UTERUS

Uterine enlargement is common and most frequently is the result of

pregnancy or leiomyomas. Less often, enlargement is from adenomyosis,
hematometra, or an adherent adnexal mass.
Leiomyomas
Leiomyomas are benign smooth muscle neoplasms that typically originate
from the myometrium. They are often referred to as uterine myomas, and
are incorrectly called fbroids because the considerable amount of
collagen contained in many of them creates a fbrous consistency. Their
incidence among women is generally cited as 20 to 2 percent, but has
been shown to be as high as !0 to "0 percent in studies using histologic or
sonographic examination #$uttram, %&"%' (ramer, %&&0' )ay $aird,
200*+.
,n many women, leiomyomas are clinically insignifcant. (on-ersely, in
some, their number, si.e, or location within the uterus can pro-o/e a
myriad of symptoms. Ta/en together, symptoms caused by these uterine
tumors constitute an important segment of gynecologic practice.
PATHOLOGIC APPEARANCE
0rossly leiomyomas are round, pearly white, frm, rubbery tumors that on
cut1surface display a whorled pattern. 2 typically in-ol-ed uterus contains
3 to ! tumors of -arying si.e #(ramer, %&&0+. Leiomyomas possess a
distinct autonomy from their surrounding myometrium because of a thin
outer connecti-e tissue layer. This clinically important arrangement allows
leiomyomas to be easily 4shelled out4 of the uterus during surgery.
5istologically, leiomyomas contain elongated smooth muscle cells
aggregated in bundles that swirl and intersect at right angles to one
another. 6itotic acti-ity, howe-er, is rare and is a /ey point in
di7erentiation from leiomyosarcoma #see (hap. *8, Leiomyosarcoma+
#9aloude/, 2002+.
The appearance of leiomyomas may -ary when normal muscle tissue is
replaced with -arious degenerati-e substances following hemorrhage and
necrosis. This process is collecti-ely termed degeneration, and these gross
changes should be recogni.ed as normal -ariants #:ig. &1%+. )egeneration
de-elops frequently in leiomyomas because of the limited blood supply
within these tumors. Leiomyomas ha-e a lower arterial density compared
with the surrounding normal myometrium #:ig. &12+. 6oreo-er, there is no
intrinsic -ascular organi.ation and this disorgani.ation lea-es some
tumors -ulnerable to hypoperfusion and ischemia #:arrer1$rown, %&!0'
:orssman, %&!3+. 2cute pain may accompany degeneration.
CYTOGENETICS
;ach leiomyoma is deri-ed from a single progenitor myocyte. Thus,
multiple tumors within the same uterus each show independent
cytogenetic origins #6ashal, %&&8' Townsend, %&!0+. The primary
mutation initiating tumorigenesis is un/nown, but identifable /aryotypic
defects are found in about 80 percent of leiomyomas #<ein, %&&"' =ing,
%&&!+. 2 number of unique defects in-ol-ing chromosomes 3, !, %2, and
%8 ha-e been identifed to correlate with rates and direction of tumor
growth #$rosens, %&&"+. ,t is anticipated that further characteri.ation of
the specifc functions of these /aryotypic changes will help to defne the
important steps in leiomyoma de-elopment.
ROLE OF HORMONES
Estrogens
Uterine leiomyomas are estrogen1 and progesterone1sensiti-e tumors
#Table &1%+. (onsequently, they de-elop during the reproducti-e years and
regress in si.e and incidence after menopause. This concept is integral in
understanding many of the ris/ factors associated with leiomyoma
de-elopment and in formulating treatment plans. >ex steroid hormones
li/ely mediate their e7ect by stimulating or inhibiting transcription and
production of cellular growth factors.
6odifed from (oo/, 2008, with permission.
Leiomyomas themsel-es create a hyperestrogenic en-ironment, which
appears requisite for their growth and maintenance. :irst, compared with
normal myometrium, leiomyomas contain a greater density of estrogen
receptors that results in greater estradiol binding. >econdly, these tumors
con-ert less estradiol to the wea/er estrone #;nglund, %&&"' ?tubu, %&"2'
@amamoto, %&&*+. 2 third mechanism described by $ulun and colleagues
#%&&8+ in-ol-es higher le-els of cytochrome A80 aromatase in
leiomyomas compared with normal myocytes. This specifc cytochrome
isoform cataly.es the con-ersion of androgens to estrogen in a number of
tissues.
There are a number of conditions associated with increased estrogen
production that encourage leiomyoma formation. :or example, the
increased years of estrogen exposure found with early menarche and with
an increased body mass index #$6,+ are each lin/ed with a greater ris/ of
leiomyomas #6arshall, %&&"' Bise, 200b+. ?bese women produce more
estrogens from increased adipose con-ersion of androgens to estrogen
and display decreased hepatic production of sex1hormone binding globulin
#0lass, %&"&+.
$ecause pregnancy is a progesterone1dominant state, it should pro-ide an
interlude from chronic estrogen exposure, and intuiti-ely at least, should
discourage leiomyoma de-elopment. ,n support of this, women gi-ing
birth at an early age, those with higher parity, and those with a more
recent pregnancy all display lower incidences of leiomyoma formation. ,n
premenopausal women, estrogen and progesterone hormone treatment
probably has no inducti-e e7ect on leiomyoma formation. Bith few
exceptions, oral contracepti-e combination pills either lower or ha-e no
e7ect on this ris/ #(hia7arino, %&&&' Aara..ini, %&&2' <oss, %&"3+.
6ost studies e-aluating the e7ects of hormone replacement therapy,
howe-er, show either a stimulatory or no e7ect on growth #Aolatti, 2000'
<eed, 2008+. Aalomba and associates #2002+ e-aluated the relationship
between leiomyoma growth and di7ering doses of medroxyprogesterone
acetate #6A2+ in hormone replacement therapy. $ecause higher doses of
6A2 were associated with leiomyoma growth, they recommended using
the lowest possible dose of 6A2 in these patients. :inally, smo/ing alters
estrogen metabolism and lowers physiologically acti-e serum estrogen
le-els #)aniel, %&&2' 6ichno-ic., %&"3+. This may explain why women who
smo/e generally ha-e a lower ris/ for leiomyoma formation #Aara..ini,
%&&2+
Progestins
The role of progesterone in leiomyoma growth is less clear, and indeed
both stimulatory and inhibitory e7ects ha-e been reported. :or example,
exogenous progestins ha-e been shown to limit leiomyoma growth in
clinical trials #0old.ieher, %&33' Tiltman, %&"+. >imilarly, epidemiologic
studies lin/ depot medroxyprogesterone use with a lower incidence of
leiomyoma de-elopment #Lumbiganon, %&&3+. ,n contrast, other studies
report a stimulatory inCuence of progestins on leiomyoma growth. :or
example, the antiprogestin, mifepristone #<U8"3+, induces atrophy in
most leiomyomas #6urphy, %&&*+. 6oreo-er, in women treated with
gonadotropin1releasing hormone #0n<5+ agonists, leiomyomas typically
decrease in si.e. 5owe-er, if progestins are gi-en simultaneously with
agonists, there may be increased leiomyoma growth #(arr, %&&*'
:riedman, %&&8+.
RISK FACTORS
)uring the reproducti-e years, the incidence of this tumor increases with
age. ,n a study by )ay $aird and colleagues #200*+, the cumulati-e
incidence by age 0 years was nearly !0 percent in (aucasians and o-er
"0 percent in 2frican12merican women. >poradic case reports such as the
one by $e//er and colleagues #2008+ document their rarity in teenagers.
2fter menopause, leiomyomas generally shrin/ in si.e, and new tumor
de-elopment is uncommon. Thus, it seems that most ris/ or protecti-e
factors depend on circumstances that chronically alter estrogen or
progesterone le-els or both.
Leiomyomas are more common in 2frican12merican women compared
with (aucasian, 2sian, or 5ispanic women. :ew studies ha-e been done to
ascertain these ethnic di7erences #2mant, 200*' Boods, %&&3+. 5eredity
li/ely plays a role in susceptibility to the initial mutation in-ol-ed with
leiomyoma de-elopment. :amily and twin studies ha-e shown the ris/ of
leiomyoma formation to be approximately two times greater in women
with a7ected frst1degree relati-es #>ato, 2002' Di/hlyae-a, %&&+.
CLASSIFICATION OF UTERINE LEIOMYOMAS
Leiomyomas are classifed based on their location and direction of growth
#:ig. &1*+. >ubserosal leiomyomas originate from myocytes adEacent to the
uterine serosa, and their growth is directed outward. Bhen these are
attached only by a stal/ to their progenitor myometrium, they are called
pedunculated leiomyomas . Aarasitic leiomyomas are subserosal -ariants
that attach themsel-es to nearby pel-ic structures from which they deri-e
-ascular support, and then may or may not detach from the parent
myometrium. ,ntramural leiomyomas are those with growth centered
within the uterine walls. :inally, submucous leiomyomas are proximate to
the endometrium and grow toward and bulge into the endometrial ca-ity.
?nly about 0.8 percent of leiomyomas de-elop in the cer-ix #Tiltman,
%&&"+. Leiomyomas ha-e also been found less commonly in the o-ary,
fallopian tube, broad ligament, -agina, and -ul-a
Leiomyomatosis
;xtrauterine smooth muscle tumors, which are benign yet infltrati-e, may
de-elop in women with concurrent uterine leiomyomas. This condition is
termed leiomyomatosis, and its categori.ation is described below. ,n such
cases, the diagnosis of malignant metastasis from a leiomyosarcoma must
be excluded.
,ntra-enous leiomyomatosis is a rare, benign smooth muscle tumor that
in-ades and extends serpiginously into the uterine and other pel-ic -eins,
-ena ca-a, and e-en cardiac chambers. 2lthough histologically benign,
the tumor can be fatal as a consequence of -enous obstruction or cardiac
in-ol-ement #:ang, 200!' Uchida, 2008+.
$enign metastasi.ing leiomyomas deri-e from morphologically benign
uterine leiomyomas which disseminate hematogenously. Lesions ha-e
been found in the lungs, gastrointestinal tract, spine, and brain #2lessi,
200*+. (lassically, these are found in women who ha-e a recent or distant
history of pel-ic surgery #9aloude/, 2002+.
)isseminated peritoneal leiomyomatosis appears as multiple small
nodules on the peritoneal surfaces of the abdominal ca-ity or the
abdominal organs or both. They are usually found in women of
reproducti-e age, and !0 percent are associated with pregnancy or
combination oral contracepti-es #<obboy, 2000+.
Treatments for these three benign conditions in-ol-e hysterectomy with
oophorectomy, tumor debul/ing, and more recently, use of 0n<5
agonists, aromatase inhibitors, and selecti-e estrogen receptor
modulators #$odner, 2002' <i-era, 2008' >obic.ews/i, 2008+
SYMPTOMS
6ost women with leiomyomas are asymptomatic. 5owe-er, symptomatic
patients typically complain of bleeding, pain, pressure sensation, or
infertility. ,n general, the larger the leiomyoma, the greater the li/elihood
of symptoms #(ramer, %&&0+.
Bee!ing
This is the most common symptom and usually presents as menorrhagia
#?lufowobi, 2008+. The pathophysiology underlying this bleeding may
relate to dilatation of -enules. $ul/y tumors are thought to exert pressure
and impinge on the uterine -enous system, which causes -enular
dilatation within the myometrium and endometrium #:igs. &18 and &1+.
2ccordingly, intramural and subserosal tumors ha-e been shown to ha-e
the same propensity to cause menorrhagia as submucous ones
#Begien/a, 200*+.
)ysregulation of local -asoacti-e growth factors are also thought to
promote -asodilatation. Bhen engorged -enules are disrupted at the time
of menstrual sloughing, bleeding from the mar/edly dilated -enules
o-erwhelms usual hemostatic mechanisms #>tewart, %&&3+.
Pe"i# $is#om%ort an! $ysmenorr&ea
2 suFciently enlarged uterus can cause pressure sensation, urinary
frequency, incontinence, and constipation. <arely, leiomyomas extend
laterally to compress the ureter and lead to obstruction and
hydronephrosis. 2lthough dysmenorrhea is common, in a population1
based cross1sectional study, Lippman and co1wor/ers #200*+ reported that
women with leiomyomas more frequently had dyspareunia or noncyclical
pel-ic pain than dysmenorrhea.
INFERTILITY AN$ PREGNANCY 'ASTAGE
2lthough the mechanisms are not clear, leiomyomas can be associated
with infertility. ,t is estimated that 2 to * percent of infertility cases are
due solely to leiomyomas #$uttram, %&"%' Gupesic, 2002+. Their putati-e
e7ects include occlusion of tubal ostia and disruption of the normal
uterine contractions that propel sperm or o-a. )istortion of the
endometrial ca-ity may diminish implantation and sperm transport.
,mportantly, leiomyomas are associated with endometrial inCammation
and -ascular changes that may disrupt implantation #2merican >ociety for
<eproducti-e 6edicine, 2008a' $rosens, 200*' :arhi, %&&+.
There is a stronger association of subfertility with submucous leiomyomas
than with tumors located elsewhere. ,mpro-ed pregnancy rates following
hysteroscopic resection ha-e pro-ided most of the indirect e-idence for
this lin/ #Dercellini, %&&&+. ,n one study, 0arcia and Turec/ #%&"8+ reported
pregnancy rates approaching 0 percent following myomectomy in
women with submucous leiomyomas as their sole source of infertility.
The relationship between subfertility and intramural and subserosal
leiomyomas that do not distort the endometrial ca-ity is more tenuous. 2
number of in-estigators ha-e reported equally good in -itro fertili.ation
success rates in women with and without leiomyomas that did not distort
the endometrial ca-ity #:arhi, %&&' ?li-eira, 2008+. ?thers, howe-er,
ha-e reported ad-erse fertility e7ects from e-en intramural and
subserosal leiomyomas #5art, 200%' 6archionni, 2008+.
$oth uterine leiomyoma and spontaneous miscarriage are common, and
an association between these has not been shown con-incingly. ,ndirect
e-idence comes from studies that cite signifcantly lower abortion rates
following resection #(ampo, 200*' Dercellini, %&&&+.
Ot&er Cini#a Mani%estations
Less than 0. percent of women with leiomyomas de-elop myomatous
erythrocytosis syndrome . This may result from excessi-e erythropoietin
production by the /idneys or by the leiomyomas themsel-es #Gohama,
2000' @o/oyama, 200*+. ,n either case, red cell mass returns to normal
following hysterectomy.
Leiomyomas occasionally may cause pseudo16eigs syndrome .
Traditionally, 6eigs syndrome consists of ascites and pleural e7usions that
accompany benign o-arian fbromas. 5owe-er, any pel-ic tumor including
large, cystic leiomyomas or other benign o-arian cysts can cause this. The
presumed etiology stems from discordancy between the arterial supply to
and the -enous and lymphatic drainage from leiomyomas. <esolution of
ascites and hydrothorax follows hysterectomy.
$IAGNOSIS
Leiomyomas are often detected by pel-ic examination with fndings of
uterine enlargement, irregular contour, or both. ,n reproducti-e1aged
women, uterine enlargement should prompt determination of a urine or
serum 1h(0 le-el.
Imaging
>onography is initially done to defne pel-ic anatomy. The sonographic
appearances of leiomyomas -ary from hypo1 to hyperechoic, depending
on the ratio of smooth muscle to connecti-e tissue and whether there is
degeneration. (alcifcation and cystic degeneration create the most
sonographically distincti-e changes #:ig. &13+. (alcifcations appear
hyperechoic and commonly rim the tumor or are randomly scattered
#Gurt., %&!&+. (ystic or myxoid degeneration typically flls the leiomyoma
with multiple, smooth1walled, round, irregularly si.ed but generally small
hypoechoic areas.
,f menorrhagia, dysmenorrhea, or infertility accompanies a pel-ic mass,
then the endometrial ca-ity should be e-aluated for submucous
leiomyomas, endometrial polyps, congenital anomalies, or synechiae #:ig.
&1!+. 2ccordingly, saline1infusion sonography #>,>+, hysteroscopy, and
hysterosalpingography #5>0+ may ha-e a role. Beinraub and associates
#%&&3+ reported use of three1dimensional >,>, howe-er, any clear
ad-antage o-er two1dimensional >,> or hysteroscopy has not been
demonstrated #de Groon, 2008+.
Leiomyomas ha-e characteristic -ascular patterns that can be identifed
by color Cow )oppler. 2 peripheral rim of -ascularity from which a few
-essels arise to penetrate into the center of the tumor is traditionally
seen. )oppler imaging can be used to di7erentiate an extrauterine
leiomyoma from other pel-ic masses or a submucous leiomyoma from an
endometrial polyp or adenomyosis #see (hap. ", Trans-aginal (olor
)oppler >onography+ #:leischer, 200*+.
6agnetic resonance #6<+ imaging may be required when imaging is
limited by body habitus or distorted anatomy. This tool allows more
accurate assessment of the si.e, number, and location of leiomyomas,
which may help identify appropriate patients for alternati-es to
hysterectomy, such as myomectomy or uterine artery emboli.ation #see
:ig. 212+ #9awin, %&&0+.
MANAGEMENT
O(ser"ation
<egardless of their si.e, asymptomatic leiomyomas usually can be
managed expectantly by annual pel-ic examination #2merican (ollege of
?bstetricians and 0ynecologists 200%+. ,f assessment of the adnexa is
hindered by uterine si.e or contour, some may choose to add annual
sonographic sur-eillance #0uarnaccia, 200%+.
,n the past, most preferred surgical remo-al of a large, asymptomatic
leiomyomatous uterus because of concerns regarding increased operati-e
morbidity and cancer ris/s. These ha-e been dispro-en, and thus
otherwise asymptomatic women with large leiomyomas can also be
managed expectantly #Aar/er, %&&8' >to-all, %&&8+. ,n addition, most
infertile women with uterine leiomyomata are management expectantly.
:or those with symptomatic tumors, surgery should be timed closely to
planned pregnancy, if possible, to limit the ris/ of leiomyoma recurrence.
$r)g T&era*y
,n some women with symptomatic leiomyomas, medical therapy may be
preferred #Table &12+. ,n addition, because leiomyomas typically regress
postmenopausally, some women choose medical treatment to relie-e
symptoms in anticipation of menopause. ,n others, medical therapy, such
as 0n<5 agonists, are used as a preoperati-e adEunct to surgery.
Nonsteroi!a Anti+In,ammatory $r)gs
Bomen with dysmenorrhea ha-e higher endometrial le-els of
prostaglandins :2 and ;2 than asymptomatic women #Billman, %&!3'
@li/or/ala, %&!"+. 2ccordingly, treatment of dysmenorrhea and
menorrhagia associated with leiomyomas is based on the role of
prostaglandins as mediators of these symptoms. 2 number of H>2,)s
ha-e pro-ed e7ecti-e for dysmenorrhea, yet there is not one considered
to be superior #Table %012+. Arostaglandins are also associated with
menorrhagia #see (hap. ", Honsteroidal 2nti1,nCammatory )rugs+
#Billman, %&!3+. That said, benefts of H>2,)s for leiomyoma1related
bleeding are less clear. The few studies done ha-e had conCicting results
#2nteby, %&"' 6a/arainen, %&&3' @li/or/ala, %&"3+. 2-ailable data do not
support their use as sole agents for leiomyoma1related menorrhagia.
Hormona T&era*y
$oth combination oral contracepti-e pills #(?(s+ and progestins ha-e
been used to induce endometrial atrophy and decrease prostaglandin
production in women with leiomyomas. :riedman and Thomas #%&&+
studied "! women with leiomyomas and reported that those ta/ing low1
dose (?(s had signifcantly shorter menses and no e-idence of uterine
enlargement. ?rsini and colleagues #2002+ reported similar results.
There are conCicting results from trials of the le-onorgestrel1releasing
intrauterine de-ice #6irena, $erlex, Bayne, HI+ to treat leiomyoma1related
menorrhagia. 2lthough, 0rigorie-a and co1wor/ers #200*+ reported
reduced blood loss and impro-ed hematocrits in these women, 6ercorio
and associates #200*+ did not confrm these fndings.
$ecause of unpredictable e7ects of progestins on leiomyoma growth with
the potential to worsen symptoms, the 2merican >ociety for <eproducti-e
6edicine #2008a+ does not recommend either progestins or combination
(?(s for leiomyoma1related symptoms.
An!rogens
$oth dana.ol and gestrinone ha-e been found to shrin/ leiomyoma
-olume and impro-e bleeding symptoms #(outinho, %&"&' )e Leo, %&&&+.
Unfortunately, their prominent side e7ects, which include acne and
hirsutism, preclude their use as frst1line agents #see (hap. %0,
2ndrogens+.
GnRH Agonists
These compounds are synthetic deri-ati-es of the 0n<5 decapeptide.
2mino1acid substitution ma/es them resistant to degradation, thereby
increasing their half1life and resulting in prolonged receptor binding. They
are inacti-e if ta/en orally, but intramuscular, subcutaneous, and
intranasal preparations are a-ailable. 2 number of 0n<5 agonists that
ha-e been studied in clinical trials are shown in Table &1*. There is no
e-idence to support the superiority of one of these regimens o-er the
others for leiomyoma treatment #(ha-e., 200%+.
These drugs shrin/ leiomyomas by targeting the growth e7ects of
estrogen and progesterone. They initially stimulate receptors on pituitary
gonadotropes to cause a supraphysiologic release of both luteini.ing
hormone #L5+ and follicle1stimulating hormone#:>5+. 2lso called a Care ,
this phase typically lasts % wee/. Bith their long1term action, howe-er,
agonists downregulate receptors in gonadotropes, thus creating
desensiti.ation to further 0n<5 stimulation. (orrespondingly, decreased
gonadotropin secretion leads to suppressed estrogen and progesterone
le-els % to 2 wee/s after initial 0n<5 agonist administration #$roe/mans,
%&&3+. 2nother possible mechanism is that leiomyomas themsel-es may
contain 0n<5 receptors, and agonists may directly decrease leiomyoma
si.e #(hegini, %&&3' Aar/er, 200!' Bi.nit.er, %&""+.
<esults with 0n<5 agonist treatment include dramatic decreases in
uterine and leiomyoma -olume. 6ost women experience a mean decrease
in uterine -olume of 80 to 0 percent, with most shrin/age occurring
during the frst * months of therapy. (linical benefts of reduced
leiomyoma -olumes include pain relief and diminished menorrhagia,
usually amenorrhea. )uring this time, anemic women are gi-en oral iron
therapy to repair red cell mass and increase iron stores #:ilicori, %&"*'
:riedman, %&&0+. 6ost recommend treatment for a total of * to 3 months.
:ollowing their discontinuance, normal menses resume in 8 to %0 wee/s.
Unfortunately, leiomyomas then regrow and uterine -olumes regain
pretreatment si.es within * to 8 months #:riedman, %&&0+. )espite
regrowth, >chla7 and co1wor/ers #%&"&+ reported symptom relief for about
% year in half of women gi-en 0n<5 agonists.
0n<5 agonists ha-e signifcant costs, ris/s, and side e7ects. >ide e7ects
result from a profound drop in serum estrogen le-els and include
-asomotor symptoms, libido changes, and -aginal epithelium dryness and
accompanying dyspareunia. ,mportantly, 3 months of agonist therapy can
result in a 3 percent loss in trabecular bone, not all of which may be
recouped following discontinuation #>charla, %&&0+. 2s a result, these
agents are not recommended for use longer than 3 months.
To ob-iate the se-erity of these side e7ects, se-eral medications ha-e
been added to 0n<5 agonist treatment. The goal of this 4add1bac/
therapy4 is to counter side e7ects without mitigating the e7ects on
uterine and leiomyoma -olume decrease. 6i.utani and co1wor/ers #%&&"+
found that 0n<5 agonists suppress leiomyoma cell proliferation and
induce cell apoptosis at the fourth wee/ of 0n<5 agonist therapy. They
proposed that add1bac/ therapy be withheld until after this time threshold.
$ecause of these and other obser-ations, add1bac/ therapy is typically
begun % to * months following 0n<5 agonist initiation.
2dd1bac/ therapy traditionally includes estrogen combined with a
progestin. 2 regimen of medroxyprogesterone acetate #6A2+ %0 mg #days
%3 to 2 of each cycle+, combined with equine estrogen 0.32 mg #days %
to 2+, or a continuous daily regimen of 6A2 2. mg and equine estrogen
0.32 mg may be used.
2dd1bac/ therapy with selecti-e estrogen receptor modulators #>;<6s+,
such as tibolone and raloxifene, has also been shown to pre-ent bone
loss. 2d-antages of >;<6s include the ability to begin them concurrently
with 0n<5 agonist treatment without negating the agonist e7ects of
leiomyoma shrin/age. Unfortunately, a high percentage of women
complain of -asomotor symptoms while ta/ing >;<6s #Aalomba, %&&",
2008+.
$ecause of the limitations of 0n<5 agonist therapy, the 2merican (ollege
of ?bstetricians and 0ynecologists #200%+ currently recommends it only as
a tempori.ing agent in women nearing menopause or as surgical
pretreatment in selected women.
Areoperati-ely, 0n<5 agonists o7er se-eral ad-antages. Their use
decreases menorrhagia and may allow correction of anemia. )ecreased
uterine si.e as a result of treatment may allow a less1complicated or
extensi-e surgical procedure. :or example, hysterectomy or myomectomy
may be performed through a smaller laparotomy incision or by -aginal
hysterectomy, laparoscopy, or hysteroscopy #(rosignani, %&&3' 6encaglia,
%&&*' >to-all, %&&8+. 2 fuller discussion of preoperati-e 0n<5 agonist use
can be found in >ection 8%1%", 6yomectomy.
GnRH Antagonists
>ynthetically deri-ed 0n<5 antagonists ha-e also been studied for
treatment of leiomyomas. 2lthough their profound hypoestrogenic e7ects
are similar to those of 0n<5 agonists, they a-oid the initial gonadotropin
Care and ha-e a more rapid action. >tudies ha-e e-aluated cetrorelix and
also Hal1glu, so named because of its glutamatic acid structural
substitution of the original 0n<5 structure. )aily subcutaneous inEections
induce leiomyoma shrin/age comparable with 0n<5 agonists #0on.ale.1
$arcena, %&&!' Gettel, %&&*+. 2 depot form of cetrorelix, howe-er, did not
pro-ide adequate or consistent suppression of estrogen production or
leiomyoma growth #:elberbaum, %&&"+.
Anti*rogestins
6ifepristone, also /nown as <U8"3, is the most widely a-ailable
antiprogestin for treatment of leiomyomas. ,t has pro-ed e7ecti-e in
decreasing leiomyoma -olume and clinical symptoms.
Arogesterone binds to either progesterone receptor 2 or $ #A<12, A<1$+.
6ifepristone exerts its e7ects mainly through A<12, which is found in
leiomyomas in greater amounts than A<1$ #Di-ille, %&&!+. 6ifepristone
diminishes leiomyoma -olume by approximately half. Darious doses ha-e
been used and include , %0, 2, or 0 mg gi-en orally daily during %2
wee/s #;isinger, 200*' 6urphy, %&&*+. ,n their re-iew, >teinauer and
colleagues #2008+ found that although there was not a consistent
correlation between increasing mifepristone dose and leiomyoma
response, increasing duration of treatment did correlate with tumor
shrin/age during *1 to 31month trials. They also reported that mifepristone
was e7ecti-e in impro-ing symptoms. ?f those treated, &% percent
de-eloped amenorrhea, ! percent reported impro-ed pain relief, and !0
percent had fewer pressure symptoms. ,n a comparison of leuprolide
acetate treatment and mifepristone therapy, <einsch and associates
#%&&8+ showed comparable decreases in uterine -olume, yet mifepristone
was better tolerated.
6ifepristone therapy, howe-er, has se-eral drawbac/s. 2pproximately 80
percent of treated women complain of -asomotor symptoms.
2ntiprogestational e7ects expose the endometrium to unopposed
estrogen, and ;isinger and associates #200*+ found simple hyperplasia in
2" percent of *3 women sampled. >erum le-els of hepatic transaminases
become ele-ated in about 8 percent of women, but these return to normal
after discontinuation in -irtually all #>teinauer, 2008+. )espite its
antiglucocorticoid potential, increased serum cortisol le-els are unusual
with mifepristone, and if ele-ated they re-ert to normal after
discontinuation #<einsch, %&&8+.
Uterine Artery Em(oi-ation
This is an angiographic inter-entional procedure that deli-ers poly-inyl
alcohol #AD2+ microspheres or other particulate emboli into both uterine
arteries. Uterine blood Cow is therefore obstructed, producing ischemia
and necrosis. $ecause -essels ser-ing leiomyomas ha-e a larger caliber,
these microspheres are preferentially directed to the tumors, sparing the
surrounding myometrium.
2n angiographic catheter is placed in either femoral artery and ad-anced
under Cuoroscopic guidance to selecti-ely catheteri.e both uterine
arteries #:ig. &1"+. :ailure to emboli.e both uterine arteries allows existing
collateral circulation between the two uterine arteries to sustain
leiomyoma blood Cow and is associated with a signifcantly poorer
outcome.
2s a result of leiomyoma necrosis, there typically are signifcant
postprocedural symptomsJKLthe postemboli.ation syndrome. This usually
lasts 2 to ! days, and it is classically mar/ed by pel-ic pain and cramping,
nausea and -omiting, low1grade fe-er, and malaise. ,ntensity of these
symptoms -aries, and pain management strategies include oral,
intra-enous, epidural, or patient1controlled analgesia regimens
#5o-sepian, 2008+.
;mboli.ation is e7ecti-e for leiomyoma1related symptoms. Aron and
associates #200*+ followed *" women after U2; and found a clinical
success rate of "0 percent for bleeding and pain and &% percent for
patient satisfaction. ,n addition, for most, U2; is associated with shorter
hospital stays and quic/er postoperati-e reco-ery than hysterectomy.
5owe-er, rates of readmission and further treatment for bleeding are
higher with U2; #;dwards, 200!' 5ehen/amp, 200' Ainto, 200*+. Long1
term data following U2; are limited. $roder and co1wor/ers #2002+ re1
e-aluated a group of these women years postprocedure and reported
that 2! percent had required further in-asi-e treatment#s+ for their
leiomyomas. The 2merican (ollege of ?bstetricians and 0ynecologists
#2008+ currently recommends U2; for short1term relief of bleeding or
pressure symptoms.
There are a number of complications associated with U2;. Leiomyoma
tissue passage is common and li/ely is seen only with leiomyomas that
ha-e contact with the endometrial surface. Hecrotic tissue that passes
into the -agina usually can be remo-ed in the oFce. Those that do not
pass spontaneously or that remain frmly attached to the uterine wall may
require dilatation and e-acuation #>pies, 2002+. Transient amenorrhea,
which lasts at most a few menstrual cycles, is also commonly seen
following U2; and is not typically associated with increased :>5 le-els or
menopausal symptoms. Aermanent amenorrhea, howe-er, de-elops
occasionally. <arely, serious complications occur following emboli.ation
and include necrosis of surrounding tissues such as the uterus, adnexa,
bladder, and soft tissues.
2 number of complications ha-e been identifed in women during
pregnancy subsequent to U2;. 0oldberg and colleagues #2008+ reported
increased ris/s for preterm deli-ery and malpresentation in women who
were treated by U2; when compared with pregnancies that followed
laparoscopic myomectomy. ,ncreased incidence of abnormal placentation
has also been identifed #Aron, 200+. )ue to lac/ of long1term outcome
data, women who desire future childbearing are not currently considered
candidates for U2; #2merican (ollege of ?bstetricians and 0ynecologists,
2008+.
2s discussed in (hapter 2, preliminary studies indicate that magnetic
resonance imagingJKMguided focused ultrasound #6<,1:U>+ therapy is a
safe and feasible, minimally in-asi-e alternati-e for leiomyoma treatment
#(hen, 200' :ennessy, 200!' >tewart, 200*, 2003+. ,t may pro-ide short1
term symptom relief with the ad-antage of a quic/er reco-ery and few
maEor ad-erse e-ents. 5owe-er, little information is a-ailable on the costs
and comparisons with other treatments such as U2;.
S)rgi#a Management
$leeding and pain symptoms may impro-e in many women using medical
treatment or U2;. 5owe-er, for many, surgical treatments for leiomyomas
are necessary and include hysterectomy, myomectomy, and myolysis.
Hystere#tomy
<emo-al of the uterus is the defniti-e and most common surgical
treatment for leiomyomas. 5ysterectomy for leiomyoma can be performed
-aginally, abdominally, or laparoscopically. $etween %&&8 and %&&&, more
than *. million hysterectomies were performed in the United >tates, and
almost a third were performed for the diagnosis of uterine leiomyoma
#Gesha-ar., 2002+. ,n a study of 8%" women undergoing hysterectomy for
benign gynecologic conditions, (arlson and co1wor/ers #%&&8+ found
hysterectomy for women with symptomatic leiomyomas resulted in
satisfaction rates greater than &0 percent. There were mar/ed
impro-ements in pel-ic pain, urinary symptoms, fatigue, psychological
symptoms, and sexual dysfunction.
<emo-al of the o-aries is not required, and the decision to perform
oophorectomy at the time of hysterectomy is made based on the usual
factors #see >ection 8%1%&, 5ysterectomy+. ?ther considerations prior to
hysterectomy include uterine si.e and preoperati-e hematocrit. ,n some
cases, preoperati-e 0n<5 agonist use may pro-ide ad-antages.
Myome#tomy
<esection of tumors is an option for symptomatic women who desire
future childbearing or for those who decline hysterectomy. This can be
performed laparoscopically, hysteroscopically, or -ia laparotomy incision
and are described in >ection 8%1%", 6yomectomy.
6yomectomy usually impro-es pain, infertility, or bleeding. :or example,
menorrhagia impro-es in approximately !0 to "0 percent of patients
#$uttram, %&"%' ?lufowobi, 2008+.
Myome#tomy "ers)s Hystere#tomy
5istorically, hysterectomy has been recommended for women not see/ing
pregnancy. 6any belie-ed that myomectomy, compared with
hysterectomy, carried a greater ris/ for perioperati-e morbidity. 2s
experience accrued, myomectomy has been shown to be e7ecti-e and to
carry perioperati-e ris/s comparable with hysterectomy. ,n a number of
reports, blood loss, intraoperati-e inEuries, and febrile morbidity were
similar #,-erson, %&&3' >awin, 2000+.
)isad-antageously, postoperati-e intra1abdominal adhesions and
leiomyoma recurrence are more common after myomectomy compared
with hysterectomy #>tric/er, %&&8+. <ecurrence rates following
myomectomy range from 80 to 0 percent #2cien, %&&3' :edele, %&&+.
Hew leiomyoma de-elopment, howe-er, appears diminished in women
who become pregnant following myomectomy, perhaps because of
protecti-e e7ects of increasing parity #(andiani, %&&%+.
La*aros#o*i# Myome#tomy
Laparoscopic leiomyoma resection may be performed with successful
outcomes #5urst, 200' 6ais, %&&3+. ,n one study, >eracchioli and co1
wor/ers #2000+ re-iewed results of %*% women following myomectomy for
at least one large leiomyoma. They reported equi-alent pregnancy rates
with fewer transfusions, shorter hospital stays, and less febrile morbidity
in women undergoing laparoscopic resection compared with laparotomy.
6oreo-er, laparoscopic myomectomy appears to incite less adhesion
formation than with laparotomy #$ulletti, %&&3' )ubuisson, 2000'
Ta/euchi, 2002+.
Limitations to a laparoscopic approach, howe-er, include uterine si.e and
laparoscopic surgical s/ills, especially suturing techniques. 6ost ad-ocate
a one1 or two1layer suture closure of leiomyoma beds following
enucleation #>einera, %&&!+. ,n addition, se-eral in-estigators ha-e
recommended limiting resection to those tumors less than " to %0 cm
because of increased hemorrhage and operating time with larger tumors
#)ubuisson, 200%' Ta/euchi, 200*+.
There are ris/s associated with laparoscopic myomectomy. ;xcision sites
ha-e been associated with uteroperitoneal fstula or with uterine rupture
during subsequent pregnancy #He.hat, %&&3+. 2t times, laparoscopic
technique requires con-ersion to laparotomy due to bleeding or diFcult
tumor enucleation. ,t is unclear whether laparoscopic myomectomy is
associated with greater ris/ of recurrence. <ossetti and co1wor/ers #200%+
found equi-alent rates of leiomyoma recurrence with laparotomy or
laparoscopic myomectomy, whereas He.hat and colleagues #%&&"+ found
higher rates following laparoscopy.
Hysteros#o*y
<esection of submucous leiomyomas through a hysteroscope has long1
term e7ecti-eness of 30 to &0 percent for the treatment of menorrhagia
#)erman, %&&%' ;manuel, %&&&' 5alle., %&&+. 5ysteroscopic leiomyoma
resection also impro-es fertility rates, especially when tumors are the sole
cause of infertility #:ernande., 200%' Dercellini, %&&&+. ,n their re-iew,
)onne. and Iadoul #2002+ calculated an o-erall pregnancy rate of 8
percent following hysteroscopic tumor resection in women with
leiomyoma as their sole identifed source of infertility.
En!ometria A(ation
There are se-eral tissue destructi-e modalities that ablate the
endometrium and they are discussed in detail in >ection 8%1*3,
;ndometrial 2blation Arocedures. These techniques are e7ecti-e for
women with dysfunctional uterine bleeding, but when used as a sole
technique for leiomyoma1related bleeding, the failure rate approaches 80
percent #0oldfarb, %&&&' @in, %&&"+. ,n some cases, ablation is used as an
adEunct to hysteroscopic leiomyoma resection in women with
menorrhagia.
Myoysis
2 number of techniques are a-ailable to induce leiomyoma necrosis and
shrin/age and include mono1 or bipolar cautery, laser -apori.ation, or
cryotherapy. 2ll of these techniques are used laparoscopically and
consume a great deal of operating room time, incite -ariable degrees of
necrosis within the leiomyoma and surrounding normal myometrium, and
produce signifcant postoperati-e pain. )ata regarding long1term
symptom relief, recurrence rates, and e7ects on fertility and pregnancy
are lac/ing. Until clinical trials are done, these are currently considered
experimental