Overview of treatment of uterine leiomyomas

Author
Elizabeth A Stewart, MD Section Editor
Robert L Barbieri, MD Deputy Editor
Sandy J Falk, MD

Last literature review version 17.1: January 2009 | This topic last updated:
November 25, 2008 (More)

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").

EXPECTANT MANAGEMENT There is 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 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. This is
especially true in patients in whom concomitant issues, such as oligoovulation,
may be contributing to abnormal uterine bleeding or infertility. However,
caution should be exercised when raising the level of steroid hormones from
the physiologic baseline, as there is indirect evidence from postmenopausal

women taking hormone replacement therapy that leiomyomas 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] .

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 oral 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.

Oral contraceptive pills (OCP) Many texts continue to suggest that oral
contraceptive pills are contraindicated in women with uterine leiomyomas.
However, clinical experience suggests some women with heavy menstrual
bleeding associated with leiomyomas respond to OCP therapy. This, plus data
that OCPs decrease the risk of forming new leiomyomas and reduce 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 bulkrelated symptoms on OCPs. Since most pill 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 other methods of

contraceptive steroid delivery (eg, ring, patch). However, with vaginal

administration (Nuva Ring), 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 a systematic review have shown a reduction in uterine volume and
bleeding, and an increase in hematocrit after placement of this IUS [8,16-18] .
The device is widely used for control of heavy menstrual bleeding and is
endorsed for this indication by many experts. The presence of intracavitary
leiomyomas amenable to hysteroscopic resection is a 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 OCPs, 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 a large cohort study that these agents may
decrease the risk of leiomyoma formation in black women [19] .

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 see "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

[13,14,20] .

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
[21] . 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 [22] . 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 [23] . (See "Myomectomy", section on Use of GnRH agonists).

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) [24] .

Rarely, GnRH-agonists are used to provide short-term relief to women close to

menopause or with acute medical contraindications to surgery [25] . 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. Options include Lupron Depo (3.75 mg/month intramuscularly for
up to three months) and Lupron Depot-3 (11.25 mg as a single intramuscular
injection that is effective for three months).

Gonadotropin-releasing hormone antagonists Similar clinical results have

been achieved with GnRH antagonists, which compete with endogenous GnRH
for pituitary binding sites [26-29] . 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 frequent injections (the doses used for leiomyomas are
quite different from those employed in fertility protocols).

Mifepristone The antiprogestin mifepristone (RU-486) reduces uterine

volume by 26 to 74 percent in women with leiomyomas, comparable to the
reduction observed with GnRH agonists [30-34] . While high dose regimens
give comparable rates of amenorrhea to GnRH agonists, lower doses achieve
an amenorrhea rate of 40 to 70 percent and, in other women, produce a
reduction in menstrual flow while maintaining cyclicity. There is accumulating
evidence that mifepristone provides symptomatic relief and improved quality of
life [31,33] .

However, as with GnRH antagonists, the doses of mifepristone currently

marketed in the United States make off-label clinical treatment of leiomyomas
difficult (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 [35] . With high dose regimens, adverse effects,
such as endometrial hyperplasia and transient elevations in serum
aminotransferases, have been reported; this appears to be a rare occurrence
with low dose regimens [30] . Regrowth occurs slowly following cessation of the
drug [33] .

Selective progesterone receptor modulators have shown promising results for

treatment of leiomyomas in pilot studies [36-38] . Use of these agents led to a
reduction in duration and intensity of bleeding and a decrease in leiomyoma
volume without deprivation of estrogen. (See "Therapeutic use and adverse
effects of progesterone receptor antagonists and selective progesterone
receptor modulators", section on Uterine myoma).

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 [39] . 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 [39] .

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 [40] . 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 [41] .
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 [42] 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 [43] .

Larger controlled trials over extended treatment intervals should be performed

to better ascertain the effect of raloxifene on leiomyomas in premenopausal
women [44] .

Aromatase inhibitors Case reports and small series have described shrinkage
of symptomatic leiomyomas in perimenopausal women given aromatase
inhibitors [45,46] . 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. These drugs are not available in the United States, but

are widely used for the control of heavy menstrual flow elsewhere and have
shown efficacy in treatment of heavy menstrual bleeding [47] . (See
"Menorrhagia").

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 [48,49] ,
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 [50,51] . (See "Pathogenesis of
uterine leiomyomas").

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 [52] . 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
[53] .

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 resonanceguided focused-ultrasound surgery (MRgFUS) and myolysis are alternative
procedures. (See "Myomectomy" and see "Endometrial ablation").

The following are indications for surgical therapy: Treatment of abnormal

uterine bleeding, pain, or pressure symptoms (See "Epidemiology, clinical
manifestations, diagnosis, and natural history of uterine leiomyomas", sections

on Increased uterine bleeding and Pelvic pressure and pain) Treatment of

infertility or recurrent pregnancy loss (See "Reproductive issues in women with
uterine leiomyomas") Evaluation when there is suspicion of malignancy Both
benign leiomyoma and malignant sarcomas can present as a uterine mass, and
current diagnostic strategies are not able to definitely distinguish between the
two. Most women with a uterine mass, even those with a rapidly enlarging
uterus or mass, do NOT have a sarcoma [54] , and a rapidly enlarging mass
alone in a premenospausal woman is not an indication for surgery [55] . It is
important to confirm that a pelvic mass is uterine, and not adnexal, before
deferring surgery.

Surgery should be considered in postmenopausal women with a new or

enlarging pelvic mass, abnormal bleeding, and pelvic pain, where the incidence
of sarcoma is higher (1 to 2 percent) [56] . Other risk factors for sarcoma
formation include prior pelvic irradiation, tamoxifen use or the presence of
cutaneous leiomyomas indicating possible HLRCC syndrome (Hereditary
Leiomyomatosis and Renal Cell Carcinoma) [57-59] .

While not definitive, imaging with magnetic resonance can, in some cases,
provide additional evidence for or against malignancy [60] . In one series, an
endometrial biopsy was useful in diagnosis in approximately one third of
sarcomas [61] . Failure to respond to conservative therapy, such as GnRHagonist therapy and uterine artery embolization, also raises the suspicion for
malignancy. (See "Uterine sarcoma: Classification, clinical manifestations, and
diagnosis").

The American College of Obstetricians has concluded that there is insufficient

evidence to support hysterectomy for asymptomatic leiomyomas solely to
improve detection of adnexal masses, to prevent impairment of renal function,
or to rule out malignancy [4] .

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 dysplasia, 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 [62] . 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 [63] . 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 perimenopausal; 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. The classic approach has
been through a laparotomy incision, but laparoscopic procedures are becoming
more common. Myomectomy complications appear to increase as the number
of leiomyomas removed increases, but the exact relationship is unclear [62] .

Although myomectomy is an effective therapy for menorrhagia and pelvic

pressure, the disadvantage of this procedure is the significant risk that more
leiomyomas will develop from new clones of abnormal myocytes. Five years
after myomectomy, 50 to 60 percent of patients will have new myomas
detected by ultrasound [64,65] , and 10 to 25 percent will require a second
major surgery after the first myomectomy [65-69] . This risk probably
underestimates the true prevalence of myomata as assessed by systematic
ultrasound investigation. If minimally invasive procedures are included, then
approximately one-third of women undergoing abdominal myomectomy will

have a second surgical procedure [70] . Risk factors for subsequent uterine
surgery include uterine size less than 12 menstrual weeks at the time of initial
surgery and weight gain in excess of 14 kg after age 18; the latter association
may reflect greater estrogen exposure. In one study, the incidence of a second
surgical procedure in women with either of these risk factors was 40 to 50
percent versus 17 to 20 percent in women with uterine size greater than 12
weeks or weight gain less than 4.5 kg [70] . Thus, performing myomectomy
while the uterus is relatively small may result in a higher overall rate of surgery.
However, others have reported different findings whereby the risk of recurrence
was highest in women who preoperatively had larger uterine sizes and multiple
leiomyomas [65] .

The risk of recurrence appears to be lower when only one leiomyoma is present
and removed and in women who give birth after a myomectomy, but data are
limited [66,71] .

Route Abdominal myomectomy A transabdominal myomectomy is the

treatment of choice when there are multiple myomas, the uterus is significantly
enlarged (myomas greater than 5 to 8 cm or volume greater than 16 weeks'
size), or the myomas are deep and intramural [3] . The operative time, blood
loss, and hospital stay are comparable to that with abdominal hysterectomy
[72,73] . The risk of unplanned hysterectomy at the time of myomectomy is
less than 1 percent for experienced surgeons [4] . (See "Myomectomy", section
on Abdominal myomectomy).

After abdominal myomectomy, the risk of uterine rupture prior to labor is very
low (about 0.002 percent) compared to after classical cesarean delivery (about
3.7 percent [74] ), although these data are based upon small series without
complete pregnancy follow-up [75,76] . The common clinical practice of
counseling women who have had a myomectomy with a transmural uterine
incision to undergo an elective cesarean delivery clearly biases and underreports the risk of rupture at term. (See "Myomectomy").

Women who undergo myomectomy with significant uterine disruption should

wait several months before attempting to conceive; recommendations for delay
range from three to six months. Also, if a woman is having difficulty conceiving
following a myomectomy, early assessment of the uterine cavity and fallopian
tubes with a hysterosalpingogram is advisable [63] . Myomectomy, particularly

near the oviduct, can cause adhesions that may impair fertility. Laparoscopic
myomectomy Laparoscopic myomectomy is an option in women with a
uterus less than 17 weeks' size or with a small number of subserosal or
intramural leiomyomas. The uterus must be small enough to allow visualization
of the procedure through an endoscope. Factors reported to lead to an
increased risk of conversion to an open procedure include size 5.0 cm,
intramural or anterior location, and preoperative use of a GnRH-agonist [77] .

Whether reapproximation of the myometrium via laparoscopic suturing gives

the uterine wall the same strength as multilayer closure at laparotomy is an
area of controversy [76,78,79] . Ten cases of uterine rupture in women who
underwent laparoscopic myomectomy have been reported, one was at 17
weeks of gestation and the remainder were at 27 to 35.5 weeks [80] . On the
other hand, one of the largest series of pregnancies after laparoscopic
myomectomy reported no uterine ruptures in 106 deliveries; 27 of the
deliveries were vaginal. Only 10 uterine cavities in this series had been entered
at myomectomy [80] .

Until further data are available, we suggest avoiding laparoscopic myomectomy

in women whose primary goal is to achieve a pregnancy, especially when there
is a deeply intramural leiomyoma. The experience of the surgeon with
laparoscopic suturing and the availability of a robotic approach may also factor
into this decision given that laparoscopic suturing is a highly complex skill. (See
"Myomectomy", section on Laparoscopic myomectomy). Hysteroscopic
myomectomy Hysteroscopic myomectomy is the procedure of choice for
type 0 (entirely within the endometrial cavity) and I (at least 50 percent
intracavitary) submucous myomas [3,81] . (See "Overview of hysteroscopy").

Although this technique requires highly skilled practitioners, it has several

advantages compared to abdominal procedures:

(1) It is performed as same day surgery

(2) Local anesthetic and sedation can be used
(3) The recuperation period is very short

(4) Good relief of symptoms is obtained. In one large series, fewer than 16
percent of women treated for menorrhagia underwent a second surgery in the
nine-year follow-up period [82] .
(5) Fertility rates are excellent and there have been no case reports of
uterine rupture after hysteroscopic myomectomy [83] .

Type II (less than 50 percent of their mass in the endometrial cavity)

submucous myomas may sometimes be approached hysteroscopically in the
hands of expert surgeons, but often require multiple procedures [81] .

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 "Endometrial ablation").

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 [82] .

Myolysis Myolysis refers to laparoscopic thermal coagulation or cryoablation

(cryomyolysis) of leiomyoma tissue [84-86] . 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 [87] . (See "Myomectomy", section on
Myolysis).

Candidates for myolysis are women with fewer than four leiomyomas with the
largest leiomyoma less than 10 cm in diameter [3] . Fertility and pregnancy
outcome after myolysis are not known; cases of both successful pregnancy and
uterine rupture have been reported [3,88] . Therefore, this procedure should be
reserved for women who have completed childbearing.

Myolysis combined with endometrial ablation is a more effective therapy than

either procedure alone. In women with menorrhagia, a descriptive study that
compared ablation alone versus with the combined procedure found that the
risks of a second surgery were 38 and 13 percent, respectively [89] .

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 [90-94] . The advantages
of this approach over UAE are that it avoids introduction of foreign bodies (eg,
polyvinyl alcohol particles, coils, Gelfoam), and it may be associated with less
postoperative pain. With laparoscopic approaches, assessment of the pelvis for
other pathology is an advantage, the disadvantage is that it requires a surgical
approach and general anesthesia. With 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 are not surgical candidates or
who wish to preserve their uterus, but the risks associated with subsequent
pregnancy are unclear. There are a number of reports of successful
pregnancies following UAE, but there have been reports of disorders of
placentation and ovarian damage in case series of young women. However, for
women in late perimenopause who view cessation of menses as an advantage,
this effect on ovarian reserve may be a benefit rather than a side effect.

A systematic review concluded that women undergoing UAE have a shortened

hospital stay and a quicker return to work than those undergoing hysterectomy
or myomectomy [95] . 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 [96,97] . Like the
situation with endometrial ablation, there appears to be a relatively high rate of
reintervention for treatment failure [98] . Research is needed to see if better
patient selection can minimize this risk. (See "Uterine fibroid embolization").

Magnetic resonance guided focused ultrasound Magnetic resonance guided

focused ultrasound surgery (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
[99-102] . This system is not indicated for leiomyomas which are resectable
with a hysteroscope, heavily calcified, in women contemplating future
pregnancy or when intervening bowel of bladder could be damaged by
treatment.

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 [103-105] . Studies are needed to determine long-term outcome and
optimal candidates for this procedure; comparative studies are also needed.
Data on pregnancy outcome are limited to case reports [106] . Adverse event
rates appear to be decreased with increased experience, despite more
extensive treatment [104] . The procedure is time consuming and costly, but
short-term morbidity is low and recovery is rapid.

INFORMATION FOR PATIENTS Educational materials on this topic are available

for patients. (See "Patient information: 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 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 [107] . 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), age of the patient
(premenopausal, perimenopausal, postmenopausal), 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 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 see "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 see "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
see "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).

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Epidemiology, clinical manifestations, diagnosis, and natural history of

uterine leiomyomas

Author
Elizabeth A Stewart, MD Section Editor
Robert L Barbieri, MD Deputy Editor
Sandy J Falk, MD

Last literature review version 17.1: January 2009 | This topic last updated:
December 10, 2008 (More)

INTRODUCTION Uterine leiomyomas (ie, fibroids or myomas) are benign

monoclonal tumors arising from the smooth muscle cells of the myometrium.
They contain a large amount of extracellular matrix (collagen, proteoglycan,
fibronectin) and are surrounded by a thin pseudocapsule of areolar tissue and
compressed muscle fibers.

Fibroids are often described according to their location in the uterus, although
many fibroids can have more than one location designation (show figure 1 and
show picture 1A-B): Intramural fibroids 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 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 [1] . 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. Types 0 and I are
hysteroscopically resectable, although significant hysteroscopic expertise may
be needed to resect type I masses. Subserosal myomas originate from the

serosal surface of the uterus. They can have a broad or pedunculated base
(show ultrasound 1) and may be intraligamentary (ie, extending between the
folds of the broad ligament). Cervical fibroids are located on the cervix, rather
than the uterine corpus.

The diagnosis and natural history of uterine leiomyomas will be reviewed here.
Treatment of uterine leiomyomas is discussed separately. (See "Overview of
treatment of uterine leiomyomas").

PREVALENCE, EPIDEMIOLOGY, AND RISK FACTORS 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 "Pathogenesis of uterine leiomyomas"
section on Steroid hormones).

Leiomyomas have not been described in prepubertal girls, but they are
occasionally noted in adolescents. Most Caucasian women with symptomatic
fibroids are in their 30s or 40s, however African American women develop
disease on average four to six years younger and may present with disease in
their 20s [2,3] . Myomas are clinically apparent in approximately 25 percent of
reproductive aged women and noted on pathological examination in
approximately 80 percent of surgically excised uteri [4,5] . 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.

The relative risk and incidence of fibroids is two- to three-fold greater in black
women than white women [6] . 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 perimenopausal black women and 35 percent of
perimenopausal white women [7] . The 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 Caucasians [7] . In a study of black women, those
with self-reported polycystic ovary syndrome were at increased risk of
developing fibroids [8] . Compared with white women, black women experience
more severe disease based on their symptoms in a proposed severity

algorithm. Also, among women undergoing hysterectomy, black women appear

to have surgery at a younger age, have larger uteri, and more severe anemia
[2,3] .

Other factors that may affect the risk of developing a leiomyoma include: Parity
(having one or more pregnancies extending beyond 20 weeks) decreases the
chance of fibroid formation [9-11] . In some cohorts, age and early age at first
birth decreases risk and a longer interval since last birth increases risk [12] .
Early menarche (<10 years old) is associated with an increased risk and may
largely account for the early onset of disease in Black women [2,12] .
Generally, oral contraceptive pills (OCPs) protect against clinically evident
fibroids [9,13] . However, in data provided by the Nurses' Health Study, OCP
use increased risk of leiomyomas in women with early exposure to OCPs
between the ages of 13 and 16 [11] . Smoking decreases the risk of having
fibroids through an unknown mechanism. Smoking does not appear to affect
estrogen metabolism [9,14] . Significant consumption of beef, ham, or other
red meats is associated with an increased relative risk of fibroids and
consumption of green vegetables with a decreased risk [15] . However, no
study has demonstrated that dietary intervention (eg, carotenoids) leads to
changes in fibroid incidence or symptomatology [16] . There is also a familial
predisposition to developing fibroids [17] . (See "Pathogenesis of uterine
leiomyomas", section on Genetics). Consumption of alcohol, especially beer,
appears to increase the risk of developing fibroids [18] . Caffeine consumption
is not a risk factor. Progestin only injectable contraceptives are associated with
a decreased risk of leiomyomas in black women [12] . Some studies show a
relationship between fibroids and obesity; however, a relationship with
increased BMI, weight gain, or body fat has not been demonstrated
consistently. 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
[13,19-23] . Hypertension and leiomyomas are positively associated with an
increased leiomyoma risk. The risk is related to increased duration or severity
of the hypertension [24] . 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 [24,25] . In
African-American women, recent studies have suggested that both polycystic
ovarian syndrome and experience of racism are positively correlated with risk
of uterine fibroid [8,26] .

CLINICAL MANIFESTATIONS 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.

Symptoms attributable to uterine myomas can generally be classified into

three distinct categories: Increased uterine bleeding Pelvic pressure and pain,
termed bulk-related symptoms Reproductive dysfunction

Although the majority of myomas are small and asymptomatic, many women
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. As an example, a 20-week size myomatous uterus is not
unusual, and is often associated with heavy menses, increasing girth, and a
sense of fullness similar to pregnancy.

Relief of symptoms related to fibroids usually occurs at the time of menopause,

when menstrual cyclicity stops, steroid hormone levels wane, and fibroids
diminish in size.

Increased uterine bleeding Abnormal uterine bleeding is the most common

symptom. Heavy and/or prolonged menses (previously termed menorrhagia or
hypermenorrhea) is the typical bleeding pattern with myomas [27] .
Intermenstrual bleeding is NOT characteristic of myomas and should be
investigated to exclude endometrial pathology. (See "Terminology and
evaluation of abnormal uterine bleeding in premenopausal women"). 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 is determined, in large part, by

the location of the fibroid; size is of secondary importance. Significant
submucosal myomas (eg, types 0 and I) are most frequently related to
significant menorrhagia, but may be less important in uteri with multiple
myomas [1,4,28] . However, these myomas are amenable to minimally invasive
therapy using the hysteroscope. 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 [29] .

Pelvic pressure and pain The myomatous uterus is irregularly shaped, in

contrast to the pregnant uterus, and can cause specific symptoms due to
pressure from myomas in 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.
Other symptoms include constipation from myomas pushing on the rectum and
dyspareunia from cervical myomas proximate to the vagina. Silent, ureteric
compression leading to renal hydronephrosis is rare.

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 [30,31] .
(See "Pathogenesis; clinical features; and diagnosis of endometriosis").

Dysmenorrhea can also be caused by fibroids. This pain, at least in some cases,
is related to heavy menstrual flow.

Effects on reproduction Leiomyomas do not interfere with ovulation, but

have been associated with subfertility and adverse pregnancy outcomes in
some [32-34] but not all [35,36] reviews. Leiomyoma size, location, and
number all appear to have a role in outcome, but it is difficult to quantitate the
impact of these factors in combination or individually because of variability
among patients [37] . Age may also be a significant confounder since the risk
of leiomyomas increases with age, as do many complications of pregnancy.

Pregnancy Observational studies have suggested that the presence of

fibroids increases the risk of specific pregnancy complications, including first
trimester bleeding, placental abruption, breech presentation, dysfunctional
labor and an increased risk of cesarean delivery [33,38] . These risks appeared
to be related to the size of the leiomyomas and the position of the placenta,
with the highest risk seen when the placenta implanted over the myoma. The
degree to which the association between these complications and presence of

fibroids reflects causation, rather than confounding by factors such as race and
age or detection bias, is not known. (See "Management of pregnant women
with leiomyomas")

Myomectomy is not indicated to prevent pregnancy complications, except in

women with a history of obstetrical complications that appear related to the
presence of leiomyomas [39] .

Fertility Leiomyomas are estimated to account for 1 to 2 percent of infertility

[4] . The mechanism by which fibroids affect fertility, particularly those that
impinge upon the endometrium, is likely through attenuated implantation and
placental growth over the myoma site, rapid fibroid growth in early pregnancy,
and/or increased uterine contractility [40-42] .

The location of a fibroid, and not its size, is the key factor regarding fertility
[41] . 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 [40,41] . In contrast, subserosal fibroids do
not impact fertility. The role of intramural fibroids in infertility is controversial
[40,41,43] . (See "Reproductive issues in women with uterine leiomyomas",
section on Infertility and miscarriage).

Other Less common symptoms of fibroid tumors include: Transcervical

prolapse into the vagina resulting in ulceration or infection Polycythemia from
autonomous production of erythropoietin [44] (see "Diagnostic approach to the
patient with polycythemia") Hypercalcemia from autonomous production of
PTHrP [45] Hyperprolactinemia [46]

DIAGNOSIS The diagnosis of uterine myomas is usually based upon the

finding of an enlarged, mobile uterus with an irregular contour on bimanual
examination or an incidental finding on ultrasound examination. Imaging
techniques are useful when it is necessary to confirm the diagnosis (eg, assess
the adnexa if these cannot be palpated separate from the suspected myoma)
or to improve localization of the myoma prior to surgery; routine radiologic
assessment is NOT required and does not improve outcome [47] . The various
imaging modalities have the following advantages and disadvantages [48] .
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 [49] . This is the most widely used
modality due to its availability and cost effectiveness. Hysterosalpingography 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. Its
major use is in women undergoing fertility evaluation since it also provides
information on tubal patency. 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. These characteristics
may be useful in 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 [50,51] . Saline infusion sonography 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 (show radiograph 1).

DIFFERENTIAL DIAGNOSIS The differential diagnosis depends upon the

clinical presentation and includes pathologies associated with abnormal uterine
bleeding (see "Terminology and evaluation of abnormal uterine bleeding in
premenopausal women" and see "The evaluation and management of uterine
bleeding in postmenopausal women"), pelvic mass (see "Overview of the
evaluation and management of adnexal masses" and see "Differential
diagnosis of the adnexal mass"), pelvic pain (see "Clinical features and
diagnosis of pelvic inflammatory disease"), and infertility (see "Evaluation of
the infertile couple").

There are several rare syndromes characterized by leiomyomas or leiomyomas

like-lesions that require differentiation from sporadic uterine leiomyomas.
Descriptive features currently distinguish most of these diseases. Different
disease classifications may evolve as information about pathophysiology is
gained.

Hereditary leiomyomatosis and renal cell carcinoma syndrome Mutations in a

specific gene, fumarate hydratase (FH), encoding one of the Krebs cycle
enzymes, underlies the rare, but serious syndrome of hereditary
leiomyomatosis and renal cell carcinoma (HLRCC) [52-54] . This is an
autosomal dominant disease characterized by cutaneous leiomyomas, uterine
leiomyomas and papillary renal cell carcinoma (RCC). The cutaneous lesions

are the key to identifying this rare variant [52] . The papillary RCC is an
aggressive phenotype that is usually metastatic at the time of diagnosis and
affects women more than men [52] . Additionally, women with HLRCC appear
to be more likely to develop uterine sarcomas and to atypically develop them
during their premenopausal years [54] . We suggest that women with
leiomyomas be asked whether they have a personal or family history of
cutaneous myomas or papillary renal cell cancer. Such women and their
families should be evaluated further, as they may be at risk of developing renal
cell cancer [52] . (See "Epidemiology; pathology; and pathogenesis of renal cell
carcinoma").

FH mutations also have been identified to lead to multiple cutaneous and

uterine leiomyomas syndrome (MCUL1 or Reed's syndrome) and the genotype
does not predict phenotype [55] . Thus, these syndromes appear synonymous
with HLRCC and we recommend the designation HLRCC be used to highlight the
predisposition to malignant disease. FH mutations appear to act via loss of
tumor suppressor mechanisms for HLRCC syndrome and may also be involved
in some cases of nonsyndromic uterine leiomyoma [55,56] .

Leiomyomatosis peritonealis disseminate Leiomyomatosis peritonealis

disseminate (LPD) or disseminated peritoneal leiomyomatosis (DPL) is a rare
clinical entity in which multiple nodules stud the pelvic and peritoneal surfaces,
often simulating disseminated carcinoma [57] . The disorder is generally benign
and is primarily found in reproductive age women, but has been described in
postmenopausal women. Many cases appear to be stimulated by either
pregnancy or oral contraceptive use. There have been cases of LPD where
recurrence following oophorectomy was stimulated by hormone replacement
therapy. However, there appears to be a waxing and waning of this disease and
many hormonal therapies have been reported to work for short periods of time.
Cytogenetics suggests this may also be a clonal process with some
commonalities to leiomyoma pathogenesis, and there is a report of familial
clustering of LPD [58,59] .

Benign metastasizing leiomyomas In the variant of benign metastasizing

leiomyomas (BML), leiomyoma-like lesions are present in the uterus and in a
distant location, most commonly the lung. There is some evidence that
oophorectomy is curative. Molecular studies suggest this is a clonal process
[60] .

Lymphangioleiomyomatosis Lymphangioleiomyomatosis (LAM) is a disease

where the primary lesion is a renal angiomyolipoma and not a uterine
leiomyoma, but it is important to this differential diagnosis for two reasons.
First, LAM must be distinguished from BLM. Both diseases present with similar
lung lesions, but in LAM there is destruction of the interstitial spaces, which can
be fatal. Second, LAM appears to share pathogenic mechanisms with
leiomyomas. Both diseases have dysregulation of the transcription factor
HMGA2 and the animal model for leiomyomas is the Eker rat model, which has
a tuberous sclerosis gene mutation, the mutated gene is LAM [61,62] . Studies
suggest that the mTOR pathway activation in this disease may produce a
therapeutic target amenable to medical therapy [63] .

Intravenous leiomyomatosis The fibroid variant of intravenous

leiomyomatosis (IVL) is characterized by leiomyoma-like lesions that extend
from the uterus into the pelvic blood vessel, and sometimes as far as the heart.
The diagnosis should be considered in women with leiomyomas and significant
dyspnea, an intracardiac mass, or evidence of right heart failure. Some
hormonal treatments have been reported to improve symptoms; however,
disease has been reported in postmenopausal women. This disorder can be
diagnosed by cytogenetic study of the involved tissue [64] . This variant is also
associated with karyotypic changes similar to those found in myomas [64,65] .
There is one case report of treatment of IVL with an aromatase inhibitor [66] .

Bannayan-Zonana syndrome In the Bannayan-Zonana syndrome (also known

as the Bannayan-Riley-Ruvalcaba syndrome), uterine leiomyomas occur with
other benign mesenchymal tumors (eg, lipomas, hemangiomas) due to a
germline mutation of the PTEN tumor suppressor gene [67,68] . No associated
malignancies have been identified.

Cellular leiomyomas Although cellular leiomyomas have typically been

considered a benign histological variant, some evidence suggests that this
phenotype, distinguished by the loss of chromosome 1p, has a gene profile
more similar to leiomyosarcomas than leiomyomas or normal myometrium [69]
. Additionally, in a small clinical series cellular leiomyomas appeared to be
associated with more aggressive clinical behavior which may warrant more
clinical attention [70] .

Leiomyomas of uncertain malignant potential Sarcomas are distinguished

from leiomyomas by three pathologic characteristics: the mitotic index, cellular
atypia, and the extent and pattern of necrosis. Lesions in the category of
leiomyomas of uncertain malignant potential (UMP) have some characteristic of
sarcomas, but do not meet full diagnostic criteria. Gene profiling will likely
inform this subgroup in the future. (See "Uterine sarcoma: Classification;
clinical manifestations; and diagnosis").

Leiomyosarcoma Rapidly enlarging uterine neoplasms are often attributed to

leiomyosarcomas, although most women with this finding do NOT have a
sarcoma. This was illustrated in a study of 1332 women admitted to either of
two community hospitals for hysterectomy or myomectomy for presumed
uterine leiomyomas: the incidence of uterine sarcomas was extremely low
(0.23 percent) [71] . Among the 341 women with a rapidly growing uterus by
clinical or ultrasound examination, only one (0.27 percent) had a uterine
sarcoma. Based upon these data, an increased risk of sarcoma among women
with "rapidly growing" leiomyomas could not be substantiated. However, the
diagnosis of a uterine sarcoma should be considered in postmenopausal
women with a pelvic mass, abnormal bleeding, and pelvic pain in whom the
incidence of sarcoma is higher (1 to 2 percent) [72] . Black women and women
with a history of tamoxifen use or pelvic radiation are also at increased risk of
sarcoma formation [73,74] . There is some evidence that both endometrial
biopsy and magnetic resonance imaging may be useful in the diagnosis of
leiomyosarcomas [75,76] .

NATURAL HISTORY

General Information on the natural history of uterine leiomyomas is limited.

The only prospective study on the course of these tumors performed two saline
infusion sonograms 2.5 years apart on 64 initially asymptomatic women (mean
age 44 years) [77] . The point prevalence of fibroids at the first and second
examination was 16 (11/64) and 27 (17/64) percent, respectively. Forty percent
of fibroids spontaneously regressed between examinations, but seven women
developed eight new tumors. Fibroids that regressed were smaller (1.1 versus
2.2 cm for persistent tumors); the growth of persistent tumors averaged 1.2 cm
over 2.5 years (range 0.9 to 6.8 cm or 0.36 to 2.72 cm/year). Hormone use did
not appear to be a factor, although the study sample was small.

In women taking hormonal therapy

Hormonal contraception Use of low dose OCPs does not cause fibroids to
grow, therefore administration of these drugs is not contraindicated in women
with fibroids [9,12,13,78,79] . One possible exception was reported in data
provided by the Nurses' Health Study, which suggested OCP use increased the
risk of leiomyomas in women with early exposure to OCPs between the ages of
13 and 16 [11] . The benefits of this contraceptive approach versus a possible
risk of future fibroids should be considered. (See "Issues concerning the use of
hormonal contraception by adolescents"). Depot-medroxyprogesterone acetate
protects against development of leiomyomas [12,79] .

Hormone replacement therapy Use of hormone replacement therapy in the

postreproductive years 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 [80] ) and type of
estrogen preparation (higher with transdermal estrogen in some studies
[81,82] , but not others [83] ).

A systematic review including five randomized controlled trials found that

hormone replacement therapy was associated with some myoma growth, but
this typically occurred without clinical symptoms [84] . These findings were
confirmed in a subsequent prospective study [85] . Thus, the presence of
leiomyomas is not a contraindication to use of hormone replacement therapy
and hormone replacement 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: 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.

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

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