Epidemiology, clinical manifestations, diagnosis, and natural history of uterine leiomyomas (fibroids)AuthorElizabeth A Stewart, MDSection EditorRobert L Barbieri, MDDeputy EditorSandy J Falk, MDDisclosures: Elizabeth A Stewart, MD Grant/Research/Clinical Trial Support: InSightec; NIH (HD060503) (uterine fibroids). Consultant/Advisory Boards: Abbott; Bayer; Gynesonics (uterine fibroids). Other Financial Interest: Massachusetts Medical Society (royalties). Robert L Barbieri, MD Nothing to disclose. Sandy J Falk, MD Employee of UpToDate, Inc.

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All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Apr 2014. | This topic last updated: Feb 18, 2014.

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 heavy or

prolonged menstrual 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 (figure 1and picture 1A-B). An

International Federation of Gynecology and Obstetrics (FIGO) staging scheme for fibroid location has

been proposed (figure 2) [4].

●Intramural myomas (FIGO type 3,4,5) – 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 (FIGO type 0,1,2) – These leiomyomas derive from myometrial cells just

below the endometrium. These neoplasms protrude into the uterine cavity. The extent of this

protrusion is described by the FIGO/European Society of Hysteroscopy classification system and is

clinically relevant for predicting outcomes of hysteroscopic myomectomy [5]. A type 0 fibroid is

completely intracavitary, type I has less than 50 percent of its volume in the uterine wall, whereas a

type II has 50 percent or more of its volume in the uterine wall (figure 3). 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 (FIGO type 6,7) – These leiomyomas originate from the myometrium at the

serosal surface of the uterus. They can have a broad or pedunculated base (image 1) and may be

intraligamentary (ie, extending between the folds of the broad ligament).

●Cervical myomas (FIGO type 8) – 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 [6].

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 [2,6,7]. In

hysterectomy specimens sectioned at 2-mm intervals, premenopausal women had an average 7.6

fibroids [6]. 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 [1,8,9]. 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 [9]. There have been studies that correlated the presence of

fibroids in African American women with polycystic ovarian syndrome [10] and self-reported experience of

racism [11].

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 [12,13]. The prevalence of fibroids in women 30 years old and

younger appears to be significantly higher with about a quarter of black women having fibroids compared

to 7 percent of white women [14]. In addition, it appears that fibroids grow at a slower rate after age 35 in

white women, but not in black women [15]. Compared with white women, black women experience more

severe disease based on their symptoms in a proposed severity algorithm and have more extensive

disease at the time of hysterectomy [12,13].

The rate of hysterectomy for fibroids is greater among black women than among white women (38 versus

16 per 10,000 women) [16]. Also, among women undergoing hysterectomy, black women appear to have

surgery at a younger age, have larger uteri, and more severe anemia [12,13]. There is also increased risk

of myomectomy and hospitalization for fibroids for black women [17]. Finally, there is increasing evidence

of increases in symptomatology for black women with fibroids apart from those seeking surgical therapy,

increased impairment of quality of life, different concerns regarding fibroids and the consequences of

fibroid therapies and less satisfaction with the information they receive about fibroids [18].

Data are mixed regarding whether Latina women have an increased risk of uterine myomas compared

with non-Latina white women [9,16]. The risk was 1.3-fold in a prospective study of 133,000 women [16].

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 [12,19-22]. Additionally, prenatal exposure to

diethylstilbestrol is associated with an increased risk of fibroids, supporting the role of early hormonal

exposure in pathogenesis [23]. 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 [20].

Parity (having one or more pregnancies extending beyond 20 weeks) decreases the chance of fibroid

formation [24-26]. It has been hypothesized that the postpartum remodeling of the uterus may have the

effect of clearing smaller fibroids [27]. Recent studies supported this hypothesis with the finding that over

a third of women with a single fibroid identified during pregnancy had none on postpartum ultrasound, and

almost 80 percent of fibroids were smaller following pregnancy [28]. In some cohorts, early age at first

birth decreases risk and a longer interval since last birth increases risk [19].

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 [19,24,29-31]. 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) [26].

Long acting progestin-only contraceptives (eg, depot medroxyprogesterone) protect against development

of leiomyomas [19,31,32]. However, recent studies of postpartum fibroid regression suggest that these

agents inhibit fibroid regression when used in the postpartum period [33].

Ovulation induction agents — There are isolated reports of leiomyoma enlargement in women treated

with clomiphene [34,35]. However, both cases reported occurred in the era before clinical use of

ultrasound and the only presurgical assessment of the size of fibroids was pelvic examination and

culdoscopy. Given the frequency of ultrasound monitoring in conjunction with current fertility treatments

and the dearth of case reports, the association of fibroid growth with agents for ovulation induction is

unlikely [36].

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 [29,37-41].

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) and fruit (especially citrus fruit) with a decreased risk [42,43]. One report suggested

that consumption of dairy products, but not soy products, is inversely related to fibroid risk in black women

[44]. Dietary consumption of carotenoids is not associated with a change in risk for uterine leiomyoma

[45]. Recent data suggest that consumption of dairy products is inversely associated with leiomyoma risk

in black women [44]. There was no confounding effect of soy consumption, which is often a substitute for

dairy products in lactose intolerant women [44]. Dietary vitamin A from animal sources may also be

associated with decreased fibroid risk [43]. Increases in dietary glycemic index or load are associated with

a weak increase in fibroid risk in some women [46]. There is increasing evidence that vitamin D deficiency

or insufficiency is linked to fibroid risk [47,48]. This is especially interesting because it is a biologically-

plausible explanation for the increased fibroid risk in black women that lends itself to prevention trials.

Consumption of alcohol, especially beer, appears to increase the risk of developing fibroids [49].

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 [24,50].

Heredity — Studies imply a familial predisposition to leiomyomas in some women. There is also

increasing evidence of specific susceptibility genes for fibroids [51-53]. (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 [54]. Environmental phthalate exposure appears to be

linked to an increased risk of fibroids, especially in women with concomitant endometriosis [55]. There

appears to be a link between a history of physical or sexual abuse and fibroids, especially in black women

[56-58].

The link between uterine infection appears to be associated with an increased risk of leiomyomas, yet

factors associated with cervical neoplasia are associated with a decreased risk [54,59]. Additional study is

indicated regarding infectious agents and fibroid risk.

CLINICAL MANIFESTATIONS — Symptoms attributable to uterine myomas can generally be classified

into three distinct categories:

●Heavy or prolonged menstrual 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 [18]. 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.

Heavy or prolonged menstrual bleeding — Heavy and/or prolonged menses is the typical bleeding

pattern with myomas and the most common fibroid symptom [60]. Intermenstrual bleeding and

postmenopausal bleeding are NOT characteristic of myomas and should be investigated to exclude

endometrial pathology. Heavy uterine bleeding may be responsible for associated problems, such as iron

deficiency anemia, social embarrassment, and lost productivity in the work force. (See "Evaluation of the

endometrium for malignant or premalignant disease".)

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 3) are most frequently related to significant

menorrhagia [2,5,61]. As an example, a retrospective study that included 912 women with leiomyomas

found that those with submucosal myomas were significantly more likely to be anemic than women with

myomas in other locations (34 versus 25 percent) [62]. 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 [63].

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 [64]. 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. Very large uteri may compress the vena cava and lead to increase in thromboembolic risk

[65-67]. At least one study suggests the risk of venous thromboembolism is likely to be the presenting

complaint associated with an enlarged uterus rather than a postsurgical complication [65].

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 [68,69]. 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. Pelvic magnetic resonance imaging with

gadolinium can be useful to make the diagnosis of degeneration since degenerating fibroids do not have

enhancement following contrast administration [70]. 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 [71,72]. (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

[73]. 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 [74]

●Hypercalcemia from autonomous production of PTHrP [75]

●Hyperprolactinemia [76]

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 "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 [77].

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 [78]. 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 (image 2). (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 [79].

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

[80,81].

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. Again, pain symptoms and

symptoms that appear significant despite modest uterine enlargement appear to indicate adenomyosis

may coexist with leiomyomas [82,83].

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. Some of these variants show no facets of malignancy. 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"Clinical manifestations and

diagnosis 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'.)

Adenomatoid tumors are an uncommon type of mass of the female reproductive tract that can be seen in

the myometrium or in the adnexa (the most common place is actually next to the fallopian tube) [84]. They

are mesothelial proliferations and are not histologically related to adenomyosis. They may grossly mimic

leiomyomas.  

In addition, fibroids must be differentiated from other etiologies of abnormal uterine bleeding, pelvic pain,

and infertility. (See "Approach to abnormal uterine bleeding in nonpregnant reproductive-age

women" and "Postmenopausal uterine bleeding" and "Clinical features and diagnosis of pelvic

inflammatory disease" and "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 [85], 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"Clinical features, diagnosis, staging, and treatment of uterine

carcinosarcoma", section on 'Epidemiology and risk factors' and "Clinical features, diagnosis, staging, and

treatment of uterine carcinosarcoma", section on 'Pathology'.)

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.

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 [15,86,87].

Prospective studies have found that between 7 to 40 percent of fibroids regress over six months to three

years [15,86]. 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) [86]. 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. [15]. 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 [88]. 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. There is also an increased appreciation of postpartum regression of

fibroids [28,33].

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 [89]) and type of estrogen preparation (higher with

transdermal estrogen in some studies [90,91], but not others [92]).

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

[93]. These findings were confirmed in a subsequent prospective study [94]. 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 — UpToDate offers two types of patient education materials, “The

Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at

the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have

about a given condition. These articles are best for patients who want a general overview and who prefer

short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated,

and more detailed. These articles are written at the 10th to 12th grade reading level and are best for

patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail

these topics to your patients. (You can also locate patient education articles on a variety of subjects by

searching on “patient info” and the keyword(s) of interest.)

●Basics topics (see "Patient information: Uterine fibroids (The Basics)")

●Beyond the Basics topics (see "Patient information: Uterine fibroids (Beyond the Basics)")

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.)Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCESOverview of treatment of uterine leiomyomas (fibroids)AuthorElizabeth A Stewart, MDSection EditorRobert L Barbieri, MDDeputy EditorSandy J Falk, MDDisclosures: Elizabeth A Stewart, MD Grant/Research/Clinical Trial Support: InSightec; NIH (HD060503) (uterine fibroids). Consultant/Advisory Boards: Abbott; Bayer; Gynesonics (uterine fibroids). Other Financial Interest: Massachusetts Medical Society (royalties). Robert L Barbieri, MD Nothing to disclose. Sandy J Falk, MD Employee of UpToDate, Inc.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

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All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Apr 2014. | This topic last updated: Jul 19, 2013.

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 treatment 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]:

Type and severity of symptoms

Size of the myoma(s)

Location of the myoma(s)

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. However, given data that fibroids

can shrink substantially and that there is substantial regression during the postpartum period, expectant

management appears to be a reasonable option for some women [6,7]. 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, and refer women with heavy

menstrual bleeding and a history suggestive of a bleeding disorder for hematologic evaluation.

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" [8]. 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 [9]. 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 [10].

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, which 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 [11-14].

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 [15,16]. These drugs can be useful in some women with heavy menstrual bleeding,

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 [17,18]. There is one study that suggests that

oral contraceptives started before age 16 may be associated with an increased risk of fibroids [17].

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 [10,19-22]. 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 "Intrauterine contraception

(IUD): Overview".)

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 consistent evidence from cohort studies that these agents

are associated with a decreased risk of leiomyoma formation [18,23].

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 [15,16,24].

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 [15]. 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 [25]. 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 in conjunction with iron supplementation to facilitate the procedure and enable

correction of anemia [26]. 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 [27].

(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 low dose 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 ofmedroxyprogesterone acetate or 5 mg norethindrone acetate) maintains

amenorrhea and the reduction in uterine volume, while preventing significant hypoestrogenic side effects

(eg, osteoporosis, vasomotor symptoms) [28]. 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 [29]. The United States Food and Drug Administration has approved

use of leuprolide and iron 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). However, the fact that these agents are best administered at specific times in the menstrual cycle

(late luteal if no chance of pregnancy or with onset of menses), cause an increase in estrogen prior to

downregulation and take a minimum of three weeks to reach this down-regulated state means that some

women who might benefit are not candidates for therapy.

Gonadotropin-releasing hormone antagonists — Similar clinical results have been achieved with

GnRH antagonists, which compete with endogenous GnRH for pituitary binding sites [30-33]. 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 — Progesterone appears to be capable of

stimulating growth in uterine fibroids. The primary clinical concern with antiprogestins and progesterone

receptor modulators (PRM) is the potential for an increased risk of endometrial hyperplasia or cancer. The

association with endometrial hyperplasia was inconsistent across studies in which endometrial sampling

was performed at baseline and then after treatment [34-38]. The reported rate of hyperplasia varied

widely from 0 to 63 percent and did not appear to correlate with dose; there were no cases of hyperplasia

with atypia or cancer.

An expert panel of pathologists, convened by the United States National Institutes of Health, reported that

a novel pattern of changes that resemble hyperplasia is found in endometrial tissue following treatment

with PRMs [39]. 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 endometrium exposed to PRMs do not appear to express the typical molecular signatures of

endometrial malignant progression [40].

Another potential complication of these agents 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

[34].

Mifepristone — The antiprogestin mifepristone (RU-486) is the most widely studied PRM and reduces

uterine volume by 26 to 74 percent in women with leiomyomas, comparable to the reduction observed

with GnRH agonists [34]. Regrowth occurs slowly following cessation of the drug [41]. 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 [34-

38,41,42]. There is accumulating evidence that mifepristone provides symptomatic relief and improved

quality of life [35,41]. 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 [43,44].

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 [45]. Other PRMs are still investigational agents.

Ulipristal acetate — Ulipristal acetate is a PRM that inhibits ovulation, but has little impact on serum

estradiol levels. Ulipristal acetate (oral, 5 mg or 10 mg once daily for 13 weeks) was compared with

placebo in one randomized trial of 242 women with menorrhagia, fibroid-associated anemia, and a uterus

that was ≤16 weeks of gestation size [46]. Ulipristal acetate resulted in a significantly higher rate of

resolution of menorrhagia (5 mg: 91 percent; 10 mg: 92 percent; placebo: 19 percent) and a significant,

but only slightly higher increase in hemoglobin (5 mg: 4.3 g/dl; 10 mg: 4.2 g/dl; placebo:

3.1 g/dl). Significant reductions in fibroid volume occurred in women treated with ulipristal acetate (5 mg: -

21 percent volume; 10 mg: -12 percent; placebo: +3 percent). There were no findings of endometrial

hyperplasia or cancer. Approximately half of patients in each group chose to undergo surgical treatment

of fibroids at the completion of the study.

Another randomized trial by the same group included 307 women with menorrhagia and a uterus that was

≤16 weeks of gestation size [47]. Participants were assigned to 13 weeks of therapy with

either ulipristal acetate (oral, 5 mg or 10 mg per day) or the GnRH-agonist leuprolide acetate

(intramuscular, 3.75 mg monthly). All groups had comparable rates of resolution of menorrhagia.

Resolution of menorrhagia was achieved more quickly in the ulipristal groups (approximately six days

compared with 30 days for leuprolide). Women treated with ulipristal had a significantly lower frequency of

moderate to severe hot flashes (in the ulipristal acetate groups, 5 mg: 11 percent; 10 mg: 10 percent

versus leuprolide: 40 percent) [47]. The reduction in uterine size was significantly lower for the ulipristal

groups (5 mg: 20 percent; 10 mg: 22 percent; leuprolide: 47 percent).

Like mifepristone, the available dose is an impediment to off-label treatment with ulipristal acetate.

Ulipristal acetate is sold in the United States as a single 30 mg dose, as opposed to 5 to 10 mg per day

evaluated for fibroid treatment [46,47]. Additionally, while supplementary data for the aforementioned

studies suggest that there is reversal of the PRM-associated endometrial changes with a drug free-

interval, and endometrial safety with long-term therapy is still uncertain [46-48].

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 [49]. 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 [50]. 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 [51]

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 [52].

Larger controlled trials over extended treatment intervals should be performed to better ascertain the

effect of raloxifene on leiomyomas in premenopausal women [53].

Aromatase inhibitors — Small series and one randomized clinical trial have described shrinkage of

symptomatic leiomyomas and a decrease in leiomyoma symptoms in women in the menopausal transition

given aromatase inhibitors [54-57]. 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

[58]. Women with fibroids made up approximately 35 percent of the women enrolled in the pivotal trial

leading to approval of this agent [59]. (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 [60,61], but because they decrease painful menses, they can be useful in this

population.

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 [62]. 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 [62]. Gestrinone is not available

in the United States.

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 [63,64]. (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 [65]. 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 [66].

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 "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 [67]. 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 [68]. 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. However, there is a

small number of reports of pregnancy following robotic-assisted myomectomy [69,70]. 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 "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 [71].

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 [72].

Myolysis — Myolysis refers to laparoscopic thermal coagulation or cryoablation (cryomyolysis) of

leiomyoma tissue [73-75]. 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 [76]. It is used infrequently in current practice, however, a new

device utilizing radiofrequency ablation has recently been published [77]. (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

[78-83]. 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'.)

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 [84]. UFE is discussed in detail separately. (See "Uterine leiomyoma (fibroid)

embolization".)

Systematic review of randomized trials concluded that women undergoing UAE have a shortened hospital

stay, less pain than following surgery and a quicker return to work than those undergoing hysterectomy or

myomectomy [84,85]. However, they have more complications, unscheduled visits, and readmissions.

Data also suggest that women with larger uteriand/or more leiomyomas at baseline are at greater risk of

failure [86,87]. Like the situation with endometrial ablation, there appears to be a relatively high rate of

reintervention for treatment failure [88]. 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 [89-92]. The maximum size of a leiomyoma

for this procedure is uncertain [92-94]. 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, labeling for the device now allows treatment in women

considering future pregnancy following counseling.

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 [92]. 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 [95]. 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 [96].

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 to 36 months

follow-up, with more complete ablation leading to better outcomes [97-101]. Adverse event rates appear

to be decreased with increased experience, despite more extensive treatment [98]. 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 [102,103] and a recent evidence

based review from the United Kingdom’s National Institute for Health and Care Excellence (NICE)

suggests the data support clinical use of this modality [104].

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 [105-109]. The case

series is drawn from all sites performing MRgFUS and describes 54 pregnancies in 51 women [109].

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 [109].

THERAPEUTIC GUIDELINES — There are few guidelines that synthesize all fibroid treatments in a

framework to guide clinicians. In the United Kingdom, both the NICE guidelines and guidelines of the

Royal College of Obstetricians and Gynaecologists (RCOG) exist for the use of specific procedures, but

not for an overview of comparative therapies [104,110]. The Society of Obstetricians and Gynaecologists

of Canada (SOGC) does have treatment guidelines, but they were last updated in 2004 [3], and

governmental guidelines do not address this topic [111]. The American College of Obstetricians and

Gynecologists (ACOG) has guidelines for surgical alternatives to hysterectomy [4] and use of hormonal

contraceptives for noncontraceptive use [112]. The most recent and comprehensive guidelines come from

France and integrate both medical and surgical options [113].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The

Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at

the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have

about a given condition. These articles are best for patients who want a general overview and who prefer

short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated,

and more detailed. These articles are written at the 10th to 12th grade reading level and are best for

patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail

these topics to your patients. (You can also locate patient education articles on a variety of subjects by

searching on “patient info” and the keyword(s) of interest.)

Basics topics (see "Patient information: Uterine fibroids (The Basics)" and "Patient information:

Uterine artery embolization (The Basics)")

Beyond the Basics topic (see "Patient information: Uterine fibroids (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

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

Women who desire fertility

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. While robotic assistance may alleviate

these problems, there are currently little data to support this contention.

Women who do not desire fertility

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 wishing to

optimize future pregnancy (Grade 2C).

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REFERENCES