumors showed characteristic Masson's trichrome staining indicative of smooth-muscle origin. In a few mice multiple tumors were observed, which mimics the situation seen in humans. Thus, these new data suggest that developmental exposure to DES is associated with smooth-muscle abnormalities, including tumors in the uterus as well as numerous other benign and malignant epithelial abnormalities throughout the reproductive tract. Unlike the rare occurrence of vaginal adenocarcinoma, the hallmark lesion of prenatal DES exposure (19), these smooth-muscle tumors have typical tumor characteristics. These data with DES support the hypothesis that exposure to endocrine-active compounds during development may, indeed, contribute to the occurrence of fibroids later in life.
The discovery of numerous polypeptide growth factors and cytokines in the past three decades, along with their complementary receptors and signaling pathways has given researchers conceptual insights into the regulation of cell behavior. In essence, growth factors have become the dialogue to coordinate the biochemical reactions that determine the cellular pleiotropy needed in a multicellular organism. The cumulative findings support the participation of multiple growth factors in events such as morphogenesis, angiogenesis, wound healing, and immune responses. Each signaling pathway recruited by a growth factor receptor results in the activation of a cascade of kinases and phosphatases, some of which are convergent points for multiple pathways. On this basis, it is reasonable to assume that mutations that functionally affect a single component of these regulatory circuits have the potential to upset the normal homeostatic controls of growth and cell-cell interactions and thereby increase the risk of tumor formation.
Although the specific mutations linked to the etiology of leiomyomas have not been defined, there has been significant evidence to support that ovarian steroids and the growth factor pathways they regulate contribute causally or permissively to this disease (20-23). Moreover, there could be a mechanistic overlap between the origins of leiomyomas and endometrial carcinomas. An increased incidence in the occurrence of endometrial carcinomas has clearly been linked to treatment with unopposed estrogens (24). The action of estrogens on the cells of the endometrium results in an increase in insulin-like growth factor (IGF)-1 mRNA (25) and activation of the IGF-1 receptor signaling pathway (26,27). Studies with IGF-1 null mutant mice indicate that this growth factor is important for the estrogen-induced uterine epithelial cell proliferation (28); these null mutants also have a markedly underdeveloped myometrium (29). In a related study, IGF-1 mRNA significantly increased in the myometrium of rhesus monkeys treated with estradiol; transcript levels were even higher when these primates were treated with estradiol plus progesterone (30). A marker for proliferation (Ki67) of the smooth-muscle cells correlated with IGF-1 mRNA levels.
These experimental findings indicate that IGF-1 is important for hormonal stimulation of the smooth-muscle cell proliferation in the uterine myometrium as well as the uterine epithelial cell. In leiomyomas, the levels of IGF-1 mRNA were higher than those of surrounding myometrial tissues [see Andersen (22) for review]; these tumors also showed an increase in IGF-1 receptors (31). An appropriate extension of these findings would be to determine whether the elevation in ligand transcript in the leiomyomas correlates with an actual increase either in tyrosine phosphorylation of the IGF-l receptor, binding of adaptor or docking proteins to the receptor, or activation of IGF-l receptor downstream signaling intermediates. This can be done by direct analysis of freshly obtained tumor tissue. Inappropriate activation of this pathway could account for or contribute to the leiomyoma phenotype.
Multiple growth factors may be important in the pathogenesis of leiomyomas, and different growth factors may engage at different stages of the disease. Basic fibroblast growth factor (FGF) and transforming growth factor-ß (TGF-ß) are other candidates considered in the pathogenesis of this disease (22). Together, these factors might account for the enhanced angiogenesis, smooth-muscle cell proliferation, and extracellular matrix production found in leiomyomas when these tumors are compared to normal myometrium (32).
Identification of growth factors and signaling pathways that contribute to the formation or progression of leiomyomas should ultimately provide specific targets for intervention strategies. This is a compelling research goal given the high occurrence of this disease.
Historically, leiomyomas have been a favorite subject of cytogeneticists because of a series of commonly observed translocations and deletions. It is these gross genetic defects that draw comparisons to malignant tumors, and these defects have been the focus of much study. The exact percentage of leiomyomas with observable cytogenetic aberrations may be as high as 50% (
33,34). One of the most commonly observed defects occurs as a reciprocal translocation involving chromosomes 12q15 and 14q24, with other frequently occurring abnormalities including chromosomes 1, 6, 7, 10, and 13, among others (
33,34). Analysis of these aberrations has provided some of the best clues to the mechanisms underlying leiomyoma development.
The 12q15 breakpoint gene was cloned from the analysis of other soft tissue tumor types including lipomas, and found to involve the HMGIC gene (35,36). In lipomas, chromosome 12q15 can translocate to a variety of other chromosomes but not frequently to 14q24. Interestingly, HMGIC, which likely functions as a DNA architectural transcription factor, was frequently observed to have chimeric transcripts in lipomas but not in leiomyomas (35,36). Translocation in lipomas typically results in expression of the amino terminal AT-hook domains of the HMGIC protein, which is necessary for DNA association fused to various DNA sequences supplied by the reciprocal chromosome (35,36). These chimeric transcripts have, in some cases, been shown to act as transactivaters. The presence of chimeric transcripts in uterine leiomyomas remains unclear. Recent reports indicate that the translocation may simply upregulate HMGIC expression in the absence of a chimeric transcript; yet others show that RAD51B is the reciprocal partner located on chromosome 14 (37,38). Other molecular data suggest that HMGIC alone is sufficient to initiate excessive growth; specifically, transgenic animals expressing a truncated HMGIC result in an overly large mouse with a lipomatosis-type phenotype (39). Conversely Hmgic-/- mice are smaller than normal and result in a pygmy phenotype (40). It is possible that the reciprocal nature of the translocation with chromosome 14 influences tissue specificity. Clearly, the resultant defects in HMGIC remain a pertinent question. Interestingly, the highly related chromosome 6 protein, HMGI/Y, is upregulated in some leiomyomas, particularly those with chromosome 6 abnormalities (41). Similar to HMGIC, overexpression of HMGI/Y is associated with various neoplasias. The exact consequences of overexpression/rearrangement of these genes in the myometrium where they are normally silent in adulthood should be addressed, as does the relative frequency of these events in leiomyomas in general rather than just in those tumors with obvious cytogenetic defects at these loci.
Whereas conventional cytogenetics has discovered a multitude of aberrations, analyses of leiomyomas by researchers hoping to uncover less obvious genetic defects have been largely unsuccessful. Specifically, the use of genomewide analysis technologies such as allelotyping and comparative genomic hybridization have failed to identify new interesting genomic regions (42-44). Despite the fact that many tumors have frequently been observed to have cytogenetic aberrations, a large proportion of leiomyomas do not have any visible cytogenetic abnormalities (33,42). These tumors may, however, have subtle defects, possibly epigenetic. Indeed, many leiomyomas aberrantly express a variety of growth and differentiation factors compared to the adjacent myometrium. Several lines of evidence suggest that leiomyomas have similarities to pregnant myometrium (20,22). Further research will help clarify these similarities, including the recent advent of cDNA microarray technologies, which may help to identify differences between gene expression in leiomyomas and myometrium. Continuing work on these and other avenues will undoubtedly start to clarify the molecular profile of these tumors, which ultimately may lead to new therapies and/or prevention strategies.
Progress toward a better understanding of the biology of uterine leiomyoma and the development of new therapies for treating this disease have been slow, partly because of a lack of suitable
in vivo models. In contrast to the many well-characterized models of epithelial oncogenesis, relatively few animal models of soft tissue tumorigenesis have been developed. The occurrence of spontaneous leiomyomas in rodents generally is rare. A low incidence of mesovarian leiomyomas can be induced in rats following chronic administration of ß-adrenergic stimulants (
45), and a low incidence of reproductive-tract leiomyomas has been reported as an aging lesion in an inbred strain of the Brown Norway rat (
46). Until recent studies using Eker rats, there had been no reports of a high incidence of spontaneous reproductive tract leiomyomas in any outbred stocks or inbred strains of laboratory rodents. Eker rats are genetically predisposed to tumor development by a germline mutation in the tuberous sclerosis 2 tumor-suppressor gene. They provide a potentially valuable new rodent model of smooth-muscle tumorigenesis (
47,48).
The infrequent finding of uterine leiomyomas as a spontaneous neoplasm in laboratory animals has resulted in efforts to establish induced experimental tumor systems. Experimental animal model systems of induced uterine leiomyoma have included the heterotransplantation of human tumors into immunocompromised murine hosts (49), hormonal induction of tumors in rodent models (50), and tumor induction in genetically altered rodents (51,52). Recent advances in the manipulation of the mouse genome combined with advances in imaging and surgical techniques in mice have created an unparalleled opportunity for the development of new animal models of human cancers. In the near future, genetic engineering in mouse models using targeted gene approaches is likely to provide new and useful models for studies of uterine smooth-muscle tumorigenesis.
Human cancers are complex multifaceted diseases, and no individual animal model is likely to recapitulate all the important features of the human disease. A thorough understanding and characterization of the biology of uterine leiomyomas in animal models is critical because women differ substantially in important aspects of reproductive tract development, anatomy, physiology, and pathology. The strengths and limitations of any individual animal model system depend greatly on the specific research questions it is asked to address. Despite the limitations, studies of uterine leiomyoma in animal models have contributed to our understanding of the cellular and molecular biology of this tumor (53-55).
Development of rodent models of uterine leiomyoma has allowed use of an in vivo/in vitro approach that combines studies in tumor-derived cell lines with experimental manipulations in live animals. This combination of in vivo and in vitro tools has contributed to our understanding of leiomyoma cell signaling pathways and the response of tumors to hormonal modulation (52,56-58). Studies using these models will probably contribute to the development of new and novel therapeutic modalities for uterine leiomyoma treatment in women. The papers contributed to this conference provide powerful examples of the importance of animal models for understanding the biology of uterine leiomyoma. As our understanding of this specific tumor biology unfolds, new and more useful animal models are likely to be developed.
Before the 1990s, the primary focus of health care in the United States was on curing disease. Uterine leiomyomas were viewed as a curable health problem, so federal funding agencies largely ignored them. The cure for leiomyomas was simple and straightforward, namely, surgery. However, since the focus in U.S. health care has shifted to include cost, leiomyomas have risen in importance. In the last few years, new surgical techniques and experimental alternatives to surgery have begun to emerge (
59). Surgical strategies have focused on ways of making surgery less invasive, which reduces the need for long periods of hospitalization and recovery. These strategies include removing leiomyomas through scopes and avoiding large incisions. However, not all leiomyomas are amenable to this approach. Hormonal therapies enjoyed an interval of popularity in American medicine as an alternative to surgery (
60); however, the wide application of this approach has been limited by the realization that the tumors do not go away. Hormonal therapies are also expensive and have other health consequences. Newer research strategies have involved embolizing the blood supply of these tumors (
61,62). There is a cohort of enthusiastic supporters of this approach today; however, it is too early to determine whether this therapy will be widely accepted by patients and the medical community. One of the potential limiting factors of this approach is that leiomyomas do not have a distinct blood supply that can be approached without treating the entire uterus. Another approach to ablating these tumors without making incisions has been to destroy the cells with probes that expose the tumors to high or low temperatures. Recently there has been interest in funding research for developing purely medical therapies for uterine leiomyomas.
Uterine leiomyomas present a unique set of challenges to the medical and research communities. These tumors demonstrate a wide diversity in their biology and presentation. Important questions must be addressed in managing them. The first clinical issue is to decide which leiomyomas to treat. For women who desire to become pregnant, it is important to know if a particular tumor has an adverse impact on reproductive function. Other important clinical issues relate to tumor size and symptoms caused by leiomyomas. Tumor number and proximity to the endometrial cavity are important factors. Tumors become more symptomatic at a smaller size, the closer they are to the endometrial cavity. The second clinical issue is to determine the best form of therapy for each patient, taking into consideration their desires with regard to the risks and benefits of each therapy and the woman's desire for future childbearing. From the standpoint of developing medical therapies for these biologically diverse tumors, it is important to determine if there are common molecular pathways that contribute to their growth and that can be manipulated in a safe and efficacious manner. Although the standard of care for these tumors is still surgical, there is hope that diverting resources into basic research may result in the development of medical therapeutic options for women (63).
Conference Summary
Uterine fibroids or leiomyomata uteri constitute a significant public health concern and represent an area of ongoing research efforts to reduce the burden of this disorder. This important conference characterized the significant challenges and opportunities inherent in leiomyoma research by embracing the need for increased emphasis on a disorder that poses a serious reproductive threat for many women. During the meeting, investigators and other experts explored the manner in which evolving basic science and clinical research could provide critical insight into leiomyoma initiation and growth and provide a foundation for future treatment strategies. All aspects of research, including basic biological processes, epidemiology, diagnostic criteria, and new clinical treatments are potential avenues that warrant further exploration. Increased knowledge about the underlying etiology and pathophysiological mechanisms would strengthen the science base and provide clues for more effective conservative management of this disorder.
Although we have gained some insight into the mechanisms that mediate leiomyoma transformation and growth and some progress has been made, many questions remain. Several priority areas in need of increased emphasis would benefit from the scientific opportunities presented during the meeting.
Future Research Directions and Recommendations
The following summary of selected conference themes and observations may provide a new scientific framework that refines the parameters of leiomyoma research. The following are specific areas of recommended research based upon discussions by scientists, clinicians, administrators, and other attendees at the meeting: a) Initiate a genomewide screen to determine the genetic liability for developing leiomyomas, with particular emphasis on racial overexpression in African-American women, twin pair correlation, and familial predisposition; b) elucidate the role of genetic alterations in the process of tumor transformation, correlating the cytogenetic abnormalities with phenotypic expression; c) open new avenues for diagnostic and conservative treatment modalities to target relevant hormonal pathways for leiomyoma development, including the design of novel pharmaceutical agents directed at these pathways; d) develop animal models to screen for candidate therapeutic agents and prevention strategies, encouraging development of targeted nonsurgical modalities for leiomyoma management; e) identify the basic molecular and cellular processes and examine the mechanism by which estrogen and progesterone induce cell transformation and promote tumor growth or suppression; f) study the potential role of selective estrogen receptor modulators (SERMs) on leiomyoma development and growth; g) further characterize endocrine disrupters and their influence on the risk of leiomyoma formation; h) assess whether growth factor expression is the framework through which abnormal myometrial cell growth can be explored to clarify the interaction between estrogen/progesterone and growth factors on leiomyoma initiation and development; i) examine the management of asymptomatic leiomyomas and capture their natural history with attention to evaluating the importance of tumor size on symptoms and treatment approaches; j) study the effectiveness of medical regimens or surgical treatment interventions in regard to symptom relief and other quality of life indicators; k) identify noninvasive biomarkers to delineate molecular alterations at specific stages of tumor pathogenesis and define molecular markers for leiomyoma progression/recurrence; l) facilitate collaborative molecular studies through the formation of a tissue bank; m) focus on designing clinical trials for the comparison of conventional surgical techniques with alternative surgical procedures and other treatment protocols; n) explore the relationship of leiomyomas to infertility and assess the impact on assisted reproductive technology.
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Last Updated: October 2, 2000
