Hacker & Moore's Essentials of Obstetrics and Gynecology: With STUDENT CONSULT Online Access,5th ed.

Chapter 19

Congenital Anomalies and Benign Conditions of the Uterine Corpus and Cervix

Anita L. Nelson, Joseph C. Gambone

Benign conditions of the uterine corpus and cervix are commonly encountered in gynecologic practice because they affect a woman’s fertility and can cause abnormal uterine bleeding or pelvic pain. In this chapter, congenital anomalies, benign neoplasms, epithelial changes, and functional disorders of the uterus (corpus and cervix) are discussed along with conventional and emerging therapies.

image Congenital Anomalies of the Uterine Corpus and Cervix

The upper vagina, cervix, uterine corpus, and fallopian tubes are formed from the paramesonephric (müllerian) ducts. The absence of a Y chromosome and the resultant absence of müllerian inhibiting substance lead to the development of the paramesonephric system, with the regression of the mesonephric system. The paramesonephric ducts first arise at 6 weeks’ gestation lateral to the cranial pole of the mesonephric duct and expand caudally. By 9 to 10 weeks, they fuse in the midline at the urogenital septum to form the uterovaginal primordium. Later, dissolution of the septum between the fused paramesonephric ducts leads to the development of a single uterus and cervix.

The most common anomalies of the uterus result from either incomplete fusion of the paramesonephric ducts, incomplete dissolution of the midline fusion of those ducts, or formation failures.Figure 19-1 shows variations of uterine and cervical development and demonstrates that communication between the dual systems can exist at several levels. Failure of fusion is most evident in uterus didelphys, which presents with two separate uterine bodies, each with its own cervix and attached fallopian tube and vagina. A bicornuate uterus with a rudimentary horn also represents a fusion failure. Less complete fusion failure is seen in the bicornuate uterus with or without double cervices. Incomplete dissolution of the midline fusion of the paramesonephrica explains the septate uterus. Failure of formation can be seen in the unicornuate uterus. In müllerian agenesis, there is complete lack of development of the paramesonephric system. The affected woman generally has incomplete development of the fallopian tubes associated with the absence of the uterus and most of the vagina. All these conditions occur in normal karyotypic and phenotypic females but can be associated with important anomalies of the urinary system such as a horseshoe or pelvic kidney.

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FIGURE 19-1 Variations in uterine development. The dotted lines within circles represent potential sites of communication or obstruction.

The most common congenital cervical anomalies are the result of malfusion of the paramesonephric (müllerian) ducts with varying degrees of separation, as seen in the didelphys cervix or septate cervix.

These different anatomies may have a significant effect on a woman’s risk for infertility and early pregnancy loss and may also cause dysmenorrhea and dyspareunia. Women with fusion anomalies may present with menstrual blood trapped in a noncommunicating uterine horn or vagina.

In addition to these macroscopic differences, subtle anomalies may exist within the uterine vascular system, such as an arteriovenous malformation, rupture of which may cause life-threatening hemorrhage.

Although all these anomalies can occur spontaneously, they may also be caused by early maternal exposure to certain drugs. The most notable of these drugs is diethylstilbestrol (DES). A DES-exposed female infant has an increased risk for a small, T-shaped endometrial cavity (Figure 19-2A) or cervical collar deformity (Figure 19-2B). DES exposure in utero can also produce fallopian tube abnormalities, although it does not appear to cause abnormalities of the urinary tract.

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FIGURE 19-2 Typical T-shaped endometrial cavity (A) and cervical collar deformity (B) more commonly seen in women exposed to diethylstilbestrol in utero.

(Courtesy of Dr. William Growdon, UCLA-Santa Monica Medical Center.)

image Benign Neoplastic Conditions

UTERINE LEIOMYOMAS

Uterine leiomyomas (“fibroids”) are benign tumors derived from the smooth muscle cells of the myometrium. They are the most common neoplasm of the uterus. Estimates are that more than 45% of women have leiomyomas by the fifth decade of life, but most are asymptomatic. However, leiomyomas can cause excessive uterine bleeding, pelvic pressure and pain, and infertility. They are the primary indication for about 200,000 hysterectomies in the United States each year. Although leiomyomas have the potential to grow to impressive sizes, their malignant potential is minimal. Sarcomatous changes occur in less than 1 per 1000 uteri with fibroids.

Risk factors for developing leiomyomas include increasing age during the reproductive years, ethnicity (African American women have at least a twofold to threefold increased risk compared with white women), nulliparity, and family history. The data are suggestive that higher body mass index is associated with a greater risk for leiomyomas. Oral contraceptive pills and depot medroxyprogesterone acetate (DMPA) injections may be associated with reduced risk.

Pathogenesis of Leiomyomas

Factors that initiate leiomyomas are not known, but ovarian sex steroids are important for their growth. Leiomyomas rarely develop before menarche and seldom develop or enlarge after menopause, unless stimulated by exogenous hormones. Leiomyomas can also enlarge dramatically during pregnancy. Leiomyomas have increased levels of estrogen and progesterone receptors compared with other smooth muscle cells. Estrogen stimulates the proliferation of smooth muscle cells, whereas progesterone increases the production of proteins that interfere with programmed cell death (or apoptosis). Leiomyomas also have higher levels of growth factors that stimulate the production of fibronectin and collagen, major components of the extracellular matrix that characterizes these lesions.

Characteristics of Leiomyomas

Leiomyomas are usually spherical, well-circumscribed, white, firm lesions with a whorled appearance on cut section. Although the leiomyoma appears discrete, it does not have a true cellular capsule. Compressed smooth muscle cells on the tumor’s periphery provide the false impression of such a capsule. Few blood vessels and lymphatics traverse the pseudocapsule, leading to degenerative changes as the tumors enlarge. The most commonly observed degenerative change is that of hyaline acellularity, in which the fibrous and muscle tissues are replaced with hyaline tissue. If the hyaline substance breaks down from a further reduction in blood supply, cystic degeneration may occur. Calcification may occur in degenerated fibroids, particularly after the menopause. Fatty degeneration may also occur but is rare. During pregnancy, 5% to 10% of women with fibroids undergo a painful red or carneous degeneration caused by hemorrhage into the tumor.

Leiomyomas always arise within the myometrium (intramural), but some migrate toward the serosal surface (subserosal) or toward the endometrium (submucosal), as depicted in Figure 19-3. Individual tumors may migrate further when they develop large pedicles. The submucosal leiomyomas can extend through the endometrial canal and abort from the cervical os. An aborting leiomyoma causes significant bleeding and cramping pain. A subserosal leiomyoma on a long pedicle can present as a mass that feels separate from the uterus. Rarely, pedunculated subserosal myomas attach to the blood supply of the omentum or bowel mesentery and lose their uterine connections to become parasitic leiomyomas. Leiomyomas can also arise in the cervix, between the leaves of the broad ligament (intraligamentous), and in the various supporting ligaments (round or uterosacral) of the uterus. Leiomyomas can invade and fill the vena cava retrograde up to the level of the atrium (intravenous leiomyomatosis).

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FIGURE 19-3 Uterine leiomyomas (fibroids) in various anatomic locations.

Symptoms of Leiomyomas

Most uterine leiomyomas cause no symptoms. On occasion, the patient may complain of a lower abdominal mass if the fibroid protrudes above the pelvis. Symptomatic women may complain of pelvic pressure, congestion, bloating, a feeling of heaviness in the lower abdomen, or lower back pain. If the fibroid presses on the bladder, there may be a problem with frequency of urination. Urinary retention and hydronephrosis are rare but result from the fact that the bladder and large leiomyomas compete for space within the pelvis.

Prolonged or heavy menstrual bleeding may be associated with intramural or submucosal myoma. Intermenstrual bleeding is not characteristic of these tumors but may occasionally occur with submucous myomas ulcerating through the endometrial lining. Excessive bleeding may result in anemia, weakness, dyspnea, and even congestive heart failure.

Fibroids are not generally painful, but severe pain may be associated with red degeneration (acute infarction) within a fibroid, which occurs most commonly during pregnancy. In addition, pressure pains may occur in the lower abdomen and pelvis if a myomatous uterus becomes incarcerated within the pelvis. Dyspareunia is also common with incarceration. There is an increased incidence of secondary dysmenorrhea in women with uterine myomas, generally caused by more frequent episodes of uterine bleeding. Although many women with uterine myomas become pregnant and carry their pregnancies to term, submucosal leiomyomas may be associated with an increased incidence of infertility because of placentation challenges.

Signs of Leiomyomas

Very large fibroids can be palpated abdominally. Those smaller than 12- to 14-week gestational size are usually confined to the pelvis. The bladder should be emptied before examination to avoid confusion with urinary retention. Although submucous fibroids may not be palpable, on bimanual pelvic examination, a firm, irregularly enlarged uterus with smoothly rounded or bosselated protrusions may be felt if the tumors are subserosal or intramural. The tumors are usually nontender. Their consistency may vary from rock hard, as in the case of a calcified postmenopausal leiomyoma, to soft or even cystic, as in the case of cystic degeneration of the tumor. In general, the myomatous masses are in the midline, but sometimes a large portion of the tumor lies in the lateral aspect of the pelvis and may be indistinguishable from an adnexal mass. If the mass moves with the cervix, it is suggestive of a leiomyoma. Often the presence of a leiomyoma precludes a proper evaluation of the adnexa, but ultrasound imaging (Figure 19-4) can help to distinguish adnexal masses from laterally placed myomas.

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FIGURE 19-4 Ultrasound image of a uterus (Ut) enlarged and irregularly distorted by multiple leiomyomas (arrows). Such studies are useful to exclude ovarian enlargement. B, bladder; Cx, cervix; V, vagina.

(From Mettler FA: Essentials of Radiology, 2nd ed. Philadelphia, Saunders, 2005.)

Differential Diagnosis for Leiomyomas

The differential diagnosis of a leiomyoma is extensive and includes other uterine pathology, such as uterine sarcoma, and other processes, such as inflammation, that can cause pelvic masses. The most common differential diagnoses are an ovarian neoplasm, a tubo-ovarian inflammatory mass, a pelvic kidney, a diverticular or inflammatory bowel mass, or cancer of the colon. Ultrasonography may visualize the fibroids and identify normal ovaries apart from the leiomyomas. Adenomyosis usually results in a uniformly enlarged uterus (see Chapter 25Figure 25-5) but may on occasion be diagnosed as a leiomyoma. Figure 19-5 shows the gross appearance of an irregularly enlarged uterus with multiple fibroids.

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FIGURE 19-5 Gross appearance of an irregularly enlarged uterus with multiple leiomyomas.

(From Voet RL: Color Atlas of Obstetric and Gynecologic Pathology. St. Louis, Mosby, 1997.)

Management of Leiomyomas

In general, if a small, asymptomatic fibroid is detected, treatment is not necessary. Unless the fibroid uterus is excessively large (>12-week gestational size) or is implicated as a cause of infertility in a woman seeking pregnancy, the first line of treatment is targeted to her symptoms.

Medical Management

Heavy or prolonged menstruation caused by fibroids may be managed hormonally in many cases. Progestin-only therapies (oral or injected medroxyprogesterone acetate, progestin-only oral contraceptive pills, or levonorgestrel-releasing intrauterine devices) or combination hormonal contraceptive methods (oral contraceptive pills, vaginal rings, or patches) are usually the first therapeutic option. The goal is to reduce monthly menstrual blood loss with cyclic hormonal methods or to eliminate menses with extended or continuous use of these methods. Dysmenorrhea is also markedly reduced by these measures.

Gonadotropin-releasing hormone (GnRH) agonists block ovarian steroidogenesis, which halts endometrial proliferation and reduces the volume of the myometrium and sometimes the volume of the leiomyomas. However, because of the intense vasomotor symptoms and the deleterious effect the GnRH agonists may have on bone mineral density, only short courses of these agonists can be administered. Usually their use is confined to women preparing for surgical treatments, such as endometrial ablation, myomectomy, or hysterectomy. Intermittent GnRH agonist administration has been shown to reduce side effects while achieving therapeutic goals longer term. Combining GnRH agonists with hormonal agents, such as low-dose progesterone or estrogen-progestin combinations, may minimize some adverse effects of hypoestrogenism (such as osteoporosis), but long-term data are not available. GnRH agonists are very expensive, even in the short term.

Clinical trials using the selective antiprogesterone receptor antagonist, mifepristone (RU 486), to reduce the size of uterine myomas have shown a reduction of 50% by volume over a 3-month period. Doses of 5, 25, or 50 mg/day for up to 6 months have been used to reduce the size of uterine myomas without producing the changes in bone density noted with GnRH agonists and without untoward glucocorticoid effects. However, this drug is not routinely available for this treatment.

Surgical Management Options

For women desiring to preserve their fertility, myomectomy may be an option if the number and size of the fibroids is limited. The surgical approach depends on the location of the myoma. Magnetic resonance imaging (MRI) can localize and estimate the volume of each myoma. Submucosal myomas may be resected hysteroscopically. Pedunculated, subserosal, and some intramural myomas may be removed laparoscopically. Laparotomy is generally reserved for larger myomas. If the endometrial cavity is entered during myomectomy, future delivery must be by cesarean birth. Myomectomy may not be successful in avoiding hysterectomy. At the time of myomectomy, if an inadequate amount of uterine tissue remains, a hysterectomy may be needed. New fibroids may form in the future, and about 25% of women treated with myomectomy require a subsequent operation.

For women desiring uterine preservation but not future fertility, surgical management of excessive bleeding is possible using procedures that ablate the endometrium. With endometrial ablation, more than 70% of women have a significant and satisfactory decrease in menstrual blood loss after one treatment, whereas others require repeat ablation or undergo hysterectomy. For women who desire uterine preservation and possible future fertility, uterine artery embolization (UAE) may be an option when a few small to moderate-sized tumors are present. UAE is a procedure performed under conscious sedation in which microspheres or small coils are introduced into the uterine artery by a transcutaneous femoral approach. These coils and particles occlude the artery feeding the fibroid, leading to necrosis of the fibroid. Fibroids often shrink 40% to 60% in size, and bleeding is reduced. After UAE is performed, pregnancy is still possible but is higher risk.

Hysterectomy provides definitive therapy. About 200,000 hysterectomies are done annually in the United States to treat fibroids. If the uterus is large or bulky, laparotomy is generally the preferred approach. Vaginal hysterectomy and total laparoscopic hysterectomy are both excellent options for women with smaller myometrial uteri. If a woman desires a supracervical hysterectomy, the vaginal approach is not possible. Usually ovarian preservation is encouraged unless the woman is older than 60 years or has risk factors for ovarian carcinoma. Table 19-1 summarizes the more common nonmedical options for patients with leiomyomas.

TABLE 19-1 INTERVENTION FOR PATIENTS WITH LEIOMYOMAS NOT AMENABLE TO MEDICAL THERAPY

Clinical Presentation

Nonmedical Options

Comments

Desired fertility

Myomectomy or uterine artery embolization (UAE)

Usually used for a limited number of leiomyomas

Desired uterine preservation or poor surgical risk

Endometrial ablation or UAE

UAE only for a limited number of leiomyomas

No desired fertility or uterine preservation

Endometrial ablation or hysterectomy

Hysterectomy is definitive therapy

Rapidly growing uterus (double in size in 6 months)

Exploratory laparotomy, abdominal hysterectomy

More extensive surgery if malignancy discovered

 Generally, failed medical therapy or large (>12-14 weeks’ gestational size) uterus.

 Pregnancies after UAE are at higher risk.

Other technologies have been developed to offer new treatment options. Cryomyolysis is a technique for destroying the myoma by the insertion of probes under laparoscopic guidance. These probes are cooled using liquid nitrogen or differential gas exchange. MRI-guided focused ultrasonography produces energy that penetrates through soft tissue to produce regions of protein denaturation and necrosis, reducing the volume of myomas. Radiofrequency ablation through a laparoscope can also be used to treat individual myomas. Each of these newer technologies lacks long-term follow-up data.

ENDOMETRIAL POLYPS

Endometrial polyps form from the endometrium to create abnormal protrusions of friable tissue into the endometrial cavity. They can cause menorrhagia and spontaneous bleeding during the reproductive years and postmenopausal bleeding after menopause. On ultrasound, endometrial polyps may appear as a focal thickening of the endometrial stripe. They can be more clearly recognized on saline infusion sonography or visualized directly by hysteroscopy (see Chapter 34Figure 34-1). Endometrial polyps may evade detection by endometrial aspiration or dilation and curettage (D&C) because they are too large to be aspirated through the sampling orifice and are very flexible and can fold out of the path of the sharp curette. Histologic evaluation of the polyp is imperative because although most are benign, endometrial hyperplasia, endometrial carcinoma, and carcinosarcomas may also present as polyps.

NORMAL CERVIX

At birth, a pale pink squamous epithelium covers the outer rim of the cervix. The inner region of the ectocervix is covered with the taller columnar cells. The junction between the two is called the original squamocolumnar junction(Figure 19-6). The columnar epithelium appears redder because of the closer proximity of its underlying blood vessels to the surface. With acidification of the vagina at menarche, the ectocervix undergoes an accelerated rate of squamous metaplasia in a radial pattern, from the squamocolumnar junction inward, which produces the transformation zone. A new squamocolumnar junction is formed that moves progressively up the endocervical canal (see Chapter 38Figure 38-1). Younger women are often found to have a reddish ring of tissue surrounding the os, which is sometimes called a cervical ectropion, but in reality, this is an area of columnar epithelium that has not yet undergone squamous metaplasia.

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FIGURE 19-6 Squamocolumnar junction. In the “ideal” cervix, the original squamous epithelium abuts the columnar epithelium. The squamocolumnar junction thus formed may be situated at the external cervical os, but in most women of childbearing age, the original squamocolumnar junction is located on the vaginal portion of the cervix.

Under the influence of estrogen (birth control pills, pregnancy), the columnar epithelium of more mature women may evert and present a similar-appearing ectropion. The columnar cells produce mucus and are more vulnerable to trauma and infection with chlamydia. Therefore women with a cervical ectropion may notice more vaginal secretions and, occasionally, postcoital spotting. Once other etiologies have been ruled out, no treatment is needed for the friable tissue.

Nabothian cysts on the cervix are so common that they are considered a normal variant. They result from the process of squamous metaplasia. A layer of superficial squamous epithelium entraps an invagination of columnar cells beneath its surface. The underlying columnar cells continue to secrete mucus, and a mucous retention cyst is created. Nabothian cysts are opaque, with a yellowish or bluish hue. They vary generally in size from 0.3 to 3 cm (Figure 19-7), although larger nabothian cysts have been reported.

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FIGURE 19-7 Cervix of a multiparous woman with nabothian cysts.

CERVICAL POLYPS

Ectocervical and endocervical polyps are the most common benign neoplastic growths of the cervix. A polyp is a localized proliferation of cells (usually columnar) located in the endocervix. Endocervical polyps tend to be more beefy red in color and arise from the endocervical canal on a long, pedunculated stalk. Ectocervical polyps are less common, are generally pale, and arise from the ectocervix to create a broad-based protrusion. Cervical polyps may be isolated or multiple and vary in diameter from a few millimeters to several centimeters. If symptomatic, they most commonly cause coital bleeding or menorrhagia. Narrow-based polyps are removed by twisting the polyp off at its base. Broader-based polyps may be better removed with cautery or other modalities that can control bleeding after removal. Although the incidence of malignancy is low (1% or less), both squamous cell carcinomas and adenocarcinomas can present as polyps. All specimens must be sent for pathologic examination.

image Trauma of the Uterine Corpus and Cervix

Most trauma to the uterus has an obstetric basis, such as uterine rupture from prolonged labor, caused by a Bandl’s ring, or along a previous uterine scar. However, uterine perforation is also possible with operative procedures such as D&C, endometrial aspiration, or intrauterine contraceptive placement. Similarly, most traumatic injuries to the cervix occur during vaginal delivery. The cervix can tear if the infant is delivered through an incompletely dilated cervical os. Lacerations can also occur when instruments such as forceps are used for delivery or during gynecologic operations, such as cervical conization, hysteroscopy, or abortion. Trauma to the cervix can occur with sexual assault.

image Epithelial Conditions of the Uterine Corpus and Cervix

ENDOMETRIAL HYPERPLASIA

Endometrial hyperplasia represents an overabundant growth of the endometrium generally caused by persistent levels of estrogen unopposed by progesterone. Hyperplasia is most frequently seen at the extremes of a woman’s reproductive years when ovulation is infrequent. It also occurs in association with unopposed estrogenic stimulation, such as the following:

1. Polycystic ovary syndrome

2. Estrogen-producing tumors such as granulosa–theca cell tumors

3. Obesity because of peripheral conversion of androgens to estrogen in adipose cells

4. Prolonged use of exogenous estrogens without progestins

5. Use of tamoxifen

A spectrum of histologic variations exists. There are two categories (simple hyperplasia and complex hyperplasia) and two subcategories (with and without atypia). Complex atypical hyperplasia has the greatest malignant potential; about 20% to 30% of cases progress to endometrial carcinoma, if untreated. Figure 19-8 shows photomicrographs of normal proliferative endometrium, simple hyperplasia (without atypia), and complex hyperplasia (with atypia).

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FIGURE 19-8 Endometrial biopsies of normal proliferative endometrium (A), simple endometrial hyperplasia without atypia (B), and complex endometrial hyperplasia with cellular atypia (C).

(From Espindola D, Kennedy KA, Fischer EG: Management of abnormal uterine bleeding and the pathology of endometrial hyperplasia. Obstet Gynecol Clin North Am 34:717-737, 2007.)

Diagnosis

Endometrial hyperplasia should be suspected especially when a woman develops intermenstrual bleeding or when a high-risk woman develops unexplained heavy or prolonged bleeding. Endometrial sampling is necessary to obtain a histologic diagnosis. Other procedures, such as fractional D&C or hysteroscopically directed biopsy, may be needed to rule out carcinoma or other pathology. In postmenopausal women, a thin (<4 mm) endometrial stripe on transvaginal ultrasound is reassuring.

Treatment

Treatment of hyperplasia in reproductive-aged women without atypia generally consists of a thorough, coordinated sloughing of the hyperplastic endometrium and therapies directed at preventing recurrence. Simple hyperplasia without atypia should be treated initially with a progestin, such as 10 days each month for 3 months, then biopsy should be repeated to confirm normalization of the endometrium. Complex hyperplasia must be evaluated with a fractional D&C and should be initially treated with daily progestin therapy for 3 to 6 months. Test of cure with another biopsy is then needed. In the long run, a source of progestin must be supplied. Complex hyperplasia with atypia is best treated by hysterectomy after carcinoma has been excluded. Endometrial ablation is absolutely contraindicated in any of these situations until the endometrium normalizes.

ASHERMAN’S SYNDROME

The endometrium is denuded and the endometrial cavity filled with adhesions in patients with Asherman’s syndrome. Bleeding disorders can range from irregular bleeding to amenorrhea depending on the amount of intrauterine scarring. Most commonly, the scarring results from curettage in high-risk settings, such as postpartum hemorrhage or septic abortion, although vigorous scraping under any circumstances can result in the loss of the endometrium and consequent adhesion of opposing myometrial surfaces. Endometrial ablation procedures are designed to deliberately destroy the endometrium and create such scarring.

image Functional Conditions of the Uterine Corpus and Cervix

Noncongenital cervical stenosis usually arises after trauma (endocervical curettage, conization) or hypoestrogenism (menopause, prolonged DMPA use). Problems arise if blood from the endometrium cannot escape into the vagina, in which case the uterus becomes grossly distended (hematometra). Similarly, sperm may be unable to enter the upper genital tract. Cervical stenosis may also cause cervical sampling for microscopic evaluation to be incomplete.

Cervical incompetence is a condition in which the cervix is unable to maintain closure under the pressure of a progressively enlarging pregnant uterus and painlessly dilates, resulting in pregnancy loss, most commonly in the second trimester (see Chapter 12). Cervical incompetence may be intrinsic (caused by poor ground substance in the cervix), the result of cervical surgery (especially loop electrosurgical excision procedure and cold-knife conization) for cervical dysplasia, or the result of DES exposure in utero.

SUGGESTED READING

American College of Obstetricians and Gynecologists (ACOG). Surgical alternative to hysterectomy in the management of leiomyomas. Practice Bulletin No.16. Washington, DC: ACOG; May 2000.

Cheng M.H., Wang P.H. Uterine myoma: A condition amenable to medical therapy. Emerg Drugs. 2008;13:119-133.

Espindola D., Kennedy K.A., Fischer E.G. Management of abnormal uterine bleeding and the pathology of endometrial hyperplasia. Obstet Gynecol Clin N Am. 2007;34:717-737.

Marshburn P.B., Matthews M.L., Hurst B.S. Uterine artery embolization as a treatment option for uterine myomas. Obstet Gynecol Clin North Am. 2006;33:125-144.

Viswanathan M., Hartman K., McDoy N., et al. Management of uterine fibroids: An update of the evidence. Evid Rep Technol Assess. 2007;154:1-122.