Uterine Leiomyomas

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Chapter 46 Uterine Leiomyomas

CLINICAL IMPACT

Although at least 50% of uterine leiomyomas are asymptomatic, many women have significant symptoms that impact their quality of life and warrant treatment. The major clinical manifestations of uterine leiomyoma can be roughly classified into three categories: increased uterine bleeding, pelvic pressure or pain, and reproductive dysfunction.

Reproductive Function

Uterine leiomyomas are believed to influence reproduction in several ways; however, their direct effect on fertility is still a subject of much debate. The incidence of infertility and uterine leiomyomas both increase with advancing maternal age, and no specific data exists to ascertain if the proportion of infertile women with leiomyomas is greater than the proportion of fertile women with leiomyomas.

Yet the indirect evidence is substantial. In one review, pregnancy rates among women with leiomyomas distorting and not distorting the uterine cavity were 9% and 35%, respectively, as compared to 40% among controls with no leiomyomas.4 Furthermore, the multiple reports of successful pregnancies among infertile women after myomectomy strongly suggest a connection.57

Although exact physiologic mechanisms for reproductive dysfunction are unclear, many plausible theories exist. There is a potential for reduced fecundity if a myoma occurs in the cornual region of the uterus, causing mechanical occlusion of a fallopian tube.3 It is possible that large leiomyomas may impair the rhythmic uterine contractions that facilitate sperm motility.8 It has further been documented that endometrial histology varies in relation to the location of the leiomyoma. Atrophy, as well as alterations in the vascular blood flow produced by sumbucosal leiomyomas, may impede implantation of an embryo, prevent delivery of hormones or growth factors involved in implantation, or interfere with the normal immune response to pregnancy.911 Submucosal leiomyomas that distort the uterine cavity are associated with first-trimester pregnancy loss, preterm delivery, abnormal presentation in labor, and postpartum hemorrhage.12

In regard to the effectiveness of assisted reproductive technology (ART), leiomyomas are generally thought to reduce the effectiveness of ART procedures. Early evidence demonstrated that both pregnancy and implantation rates were significantly lower in patients with intramural or submucosal leiomyomas.13,14 In one study, the presence of an intramural leiomyoma decreased the chances of an ongoing pregnancy after in vitro fertilization by 50%.15 The latest evidence suggests that patients with subserosal leiomyomas have ART outcomes consistent with patients lacking leiomyomas.4,16,17

EPIDEMIOLOGY OF UTERINE LEIOMYOMAS

The diagnosis of uterine leiomyomas increases with age throughout the reproductive years, with the highest prevalence occurring in the fifth decade of a woman’s life. The most common types of leiomyomas associated with heavy bleeding are intramural or submucosal myomas; these tend to be diagnosed at an earlier age and to result in more severe disease in African American women. (larger leiomyomas and greater incidence of anemia) as compared to white women.18,19

Nulliparous women have higher rates of leiomyomas than multiparous women, and the risk of developing leiomyomas decreases consistently with each subsequent term birth.20 Early age at menarche is associated with a twofold to threefold increased risk of developing leiomyomas.21

Leiomyomas clearly demonstrate their hormonal responsiveness in the fact that they form after puberty, have the potential to enlarge during pregnancy, and regress after menopause. However, studies of exogenous hormone treatments, including oral contraceptives and hormone replacement therapy, reveal conflicting data; no clear association can be inferred.22

Twin and family studies suggest a familial predisposition to developing leiomyomas, although further research in the genetics of leiomyomas has yet to be done.22 These studies are hampered by the extremely high incidence of leiomyoma formation in the general population.

According to some studies, an increase in body mass index (BMI) has been found to increase the risk for uterine leiomyomas by a factor of 2 to 3, and the evidence suggests that adult-onset obesity rather than excessive weight in childhood confers this risk. However, other studies have not observed similar associations with increased BMI.21

The majority of epidemiologic studies find that cigarette smokers are at a 20% to 50% reduced risk for the development of uterine leiomyomas through an unclear mechanism, and that the inverse association was independent of BMI. It is unclear whether this relationship varies as a function of pack-years. No clear relationship has been shown between leiomyomas and specific dietary factors or physical activity.21

PATHOLOGY AND PATHOPHYSIOLOGY

Endocrinology

The influence of steroidal hormones is central to the theory of clonal expansion of leiomyomas. Myomas are responsive to estrogen and progesterone and are therefore more likely to increase in size and cause associated symptoms in women of reproductive age. Serum concentrations of circulating estrogen or progesterone have not been found to be increased.

Tumor initiators and yet-to-be-determined genetic factors are involved in key somatic mutations that facilitate the progression of a normal myocyte into a leiomyocyte responsive to estrogen and progesterone. Estrogen receptors, progesterone receptors, and epidermal growth factor receptors (EGFR) are integral in the development of myomas.25 Studies have shown that, in comparison with the normal myometrium, myomas have an increased concentration of estrogen receptors and progesterone receptors.26,27

Aromatase p450 is overexpressed by leiomyomas.28,29 Therefore, in addition to circulating estrogen acting on the ER, the local conversion of circulating androgens to estrogens may be important in potentiating the actions of estrogen in the leiomyocyte (Fig. 46-2).30

Traditionally, estrogen was thought to be the primary hormonal mediator of myoma growth. Although progestins have been applied for the treatment of bleeding from symptomatic myomas, recent studies have shown that progesterone may play a much greater role as a mediator of myoma growth than previously thought.31 The antiprogestin RU486 (mifepristone) has been shown to decrease the size of myomas,32,33 and another study showed that myomas in the secretory phase have increased mitotic counts compared to those in the proliferative phase.34

Growth of neoplastic tumors is the result of accelerated cellular proliferation, which outpaces the inhibitory effect of apoptosis. Apoptosis has been shown to be inhibited in uterine leiomyomas. Progesterone has been shown to increase the antiapoptotic protein, bcl-2.35 Therefore, the stimulation of myoma expansion may be a function of the suppression of apoptosis by progesterone. It has been observed in vitro that the addition of progesterone to cultured leiomyoma cells increased the expression of bcl-2 when compared to controls.35 Normal myometrium did not express increased levels of bcl-2 in the presence of progesterone.

The complex process of apoptosis involves not only the bcl-2 family, but Fas/FasL and Rb-1.36 Martel and coworkers have described the various apoptotic pathways deficient in leiomyomas and potential corresponding targets for therapy of myomas. The role of apoptosis in the pathogenesis of myomas is a promising area for future research, with a great potential for clinical application.

The synergistic interplay between estrogen and progesterone signaling in the pathophysiology of myoma growth has been observed as well. The increase in progesterone receptors as a result of increased estrogen has been well established. An in vitro study showed that progesterone up-regulates the expression of EGF, and estrogen also increases the expression of EGFR.25

DIAGNOSTIC IMAGING AND LEIOMYOMAS

Imaging has become an integral aspect of the evaluation of leiomyomas. Myoma size and location can be assessed to varying degrees, depending on the imaging technology applied to the evaluation process. Ultrasonography, hysterosalpingography (HSG), and magnetic resonance imaging (MRI) are currently the modalities most commonly utilized to image myomas.

Ultrasound

Traditional ultrasound is a cost-effective technology for assessing uterine leiomyomas (see Chapter 30 for details). The transvaginal approach is more accurate than abdominal ultrasound. However, abdominal ultrasound may be a useful adjunct to transvaginal ultrasound, if a large uterine size warrants such an approach.22 The presence of myomas may be detected by ultrasound, as uterine enlargement or a nodular contour of the uterus. They may also appear as discrete, focal masses within the myometrium.37,38 Myomas can appear hypoechoic or heterogeneous when compared with the appearance of the myometrium on ultrasound, and they may be characterized by calcification and posterior shadowing.37,39 Sagittal and axial views aid in providing information on the location and size of myomas.

Additional information regarding intracavitary masses, such as submucous myomas, may be obtained by means of saline infusion sonohysterography. This imaging technique consists of real-time transvaginal ultrasound during which sterile saline solution is injected into the uterine cavity. The saline is injected transcervically via a small-caliber catheter. As the uterine cavity is distended by the saline solution, intracavitary masses may be visualized as echogenic structures against the echolucent background of the distension media.40 Intramural myomas within close proximity of the endometrial cavity may also be assessed by sonohysterography. In addition, entities such as endometrial polyps and uterine anomalies such as adhesions may also be detected. Sonohysterography can be used not only to diagnose submucous myomas, but also to assess the potential access to surgical intervention.41

Three-dimensional ultrasound42 and color Doppler ultrasound43 are increasingly being applied to the evaluation of myomas for imaging. Color Doppler ultrasound highlights vascular flow, which is usually increased at the periphery of myomas and decreased centrally.42,43

Hysterosalpingography

HSG is a screening test for intracavitary anatomic defects and entails injection of iodine contrast dye transcervically, via a catheter, into the uterine cavity with radiologic assessment under fluoroscopy (see Chapter 29). HSG is performed in the follicular phase of the menstrual cycle to avoid interfering with ovulation or a potential pregnancy. Because the HSG instillation medium contains iodine, an iodine-allergic patient requires premedication with glucocorticoids and antihistamines before the procedure.44

Hysterosalpingography allows visualization of submucous myomas as the uterine cavity is distended by the contrast medium. The size and contour of the uterus may be altered by submucous myomas. Intramural myomas may enlarge the uterine cavity in a globular manner, and fundal myomas may enlarge the space between the cornuae. Subserosal myomas are not typically noted on HSG; however, if large enough, they may be detected as a mass effect on the uterine cavity.23 In cases where a submucous myoma must be differentiated from an endometrial polyp on HSG, hysteroscopy or sonohysterography play roles as complementary, potentially confirmatory adjuncts.