Fibroids

James H. Segars

• Publisher: Wiley-Blackwell
• Year: 2012
• Print ISBN: 9780470670941
• eBook ISBN: 9781118457078
• Edition: 1
• Topic: Medicine
• Subtopic: Gynecology, Obstetrics & Midwifery

Fibroids are benign growths of the uterus. They are the most common tumours found in women (20-30% of women), usually in later reproductive years. This book covers evidence-based indications for treatment of uterine fibroids in gynecology, the management of fibroids in pregnancy, surgical treatments and outcomes, rare fibroid syndromes, and more.

1

Understanding Uterine Fibroids

Phyllis Leppert,¹ Mazen Fouany,² and James H. Segars³

¹ Department of Obstetrics and Gynecology, and Center for Uterine Fibroid Biology and Therapy, Duke University School of Medicine and Duke University Medical Center, Durham, NC, USA
² George Washington University Hospital, Washington, DC, USA
³ Reproductive Biology and Medicine Branch, NICHD, National Institutes of Health, Bethesda, MD, USA

Introduction

Uterine leiomyoma, commonly called fibroids, consist of an abundant but altered extracellular matrix. Fibroids are benign monoclonal tumors believed to be of myometrial origin. They develop in women of reproductive age, a fact that led to the concept that their growth was predominantly driven by reproductive hormones. The first sys­tematic study of their pathology was described in 1793 and the first abdominal myomectomy was reported in 1838. By the early 1900s, because of advances in surgery and anesthesia, many surgeries were done for uterine leiomyoma, as reported in the first book on the subject, Fibroids and Allied Tumors, by Cuthbert Lockyer in 1918. While the prevalence of fibroids in the United States is often quoted to be 35–50%, in fact the prevalence is likely much higher. In 1990 Cramer reported a study of hysterectomies in which fibroids were detected in 77% of uterine specimens. More recently, the group led by Baird reported that the cumulative incidence of fibroids by age 50 was 70% in US Caucasian women and approximately 80% in African-American women. Currently, one in every two women of reproductive age in the US has uterine fibroids, making the condition the most common disease of the female reproductive tract. In this chapter, we review what is known about causes of fibroids, their features, and pathophysiology.

Fibroid etiology and pathophysiology

Despite their remarkable prevalence, the etiology of fibroids remains unknown. Nonetheless, the past decade has witnessed a significant increase in ­published scientific investigations of uterine fibroid biology, initiating factors, fibroid growth and development as well as new treatment modalities. Several seminal breakthroughs in understanding of fibroid pathophysiology have occurred. Most significantly, Baird and coworkers reported that uterine fibroids grow at various rates even in the same women and that the growth rate patterns are different in Caucasian and African-American women. A second scientific observation that changes the way scientists think about fibroids were reports that these benign tumors are composes of altered collagen fibrils and display many differences in other extracellular molecules compare to normal myometrium. In addition, mechanical forces appear to play a role in the development and growth of these benign tumors. This has led to the appreciation that fibroids can be considered a fibrotic disease. Furthermore, numerous cytokines and integrins have been reported to be significantly changed in fibroids, leading to the concept that the inflammatory response also plays an important role in the etiology and pathophysiology of fibroids.

It is essential to appreciate that the molecules involved in the inflammatory response are the same as those involved in tissue remodeling during development and after injury. Thus the concept of inflammation actually fits into a theory of fibroid development based on an altered response to noxious stimuli; possibly tissue injury from extravasated menstrual blood into the myometrium or hypoxia leads to altered repair and fibrosis. The two advances discussed above suggest further studies and the need for the development of a unified systematic approach to the etiology of fibroids.

Genetics

Uterine fibroids are monoclonal in origin. Approxi­mately 40% of fibroids are cytogenetically abnormal. Cytogenetics studies demonstrated that fibroids have similar chromosomal rearrangements to other benign lesions but are distinct from the complex rearrangements and aneuploid karyotypes characteristic of leiomyosarcomas. Genetic polymorphisms in the estrogen receptor gene, insulin-like growth factor gene, and androgen receptor gene have been reported to be related to the development of fibroids.

Most of the cytogenetic alterations involve chro­mo­some 12. Translocations involving this chromo­some identified members of the high mobility group gene family, which include HMGA1 and HMGA2. Both HMGA1 and HMGA2 are aberrantly expressed in fibriods and other benign lesions such as lipomas. Three loci on chromosomes 10q24.33, 22q13.1 and 11p15.5 revealed genome-wide significant associations with uterine fibroids. It is possible that the 60% of uterine myomas with a normal karyotype may harbor a subtle genetic abnormality such as point mutation or changes in the regulatory regions of certain genes.

Some types of fibroids, such as those found in individuals with hereditary leiomymoma and renal cell carcinoma (HLRCC) syndrome, are associated with genetic mutations (see Chapter 11). It is not clear, however, if genetic susceptibility gene abnormalities will be discovered for all fibroid subtypes. Specifically, the fact that fibroids are extremely common suggests that genetic factors alone are unlikely to be a significant component of their overall etiology. Thus, further investigations are needed before the question of whether or not ­genetic susceptibility genes exist can be answered. What is interesting, however, is the fact that small RNAs, called microRNAs, are present in fibroids collected at the time of hysterectomy. These microRNAs regulate gene expression and their role in fibroid development and growth is intriguing but remains to be defined.

Recently it was reported that MED12, the mediator complex subunit 12 gene, is mutated at a high frequency in uterine fibroids. Eighteen fibroids from 17 subjects were evaluated. Ten tumors had a mutation in this gene and eight of these mutations were in codon 44. Next, an additional 207 fibroids were evaluated for codon 44 mutations. While this report has generated much interest, the results need to be confirmed in future studies with larger sample sizes, by fibroid subtype, as well as data from different populations.

Growth factors

Transforming growth factor (TGF) beta has a central role in the enlargement of fibroids. TGF-beta stimulates the production and deposition of extracellular matrix (ECM) and is considered to be a major growth factor in the development of fibrotic disease. Compared to normal myometrium, fibroids have a greater density of TGF-beta receptors. The downstream targets of TGF-beta signaling are many and include tissue inhibitor of matrix metalloproteases (MMPs) and plasminogen activator inhibitor (PAI), which promote the deposition of the ECM by complex mechanisms. Interleukin (IL)-11, under the regulatory control of TGF-beta, plays a role in the development of fibrosis and is overexpressed in fibroids. Interestingly, gonadotropin-releasing hormone (GnRH) agonists inhibit the expression of TGF-beta. GnRH agonists also change osmotic forces and decrease the water content of fibroids. Furthermore, reduced TGF-beta expression results in reduced ECM production and shrinkage of the fibroid size, indicating again the major role of TGF-beta in fibroid growth.

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CAUTION #1

In evaluating investigations of fibroid surgical specimens, it is important to bear in mind that the tissue was obtained at one point in time and that in most cases it is not known whether the particular tissue studied was from a growing, static or regressing fibroid. Since size of the fibroid also does not agree with growth state, small size per se does not imply a new or actively growing fibroid. Future studies will need to gather information on fibroid size and location, and growth rate over time.

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Several growth factors are also vasoactive and angiogenic. Therefore, they may contribute to the profuse menstrual bleeding. Examples of such growth factors include basic fibroblast growth factor (bFGF) which promotes angiogenesis, prolactin which is a proangiogenic factor, and parathyroid hormone-related protein which acts as a vasorelaxant.

The growth factors that are known to act on the myometrial cells are the following: epidermal growth factor (EGF), heparin-binding EGF (HB-EGF), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), acidic fibroblast growth factor (aFGF), and basic fibroblast growth factor (bFGF). The effect of growth factors on a target tissue is the production of cytokines including IL-1, IL-6, IL-11, IL-13, IL-15, interferon (IFN)-delta, tumor necrosis factor (TNF)-alpha, and granulocyte macrophage colony-stimulating factor (GM-CSF). These cytokines have been documented in the myometrium and fibroids.

The role of sex steroids

Sex steroids promote the local production of growth factors, which act in autocrine or paracrine mechanisms resulting in cellular growth. Fibroids are responsive to sex steroids, estrogen and progesterone but the precise mechanisms that lead to growth are unclear. Expression of a dominant negative estrogen receptor inhibited fibroid cell growth in vitro and in vivo. We do know that fibroids express higher levels of cytochrome P450 aromatase, which consequently catalyzes androgen to estrogen. Leptin is a regulator of aromatase; it also stimulates collagen production and may therefore play a role in fibroid formation. Treatment of primary fibroid cells with leptin resulted in increased aromatase expression.

Although estrogen has traditionally been identified as the most important sex steroid for fibroid growth, progesterone seems to have the dominant steroidal influence on fibroids. This dominance is supported by the increased mitotic rates in fibroids during the secretory phase of the menstrual cycle. The clinical response of mifepristone, a progesterone antagonist, in inhibiting fibroids growth supports this theory. Progesterone may influence leiomyoma growth by upregulating EGF and TGF-beta 3 expression. In contrast, progesterone reduced IGF-1 expression in cell culture. Progesterone receptor (PR) ligands regulate gene expression in leiomyoma cells by forming PR-ligand complexes that interact with gene promotors. Progesterone also inhibits MMPs. The action of MMPs on the ECM is complex but the end result is that they affect matrix assembly and deposition.

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SCIENCE REVISITED #1

Retinoic acid and fibroid growth?

Surgical specimens of fibroids demonstrated reduced expression of gene products involved in retinoic acid production and increased expression of gene products involved in retinoic acid degradation. Fibroids exhibited more rapid metabolism of retinoic acid after addition of the hormone, compared to myometrium. When retinoic acid was added to fibroid cells in tissue culture, expression of genes involved in retinoic acid production increased to expression levels similar in fibroids. Retinoic acid treatment of immortalized fibroid cells altered expression of many genes encoding ECM proteins, and levels of expression resembled expression levels observed in myometrial cells. In contrast, treatment of immortalized myometrial cells with TGF-beta 3 caused immortalized myometrial cells to develop a leiomyoma-like ECM phenotype.

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Antiprogestins have important therapeutic effects on fibroids. Selective progesterone receptor modulators represent a class of PR ligands that exerts clinically relevant tissue-selective progesterone agonist, antagonist or partial (mixed) agonist/antagonist effects on various progesterone target tissues, depending on the biological action studied.

Selective progesterone receptor modulators (SPRMs) such as asoprisnil, ulipristal and telapristone have been shown to reduce fibroid volume in vivo and to induce apoptosis in vitro. The synthesis of mifepristone, the first glucocorticoid and PR antagonist, was a starting point of drug discovery and research programs in the area of progesterone antagonists. Interestingly, the mifepristone effects were accompanied by a reduction in uterine blood flow, suggesting that progesterone plays an important role in the regulation of uterine perfusion. In clinical studies (see Chapter 6), asoprisnil significantly suppressed both the duration and intensity of uterine bleeding as well as the uterine volume of the largest fibroid, and consequently the symptoms of pressure and bloating. Administration of ulipristal acetate for 3–6 months controlled bleeding, reduced fibroid size, and improved quality of life. Variations in SPRM biological effects may be due to differences in fibroid cells, binding kinetics or ECM characteristics. Although these drugs are not FDA approved and are not on the market, their effects on fibroids show that progesterone is an important regulator of fibroid growth. Recent studies have confirmed beneficial clinical effects and these compounds may be available clinically ...

Table of contents

• Cover
• Title page
• Copyright page
• Contributors
• Series Foreword
• Preface
• 1 Understanding Uterine Fibroids
• 2 The Clinical Spectrum of Fibroid Disease
• 3 Evidence-Based Indications for Treatment of Uterine Fibroids in Gynecology
• 4 Management of Fibroids in Pregnancy
• 5 Management of Uterine Fibroids in the Older Woman
• 6 Medical Management of Women with Symptomatic Uterine Fibroids
• 7 Nonsurgical Option for Fibroid Treatment: Uterine Fibroid Embolization
• 8 Magnetic Resonance-Guided Focused Ultrasound Surgery Treatment for Uterine Fibroids
• 9 Minimally Invasive Treatment Options for Uterine Fibroids
• 10 Surgical Treatments and Outcomes
• 11 Rare Fibroid Syndromes
• 12 Counseling the Patient with Uterine Fibroids
• Index
• Plates