Clinical features and diagnosis of pelvic inflammatory disease

Authors: Charles H Livengood, III, MD, Mariam R Chacko, MD.

Last literature review version: Janeiro 2011 This topic last updated: Maio 18, 2010

INTRODUCTION — Pelvic inflammatory disease (PID) refers to acute infection of the upper genital tract structures in women, involving any or all of the uterus, oviducts, and ovaries; this is often accompanied by involvement of the neighboring pelvic organs. Involvement of these structures results in endometritis, salpingitis, oophoritis, peritonitis, perihepatitis and tubo-ovarian abscess. PID is a community-acquired infection caused by a sexually transmitted agent. Post-operative pelvic cellulitis and abscess, pregnancy-related pelvic infection, and pelvic infection secondary to spread of another infection (appendicitis, diverticulitis, tumor, tuberculous peritonitis, actinomycosis, others) produce a very similar clinical picture, and indeed are referred to as PID by some. However, the etiologic differences among these processes have significant implications for treatment and prevention. According to a National Ambulatory Medical Care Survey, the estimated number of cases of PID in women 15 to 44 years of age in the United States decreased from 189, 662 in 2002 to 168,837 in 2003. The number of hospitalizations for acute PID steadily declined through the 1980s and early 1990s and has remained relatively constant at around 70,000 cases a year since then. Visits to physician's offices for PID also have declined between 1993 and 2006 [1]. This decline in numbers is primarily due to aggressive chlamydia screening and treatment programs nationwide [1].

The last 30 years have witnessed an interesting, if circular, evolution of the clinical approach to the diagnosis of PID. Diagnostic procedures to document PID at one time replaced a primary clinical diagnosis. It is now appreciated that PID represents a spectrum of infection, that there is no single diagnostic gold standard, and that the practical value of clinical diagnosis retains central importance. The clinical features and diagnosis of PID will be reviewed here. The pathogenesis, risk factors for acquisition, treatment, and sequelae associated with this disorder are discussed separately. (See "Pathogenesis of and risk factors for pelvic inflammatory disease" and "Treatment of pelvic inflammatory disease".)

CLINICAL FEATURES — The clinical diagnosis of PID is imprecise [2]. Lower abdominal pain is the cardinal presenting symptom in women with PID although the character of the pain may be quite subtle. The recent onset of pain that worsens during coitus or with jarring movement may be the only presenting symptom of PID; the onset of pain during or shortly after menses is particularly suggestive [3]. The abdominal pain is usually bilateral and rarely of more than two weeks' duration [4].

Abnormal uterine bleeding occurs in one-third or more of patients with PID [5]. New vaginal discharge, urethritis, proctitis, fever, and chills can be associated signs but are neither sensitive nor specific for the diagnosis. The presence of PID is less likely if symptoms referable to the bowel or urinary tract predominate. While it is rare to have PID during pregnancy, the infection can occur in the first 12 weeks of gestation before the mucus plug and decidua seal off the uterus from ascending bacteria [6]. Evaluation of the patient for risk factors for sexually

transmitted disease and those that increase the probability of PID can be quite helpful. (See "Pathogenesis of and risk factors for pelvic inflammatory disease".)

Risk factors for STD include:

Age less than 25 years

Young age at first sex

Nonbarrier contraception

New, multiple, or symptomatic sexual partners

Oral contraception

Cervical ectopy

Factors that potentially facilitate PID include:

Previous episode of PID

Sex during menses

Vaginal douching

Bacterial vaginosis

Intrauterine device

On physical examination, only about one-half of patients with PID have fever. Abdominal examination reveals diffuse tenderness greatest in the lower quadrants, which may or may not be symmetrical. Rebound tenderness and decreased bowel sounds are common. Marked tenderness in the right upper quadrant does not exclude PID, since approximately 10 percent of these patients have perihepatitis (Fitz-Hugh Curtis syndrome). (See 'Perihepatitis' below.)

On pelvic examination, the finding of a purulent endocervical discharge and/or acute cervical motion and adnexal tenderness with bimanual examination is strongly suggestive of PID. Rectovaginal examination should reveal the uterus and adnexae to be the focus of tenderness. Other diagnoses should be considered if uterine and adnexal tenderness are not prominent. One study found that adnexal tenderness was the sign that correlated best with the finding of endometritis on endometrial biopsy [7]. However, significant lateralization of adnexal tenderness is uncommon in PID. The presence of a palpable adnexal mass is equally likely to represent tuboovarian abscess complicating PID and other diseases processes in the differential diagnosis. (See "Overview of the evaluation and management of adnexal masses" and "Differential diagnosis of the adnexal mass" and "Tuboovarian abscess".)

Subclinical PID — Lower genital tract infection with gonorrhea, chlamydia, or bacterial vaginosis is a risk factor for subclinical PID, defined histologically by the presence of neutrophils and plasma cells in endometrial tissue [8]. Women with tubal factor infertility apparently induced by past episodes of PID often give no history of PID [9-11]. As an example, in one study of 112 infertile women, 36 had adhesions or distal tube occlusion suggestive of

PID by laparoscopy but only 11 had a history of this diagnosis [11]. In addition, up to one-third of women without a history of PID harbor persistent Chlamydia trachomatis in the upper genital tract despite the absence of clinical findings except infertility [12,13].

Based upon these observations, it seems clear that subclinical PID severe enough to produce significant sequelae is common. Subclinical episodes are particularly common among oral contraceptive users [14,15]. This was illustrated in a study in which 43 women with endometritis but no clinical signs of PID were four times more likely to have used oral contraceptives than 111 control patients with clinical PID and endometritis [15].

An indolent presentation of PID with low-grade fever, weight loss, and abdominal pain, has also been reported with actinomycosis. An association between an indwelling IUD and risk of actinomycosis has been suggested, although this relationship remains unclear. The diagnosis of this pathogen is discussed elsewhere. (See "Abdominal actinomycosis".)

Perihepatitis — Perihepatitis (Fitz-Hugh Curtis Syndrome)

It was first associated with gonococcal salpingitis in 1920 [16] and subsequently with Chlamydia [17-21]. It consists of infection of the liver capsule and peritoneal surfaces of the anterior right upper quadrant, with minimal stromal hepatic involvement. It manifests as a patchy purulent and fibrinous exudate in the acute phase ("violin string" adhesions), most prominently affecting the anterior surfaces of the liver (not the liver parenchyma).

Symptoms are typically the sudden onset of severe right upper quadrant abdominal pain with a distinct pleuritic component, sometimes referred to the right shoulder. The severity of the pain in this location may mask the diagnosis of PID and lead to concerns regarding cholecystitis [21]. Aminotransferases are abnormal in approximately one-half of patients [22,23].

DIAGNOSTIC CONSIDERATIONS — There are several important modern concepts about PID that must be appreciated:

PID represents a spectrum of clinical disease, from endometritis to fatal intraabdominal sepsis.

There are multiple gold standards in use to establish the diagnosis, because no one among them is adequate alone. Older studies defining PID by a single standard, such as laparoscopic visualization of gross salpingitis, are now felt to lack sensitivity [5,24].

The following discussion will review the tests that have been used to confirm the diagnosis of PID and diagnostic criteria that have been proposed. As will be seen, none of these tests is highly specific and sensitive. Thus, in many cases, clinicians must have a low threshold for considering the diagnosis and be prepared to initiate empiric antibiotic therapy.

Plasma cell endometritis — Plasma cell endometritis (PCE) has been identified as an important component of PID [25]. In one study of 45 women admitted for acute PID, PCE was documented in 26 (87 percent) of 30 women with gross salpingitis; four of five women with PCE and no salpingitis had positive tests for chlamydia and/or gonorrhea in the genital tract and were also felt to have PID. In addition, the density of the plasma cell infiltrate correlated with the clinical severity of disease.

Several other studies have confirmed these findings [26,27]. In one report, endometritis was present in one-third of 44 patients with confirmed PID, four of whom had negative laparoscopic findings for salpingitis; the specificity of endometritis for the diagnosis of PID was 92 percent with a positive predictive value of 77 percent [27]. PCE correlates closely with the follicular/proliferative phase of the menstrual cycle, the interval during which most cases of PID arise [3].

Other evidence, however, tempers enthusiasm for linking the finding of PCE with the diagnosis of PID. PCE occurs among asymptomatic women with no other evidence of PID (eg, in 42 percent of women with isolated bacterial vaginosis and 13 percent with no genital tract infection) [3]. Furthermore, one study found a poor correlation between PCE and the clinical findings classically associated with PID [28]. Whether PCE when found alone is representative of the subclinical cases of PID discussed above or is, in some cases, a benign finding remains to be elucidated.

Laparoscopy — The diagnosis of PID had been almost exclusively a clinical one until a pivotal 1969 study in which laparoscopy was performed in 814 women with a clinical diagnosis of PID [29]. The presence of PID was verified by laparoscopy in 532 patients and other disorders were diagnosed in 98; 184 patients were classified as normal because of a negative laparoscopy.

Almost a generation of physicians were trained to diagnose PID based upon clinical correlates derived from this study since laparoscopy was difficult to justify in all suspected cases of acute PID and was not always available [5,30]. Subsequent studies from the 1990s found the sensitivity of laparoscopy to be as low as 50 percent with a specificity approaching 100 percent [26,27,31]. Thus, laparoscopy has substantial value in confirming the diagnosis of PID but is not sensitive enough to be considered a diagnostic gold standard. We recommend laparoscopy for the following:

A sick patient with high suspicion of a competing diagnosis (usually appendicitis, etc.)

An acutely ill patient who has failed outpatient treatment for PID

Any patient not clearly improving after approximately 72 hours of inpatient treatment for PID

Consent for laparotomy at the same procedure should be obtained in advance for these patients. We do not recommend endometrial biopsy for PCE at present unless the procedure is part of a protocol.

Diagnostic criteria and guidelines

The index of suspicion for the clinical diagnosis of PID should be high, especially in adolescent women, even if they deny sexual activity. The current favored approach to the diagnosis of PID is multifaceted [26-28,32].

A minimal set of clinical criteria has been recommended by the CDC for empirical treatment of PID, including cervical motion tenderness or uterine or adnexal tenderness in the presence of lower abdominal or pelvic pain. The following additional criteria can also be used to support a clinical diagnosis of PID [2]:

Oral temperature >101 F (>38.3 C)

Abnormal cervical or vaginal mucopurulent discharge

Presence of abundant numbers of white blood cells (WBCs) on saline microscopy of vaginal secretions

Elevated erythrocyte sedimentation rate

Elevated C-reactive protein

Patients with pelvic pain and tenderness and any one or more of the following are currently considered "confirmed" cases:

Acute or chronic (plasma cell) endometritis or acute salpingitis on histologic evaluation of a biopsy

Demonstration of N. gonorrhoeae or C. trachomatis in the genital tract

Gross salpingitis visualized at laparoscopy or laparotomy

Isolation of pathogenic bacteria from a clean specimen from the upper genital tract

Inflammatory/purulent pelvic peritoneal fluid without another source

The Centers for Disease Control and Prevention (CDC) also has issued guidelines for the "definitive" diagnosis of PID in symptomatic patients [2]. One or more of the following three findings are required:

Histologic evidence of endometritis in a biopsy

An imaging technique revealing thickened fluid-filled tubes/oviducts with or without free pelvic fluid or tuboovarian complex

Laparoscopic abnormalities consistent with PID (eg, tubal erythema, edema, adhesions; purulent exudate or cul-de-sac fluid; abnormal fibriae)

Standards for the diagnosis of subclinical PID, assuming that it exists, remain to be established.

DIFFERENTIAL DIAGNOSIS — In addition to PID, the differential diagnosis of lower abdominal pain in a young woman includes the following conditions:

Gastrointestinal: Appendicitis, cholecystitis, constipation, gastroenteritis, inflammatory bowel disease

Renal: Cystitis, pyelonephritis, nephrolithiasis, urethritis

Obstetric/Gynecologic: Dysmenorrhea, ectopic pregnancy, intrauterine pregnancy complication, ovarian cyst, ovarian torsion, ovarian tumor

DIAGNOSTIC TESTING — Noninvasive diagnostic tests for PID include general laboratory studies looking for signs of inflammation, culture testing and microscopy of cervical or vaginal secretions, and imaging studies.

All patients who are diagnosed with acute PID should also be tested for HIV infection [2].

Laboratory tests — Laboratory testing for patients suspected of PID always begins with a pregnancy test to rule out ectopic pregnancy and complications of an intrauterine pregnancy. A urinalysis (preferably on a catheterized specimen) and a stool for occult blood should be obtained since abnormalities in either lessen the probability of PID. Blood counts have limited value. Although PID is usually an acute process, fewer than one-half of PID patients exhibit leukocytosis [33]. A hematocrit of less than 0.30 makes PID less likely [33].

Gram stain and microscopic examination of vaginal discharge may provide useful information. If a cervical Gram stain is positive for Gram negative intracellular diplococci when interpreted by an experienced microscopist, the probability of PID greatly increases; if negative, it is of little use [33].

One study of 120 women showed that increased white blood cells (WBC) in vaginal fluid was the most sensitive single laboratory test for PID (78 percent for ≥3 WBC per high power field (hpf) compared to 57, 70, and 71 percent respectively for serum WBC, erythrocyte sedimentation rate (ESR), and C reactive protein) [32]. However, the specificity was only 39 percent.

A meta-analysis also concluded that there was no single test or combination that was both sensitive and specific for the diagnosis of PID [34]. However, certain combinations may have a high negative predictive value. In the series of 120 women described above, the probability of PID was only 11 percent in women with the combination of a normal peripheral WBC and ≤3 WBC/hpf from vaginal fluid; no patient had PID if the ESR also was normal [32]. The ovarian tumor marker CA-125 is apparently elevated in all cases of PID [35].

We recommend the following laboratory tests:

Pregnancy test

Microscopic exam of vaginal discharge in saline

Complete blood counts

Nucleic acid amplification tests for chlamydia and gonococcus

Urinalysis

Fecal occult blood test

C-reactive protein (optional)

Imaging techniques — Several studies have evaluated sonographic findings in PID with mixed results; a transvaginal rather than transabdominal approach is required [36].

One study of 51 outpatients compared transvaginal ultrasound with endometrial biopsy [37]. For the 13 patients with PCE, 11 had thickened, fluid-filled oviducts on ultrasound with or without free pelvic fluid (sensitivity 85 percent and specificity of 100 percent).

Another report evaluated 84 patients who met accepted clinical criteria for diagnosis of acute PID; 31 had normal sonograms including 26 with positive endocervical cultures [36].

In a third series, 55 women with clinical PID confirmed histologically or by laparoscopy underwent transvaginal sonography looking for abnormal oviducts, multicystic ovaries, and increased cul-de-sac fluid [38]. The respective sensitivities for these parameters were poor at 32 percent, 42 percent, and 37 percent, respectively; the specificities were 97 percent, 86 percent, and 58 percent. It was concluded that sonography has limited value in the diagnosis of PID.

Sonographic findings consistent with PID, especially thickened, fluid-filled oviducts, are useful to support a clinical diagnosis of PID. However, the absence of findings does not diminish the probability of PID and should not be used as a reason to delay treatment. We reserve ultrasounds for acutely ill patients with PID in whom a pelvic abscess is a consideration. One study compared pelvic ultrasonography in 60 adolescents with a clinical diagnosis of PID and 40 age-matched controls [39]. The presence of fluid in the cul-de-sac was not helpful in distinguishing patients with PID from those without, but 19 percent of adolescents with PID in this series had a tubo-ovarian abscess demonstrated by ultrasound before clinically suspected. Given the major contribution of tubo-ovarian abscess to failure of medical therapy for PID, this information is of considerable importance.

Recommendations — Despite this reservation about the CDC criteria for the diagnosis of PID, we strongly agree with their recommendation that "health care providers should maintain a low threshold for the diagnosis of PID" and that sexually active young women with the combination of lower abdominal, adnexal, and cervical motion tenderness should receive empiric treatment [2]. The specificity of these clinical criteria can be enhanced by the presence of fever, abnormal cervical/vaginal discharge, elevated ESR and/or serum C-reactive protein, and the demonstration of cervical gonorrhea or chlamydia infection. However, if PCE is used to define PID among women with genital symptoms, even the CDC minimum criteria lack sensitivity (65 percent [31] and 33 percent [28] in two studies).

To summarize, for all of the new insights into PID and its diagnosis, the practical clinical reality remains that patients will be best served if simple clinical findings (epidemiologic, symptomatic, and physical examination) suggesting PID are followed by prompt empiric treatment. Even patients with minimal findings should be treated since the consequences of withholding therapy are great. (See "Treatment of pelvic inflammatory disease".)

The differential diagnosis for PID is extensive (table 1). However, a trial of antibiotics should not be delayed while the other diagnoses are pursued when the clinical suspicion of PID is high.

Epidemiology, clinical manifestations, diagnosis, and natural history of uterine leiomyomas (fibroids)

Author: Elizabeth A Stewart, MD

Last literature review version: Janeiro 2011; This topic last updated: Fevereiro 7, 2011

INTRODUCTION — Uterine leiomyomas (fibroids or myomas) are the most common pelvic tumor in women [1-3]. They are benign monoclonal tumors arising from the smooth muscle cells of the myometrium. They arise in reproductive age women and typically present with symptoms of abnormal uterine bleeding or pelvic pain/pressure. Uterine fibroids may also have reproductive effects (eg, infertility, adverse pregnancy outcomes).The epidemiology, clinical manifestations, diagnosis, and natural history of uterine leiomyomas are reviewed here. Treatment of uterine leiomyomas, leiomyoma histology and pathogenesis, differentiating leiomyomas from uterine sarcomas, and leiomyoma variants are discussed separately. (See "Overview of treatment of uterine leiomyomas (fibroids)" and "Histology and pathogenesis of uterine leiomyomas (fibroids)" and "Differentiating uterine leiomyomas (fibroids) from uterine sarcomas" and "Variants of uterine leiomyomas (fibroids)".)

TERMINOLOGY AND LOCATION — Fibroids are often described according to their location in the uterus, although many fibroids have more than one location designation (picture 1 and picture 2A-B):

Intramural myomas – These leiomyomas develop from within the uterine wall. They may enlarge sufficiently to distort the uterine cavity or serosal surface. Some fibroids can be transmural and extend from the serosal to the mucosal surface.

Submucosal myomas – These leiomyomas derive from myometrial cells just below the endometrium. These neoplasms often protrude into the uterine cavity. The extent of this protrusion is described by the European Society of Hysteroscopy classification system and is clinically relevant for predicting outcomes of hysteroscopic myomectomy [4]. A type 0 fibroid is completely intracavitary, type I has at least 50 percent of its volume in the cavity, whereas a type II has at least 50 percent of its volume in the uterine wall (figure 1). Types 0 and I are hysteroscopically resectable, although significant hysteroscopic expertise may be needed to resect type I masses. (See "Hysteroscopic myomectomy", section on 'Myometrial penetration'.)

Subserosal myomas – These leiomyomas originate from the myometrium at the serosal surface of the uterus. They can have a broad or pedunculated base (picture 3) and may be intraligamentary (ie, extending between the folds of the broad ligament).

Cervical myomas – These leiomyomas are located in the cervix, rather than the uterine corpus.

PREVALENCE — Uterine leiomyomas are the most common pelvic tumor in women, as noted above [1-3]. A hysterectomy study found myomas in 77 percent of uterine specimens [5].

The epidemiology of leiomyomas parallels the ontogeny and life cycle changes of the reproductive hormones estrogen and progesterone. Although the growth of fibroids is responsive to gonadal steroids, these hormones are not necessarily responsible for the genesis of the tumors. (See "Histology and pathogenesis of uterine leiomyomas (fibroids)", section on 'Steroid hormones'.)

Leiomyomas have not been described in prepubertal girls, but they are occasionally noted in adolescents. Myomas are clinically apparent in approximately 12 to 25 percent of reproductive age women and noted on pathological examination in approximately 80 percent of surgically excised uteri [2,5,6]. In hysterectomy specimens sectioned at 2-mm intervals, premenopausal women had an average 7.6 fibroids [5]. Most, but not all, women have shrinkage of leiomyomas at menopause.

RISK FACTORS

Race — The incidence rates of fibroids are typically found to be two- to three-fold greater in black women than in white women [1,7,8]. In one study, the estimated cumulative incidence of fibroids of any size, including very small tumors, by age 50 was >80 percent for black women and almost 70 percent for white women [1]. Clinically relevant fibroids (uterine enlargement greater than or equal to nine weeks size, fibroid greater than or equal to 4 cm, or submucosal fibroid) are detectable by transvaginal sonography in approximately 50 percent of black women in the menopausal transition and 35 percent of white women in the menopausal transition [1].

The etiology of the increased incidence of leiomyomas in black women is unknown. It cannot be explained by known factors that vary by race [8]. There have been studies that correlated the presence of fibroids in African American women with polycystic ovarian syndrome [9] and self-reported experience of racism [10].

The natural history of leiomyomas also differs by race. Most white women with symptomatic fibroids are in their 30s or 40s; however, black women develop symptoms on average four to six years younger and may even present with disease in their 20s [11,12]. In addition, it appears that fibroids grow at a slower rate after age 35 in white women, but not in black women [13]. Compared with white women, black women experience more severe disease based on their symptoms in a proposed severity algorithm [11].

The rate of hysterectomy for fibroids is greater among black women than among white women (38 versus 16 per 10,000 women) [14]. Also, among women undergoing hysterectomy, black women appear to have surgery at a younger age, have larger uteri, and more severe anemia [11,12].

Data are mixed regarding whether Latina women have an increased risk of uterine myomas compared with non-Latina white women [8,14]. The risk was 1.3-fold in a prospective study of 133,000 women [14]. Some of this variation may be accounted for whether black Latina women are included in the analysis.

Menstrual history and parity — Early menarche (<10 years old) is associated with an increased risk of developing fibroids. This may largely account for the early onset of disease in black women in whom menarche is generally earlier than in white women [11,15-18]. In white women, a specific polymorphism in the transcription factor HMGA2 appears to be linked to both uterine leiomyomas and shorter adult height, suggesting that early menarche may be a key influence [16].

Parity (having one or more pregnancies extending beyond 20 weeks) decreases the chance of fibroid formation [19-21]. It has been hypothesized that the postpartum remodeling of the uterus may have the effect of clearing smaller fibroids [22]. In some cohorts, early age at first birth decreases risk and a longer interval since last birth increases risk [15].

Hormonal contraception — Use of low dose oral contraceptives (OCs) does not cause fibroids to grow, therefore administration of these drugs is not contraindicated in women with fibroids [15,19,23-25]. One possible exception was reported by the Nurses' Health Study, which suggested OC use increased the risk of leiomyomas in women with early exposure to OCs (13 and 16 years old) [21].

Depot-medroxyprogesterone acetate protects against development of leiomyomas [15,25,26].

Obesity — Most studies show a relationship between fibroids and increasing body mass index; however, a relationship with increased body mass index, weight gain as an adult, or body fat varies between studies. The relationship is complex and is likely modified by other factors, such as parity, and may be more related to change in body habitus as an adult [23,27-31].

Diet, caffeine, and alcohol use — Significant consumption of beef and other reds meats (1.7-fold) or ham (1.3-fold) is associated with an increased relative risk of fibroids and consumption of green vegetables (0.5-fold) with a decreased risk [32]. One report suggested that consumption of dairy products, but not soy products, is inversely related to fibroid risk in black women [33]. Dietary consumption of carotenoids is not associated with a change in risk for uterine leiomyoma [34]. There are also no data to suggest that other dietary factors or dietary supplements change leiomyoma risk or symptoms.

Consumption of alcohol, especially beer, appears to increase the risk of developing fibroids [35].

Caffeine consumption is not a risk factor.

Smoking — Smoking decreases the risk of having fibroids through an unknown mechanism. Smoking does not appear to affect estrogen metabolism [19,36].

Heredity — Studies imply a familial predisposition to leiomyomas in some women. (See "Histology and pathogenesis of uterine leiomyomas (fibroids)", section on 'Genetics'.)

Other factors — Hypertension is associated with an increased leiomyoma risk. The risk is related to increased duration or severity of hypertension [37].

Several measures of uterine infection appear to be associated with an increased risk of leiomyomas. This is consistent with the hypothesis that uterine injury may lead to leiomyoma formation [37,38].

CLINICAL MANIFESTATIONS — Symptoms attributable to uterine myomas can generally be classified into three distinct categories:

Abnormal uterine bleeding

Pelvic pressure and pain

Reproductive dysfunction

Although the majority of myomas are small and asymptomatic, many women with fibroids have significant problems that interfere with some aspect of their lives and warrant therapy. These symptoms are related to the number, size, and location of the neoplasms. Myomas can occur as single or multiple tumors and range in size from microscopic to tens of centimeters. The size of the myomatous uterus is described in menstrual weeks, as with the gravid uterus. As an example, a 20-week size myomatous uterus is not unusual, and is often associated with heavy menses, increasing abdominal girth, and a sense of abdominal fullness similar to pregnancy.

Abnormal uterine bleeding — Abnormal uterine bleeding is the most common symptom. Heavy and/or prolonged menses is the typical bleeding pattern with myomas [39]. Intermenstrual bleeding and postmenopausal bleeding are NOT characteristic of myomas and should be investigated to exclude endometrial pathology. (See "Evaluation of the endometrium for malignant or premalignant disease".) Heavy uterine bleeding may be responsible for associated problems, such as iron deficiency anemia, social embarrassment, and lost productivity in the work force.

The presence and degree of uterine bleeding are determined, in large part, by the location of the fibroid; size is of secondary importance. (See 'Terminology and location' above.) Submucosal myomas that protrude into the uterine cavity (eg, types 0 and I) (figure 1) are most frequently related to significant menorrhagia [2,4,40]. However, women with intramural myomas also commonly experience heavy or prolonged menstrual bleeding. The mechanism(s) of profuse menses are unclear, but may include both microscopic and macroscopic abnormalities of the uterine vasculature, impaired endometrial hemostasis, or molecular dysregulation of angiogenic factors [41].

Pelvic pressure and pain

Bulk-related symptoms — The myomatous uterus is irregularly shaped, in contrast to the pregnant uterus, and can cause specific symptoms due to pressure from myomas at particular locations. As examples, urinary frequency, difficulty emptying the bladder, and, rarely, urinary obstruction can all occur with fibroids; symptoms sometimes arise when an anterior fibroid presses directly on the bladder or a posterior fibroid pushes the entire uterus forward. Silent, ureteric compression leading to renal hydronephrosis is rare [42]. Fibroids that place pressure

on the rectum can result in constipation. Back pain may, on occasion, be related to the presence of myomas, but other possible causes should be considered.

Dysmenorrhea — Dysmenorrhea is also reported by many women with fibroids. This pain in many women appears to be correlated with heavy menstrual flow and/or passage of clots.

Dyspareunia — It is controversial whether women with fibroids in any location are more likely to experience dyspareunia than women without fibroids [43,44]. However, among women with fibroids, anterior or fundal fibroids are the most likely to be associated with deep dyspareunia. Number and size of fibroids do not appear to influence the incidence or intensity of dyspareunia.

Leiomyoma degeneration or torsion — Infrequently, fibroids cause acute pain from degeneration (eg, carneous or red degeneration) or torsion of a pedunculated tumor. Pain may be associated with a low grade fever, uterine tenderness on palpation, elevated white blood cell count, or peritoneal signs. The discomfort resulting from degenerating fibroids is self-limited, lasting from days to a few weeks, and usually responds to nonsteroidal antiinflammatory drugs. If acute pain is the sole indication for surgery, other disease processes, such as endometriosis and renal colic, or rare diagnoses such as pelvic tuberculosis, should be carefully excluded [45,46]. (See "Pathogenesis, clinical features, and diagnosis of endometriosis".)

Effects on reproduction — Leiomyomas that distort the uterine cavity (submucosal or intramural with an intracavitary component) result in difficulty conceiving a pregnancy and an increased risk of miscarriage [47]. In addition, leiomyomas have been associated with adverse pregnancy outcomes (eg, placental abruption, fetal growth restriction, and preterm labor and birth). These issues are discussed in detail separately. (See "Reproductive issues in women with uterine leiomyomas (fibroids)" and "Pregnancy in women with uterine leiomyomas (fibroids)".)

Other — Infrequently, a leiomyoma will present with transcervical prolapse, resulting in ulceration or infection.

Rare symptoms of fibroid tumors that appear to be related to ectopic hormone production include:

Polycythemia from autonomous production of erythropoietin [48]

Hypercalcemia from autonomous production of PTHrP [49]

Hyperprolactinemia [50]

DIAGNOSIS — The presumptive diagnosis of uterine myomas is usually based upon the finding of an enlarged, mobile uterus with an irregular contour on bimanual pelvic examination. Typically, an ultrasound is used to confirm the diagnosis and exclude the possibility of another type of uterine mass or an adnexal mass.

Pelvic examination — A thorough pelvic examination should be performed. On bimanual pelvic examination, an enlarged, mobile uterus with an irregular contour is consistent with a leiomyomatous uterus. The size, contour, and mobility of the uterus should be noted, along with any other findings (eg, adnexal mass, cervical mass). These findings are helpful to follow changes in the uterus over time and to aid surgical planning (eg, plan transverse or vertical incision).

Infrequently, on speculum exam, a prolapsed submucosal fibroid may be visible at the external cervical os. These should be removed and are distinguished from a large endocervical or endometrial polyp by the firm consistency of the tissue and by pathologic evaluation. (See "Vaginal myomectomy for a prolapsed uterine leiomyoma (fibroid)".)

Imaging — When a myoma is suspected based upon symptoms or pelvic examination findings, imaging or hysteroscopy are useful to exclude the possibility of another type of uterine mass or an adnexal mass. (See 'Differential diagnosis' below.) Computed tomography has little clinical utility in delineating the position of fibroids relative to the endometrium or myometrium [51].

Ultrasound — Transvaginal ultrasound has high sensitivity (95 to 100 percent) for detecting myomas in uteri less than 10 weeks' size. Localization of fibroids in larger uteri or when there are many tumors is limited [52]. This is the most widely used modality due to its availability and cost-effectiveness.

Saline infusion sonography (sonohysterography) improves characterization of the extent of protrusion into the endometrial cavity by submucous myomas and allows identification of some intracavitary lesions not seen on routine ultrasonography (picture 4). (See "Saline infusion sonohysterography".)

Diagnostic hysteroscopy — Diagnostic hysteroscopy can be performed in the office with a flexible or rigid hysteroscope. When the entire fibroid is visualized arising from a pedicle, or has a broad base, the lesion is hysteroscopically classified as intracavitary. However, when the fibroid abuts the endometrium or protrudes into the myometrium, the depth of penetration cannot be ascertained hysteroscopically. Additionally, hysteroscopy less accurately predicts the size of the myoma compared with ultrasound and sonohysterography [53].

Magnetic resonance imaging — Magnetic resonance imaging is the best modality for visualizing the size and location of all uterine myomas and can distinguish among leiomyomas, adenomyosis, and adenomyomas. Due to the expense of this modality, its use is best reserved for surgical planning for complicated procedures. It may also be useful in differentiating leiomyomas from leiomyosarcomas, and before uterine artery embolization since imaging patterns predict uterine artery embolization outcome [54,55].

Hysterosalpingography — A hysterosalpingogram (HSG) is a good technique for defining the contour of the endometrial cavity. It has poor ability to visualize the rest of the myometrium and can falsely identify an intramural fibroid impinging on the uterine cavity as a submucosal fibroid. It is typically used to visualize myomas only when a HSG is needed to evaluate tubal patency in women with infertility. (See "Hysterosalpingography".)

DIFFERENTIAL DIAGNOSIS — A normal nonpregnant uterus weighs approximately 70 g. The differential diagnosis of an enlarged uterus includes both benign and malignant conditions:

Uterine adenomyosis or adenomyoma

Leiomyoma variant

Pregnancy

Hematometra

Uterine sarcoma

Uterine carcinosarcoma

Endometrial carcinoma

Metastatic disease (typically from another reproductive tract primary)

The following sections will review aspects of these conditions that are relevant to distinguishing them from leiomyomas and uterine sarcoma.

Benign conditions

Adenomyosis or adenomyoma — Among the etiologies of a uterine mass, adenomyoma is the most likely to resemble a leiomyoma on pelvic imaging and intraoperative examination. Diffuse adenomyosis can also cause uterine enlargement without the presence of a discrete mass.

Similar to leiomyomas or uterine sarcoma, adenomyomas typically present with abnormal uterine bleeding. One characteristic that may distinguish adenomyomas from leiomyomas or sarcoma is the presence of dysmenorrhea as a prominent symptom. However, dysmenorrhea is a common gynecologic symptom and may be present in some women with leiomyomas. In addition, adenomyosis and fibroids often occur in the same woman, making differentiation more difficult.

Adenomyomas are generally more difficult to excise than leiomyomas. Leiomyomas are typically separated from the adjacent myometrium by a pseudocapsule. With adenomyomas, there is typically no tissue plane between the adenomyoma and the myometrium. Uterine sarcomas are also likely to be difficult to excise.

The diagnosis of uterine adenomyosis is discussed separately. (See "Uterine adenomyosis", section on 'Diagnosis'.)

Leiomyoma variant — There are a number of leiomyoma variants that manifest some facets of malignancy, yet lack others. For example, they may metastasize, but not be locally invasive and be histologically benign. These lesions appear to be exceedingly rare. (See "Variants of uterine leiomyomas (fibroids)".)

Other etiologies — Pregnancy is readily distinguishable from other uterine masses with measurement of a serum human chorionic gonadotropin and/or pelvic sonography. (See "Diagnosis and clinical manifestations of early pregnancy", section on 'Diagnosis'.)

Hematometra, a collection of blood within the uterine cavity, occurs most often following after an intrauterine procedure and/or in women with cervical stenosis and is diagnosed with pelvic imaging. (See "Overview of pregnancy termination", section on 'Hematometra'.)

In addition, fibroids must be differentiated from other etiologies of abnormal uterine bleeding (see "Terminology and evaluation of abnormal uterine bleeding in premenopausal women" and "The evaluation and management of uterine bleeding in postmenopausal women"), pelvic pain (see "Clinical features and diagnosis of pelvic inflammatory disease"), and infertility (see "Overview of infertility").

Malignant disease

Sarcoma — Uterine sarcomas are rare. The incidence was 3 to 7 per 100,000 United States (US) population from 1989 to 1999 [56], based upon data from the Surveillance, Epidemiology and End Results (SEER) US national cancer database. The median age at diagnosis is approximately 60 years old. The three most common types of uterine sarcomas are clinically indistinguishable: leiomyosarcoma, endometrial stromal sarcoma, and undifferentiated endometrial sarcoma. The prognosis of sarcoma varies somewhat by histologic type, but, in general, the prognosis is poor compared to other gynecologic malignancies. (See "Differentiating uterine leiomyomas (fibroids) from uterine sarcomas".)

Carcinosarcoma — Uterine carcinosarcomas are rare and highly aggressive tumors with a poor prognosis. The incidence of carcinosarcomas in US women age 35 years or older is approximately 1 to 4 per 100,000 US population. The median age at diagnosis is approximately 62 to 67 years old.

Historically, uterine carcinosarcoma was classified as a type of uterine sarcoma, and was termed malignant mixed müllerian tumor or mixed mesodermal sarcoma. However, these tumors are now classified as carcinomas since they derive from a monoclonal cancer cell that exhibits sarcomatous metaplasia, rather than a mixture of carcinoma and sarcoma. In addition, the epidemiology, risk factors, and clinical behavior associated with carcinosarcoma also suggest a closer relationship to endometrial carcinoma than to sarcoma. (See "Uterine carcinosarcoma", section on 'Epidemiology and risk factors' and "Uterine carcinosarcoma", section on 'Histopathology'.)

Endometrial carcinoma — Endometrial carcinoma may also result in abnormal uterine bleeding and a uterine mass. However, the diagnosis is typically made with endometrial sampling and imaging usually shows a thickened endometrium; if a mass is present, it is generally confined to the endometrium, except in women with advanced disease. (See "Endometrial cancer: Epidemiology, risk factors, clinical features, diagnosis, and screening", section on 'Diagnosis'.)

NATURAL HISTORY

Premenopausal women — With modern pelvic imaging, we have achieved an increased appreciation of the variability of growth and shrinkage of leiomyomas among women of reproductive age [13,57,58]. Prospective studies have found that between 7 to 40 percent of fibroids regress over six months to three years [13,57]. In one prospective study of 64 women (mean age 44 years) with fibroids, the average growth rate was 1.2 cm in diameter over 2.5 years (range 0.9 to 6.8 cm) [57]. As an example, a study that followed 72 women with a total of 262 fibroids with magnetic resonance imaging reported a median growth rate of 9 percent at six-month follow-up. [13]. There was wide variation in the growth of individual fibroids across all study participants (range -89 percent to +138 percent) and for different fibroids within each woman. Another example was a prospective study in which 36 women with a total of 101 fibroids were evaluated with magnetic resonance imaging at three-month intervals for one year [59]. Increase in volume of ≥30 percent in a three-month period was found in 37 myomas; rapid growth was more likely in tumors that were ≤5 cm in diameter.

Postmenopausal women — Relief of menstrual bleeding symptoms related to fibroids occurs at the time of menopause, when menstrual cyclicity stops and steroid hormone levels wane. Most, but not all, women have shrinkage of leiomyomas at menopause.

Women on hormone therapy — Use of postmenopausal hormone therapy may cause some women with leiomyomas to continue to have symptoms after menopause. The risk of symptoms may depend, in part, on the location of the fibroid (higher if submucosal [60]) and type of estrogen preparation (higher with transdermal estrogen in some studies [61,62], but not others [63]).

A systematic review including five randomized controlled trials found that postmenopausal hormone therapy was associated with some myoma growth, but this typically occurred without clinical symptoms [64]. These findings were confirmed in a subsequent prospective study [65]. Thus, the presence of leiomyomas is not a contraindication to use of postmenopausal hormone therapy and postmenopausal hormone therapy does not lead to development of new symptomatic fibroids in most women. (See "Postmenopausal hormone therapy: Benefits and risks", section on 'Uterine leiomyomas'.)

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Uterine fibroids".)We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.

SUMMARY AND RECOMMENDATIONS

Uterine leiomyomas (fibroids or myomas) are the most common pelvic tumor in women (cumulative incidence by age 50 of >80 percent for black women and almost 70 percent for white women). The incidence of leiomyomas parallels the life cycle changes of the reproductive hormones estrogen and progesterone. (See 'Prevalence' above and 'Race' above.)

Leiomyomas are benign monoclonal tumors arising from the smooth muscle cells of the myometrium. Fibroids are often described according to their location in the uterus (submucosal, intramural, subserosal, cervical). (See 'Prevalence' above.)

Symptoms attributable to uterine myomas can generally be classified into three distinct categories: abnormal uterine bleeding, pelvic pressure and pain, reproductive dysfunction. (See 'Clinical manifestations' above.)

The presumptive diagnosis of uterine myomas is usually based upon the finding of an enlarged, mobile uterus with an irregular contour on bimanual pelvic examination. Typically, an imaging study is used to confirm the diagnosis and exclude the possibility of another type of uterine mass or an adnexal mass. (See 'Diagnosis' above.)

Transvaginal ultrasound is the most widely used imaging modality for evaluating fibroids due to its availability and cost-effectiveness. Saline infusion sonography (sonohysterography) improves characterization of the extent of protrusion into the endometrial cavity by submucous myomas and allows identification of some intracavitary lesions not seen on routine ultrasonography. (See 'Imaging' above.)

Relief of symptoms related to fibroids usually occurs at the time of menopause, when menstrual cyclicity stops and steroid hormone levels wane. Most, but not all, women have shrinkage of leiomyomas at menopause. Use of postmenopausal hormone therapy may cause some women with leiomyomas to continue to have symptoms after menopause. Hormone therapy may be associated with an increase in size of existing myomas, but not with the development of new myomas. (See 'Postmenopausal women' above and 'Women on hormone therapy' above.)

Treatment of Myoma

Author: Elizabeth A Stewart, MD

Last literature review version: Janeiro 2011 This topic last updated: Dezembro 1, 2010

INTRODUCTION — Uterine leiomyomas are benign tumors. Since histological confirmation of the clinical diagnosis is not necessary in most cases, asymptomatic uterine leiomyomas can usually be followed without intervention [1]. Women with leiomyomas whose physicians prescribed "watchful waiting" experienced no significant change in symptoms or decline in quality of life, thereby providing some reassurance to women who are asymptomatic or have mild symptoms and choose to avoid intervention [2]. Prophylactic therapy to avoid potential future complications from myomas or their treatment is not recommended [3]. Possible exceptions include women with significant submucosal leiomyomas who are contemplating pregnancy and women with ureteral compression leading to moderate or severe hydronephrosis. In these women, prophylactic myomectomy may prevent miscarriage or urinary tract obstruction. Relief of symptoms (eg, abnormal uterine bleeding, pain, pressure) is the major goal in management of women with significant symptoms [4]. The type and timing of any intervention should be individualized, based upon factors such as [5]:

Size of the myoma(s)

Location of the myoma(s)

Severity of symptoms

Patient age

Reproductive plans and obstetrical history

An overview of the treatment of uterine leiomyomas will be presented here. The clinical manifestations, diagnosis, and natural history of these tumors are reviewed elsewhere. (See "Epidemiology, clinical manifestations, diagnosis, and natural history of uterine leiomyomas (fibroids)".)

EXPECTANT MANAGEMENT — There are no high quality data regarding follow-up of fibroids in patients who are asymptomatic or who decline medical or surgical treatment. We order an initial imaging study (usually an ultrasound) to confirm that a pelvic mass is a fibroid and not an ovarian mass. After an initial evaluation, we perform annual pelvic exams and, in patients with anemia or menorrhagia, check a complete blood count. If symptoms or uterine size are increasing, we proceed with further evaluation and patient counseling regarding treatment options. We also screen women with menorrhagia for hypothyroidism, a disease that is common in reproductive age women.

MEDICAL THERAPY — A comprehensive evidence-based report noted "a remarkable lack of randomized trial data demonstrating the effectiveness of medical therapies in the management of women with symptomatic fibroids" [6]. Given the high prevalence of both leiomyomas and the use of gonadal steroid preparations (eg, contraception, management of menstrual cycle abnormalities), it is difficult to isolate the effect of these drugs on mild leiomyoma-related symptoms.

Anecdotal data suggest medical therapy provides adequate symptom relief in some women, primarily in situations where bleeding is the dominant or only symptom. In general, 75 percent of women get some improvement over one year of therapy, but long-term failure rates are high [7]. A systematic review observed that in trials where women were randomly assigned to oral medical therapy, almost 60 percent had undergone surgery by two years [8].

A trial of medical therapy in premenopausal women with mild symptoms and/or mildly enlarged uteri can also be useful for helping to distinguish symptoms primarily related to leiomyomas from those primarily due to a concurrent problem, such as oligoovulation, may be contributing to abnormal uterine bleeding or infertility. However, in postmenopausal women, caution should be exercised when raising the level of steroid hormones from the physiologic baseline, as there is indirect evidence that taking hormone therapy causes leiomyomas to grow in this setting [9-12].

Hormonal therapies — Combined hormonal contraceptives and progestational agents are commonly prescribed to regulate abnormal uterine bleeding, but appear to have limited efficacy in the treatment of uterine leiomyomas [13,14]. These drugs can be useful in some women, particularly those with coexisting problems (eg, dysmenorrhea or oligoovulation); but they do not appear to be effective in decreasing bulk symptoms. There is also evidence that, in some women, contraceptive steroids may be associated with a decreased risk of uterine

fibroids; however, it is not clear that these agents are useful for either primary or secondary prevention [15,16].

Steroid hormones influence the pathogenesis of leiomyomas, but the relationship is complex. As an example, although there are high levels of both estrogen and progesterone during pregnancy and with estrogen-progestin contraceptive use, both decrease the risk of developing new leiomyomas but may lead to leiomyoma growth. The specific hormonal compound, the timing and duration of exposure, the delivery method (endogenous, oral, transdermal, depot, local) and other factors may all be important.

Estrogen-progestin contraceptives — Many texts continue to suggest that estrogen-progestin contraceptive pills (OC) are contraindicated in women with uterine leiomyomas. However, clinical experience suggests some women with heavy menstrual bleeding associated with leiomyomas respond to OC therapy. This, plus data that OCs are associated with a decreased risk of leiomyomas and reduced symptoms from other concurrent gynecologic conditions, suggests that a therapeutic trial may be appropriate before proceeding to more invasive therapies. The purported mechanism of action is via endometrial atrophy.

This approach should be reassessed if a woman has exacerbation of bulk-related symptoms on OCs. Since most formulations appear to work similarly, switching to other formulations does not appear to be effective in the woman who does not respond to a short trial of one formulation.

Data are not available regarding treatment using newer methods of contraceptive steroid delivery (eg, ring, patch). However, with vaginal administration (NuvaRing), the uterus is likely to receive a higher dose of medication than other systemic tissues, which could affect how leiomyomas respond to hormone therapy.

Levonorgestrel-releasing intrauterine system — There are no randomized trials evaluating the use of levonorgestrel-releasing intrauterine system (IUS) for the treatment of menorrhagia related to uterine leiomyomas. Observational studies and systematic reviews have shown a reduction in uterine volume and bleeding, and an increase in hematocrit after placement of this IUS [8,17-20]. The device is widely used for control of heavy menstrual bleeding and is now approved by the United States Food and Drug Administration (FDA) for this indication. The presence of intracavitary leiomyomas amenable to hysteroscopic resection is a strong relative contraindication to use. A second advantage of this treatment is that it provides contraception for women who do not desire pregnancy. (See "Approach to intrauterine contraception".)

Progestin implants, injections, and pills — As with OCs, it is difficult to discern the effectiveness of progestin-only contraceptive steroids specifically for treatment of leiomyomas. As with the breast, progesterone is a growth factor for myomas and may even be more critical than estrogen. That being said, progestin-only contraceptives cause endometrial atrophy and thus provide relief of menstrual bleeding-related symptoms. They can be considered for treatment of mild symptoms, especially for women who need contraception. There is also evidence from cohort studies that these agents are associated with a decreased risk of leiomyoma formation [16,21].

In contrast to gonadotropin-releasing agonists and antagonists, most of these "contraceptives" provide continuous exposure to low doses of hormones, which should minimize deleterious effects (see 'Gonadotropin-releasing hormone agonists' below and 'Gonadotropin-releasing hormone antagonists' below).

Gonadotropin-releasing hormone agonists — Gonadotropin-releasing hormone (GnRH) agonists are the most effective medical therapy for uterine myomas. These drugs work by initially increasing the release of gonadotropins, followed by desensitization and downregulation to a hypogonadotropic, hypogonadal state that clinically resembles menopause. Most women will develop amenorrhea, improvement in anemia (if present), and a significant reduction (35 to 60 percent) in uterine size within three months of initiating this therapy, thus achieving improvement in both categories of myoma symptomatology [13,14,22].

However, there is rapid resumption of menses and pretreatment uterine volume after discontinuation of GnRH agonists. In addition, significant symptoms can result from the severe hypoestrogenism that accompanies such therapy, including hot flashes, sleep disturbance, vaginal dryness, myalgias and arthralgias, and possible impairment of mood and cognition [13]. Bone loss leading to osteoporosis after long-term (12+ months) use is the most serious complication and most often limits therapy. A rule of thumb for women with endometriosis is that approximately 6 percent of bone is lost over 12 months of therapy and 3 percent is regained following the cessation of therapy [23]. However, women with leiomyomas tend to be older and heavier than women with endometriosis, thus they may have less bone loss.

Because of the rapid rebound in symptoms and side effects, GnRH agonists are primarily used as preoperative therapy. GnRH agonists are approved for administration for three to six months prior to leiomyoma-related surgery to facilitate the procedure and enable correction of anemia [24]. Reduction in uterine size can facilitate subsequent surgery by reducing intraoperative blood loss and by increasing the number of women who are candidates for a vaginal procedure, a transverse (rather than vertical) abdominal incision, or a minimally-invasive procedure. Since oral iron supplementation alone will improve the preoperative hematocrit in a significant number of patients, the cost and adverse effects of GnRH agonists must be weighed against their efficacy [25]. (See "Abdominal myomectomy", section on 'Reducing uterine size with GnRH agonists' and "Techniques to reduce blood loss during abdominal or laparoscopic myomectomy".)

GnRH agonists should not be used preoperatively for every myoma surgery, but with a particular endpoint in mind (volume reduction, resolution of anemia, or both). Although many physicians reflexively plan three or six months of treatment, interval assessment of goals is optimal because of the variability of response. Continuing GnRH agonist for six months prior to abdominal myomectomy to effect volume reduction is not optimal treatment if there is no volume reduction by two to three months. Likewise, treatment of a 2.8 cm leiomyoma prior to surgery is not helpful if the hysteroscopic surgeon can easily resect a 3-centimeter leiomyoma.

The side effects of long-term GnRH agonist administration can be minimized during therapy by giving add-back therapy with an estrogen-progestin after the initial phase of downregulation. A phase of downregulation is necessary to achieve shrinkage of leiomyomas even though simultaneous administration of a GnRH agonist and steroids can work for other diseases, such as endometriosis. Low dose estrogen-progestin therapy, such as used for menopausal replacement (equivalent to 0.625 mg of conjugated estrogen and 2.5 of medroxyprogesterone acetate or 5 mg norethindrone acetate) maintains amenorrhea and the reduction in uterine volume, while preventing significant hypoestrogenic side effects (eg, osteoporosis, vasomotor symptoms) [26]. Using OC add-back for leiomyomas is not indicated.

Rarely, GnRH-agonists are used to provide short-term relief to women close to menopause or with acute medical contraindications to surgery [27]. The United States Food and Drug Administration has approved use of leuprolide preoperatively in women with leiomyomas, but not for medical management of these tumors. Therapeutically equivalent options include leuprolide acetate depot (intramuscularly 3.75 mg/month or 11.25 mg/three months), goserelin acetate (3.6 mg/month subcutaneously or 10.6 mg subcutaneous implant every three months) or nafarelin acetate (administered as a twice daily intranasal spray).

Gonadotropin-releasing hormone antagonists — Similar clinical results have been achieved with GnRH antagonists, which compete with endogenous GnRH for pituitary binding sites [28-31]. The advantage of antagonists over agonists is the rapid onset of clinical effects without the characteristic initial flare-up observed with GnRH agonist treatment. However, in the United States, these agents are marketed at doses used for ovulation induction and long-acting preparations are not available. Thus, treatment of leiomyomas is cumbersome due to the need for daily injections.

Antiprogestins and progesterone receptor modulators — The antiprogestin mifepristone (RU-486) is the most widely studied progesterone modulator (PRM) and reduces uterine volume by 26 to 74 percent in women with leiomyomas, comparable to the reduction observed with GnRH agonists [32]. Regrowth occurs slowly following cessation of the drug [33]. Data from randomized trials and prospective studies have shown that high dose regimens (>10 to 50 mg/day) give comparable rates of amenorrhea to GnRH agonists, while lower doses (5 to 10 mg/day) achieve an amenorrhea rate of 40 to 70 percent and, in other women, produce a reduction in menstrual flow [32-38]. There is accumulating evidence that mifepristone provides symptomatic relief and improved quality of life [33,34]. There is also a small randomized clinical trial utilizing the PRM CDB-2914 and a pilot study utilizing asoprisnil, both of which may have similar effects to mifepristone for leiomyoma treatment [39,40].

The primary clinical concern with these agents is possible endometrial hyperplasia. The association with endometrial hyperplasia is inconsistent across studies in which endometrial sampling was performed at baseline and then after treatment. The reported rate of hyperplasia varies from 0 to 63 percent and does not appear to correlate with dose; there were no cases of hyperplasia with atypia [32,34,36-38]. An expert panel of pathologists, convened by the United States National Institutes of Health, reports that a novel pattern of changes that resemble hyperplasia is found in endometrial tissue following treatment with PRMs [41]. They term this new pattern PRM-associated endometrial changes and suggest that

long-term follow-up is indicated to define the natural history of these changes. Recent molecular studies suggest that endometriums exposed to PRMs do not appear to express the typical molecular signatures of endometrial malignant progression [42]. Another potential complication is transient elevations in serum aminotransferases, which has been reported with high dose regimens; this appears to be a rare occurrence with low dose regimens [32].

Mifepristone is not approved by the United States Food and Drug Association (FDA) for the treatment of uterine myomas. An impediment to use of mifepristone for treatment of leiomyomas is that currently available doses are not appropriate (200 mg once for termination of pregnancy versus 5 to 50 mg/day for three to six months for myoma reduction). Use of a compounding pharmacy is required and many are reluctant to provide this compound due to political, rather than medical, concerns for this off-label treatment indication [43]. Other PRMs are still investigational agents.

Danazol and gestrinone — Androgenic steroids may be an effective treatment of leiomyoma symptoms in some women, but are associated with frequent side effects.

Danazol is a 19-nortestosterone derivative with androgenic and progestin-like effects. Its mechanisms of action include inhibition of pituitary gonadotropin secretion and direct inhibition of endometriotic implant growth, and direct inhibition of ovarian enzymes responsible for estrogen production. Since it induces amenorrhea and has been shown to have a direct effect on endometriosis implants, danazol likely inhibits autologous endometrium. Danazol may control anemia related to leiomyoma-related menorrhagia, but it does not appear to reduce uterine volume. Side effects are common (eg, weight gain, muscle cramps, decreased breast size, acne, hirsutism, oily skin, decreased high density lipoprotein levels, increased liver enzymes, hot flashes, mood changes, depression).

Another androgenic steroid, gestrinone, decreases myoma volume and induces amenorrhea in women with leiomyomas [44]. An advantage of this drug is that there is a carry-over effect after it is discontinued. In one study, as an example, uterine volume remained lower than pretreatment values 18 months after discontinuation of therapy in 89 percent of women treated for six months [44]. Gestrinone is not available in the United States.

Raloxifene — The efficacy of selective estrogen receptor modulators for treatment of leiomyomas is unclear; while preclinical testing in animal models and treatment of postmenopausal women has been encouraging, clinical trials in reproductive age women have been less convincing [45]. A possible increased risk of venous thrombosis when high doses of raloxifene are used is an additional concern.

By comparison, studies in premenopausal women have been conflicting.

In a trial in which 100 symptomatic premenopausal women were randomly assigned to receive a GnRH analog with either raloxifene or placebo, the raloxifene group achieved a greater reduction in leiomyoma size than the placebo group, but this did not result in a greater reduction in leiomyoma-related symptoms [46]. This trial did not address the efficacy of raloxifene alone. Another trial by the same authors in asymptomatic premenopausal women

found no significant effect of raloxifene alone (60 to 180 mg/day for three to six months) on leiomyoma size or uterine bleeding compared to placebo [47]

A smaller trial (25 patients) found raloxifene (180 mg/day for three months) inhibited leiomyoma growth in premenopausal women compared to untreated controls, in whom leiomyomas continued to enlarge [48].

Larger controlled trials over extended treatment intervals should be performed to better ascertain the effect of raloxifene on leiomyomas in premenopausal women [49].

Aromatase inhibitors — Case reports and small series have described shrinkage of symptomatic leiomyomas in women in the menopausal transition given aromatase inhibitors [50,51]. Although these agents have fewer side effects than many of the hormonal therapies discussed above, their potential role in management of uterine myomas requires further study to establish the duration of response, risks, and cost-effectiveness.

Antifibrinolytic agents — Antifibrinolytic agents, which are useful in the treatment of idiopathic menorrhagia, have not been well studied in leiomyoma–related menorrhagia. One drug (tranexamic acid) is now available in the United States and FDA-approved for the treatment of heavy menstrual bleeding [52]. (See "Chronic menorrhagia or anovulatory uterine bleeding".)

Nonsteroidal antiinflammatory drugs — Nonsteroidal antiinflammatory drugs (NSAIDs) have not been extensively studied in leiomyoma-related menorrhagia. NSAIDs do not appear to reduce blood loss in women with myomas [53,54], but because they decrease painful menses, they can be useful in this population.

Future directions — The biology of uterine leiomyomas has traditionally been explained in terms of steroid hormones; thus, virtually all current medical therapies are based upon manipulation of these hormones. However, an expanded view of the biology of this benign tumor (eg, the specific genes that are dysregulated) may open new avenues of pharmaceutical intervention and ultimately lead to new strategies for prevention [55,56]. (See "Histology and pathogenesis of uterine leiomyomas (fibroids)".)

Regulation of growth factor pathways is one area of innovative treatment. There is evidence that interferons can reverse the proliferative effects of basic fibroblast growth factor on leiomyoma cells in culture [57]. In a case report, a woman undergoing treatment with interferon-alfa for hepatitis C had dramatic and sustained shrinkage of a uterine leiomyoma after seven months of therapy [58].

SURGERY

Indications — Surgery is the mainstay of therapy for leiomyomas. Hysterectomy is the definitive procedure; myomectomy by various techniques, endometrial ablation, uterine artery embolization (UAE), magnetic resonance-guided focused-ultrasound surgery (MRgFUS), and myolysis are alternative procedures. (See "Vaginal myomectomy for a prolapsed uterine leiomyoma (fibroid)" and "An overview of endometrial ablation" and "Abdominal myomectomy".)

The following are indications for surgical therapy:

Abnormal uterine bleeding or bulk-related symptoms (See "Epidemiology, clinical manifestations, diagnosis, and natural history of uterine leiomyomas (fibroids)", section on 'Clinical manifestations'.)

Infertility or recurrent pregnancy loss (see "Reproductive issues in women with uterine leiomyomas (fibroids)")

Evaluation for malignancy is not an indication for surgery in most women with leiomyomas. Examples of this are women in whom a leiomyomatous uterus limits the evaluation of the adnexa or who have a large or rapidly growing uterine mass. (See "Differentiating uterine leiomyomas (fibroids) from uterine sarcomas", section on 'Should hysterectomy be performed to exclude uterine sarcoma?' and "Abdominal myomectomy", section on 'Evaluation of pelvic malignancy'.)

Hysterectomy — We suggest hysterectomy for (1) women with acute hemorrhage who do not respond to other therapies; (2) women who have completed childbearing and have current or increased future risk of other diseases (cervical intraepithelial neoplasia, endometriosis, adenomyosis, endometrial hyperplasia, or increased risk of uterine or ovarian cancer) that would be eliminated or decreased by hysterectomy; (3) women who have failed prior minimally invasive therapy for leiomyomas; and (4) women who have completed childbearing and have significant symptoms, multiple leiomyomas, and a desire for a definitive end to symptomatology.

Leiomyomas are the most common indication for hysterectomy, accounting for 30 percent of hysterectomies in white and over 50 percent of hysterectomies in black women [59]. The cumulative risk of a hysterectomy for leiomyomas for all women between ages 25 and 45 is 7 percent, but is 20 percent in black women.

The main advantage of hysterectomy over other invasive interventions is that it eliminates both current symptoms and the chance of recurrent problems from leiomyomas. For many women who have completed childbearing, this freedom from future problems makes hysterectomy an attractive option.

The morbidity associated with hysterectomy may outweigh the benefits when there is a solitary subserous myoma, a pedunculated myoma, or a submucosal myoma readily excised via laparoscopy or hysteroscopy [60]. In these cases, an endoscopic myomectomy is a less morbid option. Avoiding the morbidity of hysterectomy should also be considered by women whose only symptom is bleeding, or who are in the menopausal transition; these women are often effectively treated with either a levonorgestrel-releasing IUS or endometrial ablation.

Myomectomy — Myomectomy is an option for women who have not completed childbearing or otherwise wish to retain their uterus. Although myomectomy is an effective therapy for menorrhagia and pelvic pressure, the disadvantage of this procedure is the risk that more leiomyomas will develop from new clones of abnormal myocytes.

The classic approach to removing subserosal or intramural myomas has been through a laparotomy incision, laparoscopic and robotic-assisted procedures are becoming more common. Hysteroscopic myomectomy is the procedure of choice for removing intracavitary myomas (submucosal and intramural myomas that protrude into the uterine cavity). When a fibroid prolapses through the cervix, myomectomy can be performed vaginally. (See "Abdominal myomectomy" and "Laparoscopic myomectomy and other laparoscopic treatments for uterine leiomyomas (fibroids)" and "Hysteroscopic myomectomy" and "Vaginal myomectomy for a prolapsed uterine leiomyoma (fibroid)".)

Endometrial ablation — In women who have completed childbearing, endometrial ablation, either alone or in combination with hysteroscopic myomectomy, is an option for management of bleeding abnormalities. Since intramural and subserosal leiomyomas are not affected by this procedure, bulk or pressure symptoms are unlikely to improve.

Some devices for endometrial ablation are designed only for use in a normal size cavity and cannot conform to an irregular cavity. When a submucous leiomyoma is present, microwave ablation is possible if the leiomyoma is less than 3 cm and leiomyoma resection with rollerball ablation is indicated if the leiomyoma is greater than 3 cm. (See "An overview of endometrial ablation".)

In a recent population based study of outcomes of endometrial ablation, a decrease in the rate of amenorrhea was found with an enlarged uterine cavity (uterine length greater than 9 cm), but not with the presence of either submucous or intramural fibroids [61].

Although most case series of endometrial ablation have excluded women with significant myomas, one study that examined endometrial ablation with hysteroscopic myomectomy reported only an 8 percent risk for a second surgery after a mean of six years of follow-up [62].

Myolysis — Myolysis refers to laparoscopic thermal coagulation or cryoablation (cryomyolysis) of leiomyoma tissue [63-65]. This technique is easier to master than myomectomy, which requires suturing. However, localized tissue destruction without repair may increase the chance of subsequent adhesion formation or rupture during pregnancy [66]. It is used infrequently in current practice. (See "Laparoscopic myomectomy and other laparoscopic treatments for uterine leiomyomas (fibroids)" and "Laparoscopic myomectomy and other laparoscopic treatments for uterine leiomyomas (fibroids)", section on 'Myolysis'.)

Uterine artery occlusion — Occlusion of uterine vessels either via laparoscopy or a vaginally-placed clamp has been proposed as an alternative to uterine artery embolization (UAE), but experience is limited [67-71]. Currently, it appears that UAE is preferable to laparoscopic uterine artery occlusion. (See "Laparoscopic myomectomy and other laparoscopic treatments for uterine leiomyomas (fibroids)", section on 'Uterine artery occlusion'.)

Transvaginal occlusion of the uterine arteries is performed under Doppler ultrasound guidance, by placing a specially designed clamp in the vaginal fornices positioned to occlude the uterine arteries. The clamp is left in place for six hours and then removed. Results are preliminary, but this technique may develop into an alternative, non-invasive method to decrease myoma size [72]. As with laparoscopic uterine artery occlusion, the advantage of

transvaginal occlusion compared with UAE is the avoidance of introduction of foreign bodies (eg, polyvinyl alcohol particles, coils). However, the transvaginal approach, ureteral injury is a potential problem.

INTERVENTIONAL RADIOLOGY

Uterine artery embolization — Uterine artery embolization (UAE), or uterine fibroid embolization (UFE), is a minimally invasive option for management of leiomyoma-related symptoms; excellent technical and clinical success has been reported. It is an effective option for women who wish to preserve their uterus and are not interested in optimizing future fertility. UFE results in shrinkage of myomas of approximately 30 to 46 percent [73]. UFE is discussed in detail separately. (See "Uterine leiomyoma (fibroid) embolization".)

A systematic review of three randomized trials concluded that women undergoing UAE have a shortened hospital stay and a quicker return to work than those undergoing hysterectomy or myomectomy [73]. However, they have more complications, unscheduled visits, and readmissions. Data also suggest that women with larger uteri and/or more leiomyomas at baseline are at greater risk of failure [74,75]. Like the situation with endometrial ablation, there appears to be a relatively high rate of reintervention for treatment failure [76]. Research is needed to see if better patient selection can minimize this risk. (See "Uterine leiomyoma (fibroid) embolization".)

Magnetic resonance guided focused ultrasound — Magnetic resonance guided focused ultrasound surgery (MRgFUS) (eg, ExAblate 2000) is a more recent option for the treatment of uterine leiomyomas in premenopausal women who have completed childbearing. This noninvasive thermoablative technique converges multiple waves of ultrasound energy on a small volume of tissue, which leads to its thermal destruction, and can be performed as an outpatient procedure [77-80]. The maximum size of a leiomyoma for this procedure is uncertain [80-82]. It is not typically size alone that limits treatment, but size, vascularity, access and other factors.

This system is not indicated for leiomyomas which are resectable with a hysteroscope, heavily calcified, or when intervening bowel of bladder could be damaged by treatment. While desire for future pregnancy was originally a contraindication for this therapy, a multicenter clinical trial for women actively seeking fertility is underway (www.clinicaltrials.gov).

The maximum size of fibroids that can be treated with this method is uncertain. In a case series, 50 women with leiomyomas exceeding 10 cm were pretreated with a GnRH agonist and were then successfully treated with MRgFUS, but individual fibroid measurements before and after pretreatment were not reported [80]. According to a survey, MRgFUS practitioners consider a fibroid >10 cm to be somewhat of an impediment, but not an absolute contraindication to the procedure. Factors reported as the most important contraindications included severe adenomyosis, five or more fibroids, and nonenhancement with gadolinium [83]. Further study is needed to determine the optimal fibroid size threshold for MRgFUS. It appears that MRgFUS results in a reduction in myoma volume of approximately 37 to 40 percent [84].

Magnetic resonance imaging gives good visualization of the anatomic structures and provides real-time thermal monitoring to optimize tissue destruction. Symptomatic improvement is observed within the first three months postprocedure, and this improvement has been maintained at least through 24 months follow-up, with more complete ablation leading to better outcomes [85-87]. Adverse event rates appear to be decreased with increased experience, despite more extensive treatment [86]. The procedure is time consuming and costly, but short-term morbidity is low and recovery is rapid. However, analyses based on quality of life measures have found the procedure to be cost-effective [88,89].

Studies are needed to determine long-term outcome and optimal candidates for this procedure; comparative studies are also needed.

There are several case reports and one case series of pregnancy following MRgFUS [90-94]. The case series is drawn from all sites performing MRgFUS and describes 54 pregnancies in 51 women [94]. Mean birth weight was 3.3 kgs and there was a 64 percent vaginal delivery rate. There was no specific pattern of complications. Nine percent of women had placentation problems, but in this series, all had prior uterine surgery as a risk factor for this complication [94].

SUMMARY AND RECOMMENDATIONS — A research group found over 1000 articles in the literature on management of leiomyomas, but was unable to perform meta-analysis or determine clear evidenced-based answers to any of their nine predetermined clinical questions because the studies had multiple design and reporting flaws [95]. Therefore, treatment recommendations for management of uterine myomas are primarily based upon outcomes described in nonrandomized, and often uncontrolled, reports. Choice of treatment modality is also based upon the size and location of the leiomyomas (large versus small, submucosal/intramural/subserosal), type of leiomyoma-related symptoms (bleeding, pain, pressure, infertility), menopausal status, and patient preference (cost, convenience, desire for uterine conservation, side effects).

Asymptomatic women

We suggest expectant management of asymptomatic women, except in the case of a woman with moderate or severe hydronephrosis or a woman with a hysteroscopically-resectable submucous leiomyoma who is pursuing pregnancy (Grade 2C). (See 'Expectant management' above.)

Postmenopausal women

In the absence of postmenopausal hormonal therapy, leiomyomas generally become smaller and asymptomatic in postmenopausal women; therefore, intervention is not usually indicated. We suggest evaluation to exclude sarcoma in a postmenopausal woman with a new or enlarging pelvic mass (Grade 2C). The incidence of sarcoma is 1 to 2 percent in women with a new or enlarging pelvic mass, abnormal uterine bleeding, and pelvic pain. (See 'Surgery' above.)

Submucosal leiomyomas

We recommend hysteroscopic myomectomy for women with appropriate submucosal leiomyomas that are symptomatic (eg, bleeding, miscarriage) (Grade 1C). This procedure allows future childbearing, usually without compromising the integrity of the myometrium, but is also an appropriate option in women who have completed childbearing since it is minimally invasive. Abdominal myomectomy is performed in women with significant symptoms and a submucous leiomyoma(s) not amenable to hysteroscopic resection. (See 'Myomectomy' above.)

Premenopausal women

Fertility optimization or preservation is desired

Given the lack of information about the safety of pregnancy after other invasive procedures, we recommend abdominal myomectomy for treatment of symptomatic intramural and subserosal leiomyomas in women who wish to preserve their childbearing potential and who have no major contraindications to a surgical approach (Grade 1B). Hysteroscopic myomectomy is the preferred approach to submucosal leiomyomas. (See 'Myomectomy' above.)

However, for women for whom risk of intraoperative conversion to hysterectomy is high, or women who are considering a future pregnancy but will accept impaired fertility in exchange for an expedited recovery phase, other options such as uterine artery embolization and magnetic resonance guided focused ultrasound may be considered appropriate treatment options. (See 'Uterine artery embolization' above and 'Magnetic resonance guided focused ultrasound' above.)

Laparoscopic myomectomy is an option for women with a uterus less than 17 weeks' size or with a small number of subserosal or intramural leiomyomas. Future childbearing is possible; however, the integrity of the uterine incision during pregnancy has not been evaluated adequately and may be inferior to abdominal myomectomy. Due to reports of uterine rupture in pregnancy following some laparoscopic myomectomies, surgeons should discuss the risks and benefits of each option with patients, including possible risk of uterine rupture, as well as provide information regarding their experience with laparoscopic suturing.

Fertility preservation is not desired

Hysterectomy is the definitive procedure for relief of symptoms and prevention of recurrent leiomyoma-related problems. (See 'Hysterectomy' above.)

We suggest use of GnRH agonists prior to a potentially complicated hysterectomy (or myomectomy) if the surgeon feels reduction in uterine/myoma volume will significantly facilitate the procedure or if there is significant anemia which has not responded to iron therapy (Grade 2B). (See 'Gonadotropin-releasing hormone agonists' above.)

For women with abnormal uterine bleeding related to leiomyomas who wish to undergo the least invasive procedure, we suggest a trial of placement of a levonorgestrel-releasing

intrauterine contraception over other drug therapies (Grade 2C). (See 'Medical therapy' above and 'Levonorgestrel-releasing intrauterine system' above.)

Several more invasive options, both surgical and using interventional radiology, are available to symptomatic women (bleeding, pain, pressure) who have completed childbearing but wish to retain their uterus. There is no high quality evidence to recommend one procedure over another. (See 'Surgery' above and 'Interventional radiology' above.)

Since fertility and pregnancy outcome may be adversely affected after many of these procedures, we suggest not performing these procedures (other than myomectomy) for women considering future pregnancy (Grade 2C).