Uterine Fibroids - Chapter 11 PDF

CHAPTER 11 Uterine Fibroids William H. Parker Origins of Uterine Fibroids Incidence Etiology Genetics Hormones Growth Factors Risk Factors Symptoms Abnormal Bleeding Pain Urinary Symptoms Natural History of Fibroids Rapid Fibroid Growth Uterine Sarcoma Diagnosis Pelvic Examinat...

CHAPTER 11 Uterine Fibroids William H. Parker Origins of Uterine Fibroids Incidence Etiology Genetics Hormones Growth Factors Risk Factors Symptoms Abnormal Bleeding Pain Urinary Symptoms Natural History of Fibroids Rapid Fibroid Growth Uterine Sarcoma Diagnosis Pelvic Examination Fibroid Location Fibroid Variants Imaging Imaging of Uterine Sarcomas 533 Fertility Fibroids and Pregnancy Incidence of Fibroids During Pregnancy Effect of Pregnancy on Fibroids Fibroid Degeneration During Pregnancy Influence of Fibroids on Pregnancy Treatment Watchful Waiting Medical Therapy Surgical Treatment Options Treating Preoperative Anemia Abdominal Myomectomy Laparoscopic Myomectomy Tissue Morcellation Adhesions Following Myomectomy Hysteroscopic Myomectomy Endometrial Ablation for Abnormal Bleeding Associated With Fibroids New Appearance of Fibroids Clinical Follow-Up Prognostic Factors Related to New Appearance of Fibroids Uterine Artery Embolization Uterine Artery Embolization Technique Uterine Artery Embolization Outcomes Uterine Artery Occlusion Magnetic Resonance–Guided Focused Ultrasound Management Summary KEY POINTS 1 Fibroids are very common; most are asymptomatic and can be managed expectantly. 2 There is no definite relationship between oral contraceptives and the presence of fibroids. 3 First-degree relatives of women with fibroids have a 2.5 times increased risk of developing fibroids. 4 The risk of having fibroids is 2.9 times greater in African American women than in white women. 5 Women with fibroids are only slightly more likely to experience pelvic pain than women without fibroids. 6 Rapid uterine growth is not well defined, and almost never indicates sarcoma in premenopausal women; sarcomas are rare and more likely occur in postmenopausal women with symptoms of pain and bleeding. 534  7 Sonography is the most readily available and least costly imaging technique to differentiate fibroids from other pelvic pathology; however, MRI permits more precise evaluation of the number, size, and position of fibroids, including the proximity to the endometrial cavity. 8 The presence of submucosal fibroids decreases fertility and removing them can increase fertility; subserosal fibroids do not affect fertility and removing them does not increase fertility; intramural fibroids may slightly decrease fertility, but removal does not increase fertility. 9 Most fibroids do not increase in size during pregnancy. 10 For women who are mildly or moderately symptomatic with fibroids, watchful waiting may allow treatment to be deferred, perhaps indefinitely. 11 As women approach menopause, watchful waiting may be considered because there is limited time to develop new symptoms, and after menopause bleeding stops and fibroids decrease in size. 12 Surgical treatment options include abdominal myomectomy, laparoscopic myomectomy, laparoscopic radiofrequency ablation, hysteroscopic myomectomy, endometrial ablation, and abdominal, vaginal, or laparoscopic hysterectomy. 13 An inability to evaluate the ovaries on pelvic examination is not an indication for surgery. 14 Myomectomy should be considered as a safe alternative to hysterectomy, even for those women who have large uterine fibroids and wish to retain their uterus. 15 Submucous fibroids, sometimes associated with increased menstrual bleeding or infertility, often can be removed hysteroscopically. 16 Routine ultrasound follow-up is sensitive, and may detect many clinically insignificant fibroids. 17 Uterine artery embolization (UAE) is an effective treatment for selected women with uterine fibroids. The effects of UAE on early ovarian failure, fertility, and pregnancy are unclear. Fibroids (leiomyomas, myomas) are an important health care concern because they are the most frequent indication for the performance of hysterectomy, accounting for nearly 240,000 such procedures in the United States (1). In comparison, approximately 30,000 myomectomies are performed every year. Inpatient surgery for fibroids costs $2.1 billion per year in the United States, and the cost of outpatient surgeries, medical and nonmedical costs, and time away from work or family add significantly to these expenditures (2). ORIGINS OF UTERINE FIBROIDS Fibroids are benign, monoclonal tumors of the smooth muscle cells of the myometrium and contain large aggregations of extracellular matrix composed of 535 collagen, elastin, fibronectin, and proteoglycan (3). Incidence Fibroids are remarkably common. Fine serial sectioning of uteri from 100 consecutive women subjected to hysterectomy discovered fibroids in 77%, some as small as 2 mm (4). A random sampling of women aged 35 to 49, screened by self-report, medical record review, and sonography, found that among African American women by age 35 the incidence of fibroids was 60%, and it was over 80% by age 50 (Fig. 11-1). White women have an incidence of 40% at age 35 and almost 70% by age 50 (5). 536 537 FIGURE 11-1 A: Age- and race-specific incidence of myomectomy, 1997, based on NIS and U.S. Census Bureau estimates. B: Age- and race-specific incidence of hysterectomy for fibroids, 1997, based on NIS and U.S. Census Bureau estimates. (From Health Services/Technology Assessment Tests [HSTAT]. Available online at http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat1.section.48317.) Etiology Although the precise causes of fibroids are unknown, advances have been made in understanding the molecular biology of these benign tumors and their hormonal, genetic, and growth factors (6). Genetics Fibroids are monoclonal and are made up of concentric smooth muscle fibers and fibrous connective tissue surrounded by a vascular pseudocapsule. Some authors postulate that hypoxic conditions, perhaps associated with menstruation, induce mutations in a single myometrial smooth muscle stem cell. Approximately 40% to 50% of fibroids display nonrandom and tumor-specific chromosome rearrangements involving mostly deletions, duplications, and translocations of chromosomes 6, 7, 12, and 14. These complex molecular changes affect energy metabolism, extracellular matrix remodeling, and estrogen and progesterone receptor status. Growth factors, small proteins that act as signaling molecules, interact with specific receptors on the cell surface and are important for the development of fibroids. Transforming growth factor-β (TGF-β), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and insulinlike growth factor (IGF) modulate cellular growth, proliferation, and differentiation. The TGF-β family upregulates the synthesis of many extracellular matrix components that increase the fibrous component of fibroids. Proliferation of smooth muscle cells are induced by bFGF, which promotes angiogenesis. Estrogen and progesterone influence fibroid development by regulating growth factors and their signaling pathways. Fibroids may be affected by environmental chemicals, which can increase or decrease estrogen and/or progesterone receptors. Genetic differences between fibroids and leiomyosarcomas (LMSs) indicate that LMSs do not result from the malignant degeneration of fibroids. Cluster analysis of 146 genes found that the majority are downregulated in LMSs but not in fibroids or myometrium. Comparative genomic hybridization did not find specific anomalies shared by fibroids and LMSs (7). 538 Hormones Estrogen and progesterone appear to promote the development of fibroids. Fibroids are rarely observed before puberty, are most prevalent during the reproductive years, and regress after menopause. Factors that increase overall lifetime exposure to estrogen, such as obesity and early menarche, increase the incidence. Decreased exposure to estrogen found with smoking, exercise, and increased parity is protective (8). Serum levels of estrogen and progesterone are similar in women with and without clinically detectable fibroids. As a result of increased levels of aromatase within fibroids, de novo production of estradiol is higher than in normal myometrium (8). Progesterone is important in the pathogenesis of fibroids, which have increased concentrations of progesterone receptors A and B compared with normal myometrium (9,10). The highest mitotic counts are found in fibroids at the peak of progesterone production (11). Gonadotropin-releasing hormone (GnRH) agonists decrease the size of fibroids, but progestin given concurrently with GnRH prevents a decrease in size (12). Human fibroid tissue, grafted to immunodeficient mice, increased in size in response to estradiol plus progesterone, but the growth was blocked by the antiprogestin RU486 (12). The volume of grafted fibroid tissue decreased after progesterone withdrawal. Treatment with estradiol alone did not increase the graft size, but did induce expression of progesterone receptors and supported the action of progesterone on the grafts (12). Growth Factors Growth factors, proteins, or polypeptides, produced locally by smooth muscle cells and fibroblasts, appear to stimulate fibroid growth primarily by increasing extracellular matrix (6). Many of these growth factors are overexpressed in fibroids and either increase smooth muscle proliferation (TGF-β, bFGF), increase DNA synthesis (epidermal growth factor [EGF], PDGF), stimulate synthesis of extracellular matrix (TGF-β), promote mitogenesis (TGF-β, EGF, IGF, prolactin [PRL]), or promote angiogenesis (bFGF, VEGF). Risk Factors Prospective, longitudinal studies characterize the factors that influence the development of uterine fibroids (4,13,14). Although selection bias may limit epidemiologic studies, risk factors are considered. Age The incidence of fibroids increases with age, 4.3 per 1,000 woman-years for 25 539 to 29 year olds and 22.5 for 40 to 44 year olds. African American women develop fibroids at an earlier age than white women (13). Endogenous Hormonal Factors Greater exposure to endogenous hormones, as found with early menarche (younger than 10 years of age), increases and late menarche decreases the likelihood of having uterine fibroids (14). Fibroids are smaller, less numerous, and have smaller cells in hysterectomy specimens from postmenopausal women, when endogenous estrogen levels are low (4,15). Family History First-degree relatives of women with fibroids have a 2.5 times increased risk of developing fibroids (26). Monozygous twins are reportedly hospitalized for treatment of fibroids more often than heterozygous twins, but these findings may be the result of reporting bias (27). Ethnicity African American women have a 2.9 times greater risk of having fibroids than white women, unrelated to other known risk factors (28). African American women have fibroids develop at a younger age and have more numerous, larger, and more symptomatic fibroids (29). It is unclear whether these differences are genetic or result from known differences in circulating estrogen levels, estrogen metabolism, diet, or environmental factors. Weight A prospective study found that the risk of fibroids increased 21% with each 10 kg increase in body weight, and with increasing body mass index (BMI) (20). Similar findings were reported in women with greater than 30% body fat (21). Obesity increases conversion of adrenal androgens to estrone and decreases the sex hormone–binding globulin (SHBG). The result is an increase in biologically available estrogen, which may explain the increase in fibroid prevalence and/or growth. Diet Few studies examined the association between diet and the presence or growth of fibroids (22). A diet rich in beef, other red meat, and ham increased the incidence of fibroids, while a diet rich in green vegetables decreased this risk. These findings are difficult to interpret because calorie and fat intake were not measured. 540 Exercise Women in the highest category of physical activity (approximately 7 hours per week) were significantly less likely to have fibroids than women in the lowest category (less than 2 hours per week) (23). Oral Contraceptives There is no definite relationship between oral contraceptives and the presence of fibroids. An increased risk of fibroids with oral contraceptive use was reported, but a subsequent study found no increased risk with the use or duration of use (24,25). Studies in women with known fibroids who were prescribed oral contraceptives showed no increase in fibroid growth (20,26). The formation of new fibroids does not appear to be influenced by oral contraceptive use (27). Menopausal Hormone Therapy For the majority of postmenopausal women with fibroids, hormone therapy will not stimulate fibroid growth. If fibroids do grow, progesterone is likely to be the cause (28). One study evaluated postmenopausal women with fibroids who were given 2 mg of oral estradiol daily and randomized to 2.5 or 5 mg of medroxyprogesterone acetate (MPA) per day (28). One year after starting treatment, 77% of women taking 2.5-mg MPA had either no change or a decrease in fibroids diameters and 23% had a slight increase. However, 50% of women taking 5-mg MPA had an increase in fibroid size (mean diameter increase of 3.2 cm). Postmenopausal women with fibroids treated with 0.625 of conjugated equine estrogen (CEE) and 5-mg MPA were compared over 3 years to a similar group of women not taking hormone therapy (29). By the end of the third year, only 3 of 34 (8%) treated and 1 of 34 (3%) untreated women had any increase in fibroid volume over baseline (28). Postmenopausal women with known fibroids, followed with sonography, were noted to have an average 0.5-cm increase in the diameter of fibroid after using transdermal estrogen patches plus oral progesterone for 12 months (29). Women taking oral estrogen and progesterone had no increase in fibroid size (34). Pregnancy Increasing parity decreases the incidence and number of clinically apparent fibroids (31–33). The remodeling process of the postpartum myometrium, a result of apoptosis and dedifferentiation, may be responsible for the involution of fibroids (34). Another theory postulates that the vessels supplying fibroids regress during involution of the uterus, depriving fibroids of their source of nutrition (35). 541 Smoking Smoking reduces the incidence of fibroids. Reduced conversion of androgens to estrone, caused by inhibition of aromatase by nicotine, increased 2-hydroxylation of estradiol, and stimulation of higher levels of SHBG decrease bioavailability of estrogen (36–38). Tissue Injury Cellular injury or inflammation resulting from an environmental agent, infection, or hypoxia was proposed as a mechanism for initiation of fibroid formation (39). Repetitive tissue injury to the endometrium and endothelium might promote the development of monoclonal smooth muscle proliferations in the muscular wall. Frequent mucosal injury with stromal repair (menstruation) may release growth factors that promote the high frequency of uterine fibroids (39). No increased incidence was found in women with prior sexually transmitted infections, prior intrauterine device (IUD) use, or prior talc exposure (31). Herpes simplex virus (HSV) I or II, cytomegalovirus (CMV), Epstein–Barr virus (EBV), and chlamydia were not found in fibroids. SYMPTOMS Fibroids are almost never associated with mortality, but they may cause morbidity and significantly affect the quality of life (40). Women who have hysterectomies because of fibroid-related symptoms have significantly worse scores on SF-36 quality-of-life questionnaires than women diagnosed with hypertension, heart disease, chronic lung disease, or arthritis (40). Of 116 women with fibroids larger than 5 cm on sonographic examination and uterine size greater than 12 cm on pelvic examination, 42% were satisfied with their initial level of symptoms, including stress, bleeding, and pain (41). Most of the 48 women who chose to have treatment within 1 year were more likely to have higher scores on bleeding and pain scales and be more concerned about their symptoms. Most women chose myomectomy (n = 20), hysterectomy (n = 15), or hysteroscopic myomectomy (n = 4), and symptom scores improved markedly during the 7.5 months (mean) of follow-up. Abnormal Bleeding The association of fibroids with heavy menstrual bleeding is not clearly established. Therefore, other possible etiologies, including coagulopathies such as the von Willebrand disease, should be considered in a woman with heavy menstrual bleeding (42). 542  Type 0 and 1 fibroids have been associated with anemia. Of 1,665 women having office hysteroscopic evaluation for heavy menstrual bleeding, 259 women had a submucous fibroid diagnosed; 63 were type 0, 110 type 1, and 52 were type 2 (25 were not documented). Hemoglobin concentrations below 12 were significantly associated with submucous fibroids and most strongly correlated with type 0 fibroids (43). Another study found that women with fibroids used 7.5 pads or tampons on the heaviest day of bleeding compared with 6.1 pads or tampons used by women without fibroids (44). Women with fibroids larger than 5 cm had slightly more gushing and used about 3 more pads or tampons on the heaviest day of bleeding than women with smaller fibroids. Pain Women with fibroids are only slightly more likely to experience pelvic pain than women without fibroids. Transvaginal sonography (TVS) was performed on a population-based cohort of 635 non–care-seeking women with an intact uterus to determine the presence of uterine fibroids (45). Dyspareunia, dysmenorrhea, or noncyclic pelvic pain was measured by visual analog scales. The 96 women found to have fibroids were only slightly more likely to report moderate or severe dyspareunia or noncyclic pelvic pain and had no higher incidence of moderate or severe dysmenorrhea than women without fibroids. Neither the number nor the total volume of fibroids was related to pain. However, women who present for clinical evaluation for fibroid-associated pain may be different from those in the general population (45). Fibroid degeneration may cause pelvic pain. As fibroids enlarge, they may outgrow their blood supply, with resulting cell death (46). Types of degeneration determined both grossly and microscopically include hyaline degeneration, calcification, cystic degeneration, and hemorrhagic degeneration. The type of degeneration appears to be unrelated to the clinical symptoms (46). Pain from fibroid degeneration is often successfully treated with analgesics and observation. Torsion of a pedunculated subserosal fibroid may produce acute pelvic pain that requires surgical intervention (47). Urinary Symptoms Fibroids may cause urinary symptoms, although few studies examined this association. Following uterine artery embolization (UAE) with a 35% reduction in the mean uterine volume, frequency and urgency were greatly or moderately improved in 68% of women, slightly improved in 18%, and unchanged or worse in only 14% (48). This finding suggests that increased uterine volume 543 associated with fibroids is related to urinary symptoms. Fourteen women with large fibroids and urinary symptoms were given six monthly injections of GnRH agonist (GnRH-a) with a resulting 55% decrease in uterine volume (49). Following therapy, urinary frequency, nocturia, and urgency decreased. There were no changes in urge or stress incontinence as measured by symptoms or urodynamic studies. It is not clear whether these findings are related to a decrease in uterine volume or to other effects of GnRH treatment. NATURAL HISTORY OF FIBROIDS Most fibroids grow slowly. A prospective, longitudinal study of 72 premenopausal women (38 African American, 34 white) using computer analysis of serial MRI found that the median growth rate was 9% over 12 months (13). Multiple fibroids in the same individual were found to have highly variable growth rates, suggesting that growth results from factors other than hormone levels. After age 35, growth rates declined with age for white women but not for African American women, which likely explains the increased fibroid-related symptoms noted in African American women. Seven percent of fibroids regressed over the study period. Continued follow-up of these women is planned and may provide a better understanding of this issue. Rapid Fibroid Growth In premenopausal women, “rapid uterine growth” almost never indicates the presence of uterine sarcoma. One study found only 1 sarcoma among 371 (0.26%) women operated on for rapid growth of presumed fibroids (50). No sarcomas were found in the 198 women who had a 6-week increase in uterine size over 1 year, which is the definition of rapid growth that was used in the past. Uterine Sarcoma Women found to have uterine sarcoma are often clinically suspected of having a pelvic malignancy (50,51). Women with pain and bleeding and who are closer to menopause or postmenopausal may have a rare sarcoma. Of nine women found to have uterine sarcomas, all were postmenopausal and eight were admitted with abdominal pain and vaginal bleeding (51). All eight had presumed gynecologic malignancies: uterine sarcoma in four, endometrial carcinoma in three, and ovarian cancer in one. One additional woman had surgery for prolapse and a sarcoma was found incidentally (51). The Surveillance, Epidemiology, and End Results (SEER) database identified 13,089 patients diagnosed with uterine sarcoma in the period from 2000 to 2012. 544 The mean age of patients with sarcomas was 68 for carcinosarcoma; 55 for LMS; 54 for stromal sarcoma; and 59 for adenosarcoma (52). A literature review found a mean age of 36 years in women subjected to myomectomy (50). DIAGNOSIS Pelvic Examination Clinically significant subserosal and intramural fibroids can usually be diagnosed by pelvic examination based on findings of an enlarged, irregularly shaped, firm, and nontender uterus. Uterine size assessed by bimanual examination, even for most women with BMI greater than 30, correlates well with uterine size and weight at pathologic examination (53). Routine sonographic examination is not necessary when the diagnosis is almost certain. A definite diagnosis of submucous fibroids often requires saline-infusion sonography (SIS), hysteroscopy, or magnetic resonance imaging (MRI) (54). Fibroid Location The FIGO fibroid classification system categorizes submucous, intramural, subserosal, and transmural fibroids. Type 0—intracavitary (e.g., a pedunculated submucosal fibroid entirely within the cavity) Type 1—less than 50% of the fibroid diameter within the myometrium Type 2—50% or more of the fibroid diameter within the myometrium Type 3—abut the endometrium without any intracavitary component Type 4—intramural and entirely within the myometrium, without extension to either the endometrial surface or to the serosa Type 5—subserosal at least 50% intramural Type 6—subserosal less than 50% intramural Type 7—subserosal attached to the serosa by a stalk Type 8—no involvement of the myometrium; includes cervical lesions, those in the round or broad ligaments without direct attachment to the uterus, and “parasitic” fibroids Transmural fibroids are categorized by their relationship to both the endometrial and the serosal surfaces, with the endometrial relationship noted 545 first, for example, types 2 to 3 (Table 11-1; Fig. 11-2) (55). Table 11-1 FIGO Leiomyoma Classification System SM— 0 Pedunculated intracavitary submucosal 1