OBSTETRICS & GYNECOLOGY New and Emerging Treatments

for Uterine Leiomyomas

Alison F. Jacoby, MD

A BSTRACT
PURPOSE: To review new treatment options for women with uterine leiomyomas.
EPIDEMIOLOGY: Leiomyomas, popularly referred to as fibroids, are the most common
pelvic tumors, affecting 20% to 40% of premenopausal women. More than 200 000 sur-
gical procedures are performed each year in the United States to relieve associated symp-
toms such as heavy menstrual bleeding, pelvic discomfort, and bladder dysfunction.
REVIEW SUMMARY: New treatments for symptomatic leiomyomas, including uterine artery
embolization, magnetic resonance-guided focused ultrasound, and laparoscopic myoly-
sis, offer alternatives to hysterectomy and myomectomy. Promising research is under way
to develop novel pharmacologic and gene therapies.
TYPE OF AVAILABLE EVIDENCE: Randomized controlled trials, systematic reviews, cohort

U
studies, clinical case series.
GRADE OF AVAILABLE EVIDENCE: Fair.
CONCLUSION: The future holds hope for new therapies and new choices for women with
leiomyomas.
(Adv Stud Med. 2006;6(6):260-266)

terine leiomyomas, commonly Leiomyomas are the primary indication for

known as fibroids, are the most
common neoplasm of the female
reproductive tract, affecting 20%
to 40% of premenopausal
women.1 Leiomyomas are benign, monoclonal
tumors composed of smooth muscle cells and an
abundant extracellular matrix of collagens, proteo-
glycans, and fibronectin. Many leiomyomas are
small and asymptomatic, but larger leiomyomas
and those in specific locations can cause debilitat-
ing health problems. Common symptoms include
heavy or prolonged menstrual bleeding, pelvic dis-
comfort, dyspareunia, and bladder dysfunction.
Leiomyomas also have been implicated in repro-
ductive difficulties such as infertility, multiple mis-
carriages, and preterm labor.2
hysterectomy, leading to at least 140 000 hys-
terectomies and 37 000 myomectomies each
year in the United States.3 Based on hospital dis-
charge information, more than $2 billion was
spent on inpatient charges for procedures in
1997 alone.3
Although their exact etiology is uncertain,
leiomyomas are likely the end result of a conflu-
ence of genetic, hormonal, and environmental
factors. Estrogen, progesterone, and local growth
factors stimulate the proliferation of uterine
smooth muscle cells and may alter the normal
course of programmed cell death.4
Approximately 40% of leiomyomas have non-
random chromosomal rearrangements, translo-
cations, or deletions.5 Malignant transformation

Dr Jacoby is Associate Professor, Department of Obstetrics, Gynecology, and Reproductive Sciences, and Director,
Comprehensive Fibroid Center, University of California, San Francisco.
Conflict of Interest: The author was an investigator for and received grants/research support from TAP Pharmaceutical
Products, Inc (2003-2004).
Off-Label Product Discussion: The author discusses off-label/unapproved use of mifepristone and asoprisnil for treatment
of uterine leiomyomas.
Address Correspondence to: Alison F. Jacoby, MD, Department of Obstetrics, Gynecology, and Reproductive Sciences,
2356 Sutter St, 6th Floor, San Francisco, CA 94115-1648. E-mail: jacobya@obgyn.ucsf.edu.

260 Vol. 6, No. 6 n June 2006


of leiomyomas is extremely rare. Epidemiologic studies
have shown that African American women are about 3
times more likely than white women to be diagnosed
with leiomyomas.6,7 Other risk factors include early
menarche, nulliparity, late age at first birth, high body
mass index, and familial predisposition.7,8
The list of treatment options for women with
symptomatic leiomyomas is expanding at a rapid rate.
Gone are the days when a woman was restricted to hys-
terectomy or myomectomy. Laparoscopic myolysis,
introduced in Europe in the late 1980s, has been slow
to gain popularity in the United States.9 New proce-
dures such as uterine artery embolization (UAE) and
high-intensity focused ultrasound (HIFU) are in
demand by women who want to preserve their uteri
and minimize recovery time.
Although hormonal manipulation using birth con-
trol pills or gonadotropin-releasing analogues can ame-
liorate abnormal uterine bleeding temporarily, there
are no effective pharmacologic therapies on the market
at this time. On the horizon are medical therapies tar-
geting sex steroid receptors,10 enzymes of estrogen
metabolism,11 and peptide growth factors.4 Also in
development are a variety of gene therapies in which
genetic material, delivered into target cells, can alter
replication or hasten cell death.12 Although some of
these therapies are years away from clinical implemen-
tation, others are in use today. It is important for
healthcare providers to review the efficacy and quality-
of-life outcomes for traditional therapies as well as to
learn how to counsel patients about new and emerging
approaches to management of uterine leiomyomas.
TRADITIONAL THERAPIES
From the 1950s to the 1980s, treatment options
for women with symptomatic leiomyomas were limit-
ed to hysterectomy and myomectomy.
HYSTERECTOMY
Hysterectomy remains the most common treat-
ment for leiomyomas because it provides guaranteed
resolution of bleeding and eliminates the possibility
of new leiomyoma growth. A number of factors,
including uterine size, prior pelvic surgery, and a sur-
geon’s expertise, dictate whether a hysterectomy can
be performed via a laparotomy, laparoscopy, or trans-
vaginally. Data have shown that the majority of
women who undergo hysterectomy report improve-
ment in health-related quality-of-life scores and
rarely experience detrimental effects on their sexual
function.13,14 Nonetheless, hysterectomy is associated
with a 4- to 8-week recovery and risk for major com-
plications. Injury to pelvic structures and hemor-
rhage, possibly requiring blood transfusions, are
relatively common events.
Johns Hopkins Advanced Studies in Medicine
UTERINE FIBROIDS
MYOMECTOMY
Myomectomy, a procedure in which leiomyomas are
excised and the uterus preserved, can be performed by
laparotomy, laparoscopy, or hysteroscopy. Although
rates of symptom improvement exceed 80%, the risk of
new leiomyoma growth is as high as 50% after 5 years
using this procedure.15 Traditionally, myomectomy was
reserved for women who desired future childbearing,
however, recently women of all ages are choosing to con-
serve their uteri despite the chance for persistent symp-
toms and future leiomyoma development.
NEW THERAPIES
UTERINE ARTERY EMBOLIZATION
UAE for leiomyomas, first described by Ravina et
al in 1995,16 has gained tremendous popularity in the
United States and Europe, with an estimated 14 000
procedures performed annually in the United States
alone. The goal of UAE is to significantly reduce per-
fusion of leiomyomas by occluding the uterine arteries.
It is performed by an interventional radiologist who
introduces a catheter into a patient’s femoral artery and
uses real-time fluoroscopic imaging to guide it through
the pelvic vasculature and into the uterine arteries.
Small particles of polyvinyl alcohol or tris-acryl gelatin
microspheres, injected into each uterine artery, adhere
together to form an obstruction to blood flow.
Without sufficient perfusion, the leiomyomas become
ischemic, leading to degeneration and involution.
Collateral blood flow through ovarian and cervical
arteries prevents uterine necrosis. Patients undergoing
UAE receive conscious sedation and usually remain 1
night in the hospital for pain control. Many women
resume light activities within a few days and the major-
ity of women are able to return to normal activities
within 7 to 10 days.17
Figure 1 illustrates the abundant vascularity associ-
ated with leiomyomas before UAE and the absence of
blood flow after UAE. Figure 2 shows the sequence of
contrast-enhanced magnetic resonance (MR) images
before and after UAE in a 53-year-old woman with
menorrhagia and a large fundal leiomyoma. In panel 1,
the hypervascular leiomyoma and enlarged uterus sig-
nificantly compress the bladder. Subsequent images
demonstrate the loss of perfusion into the leiomyoma,
reduction in leiomyoma size, and restoration of full
bladder capacity.
Observational studies have described the outcomes
of more than 3000 patients who have undergone UAE.
Overall, the mean reduction in leiomyoma size report-
ed by individual studies ranged from 31% to 52%.16,18-23
Based on patient self-reports, 85% to 90% experience
significant improvement in both bulk-related symp-
toms and menorrhagia following UAE.16,18-23
The Fibroid Registry for Outcomes Data
261
OBSTETRICS & GYNECOLOGY
(FIBROID), the largest multicenter prospective registry,
recently published the outcomes of 1700 women who
have completed 1 year of follow-up.24 The mean symp-
tom score and mean health-related quality-of-life score
improved significantly, with only 5% of the subjects
reporting no improvement. After 1 year, 82% of the
women would recommend UAE to family members or
friends. Predictors for symptom improvement included
small leiomyoma size, submucosal location, and prepro-
Figure 1. Arteriogram of Myomatous Uterus
Pre-UAE Post-UAE
Uterine leiomyoma with increased vascularity before uterine artery
embolization (UAE) (white arrows) and occlusion of uterine arteries after
UAE (black arrows).
Images courtesy of James P. Spies, MD, Georgetown University Hospital.
Figure 2. Contrast-Enhanced Pelvic Magnetic
Resonance Imaging
Pre-UAE 3 mths 6 mths 1 yr
Serial images before and after uterine artery embolization showing pro-
gressive reduction in leiomyoma size (arrow) and vascularity (dark after
embolization) as well as improvement in bladder capacity, noted by the
asterisk (*).
Images courtesy of W. J. Walker, MD, The Royal Surrey County Hospital, UK.
262
cedure menorrhagia. In the first 12 months after UAE,
slightly fewer than 10% of the patients underwent an
additional surgical procedure, such as hysterectomy,
myomectomy, or dilatation and curettage.
Long-term, prospective outcome data are limited to
one study of 200 women who were followed for 5
years.25 Of the 91% who completed follow-up, 73%
had durable symptom improvement and 20% had
undergone a major surgical intervention. Among the
76% reporting satisfaction, predictors for a positive
experience were diminished bleeding and pain as well
as a greater reduction in leiomyoma volume than expe-
rienced by their less satisfied counterparts.
PATIENT SELECTION
Patient selection for UAE must take several factors
into consideration, including uterine size, leiomyoma
size and location, and desire for future childbearing.
Published data are inconsistent regarding the effect of
uterine and leiomyoma size on UAE success. One
small case series evaluating uterine size found that effi-
cacy was not decreased in women with uterine size ≥24
week gravid uterus.26 Similarly, a study of 47 women
with leiomyomas ≥10 cm experienced no increased
risks and had comparable clinical outcomes with those
of 105 women who had smaller leiomyomas.27
Conversely, data from another study showed that
women with leiomyomas larger than the median base-
line volume were 3 times more likely to fail than were
those with smaller leiomyoma volumes.25
The association between leiomyoma location and
UAE outcomes has not been formally studied, howev-
er anecdotal evidence suggests that leiomyomas within
the uterine cavity are associated with higher rates of
persistent abnormal bleeding, transcervical leiomyoma
expulsion, and endomyometritis. Similarly, emboliza-
tion of exophytic subserosal leiomyomas may result in
higher rates of pelvic pain, hysterectomy, and systemic
infectious morbidity.
At this author’s institution, UAE is not offered to
women who hope to have children in the future, except
in special cases in which myomectomy is not feasible.
In a recent study, 7.3% of the 1701 women followed
for 1 year after UAE developed ovarian failure.24
Although this was more likely to occur in women in
their 40s, 3 of the 125 women in their 30s were affect-
ed.24 Because ovarian failure is irreversible and can
occur at any age, UAE should be reserved for women
who have completed childbearing.
Nonetheless, several small case series have been pub-
lished describing pregnancy outcomes among women
who have undergone UAE. One review of 34 pregnan-
cies reported high rates of miscarriage (32%), malpresen-
tation (22%), cesarean delivery (65%), preterm delivery
(22%), and postpartum hemorrhage (9%).28 A separate
Vol. 6, No. 6 n June 2006

study comparing UAE and laparoscopic myomectomy
found comparable pregnancy outcomes in both groups
for most of these complications.29 However, UAE was
associated with a greater risk for preterm delivery and
malpresentation than was laparoscopic myomectomy.
UTERINE ARTERY EMBOLIZATION VERSUS
HYSTERECTOMY AND MYOMECTOMY
Women choosing between UAE and hysterectomy
should take into consideration data comparing the 2
treatments. A multicenter, prospective study of 102
patients treated with UAE and 50 patients having hys-
terectomy reported shorter hospital stays, fewer compli-
cations, and a faster return to work following UAE.30
Both procedures demonstrated marked improvement in
patient assessment of overall health. After 12 months of
follow-up, women who had undergone hysterectomy
had improvement in pelvic pain compared with the UAE
group (98% vs 84%, P = .021). Overall morbidity was
significantly higher in the hysterectomy group (34% vs
15%; P = .01), specifically in regards to hemorrhage dur-
ing the procedure (8% vs 0%; P = .01).
A randomized controlled trial of 177 premenopausal
women previously scheduled for hysterectomy was per-
formed to evaluate the peri- and postprocedure compli-
cation rates in women undergoing hysterectomy and
UAE.31 Although major and minor complication rates in
both groups were comparable, minor complications were
statistically higher in the UAE group during the first 6
weeks after discharge from the hospital.
A recent, multicenter, prospective cohort study com-
pared the outcomes of 149 women who underwent UAE
with 60 women who underwent myomectomy.32 Both
groups experienced statistically significant improvements
in the uterine leiomyoma quality-of-life score, menstrual
bleeding patterns, and uterine volume reduction.
Women undergoing UAE required fewer days in the hos-
pital (1 vs 2.5 days), fewer days off from work (10 vs 37
days), and had fewer adverse events (20.1% vs 40.1%)
compared with the myomectomy group.
CONCLUSIONS AND RECOMMENDATIONS
UAE is an effective procedure for women who have
completed childbearing. Advantages over myomecto-
my and hysterectomy include avoidance of general
anesthesia, shorter hospital stays, and faster return to
daily activities. Nonetheless, women should be aware
that complications such as uterine infections necessi-
tating a hysterectomy (<0.5%), partial leiomyoma
expulsion requiring hysteroscopic removal (~2%),33
and ovarian failure leading to an early menopause can
occur in as many as 5% of women in their 40s.34
Relative contraindications to UAE are submucosal
leiomyomas that extend to ≥50% of the uterine cavity,
which should be removed hysteroscopically, and exo-
Johns Hopkins Advanced Studies in Medicine
UTERINE FIBROIDS
phytic, pedunculated leiomyomas, which should be
excised laparoscopically or by minilaparotomy.
HIGH-INTENSITY FOCUSED ULTRASOUND
HIFU is a promising technology that has been used in
a variety of medical settings, including the treatment of
benign prostatic hyperplasia, prostate cancer, and soft-tis-
sue tumors of the liver and kidney.35 Unlike diagnostic
ultrasound in which sound waves generated by the trans-
ducer are parallel to one another, HIFU uses converging
sound beams to create a focus of intense heat within a well-
defined area. This principle allows for harmless transmis-
sion of energy through the skin and internal structures,
but the creation of temperatures in excess of 60ºC within
targeted tissues. This results in protein denaturation,
coagulative necrosis, and irreversible cell damage.
To enable accurate tissue targeting, both MR-guid-
ed and ultrasound (US)-guided imaging systems have
been coupled to HIFU.35,36 An advantage of the MR-
guided focused ultrasound (MRgFUS) is the ability to
measure the temperature within the targeted tissue in
real time, allowing the physician to adjust treatment
parameters as needed. Following therapy, contrast-
enhanced MR imaging is used to map the regions of
ablated tissue (Figure 3).37,38
The first commercially available MRgFUS system
Figure 3. Magnetic Resonance-Guided Focused Ultrasound37
A B
C D
A: Sagittal T2-weighted MR image of the uterus used to locate the leiomyoma and
ensure proper patient positioning.
B: The designated region intended for treatment of the leiomyoma (orange). The sys-
tem marks the area targeted for sonications (green circles).
C: Accumulated dose during treatment. Thermal imaging displays areas that have
exceeded the threshold sufficient for 100% cell necrosis (blue).
D: Post-treatment T1-weighted contrast enhanced MR image shows the nonperfusing
treatment area.
Images courtesy of InSightec and Sheba Medical Center, Israel.
263
OBSTETRICS & GYNECOLOGY
was approved by the US Food and Drug
Administration (FDA) for the treatment of leiomy-
omas in October 2004. For the duration of the 2- to 4-
hour outpatient procedure, a woman lays prone with
her abdomen positioned over the HIFU apparatus and
within the MR magnet. Pain control consists of nar-
cotics, nonsteroidal anti-inflammatory drugs, and ben-
zodiazepines. The recovery time is minimal with most
women returning to full activities in 1 to 2 days.
The first published study of MRgFUS confirmed
the safety and feasibility of the procedure in 55 sub-
jects.38 A second study evaluated symptom improve-
ment in 109 patients undergoing MRgFUS.39 Study
inclusion criteria were a leiomyoma size ≤10 cm and
uterine size ≤24 weeks. The FDA-approved study had
stringent safety guidelines requiring a minimum mar-
gin of 1.5 cm from the edge of the ablated tissue to
the serosa of the uterus. As a result, on average, only
10% of the leiomyoma volume was sonicated. In spite
of the strict treatment guidelines, 71% of the patients
reported significant symptom improvement after 6
months and 51% reported persistent improvement
after 12 months. Reduction in leiomyoma volume at
6 and 12 months correlated with the treatment
area.38,39 Complications were rare and most women
reported high satisfaction.
CONCLUSIONS AND RECOMMENDATIONS
HIFU is a powerful technology with the potential
for treating leiomyomas as well as a variety of other
tumors. Given the limited data, it is too early to verify
the efficacy and safety of MRgFUS at this time. US-
guided HIFU may diminish the cost associated with
MR, however, technical barriers remain before human
trials can begin.
MYOLYSIS
Laparoscopic myolysis is another method for the
thermal destruction and devascularization of leiomy-
oma tissue. Different energy sources, including the
Nd:YAG laser, carbon dioxide laser, bipolar needles,
and radiofrequency needle electrodes, have been used
to make multiple perforations into the leiomyoma over
the entire surface.40 Similarly, laparoscopic cryomyoly-
sis employs a probe that causes cell necrosis by reduc-
ing the tissue temperature to -20°C.41 The literature
contains a number of small case series claiming suc-
cessful reduction in leiomyoma volume and symptoms,
but all of these studies have short follow-up and lack
comparison groups. Another limitation of this
approach is the finding of dense adhesions between the
uterus and surrounding structures in 10% to 50% of
the women treated with the Ng:YAG laser and bipolar
needles.40 The safety of myolysis in women who want
to conceive has not been established.
264
FUTURE DIRECTIONS FOR THERAPY
SELECTIVE PROGESTERONE RECEPTOR MODULATORS
AND PROGESTERONE ANTAGONISTS
For many years, it has been known that the female
hormones estrogen and progesterone play an impor-
tant role in promoting growth of leiomyomas.
Recently a new class of medications that selectively
blocks progesterone receptors has been investigated for
its beneficial effects on leiomyomas.42 This class of
drugs known as selective progesterone receptor modu-
lators (SPRMs) has many favorable characteristics. For
example, these agents are highly selective for the
endometrium and myometrium and are highly specif-
ic to the progesterone receptor. By competitively bind-
ing to progesterone receptors, they prevent the biologic
effects of the endogenous hormone. As a class, these
drugs have a range of activity, with some acting as com-
plete progesterone antagonists and others exhibiting
partial agonist and antagonist effects. Because they are
progesterone selective, they do not suppress estrogen
production.
Mifepristone, also known as RU-486, was the first
progesterone antagonist investigated for leiomyoma
treatment. Although mifepristone is an FDA-approved
therapy for medical abortions, it is not approved for
the treatment of leiomyomas. In the setting of preg-
nancy terminations, mifepristone is administered in a
200-mg dose. Conversely, in clinical trials of women
with leiomyomas, mifepristone doses ranged from 5
mg to 25 mg daily for 3 to 6 months. A systematic
review of 6 investigative studies of mifepristone for
leiomyomas reported uterine and leiomyoma size
reduction ranging from 26% to 74%.43 In addition,
overall symptoms improved in 70% to 75% of the
treated subjects.
Although apparently effective, mifepristone does
have several side effects.43 Nearly all treated women
experienced amenorrhea, which reversed following dis-
continuation of mifepristone. Interestingly, hot flushes
were reported by 38% of the subjects even though
estradiol levels were within the early follicular range.
The most significant adverse effect was endometrial
hyperplasia resulting from unopposed estrogen effects
on the endometrium. Simple endometrial hyperplasia,
detected in approximately 10% of the subjects, could
prohibit further clinical development of this agent. No
cases of cellular atypia or complex hyperplasia were
reported, but long-term data are needed in this area.
Asoprisnil, which has yet to be FDA-approved for
any indication, is the first SPRM to reach advanced
clinical development in multiple, large, placebo-con-
trolled trials.44 In theory, because asoprisnil is a partial
progesterone agonist, it may cause less endometrial
hyperplasia than mifepristone, but that has not been
proven. Phase II trials showed a progressive reduction in
Vol. 6, No. 6 n June 2006

uterine and leiomyoma size over time, with a correlation
between dose and effect.44 In addition, more than two
thirds of subjects receiving asoprisnil reported symptom
improvement compared with one third of the subjects
receiving placebo. Although the incidence of side effects
is not yet known, rates of amenorrhea in subjects taking
10 mg/day and 25 mg/day were 64% and 83%, respec-
tively. In animal models, exposure to asoprisnil during
pregnancy caused craniofacial abnormalities.
CONCLUSION AND RECOMMENDATIONS
The prospect of a medical treatment for leiomy-
omas is exciting and promising, but many questions
remain. Although mifepristone is efficacious for reduc-
ing leiomyoma size and symptoms, the manufacturer
has not pursued FDA approval for this indication thus
far. Clinical trials of asoprisnil are ongoing but several
hurdles remain. Because asoprisnil is teratogenic at low
doses in animals, effective, nonhormonal birth control
methods will be imperative for users.
GENE THERAPY
Leiomyomas have several inherent biologic features
that make them favorable targets for gene therapy.
In1998, Niu et al were the first to describe the suc-
cessful transfer of a gene lethal to human and rat cul-
tured uterine leiomyoma cells.12 Importantly, the genetic
material was cytotoxic not only to the 5% of transfected
cells but it also mediated a “bystander effect” in which
cell death occurred in 48% of the nontransfected cells.
Another potential target for gene therapy is the signaling
pathway for estrogen and progesterone. Al-Hendy et al
were able to transfect a human leiomyoma cell line with
a gene coding for an abnormal estrogen receptor (ER).45
The mutant ER adhered to the wild-type ER, making it
unable to bind the estrogen-responsive element and
unable to activate transcription. Although this work is
still far from clinical application, leiomyoma-specific
gene therapy may provide women with a nonsurgical
alternative in the future.
CONCLUSION
The last 10 years have seen a virtual explosion in
less-invasive treatment options for leiomyomas,
including uterine artery embolization, MR-guided
focused ultrasound, and myolysis. Although prelimi-
nary results are promising, complications can occur,
long-term data are lacking, and appropriate patient
selection is paramount. Physicians need to be pre-
pared to discuss these options with their patients,
many of whom will have researched them online
prior to their office visit. Even if a traditional hys-
terectomy is ultimately the best clinical choice,
reviewing the alternatives is essential for informed
decision making.
Johns Hopkins Advanced Studies in Medicine
UTERINE FIBROIDS
Prior to undergoing peer review, this article was devel-
oped with the assistance of a staff medical writer. The author
had final approval of the article and all its contents.
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