Abnormal uterine bleeding is the most common symptom reported by women with leiomyomas. The most common types of leiomyomas associated with heavy bleeding are intramural or submucosal myomas. The typical bleeding patterns are heavy menstrual regular bleeding or intermenstrual bleeding. Intermenstrual bleeding can indicate the presence of an intracavitary myoma or specific endometrial pathology; therefore, a more detailed evaluation of the uterine cavity is warranted in these cases. The terms used to describe the abnormal bleeding are reviewed in the chapter on AUB and adhere to the FIGO classification. Heavy vaginal bleeding can lead to problems such as iron-deficiency anemia, which can be severe enough to require blood transfusions, and frequent changes of sanitary protection can cause significant distress in work or social situations.

Pelvic pain or pressure is the second most common complaint and is frequently described as analogous to the discomfort associated with uterine growth during pregnancy. The pain can occur both during and between bleeding episodes. Posterior leiomyomas may give rise to low back pain, whereas anterior leiomyomas may compress the bladder. Leiomyomas that become large enough to fill the pelvis may potentially interfere with voiding and defecation or cause dyspareunia. Very large leiomyomas can, on occasion, outgrow their blood supply, leading to tissue ischemia and necrosis clinically manifested as acute, severe pelvic pain. Pedunculated leiomyomas can suffer torsion, which can lead to ischemia and acute pain. During pregnancy, leiomyomas have been known to undergo “red degeneration,” where hemorrhage occurs within the myoma, leading to acute pain.

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 increase with advancing maternal age, and no specific data exist 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 [5]. Furthermore, the multiple reports of successful pregnancies among infertile women after myomectomy strongly suggest a connection [6, 7].

Though 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 due to mechanical occlusion of a fallopian tube. 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. Submucosal leiomyomas may be associated with localized endometrial atrophy as well as alterations in the vascular blood flow, which may impede the implantation of an embryo, the delivery of hormones or growth factors involved in implantation, or interfere with the normal immune response to pregnancy [9–11]. Submucosal leiomyomas, which 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, submucosal and intramural leiomyomas are generally thought to reduce the effectiveness of assisted reproductive 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 by 50% following in vitro fertilization [15]. Evidence suggests that patients with subserosal leiomyomas have assisted reproductive technology outcomes consistent with patients without leiomyomas [14, 16, 17].

Leiomyomas are defined as monoclonal proliferations of benign smooth muscle [23]. Each monoclonal myoma may be associated with various chromosomal translocations, duplications, and deletions [24]. Many, but not all, myomas contain nonrandom cytogenetic abnormalities, while the myometrium has a normal karyotype. Most of the mutations occur in genes that are involved in cellular growth or are responsible for architectural transcription.

Two hereditary disorders have been reported in which uterine leiomyomas are part of a syndrome complex that demonstrate the potential genetic contribution to myoma formation. The first is hereditary leiomyomatosis and renal cell cancer complex. This is an autosomal dominant syndrome with smooth muscle tumors of the uterus, skin, and kidney. The second is a syndrome of pulmonary leiomyomatosis and lymphangiomyomatosis (LAM) that is the result of mutations in one of the two genes responsible for tuberous sclerosis, a syndrome that results in multiple hamartomas.

Grossly, myomas usually appear as discrete, round masses that are lighter in color than the surrounding myometrium, with a glistening, pearly white appearance. Histological features include smooth muscle fibers that form interlacing bundles, with excessive fibrous tissue in between the bundles.

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 undetermined 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 receptor (ER) , progesterone receptor (PR) , and epidermal growth factor receptor (EGFR) are integral in the development of myoma [25]. Studies have shown that, in comparison with the normal myometrium, myomas have an increased concentration of ER and PR [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. 22.2) [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 that 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 also Fas/FasL and Rb-1 [36]. Martel et al. 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 upregulates the expression of EGF, and estrogen also increases the expression of EGFR [25].

The influence of the pregnancy-induced endocrine milieu on a leiomyoma is complex. There are many reports of dramatic leiomyoma growth in pregnancy; however, all prospective studies have shown that most leiomyomas demonstrate no change in diameter from the first trimester to delivery. Essentially, it is impossible to predict which myoma will grow. The main potential complications in pregnancy are pain and pregnancy wastage. Pain can be the result of myomatous degeneration. This phenomenon can be the consequence of necrosis from decreased blood supply to a subserosal or pedunculated myoma. Usually there is localized pain and a cystic or heterogeneous pattern on ultrasound.

Pregnancy wastage is often due to retroplacental myomas that may cause abruptio placenta, bleeding, and premature rupture of membranes. Lower uterine segment myomas may increase the probability of Cesarean section due to obstruction or malpresentation.

Traditional ultrasound is a cost-effective technology for assessing uterine leiomyomas. 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 evidenced by 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 is injected into the uterine cavity. The saline is injected transcervically via a catheter of small caliber. As the uterine cavity is distended by the saline, intracavitary masses may be visualized as echogenic structures against the echolucent background of the distending 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 ultrasound [42] and color Doppler ultrasound [43] 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 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. Hysterosalpingography is performed in the follicular phase of the menstrual cycle in order to avoid interfering with ovulation and/or a potential pregnancy. Since the hysterosalpingography instillation medium contains iodine, an iodine-allergic patient would require premedication with glucocorticoids and antihistamines prior to 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 cornua. Subserosal myomas are not typically noted on hysterosalpingography; however, if large enough, they may be detected as a mass effect on the uterine cavity [37]. In cases where a submucous myoma must be differentiated from an endometrial polyp on hysterosalpingography, hysteroscopy and sonohysterography play roles as complementary, potentially confirmatory adjuncts .

MRI is increasingly being utilized for imaging leiomyomas. The location of myomas can be accurately documented, more so with MRI than with ultrasound. It is often used to evaluate the precise location for surgical planning or prior to uterine artery embolization mapping.

Disadvantages of MRI include cost, limited availability, and an inability to perform the procedure in patients with morbid obesity or claustrophobia. Traditionally, cost had been more of a disadvantage; however, as the expense of MRI decreases, it is more commonly employed in clinical and presurgical evaluation. MRI is contraindicated in patients with pacemakers, defibrillators, metallic foreign bodies, and in rare cases of allergy to gadolinium [45].

In T2-weighted images, the endometrial stripe is visualized as a central, high signal; the junctional zone is a low signal; and the myometrial areas are an intermediate signal [46]. Leiomyomas are represented by variable signal density. Most of the time, they appear as hypodense, well-demarcated masses; however, increased cellularity [47] and degeneration may be seen as high signal intensity [46].

There is less distinction of the endometrial lining, junctional zone, and myometrium in T1-weighted images. These components are usually homogeneous and, consequently, obscured in appearance. Fatty or hemorrhagic degeneration may be represented by a high signal intensity [48].

Gonadotropin-releasing hormone (GnRH) agonists are an effective means of medically treating patients with symptomatic leiomyomas. After affecting an initial flare of LH and FSH, GnRH agonists down regulate the hypothalamic-pituitary-ovarian axis via action on pituitary receptors. The flare effect is due to an initial stimulation of FSH and LH owing to the binding of pituitary receptors, after which these receptors are desensitized, with a subsequent decrease in FSH and LH secretion [49]. This results in decreased estrogen production.

GnRH agonists have been shown to directly inhibit local aromatase p450 expression in leiomyoma cells [50], thereby presumably resulting in decreased local conversion of circulating androgens to estrogens within the leiomyocyte. Several studies have concluded that GnRH agonists can directly induce apoptosis and also suppress the cellular proliferation of myomas presumably via action on peripheral GnRH receptors.

Maximum reduction of the mean uterine volume occurs within 3 months of GnRH agonist administration. The decrease in volume is usually in the range of 40–80%. However, after the discontinuation of GnRH agonists , myomas will rapidly grow back to their pretreatment size, usually in the span of several months [51].

Advantages of GnRH agonists include their use in the perimenopausal transition with add-back therapy for the goal of avoiding hysterectomy. Additionally, laparoscopic myomectomy may be made more feasible with GnRH-agonist pretreatment, and GnRH agonists can also be beneficial in a patient who is to undergo hysterectomy to facilitate a vaginal approach rather than an abdominal incision. In a randomized clinical trial comparing the study group (patients receiving GnRH agonist and iron) to a control group (iron alone), preoperative hematologic parameters were improved [52].

Although decreased tumor bulk and a decrease in associated symptoms are attained, the potential for unwanted long-term side effects exists; therefore, treatment with GnRH agonist is recommended for no more than 6 months. Common side effects include hot flashes, vaginal dryness, headache, and mood swings. Most importantly, in terms of bone health status, there is a recognized decrease in bone mineral density during therapy [53]. Although add-back doses of steroidal hormones can be used with the aim of decreasing this bone loss; the long-term use of GnRH agonists with add-back is impractical and not recommended, especially in younger patients .

Selective estrogen receptor modulators (SERMs) are compounds that bind to the ER and confer an agonist or antagonist effect, depending on tissue specificity. They have been applied to the treatment and prevention of estrogen-responsive breast cancer; examples include the use of tamoxifen and raloxifene. Tamoxifen, a triphenylethylene, has antagonist activity in the breast and displays a desirable agonist activity in the bone and the cardiovascular system as well as a mild agonist activity in endometrial tissue [54, 55]. Raloxifene, a benzothiophene, has a similar profile and the added benefit of not acting as an agonist in the endometrium [56].

In animal models, SERMs have been shown to be effective in decreasing the growth of myomas. Eker rats are a rat strain with a tuberous sclerosis 2 (TS-2) gene defect that can spontaneously develop leiomyomas. In studies, the administration of SERMs was associated with the inhibition of leiomyoma formation in Eker rats [57, 58]. Guinea pigs require long-term exposure to estrogen in order for leiomyoma formation to occur. Two groups of oophorectomized guinea pigs, an estrogen-only group and an estrogen plus raloxifene group, were compared for myoma formation. A decrease in the size of the induced myomas was observed in the estrogen plus raloxifene group [59].

In humans, raloxifene appears effective in decreasing the size of myomas in postmenopausal women [60], but beneficial effects were not significant in premenopausal women [61]. A recent study has demonstrated that a combination of raloxifene and GnRH agonist is more effective in reducing leiomyoma volume [62] and preventing a decrease in bone mineral density [63] than the use of GnRHa alone. A Cochrane review of three studies showed no consistent evidence from a limited number of studies that SERMs reduce fibroid size or improve clinical outcomes and suggested that further studies be conducted to establish benefit [64].

This class of compounds has either agonist or antagonist effects on the progesterone receptor, based on tissue specificity [65]. Asoprisnil is a selective progesterone receptor modulators (SPRM) that, along with its major metabolite, J912, has high affinity for the PR , moderately binds growth hormone receptor, and has a very low binding potential for androgen receptors (◘ Fig. 22.3). Asoprisnil has virtually no affinity for ER or mineralocorticoid receptors [66]. It differs from the long-term effect of progesterone on the endometrium in that amenorrhea is rapidly established without breakthrough bleeding [67].

The oral SPRM ulipristal acetate has successfully completed phase III clinical trials and is approved for use in the European Union. It has not received FDA approval for use in the USA [68]. A randomized trial of ulipristal acetate vs. placebo for fibroid treatment before surgery has shown that treatment for 13 weeks effectively controlled excessive bleeding and reduced the size of fibroids [69]. Further clinical research is underway to study long-term effects of SPRMs on the endometrium. As SPRMs are studied and tested further in clinical trials, there may be a practical use for this class of medications in the long-term medical treatment of leiomyomas, especially in women with menorrhagia who are interested in avoiding surgery or maintaining future fertility .

Aromatase inhibitors (AI) were originally used for the treatment of breast cancer, and this class of medications is FDA approved for this purpose. In recent years, the use of AI has expanded within the field of reproductive medicine, and its application in the potential treatment of uterine fibroids has been investigated in several studies. The rationale behind AI is due to the finding that aromatase p450 enzyme concentrations are elevated at the local level in leiomyoma tissues [28, 29]. Interestingly, aromatase expression has been shown to be highest among African-American women (83-fold) when compared to that of Caucasian (38-fold) and Japanese women (33-fold) [70]; this higher expression may be one underlying mechanism that may explain the higher prevalence of uterine fibroids among African-American women when compared to women of other ethnic backgrounds.

In a prospective study by Gurates et al., a 3-month course of the AI letrozole at 5 mg per day was found to significantly decrease uterine and leiomyoma volume without changes in lumbar spine BMD or biochemical markers of bone metabolism; in addition, heavy menstrual bleeding associated with leiomyoma was improved [71]. Furthermore, an RCT that compared the effects of AI treatment with GnRHa on myoma volume and hormonal status in premenopausal women with leiomyomas showed promise as well. Treatment duration for both groups was 12 weeks. Leiomyoma volume was significantly reduced in the AI and GnRHa groups without a difference between groups. The AI group did not have a significant change in hormonal milieu from baseline in contrast to the GnRHa group. The authors concluded that uterine leiomyomata may be successfully managed by the use of AI, which may be most useful in the setting of pretreatment for surgery. Advantages of AI over GnRHa may include rapid onset of action as well as the avoidance of the GnRHa flare [72].

Hysterectomy has been described as the definitive management for symptomatic leiomyomata. When employed, it is highly effective for the carefully selected patient with symptomatic leiomyomata who does not desire future fertility. Among hysterectomies performed abdominally vs. vaginally for uterine leiomyomas, the abdominal route has been chosen approximately 75% of the time based on data from the late 1980s and early 1990s [74].

Vaginal hysterectomy is associated with a lower complication rate and decreased need for blood transfusion. Another advantage of vaginal hysterectomy is the association with shorter operating times [75]. Myoma size and location, total uterine size, and the surgeon’s skill are factors that may determine the feasibility of vaginal hysterectomy.

Laparoscopy-assisted vaginal hysterectomy, total laparoscopic hysterectomy, and laparoscopic supracervical hysterectomy are minimally invasive surgical methods that are associated with decreased postoperative pain and recovery time in comparison to vaginal and abdominal hysterectomy [76]. These surgical modalities may incur increased hospital costs in terms of equipment and operating room time, but they have the recognized advantages listed above. In addition, these options provide the ability to assess the pelvis if the patient also complains of pelvic pain .

Hysterectomy has long been considered the definitive treatment for symptomatic uterine leiomyomas. Yet as more and more women delay childbearing, the incidence of uterine leiomyomas among patients suffering with infertility increases, and hysterectomy becomes an unacceptable management option. Therefore, abdominal, laparoscopic, and hysteroscopic myomectomies have become increasingly common treatment modalities for women with leiomyomas and infertility.

Myomectomy is the surgery of choice for treating women with symptomatic myomas in those who desire to preserve fertility or to otherwise keep their uteri. It is most useful for subserosal, especially pedunculated subserosal, myomas as well as intramural leiomyomas. Myomectomy entails the surgical removal of myomas by enucleation. It is preferable to use as few incisions as possible to remove myomas from the uterus, in order to minimize adhesion formation as well as to minimize any compromise of the myometrial integrity. The surgeon must be diligent regarding the orientation of the uterus, especially during the repair, in order to preserve the integrity of the endometrial cavity. Several techniques have been described to decrease blood loss with an abdominal myomectomy and include the use of tourniquets around the lower segment of the uterus to occlude the uterine arteries, the use of dilute vasopressin and misoprostol preoperatively [77].