Fibroids

Preface

A newspaper reporter once asked me, "Why do you study uterine fibroids? My reply was, Because of the patients I treat with fibroids. Patients with fibroids suffer a great deal and treatment options are so limited – we need to develop new treatments!" I rather suspect the reporter was looking for another response, perhaps an erudite scientific rationale, but many women with fibroids experience significant health consequences. The following stories reflect the pain and suffering caused by uterine fibroids.

Because of my fibroids my cycle was very heavy which meant that I had to visit the ladies room every one to two hours to change my tampon and pad. I feared that my clothes would get soiled in public so I would rarely socialize. I was severely anemic and had no energy so I felt weak, lethargic and lacked enthusiasm most of the time. In addition, I frequently had the urge to urinate only to find out it was just a few drops of urine, and not to mention it would take an act of congress to have a bowel movement. I felt bloated, my stomach got bigger and I always had a feeling of discomfort. I did not know when to expect the bleeding so I was always nervous as to when it would happen. I felt lots of pressure in my pelvic area and was not interested in sex because I feared that I would bleed.

In addition to acute issues, fibroids can be a life-altering disease, as is so poignantly illustrated by the next story.

I am 73 years old. Persons my age look back upon life and weigh pleasures and disappointments, joys and sadness and satisfactions and regrets. My greatest regret is that I never had children of my own. I never had children because I lost the capacity to bear children. A large fibroid causing great pain, pressure and debilitating bleeding necessitated a hysterectomy in my thirties. At the time of surgery the fibroid was measured as 14 by 14 ­centimeters. At the time of my surgery my widowed mother cried as I would not have children. I do not regret the hysterectomy because I felt so much better physically. But the loss of the ability to have at least one child has haunted me.

    My gynecologists were caring people for their time. I had been told 4 years before the surgery that I had a questionably slightly enlarged fibroid on the left side but this is not for sure. I put this in quotes as it is comes directly from my medical record, copies of which I have kept in my files all these years.

Seven months later the fibroid was probably 3–4 centimeters. Almost 2 years later it was either 5–6 centimeters or 7 x 7 centimeters depending on the examining gynecologist. I was told that I should have a baby and then come back for surgery. Well, the pregnancy option was not so easily arranged. I had just broken off a relationship, but even if I had still been involved with that particular person I was not really sure that marriage to him was a good idea. Throughout this whole period of time my friends and colleagues kept asking me: Isn’t there a medical treatment? Why can’t you just take a pill? Why is hysterectomy the only treatment?

While I grieve my lack of biological children it is even harder today to come to terms with the lack of knowledge available to physicians practicing in 1975 regarding the biology of fibroids, knowledge that would have provided the foundation for nonsurgical treatment possibilities. While physicians and scientists over the past 37 years have learned more about these benign but burdensome tumors called by various names – leiomyomata, myomas or simply fibroids – and there are currently imaging techniques that allow precise measurement of fibroid size and growth, nonsurgical medical therapies still elude us. Fibroids are so common and affect over 70–80% of women. I cannot accept the fact that more has not been done. I grieve that society in general and funding agencies in particular have not been able to provide the really extensive resources needed to find medical treatment. Thirty seven years is a long time.

As a physician caring for women with fibroids, it is painful to bear witness to the pain, frustration, and angst caused by uterine fibroids. Without question, more needs to be done. The issue is further magnified by the prevalence of uterine fibroids, which now affect one in every two women in the US. There are millions of women who have been affected and have stories to tell about the adverse impact of fibroids in their lives.

Strangely, for a condition that affects millions of women worldwide, few books have been written about fibroids and their treatment. There is a need to shed light on this extremely prevalent condition, not only to educate providers but also to explain options for treatment for women who suffer from the condition. For this reason, I enthusiastically accepted the invitation of Dr Arici to edit this book.

The intent of this book is to provide a succinct, pithy summary of current understanding and evidence-based treatment of fibroid disease. In addition, it is my hope that the book will help to stimulate interest for future research and development of understanding of these enigmatic tumors.

To bring the reader up to date with current understanding of fibroids, Chapter 1 includes a description of the pathophysiology of the disordered growths we call fibroids.

Fibroids are a very diverse disease with a complexity that is almost infinite. That is, the location, size, and number of fibroids are so extremely varied between patients that what might otherwise be a simple disease to treat is actually extremely complex. In Chapter 2, the clinical spectrum of fibroids is examined to lay the foundation for Chapter 3, in which an evidence-based approach to fibroid management is provided. Since the effects of fibroids upon reproductive health vary greatly depending on the age of the woman, Chapter 4 examines pregnancy-related consequences of fibroids, whereas Chapter 5 focuses on considerations unique to fibroid disease in the older woman.

Currently, there is no effective preventive therapy for fibroids. Accordingly, available treatment options are reviewed in detail, with particular attention paid to the evidence supporting the different options and the expected benefit, beginning with medical therapy in Chapter 6. Nonsurgical treatment options, uterine artery embolization and magnetic resonance-guided focused ultrasound are discussed in Chapters 7 and 8, respectively. Some patients will require surgical intervention, and newer methods of minimally invasive surgery are reviewed in Chapter 9. Notably, the treatments reviewed in Chapters 6 through 9 are not typically associated with a long recuperation, and use of such treatment approaches will minimize the disruption caused by a lengthy recovery period.

Should the more patient-friendly options reviewed in Chapters 6 through 9 not be sufficient, standard surgical treatments, abdominal myomectomy and hysterectomy, are reviewed in Chapter 10, with discussion of expected outcomes and attendant complications. Although uncommon, in some cases fibroids are associated with rare genetic conditions that require a different approach, and current understanding of these diseases is discussed in Chapter 11.

Finally, counseling of the patient with fibroid disease is reviewed in Chapter 12, an important chapter given the varied nature of the disease. The role of diet and current understanding of prevention are reviewed in detail. Still, more needs to be done. Research and understanding are vital to the future treatment and ideally prevention of uterine fibroids.

In closing, I would like to acknowledge the contributors to this book for their work and dedication that made this possible; specifically, the students, residents, fellows, and faculty who share my passion for advancing understanding and treatment of fibroid disease. Finally, it is important to acknowledge key individuals who have, at critical times, kindled and supported my research interest on uterine fibroids. Drs Phyllis Leppert and Vivian Pinn have had a profound and lasting stimulation on my research on uterine fibroids. There have been many individuals at NIH who have supported our research on fibroids, most notably Drs Alan DeCherney, Duane Alexander, Yvonne Maddox, and George Chrousos. These mentors and leaders have provided guidance, inspiration, and ideas, and by so doing, have established a foundation for future research that is so desperately needed for this debilitating condition.

James H. Segars

Bethesda

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.

   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.

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.

   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.

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 in the future.

Myometrial hyperplasia: a possible precursor to fibroids

Myometrial hyperplasia, a common structural variation of the myometrium, is an irregular area of myometrial hypercellularity and increased nucleus/cell ratio and was first described by Cramer in 1995. It is diagnosed by a pathologist by observation of increased blue areas on H&E slides and on scanning magnification. These areas can be correlated with bulges and firm pale areas of the fixed gross specimens. With further light microscopic observation, a dramatic difference in cellularity and nucleus/cell ratio between these blue-staining areas and adjacent myometrium is apparent. Finally, microscopic pressure effects of vascular dilation (ectasia) and interstitial edema are noted in the outer myometrium.

The onset of myometrial hyperplasia occurs in adolescence around the time of menarche. After years of careful observation, Cramer reported the association of fibroids <1 cm in size or seedling myomas with myometrial hyperplasia, which suggests that myometrial hyperplasia is a precursor lesion for fibroids. It is quite intriguing that both myometrial hyperplasia and uterine fibroids produce evidence of the pressure effects of vascular dilation and interstitial edema in tissue specimens. Although not accepted as a discrete entity by all pathologists, myometrial hyperplasia deserves to be more fully scrutinized and investigated.

Fibroid growth

As noted above, Baird and colleagues recently published a report on the growth of fibroids that has changed thinking about this condition. By showing that fibroids grow at different rates in the same woman and that some grow, some are static and some actually regress in size, despite a uniform hormonal milieu, their study indicated that growth is not dependent on circulating levels of systemic hormones, but that other factors are at work. In the same study, they report that while black and white women less than 35 years of age had the same fibroid growth rates, growth rates declined with age in white women even before menopause but not in blacks, and that fibroid size did not predict fibroid growth. The same group also reported that fibroids regress in size in pregnancy. This study suggests that the effect of reproductive hormones on fibroid growth is not as straightforward as previously thought.

EVIDENCE AT A GLANCE

Fibroid growth is variable and not wholly dependent on circulating sex steroid levels

Baird and colleagues tracked the growth of 262 fibroids that ranged in size from 1 to 13 cm in diameter from 38 black women and 34 white women. They measured fibroid volume by MRI scans over 12 months. Median growth rate was 9% with the large range of –89% to +138%. 7% of the fibroids regressed in size with a >20% shrinkage. Tumors from the same woman grew at different rates as within-woman variation was twice that of the variation among different women (p <0.001). The odds among whites of a tumor growing >20% in 6 months decreased with age but not for blacks (p <0.01) (Peddada et al., 2008).

Classification of fibroids

Fibroids arise from a very heterogeneous disease process. In fact, clinical acumen suggests there are different fibroid phenotypes, one being a uterus that is chock-full of multiple fibroids of all sizes and a second condition where only one fibroid is present. Currently, there is not a universally accepted classification for fibroids that is agreed upon by clinicians and scientists working in the field of fibroid biology. The most commonly used system classifies fibroids in relation to where the fibroid is located in the uterine myometrium: submucosal, intramural, and subserosal. Submucosal refers to the region that is below the endometrium but the term is actually a misnomer as the uterus does not contain any mucosal tissue, so the term subendometrial would be more accurate. Intramural fibroids are those that do not distort the endometrial cavity whatsoever, and have <50% protrusion beyond the serosal surface. Subserosal fibroids are then defined as those with >50% protrusion beyond the serosal surface of the uterus (Figure 1.1).

Figure 1.1 Uterine leiomyoma may be classified based on location in the uterine muscle. Submucous, intramural, and subserosal types of fibroids are shown. Such a system is useful for communication but does not account for fibroid size or overall uterine size in cases of more severe disease when multiple fibroids are present (Drawing provided by Anne Kelley).

Submucosal fibroids have been further classified and subdivided, to allow for distinction and for clinically relevant surgical approaches (see Chapters 9 and 10). Submucosal fibroids distort the uterine cavity and have been subclassified into three types – type 0, type I, and type II – based on the ESHRE/ESGE classification. Type 0 are >90% within the uterine cavity and are also called pendunculated or intracavitary fibroids. Type I are sessile submucosal fibroids that are >50% in the cavity, and type II are <50% in the cavity. A more detailed classification system known as STEPW, that includes fibroid size, location and depth of invasion, has been proposed with the goal of more accurately predicting the success of treatment. While the ESHRE/ESGE system is very useful for hysteroscopic surgery, no