CHAPTER 27
Benign Uterine
Diseases
Zaraq Khan
Elizabeth A. Stewart
The traditional concept of the uterus is that the endome-
trium is the dynamic tissue, providing an intricate set of
functions throughout the menstrual cycle that rarely cul-
minates in implantation and pregnancy. The myometrium
has been viewed as an inert tissue, chiefly important during
pregnancy and when abnormal, providing the surgical liveli-
hood of clinical gynecologists.
However, to understand both the physiology of menstru-
ation and the pathophysiology of abnormal uterine bleed-
ing, both the myometrial and the endometrial layers of
the uterus are important. First, both myometrial processes
(adenomyosis and leiomyomas) and endometrial processes
(polyps) can result in abnormal uterine bleeding. Secondly,
on the molecular level, since the mass of the myometrial
layer is so much greater than that of the endometrial layer,
the myometrium can act as a reservoir of growth factors or
immune cells that then may act on the endometrium in a
paracrine or local endocrine fashion.
The study of uterine molecular mechanisms is in its
infancy. Study of the human uterus is difficult since all of the
surgical specimens available for in vitro study are by defini-
tion abnormal. Additionally, many of the disorders that cause
abnormal uterine bleeding (such as leiomyomas) appear to
be heterogeneous in their molecular mechanisms. Just as the
clinical phenotype of polycystic ovaries can result from vari-
ous molecular defects, leiomyomas likely have many under-
lying genetic etiologies and environmental stimuli.
Nevertheless, basic investigation is beginning to reveal
that a number of common molecular mechanisms are shared
by phenotypically different diseases such as leiomyomas,
adenomyosis, and endometrial polyps. We can speculate
that in the future these diseases may be classified on the
basis of molecular defects rather than on microscopy. This
would allow us to understand the genotype-phenotype rela-
tionships that we currently find puzzling: for example, why
some women have profound heavy menstrual bleeding with
these diseases and others are asymptomatic. Understanding
new elements of the biology of these diseases will lead to
innovative therapy.1
Our lack of understanding of molecular physiology and
pathophysiology has left us with extirpative surgical treat-
ment as our therapeutic mainstay. While we have become
more elegant in our surgical approach, the high risk of
recurrent disease following conservative surgeries indicates
that understanding the underlying mechanism and moving
toward prevention is likely to be more successful.
586
The fact that modern women spend a larger percent-
age of their lifespan menstruating compared with women
in previous centuries and females of other species may also
contribute to many pathological conditions. Many genes are
differentially regulated at specific parts of the menstrual
cycle. Thus, constantly turning the same molecular switches
on and off may have the same effect as constantly turning
a light switch on and off: the system becomes disrupted.2
This fact, as well as species differences, has made it difficult
to use animal models to study the function of uterine tissue.
Finally, the economic implications of these diseases are
significant. The cost of leiomyomas alone in the U.S. has
been estimated at $5.9 to 34.4 billion annually.3 Lost pro-
ductivity due to clinically significant leiomyomas are also
a substantial cost, accounting for over 40% of total costs
which average in excess of $4800 per woman per year in a
commercially-insured population.4 Neither of these figures
takes into account the cost of sanitary protection, alterna-
tive and complementary remedies or the costs of women
who are symptomatic but not seeking care.
Uterine Leiomyomata
Epidemiology
Uterine leiomyomas, frequently termed myomas or fibroids,
are benign clonal smooth muscle-cell tumors ranging in size
from several millimeters to many centimeters (Fig. 27.1).
Clinically, fibroids are appreciated in approximately 25% of
all women and in African American women they appear to
have a threefold increased incidence and relative risk.5 Care-
ful pathological study of surgical specimens suggests more
than 80% of African American and 70% of Caucasian women
have detectable leiomyomas which parallels the lifetime
incidence of the clinical disease.6,7 Thus, in African Ameri-
can women, it appears there is little occult disease. This sug-
gests that in this group, growth acceleration of transformed
myocytes into clinical fibroids may be ubiquitous.7,8 African
American women are not only significantly more likely to
have leiomyomas than Caucasian women but to be younger
at the time of diagnosis and hysterectomy.5,9-11 They also
have more severe diseases,9,11,12 and are two to three times
more likely to have hysterectomy for leiomyomas and six-
fold more likely to have a myomectomy (Table 27.1).13,14
Known risk factors don’t adequately explain this racial
disparity.15,16 Newly discovered genetic polymorphisms
 CHAPTER 27  Benign Uterine Diseases 587

leading to increased risk for African American women is a

key research agenda for leiomyomas. There is mixed data
regarding fibroid risk in Latina women.5,14,25
Reproductive factors affect the risk of leiomyomas.
Numerous studies have shown that parity is associated
with decreased fibroid risk.16,26,27 One hypothesis is that
the remodeling of the postpartum uterus can clear nascent
fibroids.28 Support for this hypothesis came from recent
studies.29,30 In one of these reports of women beginning
with pregnancy, 36% of them had no identifiable lesion
on ultrasonography postpartum and 79% of the remaining
fibroids had decreased in size.31 Progestin use in the post-
partum period was the only significant risk factor for limited
regression of fibroids postpartum.30 The fact that this study
contrasts with previous reports, that progestin only inject-
able contraceptives are associated with decreased fibroid
risk32,33 and progestin only contraceptives are widely used
in breastfeeding women make it critical to further explore
this area. Although clinical dogma traditionally suggested
that oral contraceptive pills (OCPs) were contraindicated
for women with myomas, OCPs instead appear to protect
FIGURE 27.1  A T2-weighted fast-spin echo (FSE) sagittal image of a
leiomyomatous uterus with multiple type 2 submucosal fibroids. This against clinically evident fibroids with the caveat that timing
sagittal image allows the endometrial cavity to be visualized from the of use may be important.16,26,27 Exposure to OCPs between
fundus to the cervix, indicating that these fibroids are not displacing ages 13 and 16 for women in the Nurses’ Health Study led
the cavity laterally. This series of images is typically best to visualize to an increased relative risk of leiomyomas, while later OCP
clinically important submucous fibroids. Visualization of the sacrum use was protective in direct proportion to duration of use.16
and coccyx, bladder and rectum allows assessment of bulk effects of Postmenopausal hormone replacement therapy (HRT) has
the fibroid in the pelvis. been associated with a higher likelihood of having fibroids
on pathology after surgery in one report, although this may
have been due to bias, since HRT may have inhibited normal
Table 27.1  Table Depicting Increased Burden postmenopausal fibroid regression.25 Early menarche is also
of Fibroid Disease in African American Population associated with increased risk of developing fibroids,11 and
African American vs. Reference may explain earlier disease in African American women in
Fibroid Characteristic Caucasian Women Number whom menarche is earlier than Caucasian women.34
Environmental and dietary habits also appear to influence
Incidence of uterine Threefold increase 5
fibroids risk of myoma formation. Decreased vegetable and fruit
Relative risk Threefold increase 5 intake, especially citrus fruits35 and significant consump-
Age at diagnosis 3-5 years younger 11 tion of red meats was associated with an increased relative
Severity of disease Fivefold increase 11 risk of fibroids and consumption of green vegetables with
Fibroid growth at older Sevenfold-eightfold 53
age (≥45 years) increase
a decreased risk of myomas.36 Reduced dairy consump-
Myomectomy risk Sixfold increase 13 tion,37 use of hair relaxer,38 and increased intake of alcohol,
Hysterectomy risk Twofold-threefold 14 especially beer, appears to increase risk in African Ameri-
increase can women.39 Association of fibroid risk with high alcohol
intake has also been reported in Japanese women.40 No one
has however, demonstrated that dietary intervention leads
that include abnormal transcriptional factors, increased aro- to changes in fibroid incidence, symptomatology, or fibroid
matase activity and signal transduction genes may dictate a regression. Major life events and stress,41 as well as a history
more severe phenotype of the disease in African American of abuse in childhood42 have been linked to presence of uter-
women.17,18 Polymorphism of catechol-O-methyltransferase ine fibroids. In utero exposure to diethylstilbestrol (DES) in
(COMT), an essential enzyme for estrogen metabolism, animals43 and humans44 as well as consumption of soy for-
has been shown to be linked to fibroid formation and is mula in infancy, low childhood socioeconomic status, early
more common in African American women.19 Vitamin D gestational age at birth and maternal pre-pregnancy or ges-
has been shown to inhibit fibroid proliferation via COMT tational diabetes status have all been associated to increase
pathway20 and also reduces fibrosis caused by transforming fibroid development risk.15,44 Caffeine consumption was
growth factor-β3 (TGFβ3).21 Role of vitamin D has been not noted to be a risk factor39 and smoking is considered
reproduced in the Eker mouse model,22 where supplemen- protective through an unknown mechanism.26,45 Dietary
tation with 1,25 dihydroxyvitamin D3 at 0.5 μg/kg per Vitamin A from animal sources appears protective.35
day for 3 weeks, lead to reduced myoma size compared to Increased body mass index (BMI) or weight gain since
controls.22 There have seen studies on African American age 18 also appears to influence myoma risk in some
women that correlate fibroid risk to polycystic ovarian syn- cohorts.10,46-48 High dietary glycemic index and glycemic
drome23 and self-reported experience of racism.24 Under- load49 and decreased physical activity50 are also risk fac-
standing the unique genetic and environmental factors tors. Finally, women with leiomyomas appear to be more
588 PART 2  Pathophysiology and Therapy
likely to have hypertensive disease than control women.51
It is unclear whether this commonality is due to a common
underlying mechanism since leiomyomas have been shown
to share pathogenic features with development of metabolical
syndrome.52
Pathophysiology
Leiomyomas have a median of 9% change in volume in a
6-month period.53 Growth appears to be race related. Afri-
can American and Caucasian women had similar growth till
35 years of age, after which growth rates declined for Cau-
casian women.53 It is also shown that growth in fibroids is
not dependent on position of the fibroid in the uterus.54
Size of fibroids may be important as greater than 5 cm
diameter lesions have less short-term change.54
Gonadal Steroids: Estrogen and Progesterone
There are substantial in  vitro data supporting major roles
for both estrogen and progesterone in the biology of uterine
leiomyomas. The role of progesterone on myoma growth
has moved beyond the simplistic concept of increasing
mitosis to include inhibiting the apoptosis pathway via
B-cell lymphoma 2 (Bcl 2) induction.55-57 The apoptotic
inhibitor Bcl2 is present in leiomyomas but is largely unde-
tectable in myometrium. Recently the role of Kruppel-like
transcription factor 11 (KLF11) in integrating progesterone
mediated myoma cell signaling and proliferation has been
shown.58,59 Likewise, regarding estrogen action, local action
is likely key via an up-regulation of the enzyme aromatase
P450 and its gene CYP19.60-62 Other elements of estrogenic
response in myomas can also come into play as myoma cells
have a modest increase in type I isotype of 17β hydroxyster-
oid dehydrogenase.63
Modulation of steroid receptors is also important. Leio-
myomas have increased amounts of both estrogen and pro-
gesterone receptor (ER and PR) messenger ribonucleic acid
(mRNA) compared with normal myometrial tissue.64-66
Both the A- and the N-terminally truncated B-isoforms of
the PR appear to be present in both leiomyomas and myo-
metrium, however, the A-isoform predominates.67 Simi-
larly, ER-α rather than ER-β appears to be the predominant
form in leiomyomas.68 In addition to the direct action of
ovarian steroids on the uterus, it is possible that the repro-
ductive axis may also influence uterine metabolism through
the direct action of pituitary gonadotropins on the uterus.
Gonadotropin-releasing hormone (GnRH), which is clini-
cally used to reduce myoma size, abolishes gene expression
differences between normal myometrium and myomas.69
The placental glycoprotein chorionic gonadotropin (hCG)
has been shown by several laboratories to have direct
actions on myometrial metabolism.70-72 Additionally, work
has shown that follicle stimulating hormone (FSH), lutein-
izing hormone (LH), thyroid stimulating hormone (TSH),
and their common α-subunit can all have stimulatory effects
on uterine prolactin production.71,73 There appears to be a
variant LH/hCG receptor present in human uterine tissue
that may modulate this action.74,75 LH has also been associ-
ated with myoma formation but not growth independent of
the patient’s age.76 Finally genome wide microarray studies
have shown a strong role of glucocorticoids in pathogenesis
of fibroids.77
FIGURE 27.2  Histological evaluation of fibroid using hematoxylin
and eosin staining highlights both cellular bundles and the acellular
extracellular matrix. The extracellular matrix not only contains sig-
nificant amounts of collagen type I and III but can also act as a reser-
voir for growth factors such as basic fibroblast growth factor (bFGF).
Fibrotic Factors
Leiomyomas can also be viewed as fibrotic tumors with a
dynamic extracellular matrix (ECM) playing an important role
in pathophysiology (Fig. 27.2).78 This hypothesis dates back to
the 1990s where experiments demonstrated that the ECM
characterizing fibroids contains significant amounts of colla-
gen types I and III protein, and up-regulation of mRNA levels
occurs during the proliferative phase of the menstrual cycle
in leiomyomas but not myometrium.79 Other matrix compo-
nents including matrix metalloprotease stromelysin 3 (MMP
11) and dermatopontin (a collagen binding protein, also having
decreased expression in keloid scars) have also been shown
to be dysregulated in leiomyomas.80,81 Morphological arrange-
ment of extracellular proteins is also abnormal in myomas.82
The transforming growth factor-β (TGF-β) system also
appears to be involved in the pathophysiology of leiomyomas,
as in other fibrotic processes. A complete review of this topic
is beyond the scope of this chapter. Leiomyomas appear to
have higher levels of TGF-β and particularly TGF-β3 mRNA
and protein and this in turn affects cellular proliferation.1,83,84
Vitamin D supplementation has recently shown reversal of
TGF-β3 induced fibrosis in fibroids.85 Additionally, Granu-
locyte macrophage colony-stimulating factor (GM-CSF), con-
nective tissue growth factor (CTGF), TGF-β4 (also known as
lefty or ebaf, endometrial bleeding-associated factor), the sma
and mad related (SMAD) family of transcriptions factors and
the mitogen-activated protein kinase (MAPK) signaling path-
way appear to be part of the fibrotic pathway dysregulated in
myomas, or the myometrium or endometrium of the uterus
in women with leiomyomas or abnormal uterine bleed-
ing.86-92 Alterations in ECM can modify mechanical stress on
cells, leading to activation of Rho-dependent signaling. Acti-
vation of this solid state signaling and altered state of stress
may also contribute to fibroid growth.93,94
Angiogenesis
Angiogenesis, the formation of new blood vessels, is physi-
ological in the female reproductive tract as opposed to most
other tissues where it is pathological. Abnormalities in uterine

blood vessels and angiogenic growth factors also appear to
play a role in the pathobiology of myomas. The myomatous
uterus shows increased numbers of arterioles and venules as
well as venule ectasia.95 These changes are not confined to
the leiomyoma itself but also involve the myometrium and
the endometrium.96,97 Although such venous abnormalities
were originally postulated to be the result of physical com-
pression of the vascular structures by bulky myomas,1 it is
likely that molecular alterations are actually responsible for
increased vessel number or abnormal function.1,98
The process of angiogenesis involves interactions with
specific components of the ECM that are dysregulated in
fibroids such as collagens type I and III.99 There is also con-
flicting data regarding whether the resident immune cells
(especially mast cells) contribute to myoma physiology by
modulating angiogenesis.100
The basic fibroblast growth factor (bFGF) receptor-
ligand system appears to be a significant factor in leiomyoma
pathophysiology. In addition to promoting angiogenesis,
bFGF is a smooth muscle-cell mitogen and acts similarly
to estradiol on leiomyoma smooth-muscle cells.101-103 Leio-
myomas have increased levels of bFGF mRNA compared
to matched myometrium, a reservoir of bFGF protein in
the ECM and dysregulation of the endometrial type I bFGF
receptor.104,105
Genetic Influences: Clinical
There are several lines of evidence that suggest that fibroids
have a genetic component. First, monozygotic twins have
twice the rate of concordance for hysterectomy of dizygotic
twins.106,107 There is also familial clustering; with a two-
fold to sixfold increased risk of a woman having fibroids if
a woman has an affected first-degree relative.108,109 Finally,
there are also specific syndromes that have a demonstrated
genetic component and whose phenotype includes uterine
leiomyomas in association with other specific lesions:
Hereditary Leiomyomatosis and Renal Cell Cancer
(HLRCC, MIM 605839)*
This syndrome is autosomal dominant, and affected fami-
lies manifest cutaneous leiomyomas and papillary renal cell
carcinoma (RCC).110-112 Affected women can have uterine
leiomyomas as well as uterine leiomyosarcomas.110 Both
malignancies (sarcomas and RCC) are atypical in their pre-
sentation compared to their sporadic counterparts; uterine
sarcomas can appear in young premenopausal women, and
the papillary RCC is often metastatic at presentation and
more likely to be seen in women.110 Two other syndromes
had described only the association of cutaneous and uter-
ine leiomyomas, but lessons form molecular genetics sug-
gest these are incomplete forms of the HLRCC syndrome
and should be of historical interest only (Reed Syndrome
or Multiple Cutaneous and Uterine Leiomyomas [MCUL],
Mendelian Inheritance in Man [MIM] 150800).113,114
Fumarate hydratase (FH), an enzyme that is part of
the Krebs tricarboxylic acid cycle, is the gene mutation at
1q 42-43 responsible for hereditary leiomyomatosis and
renal cell cancer (HLRCC) syndrome.110,111,115,116 Germ-
line mutations appear to result in absent or nonfunctional
*The Web site: http://www3.ncbi.nlm.nih.gov/omim/contains the full
online catalog of these genetic disorders.
CHAPTER 27  Benign Uterine Diseases 589
proteins, and thus, FH appears to act as a tumor sup-
pressor.112,117,118 FH appears to play a role in a small per-
centage of nonsyndromic leiomyomas and in Caucasian
women.119,120
Although work on elucidating the pathogenesis of
HLRCC syndrome continues, FH mutations appear to
induce a change toward a hypoxic phenotype.120,121 Thus,
the hypothesized relationship between hypoxia and myoma
pathogenesis appear linked for this subset of leiomyomas.122
Currently identifying women at higher risk of malignancy
due to HLRCC syndrome is an important clinical task, just
as identifying women whose families carry the breast cancer
gene (BRCA) mutations.123 However, in the future, indi-
vidualized therapy will likely be possible based on genotype
and underlying predisposition genes.123
Cowden Disease (MIM 158350)
This disease is a type of hamartomatous polyposis syndrome
characterized by leiomyomas as well as other benign tumors,
including lipomas and hamartomas. It is autosomal dominant
in inheritance and has involvement of the candidate gene,
phosphatase and tensin homologue (PTEN).124-128 Patients
with Cowden disease have increased risk of endometrial, thy-
roid, kidney, and colorectal cancers. Around 40% of women
with Cowden disease are reported to have fibroids.129
Cytogenetic and Molecular Genetics
There is also cytogenetic and molecular genetic evidence
for the role of genetics in leiomyomas. Leiomyomas are
monoclonal, and each tumor is an independent clonal event.
Although this fact was originally investigated using G6PD
polymorphisms, androgen receptor polymorphism studies
concur.130,131
Secondly, certain cytogenetic rearrangements characterize
leiomyomas. Although 40% of fibroids are 46,XX,132 there
are specific karyotypic abnormalities that have been consis-
tent in a number of studies: t(12;14)—Translocations between
chromosomes 12 and 14, Trisomy 12, rearrangements of 6p,
10q, and 13q, and Deletion of 3q and 7q.123,132,133 There is
evidence that karyotypic evolution is a late event in the patho-
genesis of leiomyomas.131 There is also some evidence that
genotype is related to both fibroid size and location and that
specific karyotypic groups have specific gene expression pro-
files.132,134,135 Thus, many of the characteristics we attribute
to submucous fibroids, as an example, may be related to geno-
type and thus, the clinical heterogeneity we see may be more
intelligible when genotypic information is available.136
Many candidate genes identified for uterine fibroids
map to the regions involved in these karyotypic groups.
High mobility group protein A2 (HMGA2, formerly called
HMGI-C) is an architectural transcription factor located
on chromosome 12 that is involved in the pathogenesis of
fibroids with t(12;14).137,138 The HMGA2 gene is very large
(13 kb with 5 exons) and most translocations involving leio-
myomas map to the 5′ region of the gene.137,139 However,
recent evidence suggests that unique transcripts from the
opposite deoxyribonucleic acid (DNA) strand may also
play a role in pathogenesis.140 Diminished stature, early
age at menarche and higher risk of formation of fibroids
has been linked to HMGA2.141 HMGA1 (HMGI[Y])
codes for a related gene on chromosome 6p.142,143 Inter-
estingly, abnormalities in expression of HMGA2 in a
590 PART 2  Pathophysiology and Therapy
murine model produce abnormalities of fat deposition and
metabolism.144,145 Abnormal expression of HMGA2 could
therefore potentially explain the correlation of metabolical
syndrome in patients with fibroids.52
A genome wide association study (GWAS) from Japan,
determined significant associations with uterine fibroids in
three chromosomes 10q24.33, 22q13.1, and 11p15.5.146
Subgroup analyses revealed strong association of marker
­single-nucleotide polymorphisms (SNPs) with uterine
fibroids regardless of presence or absence of heavy or pain-
ful menstrual bleeding suggesting these SNPs are associated
with predisposition genes.146
Finally the role of mediator complex subunit 12 (MED12)
transcriptional factor, a mediator of both global and specific
gene transcription located on chromosome Xq13.1 has also
been described in the pathogenesis of uterine fibroids.147
MED12 was altered in 70% of tumors from 80 patients
studied in this report from Scandinavia and pathway
analysis suggested that ECM receptor interaction, Wing-
less family (Wnt) signaling and focal adhesion pathways
were altered by this change. 147 Whole genome sequencing
has recently shown MED12 mutations to be present fre-
quently in fibroids in racially and ethnically diverse Ameri-
can women confirming its importance as a key molecule in
fibroid pathobiology.148
Rad51L1, (hREC2) encodes an enzyme which repairs
double-stranded DNA breaks and is the only gene where
a fusion transcript appears to play a role in fibroid biology.
Rad51L1 is on chromosome 14, and there are reports that
in rare myomas with t(12;14) it forms a fusion transcript
with 5′ HMGA2.149-151 Inactivation of a tumor suppressor
gene, cut-like homeobox gene (CUTL1), acts in some myo-
mas to suppress transcription of the C-Myc oncogene.152
Finally, the Eker Rat model for leiomyomas has a germ-
line defect in the tuberous sclerosis complex 2 (Tsc-2) tumor
suppressor gene.153 In this model, recent work suggests
that there is a developmental window where the expres-
sion of disease is modulated by the effect of interaction of
the tumor suppressor and the steroidal milieu.153 This ani-
mal model and especially cell lines that have been created
from it have been a major asset for fibroid research. How-
ever, there are some facets of the Eker rat model that sug-
gest it may be a better model for syndromic fibroids such
as those seen in HLRCC syndrome rather than sporadic
fibroids. New murine models are under development that
may also aid researchers and also give insights into fibroid
pathogenesis.154 The high incidence of myomas may be
explained in part by the predominance of tumor suppres-
sor mechanisms.
A significant limitation of genetic studies is that they
have largely been conducted in areas where Caucasians
predominate and may not accurately reflect the karyotypes
seen in African American women. Given the different clini-
cal behavior of myomas in African American women, it is
reasonable to believe that unique genes may be contributing
to this risk. Association of a polymorphism in the catechol-
O-methyltransferase (COMT) gene seen more frequently in
African-American women was linked to leiomyoma risk.19
In  vitro work also suggests there may be differences in
growth factor regulation in leiomyomas from African Amer-
ican women.155 Linkage analysis for FH in non-syndromic
leiomyomas demonstrated a significant effect of race with
linkage only seen in Caucasian women and a negative rela-
tion in African American patients.120
Other Influences
Epidermal growth factor (EFG) is a growth factor mitogenic
for smooth-muscle cells and EGF mRNA is up-regulated in
leiomyomas only in the secretory phase of the cycle.156,157
Receptor levels appear to be similar in leiomyomas and
myometrium.158 Latest work concentrates on the role of
nicotinamide adenine dinucleotide phosphate (NADPH)
oxidase derived reactive oxygen species (ROS) for signaling
EGF and platelet derived growth factor (PDGF) signaling
pathway, leading to myoma cell proliferation.159
Heparin-binding growth factors are important biologi-
cal regulators in leiomyomas since they can be secreted
and bound to the reservoir of heparin sulfate proteoglycans
filling the leiomyomatous ECM. Heparin-binding epider-
mal growth factor (HBEGF), vascular endothelial growth
factor (VEGF), platelet-derived growth factor (PDGF),
­hepatoma-derived growth factor (HDGF), and the previ-
ously described basic FGF are all found in myomas.104,160
Many have also been documented to be stored in the ECM.
Insulin-like growth factors (IGFs) can act as smooth
muscle-cell mitogens and were originally shown to have
increased binding to leiomyomas compared to myome-
trium.158 However, assessment of mRNA levels suggests
that gene expression differed among studies.161-163 Later
studies suggested specific modulation of the IGF-binding
proteins.164 Recent work has shown the role of activation of
tyrosine kinases and especially the IGF-1 signaling pathway
in fibroids.165 Regulation of these factors following GnRH-
agonist treatment has also been reported.166 There may
also be increased prevalence of leiomyomas in women with
acromegaly.167
Prolactin also appears to play an important role in myoma
pathogenesis. In vitro studies suggest that it is mitogenic for
leiomyoma and myometrial smooth-muscle cells and that
the prolactin receptor is present in these tissues, setting
up an autocrine or local endocrine system.168 Additionally,
agents that appear to cause clinical regression of uterine
leiomyoma also appear to decrease prolactin production
in vitro.67,73
The resident immune cells also appear to influence leio-
myoma biology. Mast cells have been implicated in leiomy-
oma pathobiology given that they are generally uniformly
distributed in myometrium but highly variable in leiomyo-
mas.73 Recent work has suggested a correlation of mast cell
number with vasculature.169 A number of cytokines have
also been shown to be differentially regulated in leiomyo-
mas and myometrium. Interleukin 8 (IL8) has decreased
expression of both the ligand and its receptor in myome-
trium compared to leiomyomas.170 The functional signifi-
cance of this is shown by the fact that neutralizing antibody
to IL8 decreases cellular proliferation in  vitro.170 Mono-
cyte chemotactic protein-1 (mcp1) is largely undetectable
in normal samples of leiomyoma and myometrium but is
increased significantly following GnRH-agonist therapy.171
Wnt 7a, the human homolog of the wingless Drosophila
genes involved in anteroposterior (AP) axis formation and
smooth muscle-cell patterning, appears to be suppressed in
leiomyomas compared to normal myometrium and to be
inversely related to ER-α expression.172 In contrast, secreted

frizzled related protein 1 (sFRP1), a modulator of Wnt sig-
naling, is increased in leiomyomas (particularly in the late
proliferative phase) and increased by estradiol treatment and
hypoxia.173 HOX gene expression does not appear to differ
between leiomyomas and myometrium.174 The mRNA for
proto-oncogenes cfos and cjun are also overexpressed in leio-
myomas compared to normal myometrium.175
Parathyroid hormone-related peptide (PTHrP) mRNA is
also overexpressed in leiomyomas compared with normal
myometrium.176 Serum overexpression of this protein origi-
nating from a fibroid simulating the hypercalcemia of malig-
nancy has been reported in the literature.177-180
Micro RNAs (miRNAs) are small noncoding RNAs which
generally inhibit gene expression and appear to have a key
role in leiomyoma pathogenesis. While early studies showed
there was differential expression of specific miRNAs
between leiomyomas and normal myometrium and associa-
tion of key miRNAs with leiomyoma size and patient race,
more recent studies have started to define the key regula-
tory pathways they influence.181-184 In particular, dysregu-
lated miRNAs appear to be involved in multiple adhesion
pathways and multiple signally pathways including MAPK,
calcium, and insulin.183
Principles of Treatment
Uterine leiomyomas do not always necessitate treatment.
Generally, expectant management is appropriate until the
woman develops enough symptoms that she requests treat-
ment. The U.S. Agency for Healthcare Research and Qual-
ity on comparative management of fibroids has noted the
lack of published data that examines the effectiveness of
treatment strategies.185 There are two important caveats
to this generalization. First, although bleeding symptoms
are usually evident, bulk symptoms can be insidious in
their onset and often attributed to other processes such
as aging. An initial assessment of whether bleeding, bulk-
related symptoms, or both are prompting therapy helps to
guide appropriate therapeutic options.2 Women not elect-
ing therapy cannot reflexively be termed asymptomatic;
they may have substantial symptoms but view the therapies
they are offered as worse than the disease.2 As a second
step, assessing the patient’s desire regarding reproduction
helps refine the available options. In general, women with
complaints of heavy menstrual bleeding alone tend to have
more options for therapy (e.g., endometrial ablation, hys-
teroscopic myomectomy and hormonal therapy including
progestin containing intrauterine device (IUD) than women
with concurrent bulk-related symptomatology.
Finally, menopause can be a cure for women with myo-
mas. Clearly, heavy menstrual bleeding ceases with the
onset of menopause. However, not all women have enough
volume reduction to alleviate their symptoms. In addition,
bleeding symptoms may continue for women who elect
postmenopausal hormone replacement therapy (HRT), and
studies have suggested growth of myomas in women who
take HRT.25,186
Surgical Therapies
Hysterectomy provides the only cure for fibroids and will
remain a viable treatment option for the near term. Addi-
tionally, short-term outcome studies suggest that women
CHAPTER 27  Benign Uterine Diseases 591
with myomas experience improved quality of life following
hysterectomy, and hysterectomy also eliminates concomi-
tant conditions including adenomyosis, endometrial polyps,
and abnormal pap smears.2,187,188 Unlike the case in hyster-
ectomy for endometriosis, the ovaries can be retained with-
out losing therapeutic efficacy. Generally, women weigh
the risk of menopausal symptoms against the risk of ovar-
ian tumors in making this decision. The attention paid to
the ovary’s production of androgens postmenopausally and
their possible importance in mood and libido appears to be
leading to an increase in number of women who retain their
ovaries even if they are perimenopausal.189 The fact that
hysterectomy, even without oophorectomy, decreases the
risk of ovarian cancer may also affect decision-making on
this issue.190,191 Laparoscopic, rather than open hysterec-
tomy if possible should be a goal if this treatment modality
is chosen. As robot-assistance has shown reduction in likeli-
hood of conversion to laparotomy at time of hysterectomy,
there may be hidden potential in this new modality com-
pared to traditional aggressive surgery.192 Despite definitive
treatment, hysterectomy alone (without oophorectomy)
has been linked to increased incidence of cardiovascular
morbidity,193,194 prolapse,195 and worsening cognitive func-
tion including Alzheimer and Parkinson disease.196 These
long-term adverse outcomes should be kept in mind when
recommending hysterectomy as a surgical therapy.
Finally, the use of supracervical or subtotal hysterectomy
in women with leiomyomas is debated. The fact that 7%
of women in an unselected population have cyclic bleeding
following this type of hysterectomy deserves further study
to see whether these women had bleeding complaints or
fibroids prior to hysterectomy.197 Women may also run the
theoretical risk of the formation of cervical fibroids follow-
ing supracervical hysterectomy. Finally, accumulating data
suggests that, at least in the short term, sexual functioning is
not improved with supracervical hysterectomy.198,199
Nonetheless, as women seek less invasive and the health-
care system seeks less costly options, alternatives to hys-
terectomy will become more widely used. All surgical
alternatives to hysterectomy, however, share the risk of new
myoma formation what is commonly but incorrectly termed
fibroid “recurrence.” Unlike the similar phenomenon after
surgery in malignant disease, this is unlikely to be persis-
tence of the same tumor but instead growth of additional
tumors that may have been missed, not treated, resistant to
treatment, or not yet present at the time of initial therapy.
Thus, following a variety of techniques, including abdominal
myomectomy and uterine artery embolization, the risk of
subsequent procedures is significant.200,201
Since the 1930s, abdominal myomectomy has been the
traditional alternative to hysterectomy, because it preserves
the uterus and allows childbearing.202 However, open myo-
mectomy does have morbidity similar to that of hysterec-
tomy and has significant risk of subsequent surgery.203-205
Myomectomies are now increasingly being performed
laparoscopically, with or without robot-assistance. Rates of
conversion to laparotomy have been reported as low as 2%
after laparoscopic myomectomy206 and it has shown fewer
complications when compared to open myomectomy.207,208
Patients undergoing traditional myomectomy via laparot-
omy, when compared to robot-assisted myomectomy, had
more estimated blood loss and a longer length of stay in
592 PART 2  Pathophysiology and Therapy
the hospital.209,210 When outcomes from robot-assisted
laparoscopic myomectomy, standard laparoscopic myo-
mectomy and open myomectomy were compared, patients
with laparoscopic and robot-assisted procedures had similar
blood loss and length of stay, both of which were reduced
compared to the open procedure.211 Short-term surgical
outcomes are similar after robot-assisted myomectomy
and standard laparoscopic myomectomy.212 Reports have
shown increased operating time with robotic procedures,
however rate of complications are low compared to open
surgery.211,213,214 Using single port laparoscopy or laparoen-
doscopic single-site surgery (LESS) has led to success for
myomas; however, since this is the newest form of laparo-
scopic innovation, data is limited.215-217
Abdominal myomectomy permits healthy pregnancies
after surgery and pregnancy rates have been reported to
be in the 50% to 60% range.218 Uterine rupture following
myomectomy is very rare at 0.5% to 1% and is suggested
that it may be related to surgical technique.219 The com-
mon clinical practice of counseling women who have had a
myomectomy with a transmural uterine incision to undergo
an elective cesarean section is based on this risk of uter-
ine rupture following classical cesarean delivery. However,
there is no evidence they are analogous situations.220 There
is enough evidence to question the rationale for the con-
ventional practice and recommendation of cesarean delivery
after myomectomy, even if the endometrial cavity has been
breached.221-225
Though laparoscopic myomectomy involves much
smaller incisions and a quicker recovery time, it does
require a surgeon skilled in laparoscopic suturing and not all
women have the size and number of fibroids amenable to
this technique. While updated series suggest that the risk of
uterine rupture is low following laparoscopic myomectomy,
rare cases continue to be reported.226-230 Because these
uterine ruptures typically occur remote from term, appro-
priate counseling for patients contemplating pregnancy
is important, especially if devascularization with cautery
occurs intraoperatively. Data is very limited on obstetrical
outcomes following robot-assisted myomectomy, but the
few reports have been reassuring.231,232
Myolysis is a variation on the technique of laparoscopic
myomectomy in which the leiomyoma tissue is coagulated
rather than removed.233 While this technique is easier to
master than laparoscopic morcellation or suturing, localized
destruction without repair may also increase the chance of
uterine rupture and adhesion formation.234
For women with submucous myomas, the use of hys-
teroscopic myomectomy has distinct advantages. With
their accessible location, type 0 and I (European Society
of Hysteroscopy Classification) myomas can be resected
with an intrauterine operative endoscope with good long-
term results.235 Although this procedure requires highly
skilled practitioners, it can be done as outpatient surgery,
often with a regional or local anesthetic and sedation
that eases recuperation. Symptomatic relief is good with
fewer than 16% of women in one large series who were
treated for menorrhagia reporting second surgeries after
9 years.235-237 Fertility rates appear excellent after hystero-
scopic myomectomy, and there have been no case reports
of uterine rupture after uncomplicated hysteroscopic
myomectomy.238
For women who have completed childbearing and for
whom bleeding is the primary problem, endometrial abla-
tion, either alone or in combination with hysteroscopic
myomectomy, may give relief with minimal invasiveness.239
Increasingly, a levonorgestrel IUD can be used for a “revers-
ible endometrial ablation.”240,241 In addition to providing
effective control of bleeding, it provides contraception for
women in this premenopausal age group, in contrast to sur-
gical endometrial ablation which leaves women at risk for
tubal and cervical and cervical ectopic pregnancies.
Uterine Artery Embolization (UAE)
Transcatheter arterial embolization has long been an effec-
tive percutaneous technique for controlling bleeding in a
wide variety of disorders. Its use for the treatment of leio-
myomas was first reported in 1995.242 Although initially
used as an alternative for patients who were felt to be poor
surgical candidates, the resolution of symptoms in the initial
cohort encouraged the use of this technique as a primary
therapy.
UAE is increasingly the first line alternative to hysterec-
tomy for women with bulk-related symptoms and no desire
for future pregnancy,243,244 and has been recommended
by the American Congress of Obstetrics & Gynecology
(ACOG) as a safe and effective form of uterine preserving
treatment for fibroids.220 It provides a decrease in heavy
menstrual bleeding and bulk-related symptoms in 75% to
85% of women and a volume reduction of 30% to 46% over
up to 5 years of follow-up.244 Need for a second form of
intervention after UAE is noted to be somewhere between
9% and 32%.245-248 Previously thought of as a contraindica-
tion, fibroids greater than 10 cm diameter in size, have been
shown to be treated successfully with UAE.249,250
A series of randomized clinical trials (RCT), mostly con-
ducted in Europe, have compared outcomes of up to 5 years
for women undergoing UAE and surgery (which included
hysterectomy and/or myomectomy). These studies show
women undergoing UAE have less pain, shorter hospital stay,
a quicker return to work, equal post treatment symptom
scores (based on standardized and validated questionnaires),
no difference in health-related quality of life years and less
healthcare costs when compared to surgery.245,246,248,251-253
It is relatively common for submucous myomas to be
expelled vaginally after treatment244 and thus, most hys-
teroscopically-resectable fibroids are still approached sur-
gically. Similarly, the presence of pedunculated subserosal
fibroids has historically been considered a relative contra-
indication to UAE therapy although no cases have been
reported of intraperitoneal expulsion. There is some data
that suggests that UAE can still be performed in these cases
of pedunculated fibroids.254,255 A laparoscopic approach
can also be considered in such patients. Studies also sug-
gest that high T2 signals predict greater volume reduc-
tion and complete devascularization predicts outcome at
5 years.256-258
Most patients develop significant pain and some vagi-
nal discharge following the procedure and usually require
intravenous narcotics for pain control. “Postembolization
syndrome,” defined as the combination of diffuse abdomi-
nal pain, mild fever, and mild leukocytosis is common and
can occur in 30% to 40% of patients and gradually improves
over a week.

It is important to assess the effects of UAE on the abil-
ity of women to become pregnant subsequently or to
carry a pregnancy to term. Thus far, there are a number of
reported patients who became pregnant following UAE.259-265
Although no difference in intrapartum adverse outcomes
was noted when patients after UAE were compared to
patients after myomectomy, cesarean delivery rate was
increased in both groups.260,263 Pregnancy clearly can and
does occur following UAE with success rates reported from
20% to 60%,263,265 however, the risk of spontaneous miscar-
riage in these women has been noted to be higher compared
to women with fibroids that have not undergone UAE treat-
ment.266 There are two major areas of caution for women
wishing to optimize their fertility potential: effects on ovar-
ian function and myometrial wall integrity.
Due to increased placental implantation issues after
UAE, close monitoring of the placental status has been rec-
ommended.264 Around 13% of women in one series, who
were nulliparous and had no other risk factors, had some
form of placenta previa or accreta in one series.264 The early
data on ovarian damage used amenorrhea as the indicator
of perturbed ovarian function.267,268 It is clear that amen-
orrhea risk is age related with women under 40 having a
3% risk and women over 50, a 41% risk.267 Newer stud-
ies evaluate follicle stimulating hormone (FSH) and anti-
müllerian hormone (AMH) levels to detect more subtle
damage.269-272 While studies with short-term outcome may
not show impact,270 most have shown an age dependent
risk, with risk increasing more so after 45 years of age.269,271
Compared to hysterectomy, UAE causes more of a decre-
ment in AMH levels after a 2-year follow-up following UAE
treatment.272 However, it is often overlooked that surgery
also has an adverse impact on ovarian reserve. A putative
mechanism is suggested in another report that indicated sig-
nificantly increased FSH levels following UAE in patients
with utero-ovarian vascular anastomoses.271
Focused Ultrasound: Non-Invasive Treatment
MRI guided focused ultrasound surgery (MRgFUS) pro-
vides a noninvasive ablation method that is FDA-approved
for the treatment of uterine fibroids since 2004. While pio-
neered for the treatment of uterine fibroids, this modality
can be used to treat multiple diseases and may prove to be
the next step in surgical innovation from open to minimally
invasive to noninvasive approaches.
Just as a laser amplifies and collates light into a thera­
peutic modality, FUS can deliver a large amount of energy
to target tissues in a noninvasive way. Treatment is accom-
plished by placing a transducer against the abdomen, target-
ing an intraabdominal myoma without breaching the skin.
The intensity of FUS used for treatment is significantly
higher than that used in diagnostic ultrasound and can rapidly
increase temperature at the focal point in excess of 70° C.
At this temperature, coagulative necrosis will occur.273 The
procedure is performed under conscious sedation. After
T2-weighted images are obtained (to develop a treatment
plan), FUS sonications are targeted at the fibroid while MRI
provides continuous thermal feedback.
The strongest predictor of MRgFUS success is the
nonperfused volume (NPV) or the area devascularized by
treatment that is nonperfusing in post treatment gadolin-
ium imaging in the fibroid achieved after treatment.274-280
CHAPTER 27  Benign Uterine Diseases 593
Seventy one percent of women reached a target symptom
reduction score on the uterine fibroid symptom and quality
of life (UFS-QOL) questionnaire281 at 6 months and 51%
maintained this at 12 months in one of the pivotal trials.276
In newer studies as higher NPV rates were achieved, quality
of life improved.282 Volume reduction is again proportional
to NPV achieved after treatment. Up to 40% reduction in
volume has been noted in fibroids after MRgFUS treat-
ment.280 When low NPV (of around 26%) was achieved,
28% of patients ended up with an alternative form of treat-
ment at 12 months after MRgFUS.282 Newer reports with
higher NPV achieved (around 60%) led to failure of treat-
ment in only 8% of women.283
Complications from MRgFUS are very rare. The most
common complication is skin burns. These can occur
because of poor coupling or abdominal scars on the patient
that are encountered within the FUS bean pathway. An early
trial reported around 5% risk of burns.276 Only one case of
extensive skin burns has been reported.284 Use of acoustic
reflectors (like cork or foam) and an energy-blocking patch
on scars has shown success in prevention of burns.285,286
A parallel enrollment trial compared MRgFUS to
abdominal hysterectomy, and recorded significant clinical
complications and short form health survey (SF-36) at 1,
3, and 6 months. Clinically significant complications were
lower in MRgFUS group, with SF-36 scores improved in
both arms at 6 months, however, they were significantly
better in the hysterectomy group.287 There is currently an
NIH funded randomized clinical trial comparing MRgFUS
to UAE (NCT00995878, clinicaltials.gov) which should
provide important information. Studies have also shown
MRgFUS to be in the range of currently accepted criteria
for cost effectiveness.288,289
Subsequent pregnancy related complications after MRg-
FUS treatment are minimal. Forty five pregnancies in 51
women were reported in the only published series.290 Live
birth rate of 41%, mean birth weight of 3.3 Kg, spontaneous
abortion rate of 28%, and term delivery rate of 93% was
noted.290 At least one patient with a fibroid impinging on
the cavity and unexplained infertility, conceived spontane-
ously after MRgFUS treatment.291
Ultrasound-guided focused ultrasound (typically referred
to as high intensity focused ultrasound, HIFU) has been used
to treat several solid tumors outside the United States.292
Since feasibility studies showed promising results for use
of ultrasound guided-HIFU for uterine fibroids293,294 larger
studies have been reported. These reports have not only
demonstrated safety and efficacy of ultrasound guided-
HIFU for treatment of uterine fibroids,295-297 but also
shown safety of pregnancy within 1 year of treatment in
one report.298
Medical Therapies
There is a lack of randomized trials to demonstrate effec-
tiveness of medical management of fibroids.299 Oral con-
traceptive pills, progestins, nonsteroidal antiinflammatory
drugs, antifibrinolytic agents, androgenic compounds, and
progestin loaded intrauterine devices, all of which are use-
ful in the treatment of idiopathic heavy menstrual bleeding,
have not been studied with leiomyoma–related bleeding.
Nonetheless, they are widely used and are likely effective
in at least a subset of women with fibroids. A systematic
594 PART 2  Pathophysiology and Therapy
review suggested that in trials when women were assigned
to medical therapy at least 60% of them had undergone sur-
gery by 2 years.240
GnRH-Agonists
Since the action of native GnRH depends on its pulsa-
tile release, the effects of GnRH-agonists depend upon
their continuous presence. They first cause a time-limited
increase in gonadotropin release, termed the flare. This sub-
sequently leads to receptor downregulation, followed 1 to
3 weeks later by a hypogonadotropic hypogonadal state. It
is this down-regulated phase that is useful clinically in the
treatment of myomas. Alterations of the GnRH molecule,
typically at the two glycine (G) residue positions 6 and 10,
produce a longer half-life and are more useful for clinical
purposes.
Many studies have focused on the efficacy and benefits
of GnRH-agonist treatment for women with fibroids. Most
women experience a substantial reduction in mean uterine
volume of 30% to 60% over 3 to 6 months of therapy.300,301
However, there is a wide range of responsiveness with rare
individuals achieving no volume reduction. Both the estra-
diol levels at week 12 and the weight of the woman are cor-
related with the degree of uterine shrinkage.301
The other primary benefit of GnRH-agonist treatment
is the induction of amenorrhea. Menses typically return 4
to 10 weeks following the end of GnRH-agonist treatment.
Fibroid and uterine volume usually returns to pretreatment
size within 3 to 4 months. The rapid return of ovarian ste-
roidogenesis, coupled with an increase in the concentra-
tion of estrogen receptors in fibroids recently treated with
GnRH-agonists, may contribute to the rapid regrowth of
these tumors.302
GnRH-agonists can have significant adverse effects,
the most important of which is bone loss. Six months of
GnRH-agonist treatment can cause a 6% loss in trabecu-
lar bone, not all of which is reversible on discontinuation
of therapy.300 Symptomatic side effects of GnRH-agonist
therapy are common. Hot flashes are universal in women
undergoing treatment. Other less common side effects
include sleep disturbance, irregular vaginal bleeding, vaginal
dryness, headache, depression, hair loss, and musculoskel-
etal symptoms.300
Because of the concerns regarding bone loss with GnRH-
agonists, clinical use of these drugs is typically confined to
use as preoperative therapy or in women for whom a short
period of treatment will be effective. The GnRH-agonist,
Lupron® is FDA-approved for the presurgical treatment of
uterine fibroids to correct anemia in conjunction with iron
administration.303 This is the only medical treatment FDA
approved for treatment of this disease.
Administration prior to either hysterectomy or myo-
mectomy is the most common current use of these agents.
Length of therapy varies from 1 to 6 months depending
on the surgical and hematological goals and the planned
procedure. The amenorrhea induced by GnRH therapy
leads to improved hemoglobin concentrations, which per-
mits women who are anemic to correct this problem and
potentially to donate their own blood for transfusion. Pre-
operative GnRH therapy also has been shown to reduce
intraoperative blood loss significantly.303 Although current
guidelines from ACOG suggest that use of GnRH-agonists
is beneficial preoperatively, they also state that for each
individual the benefit must be weighed against the cost and
the side effects.220
GnRH-Agonist Therapy with Estrogen and Progestin
Add-Back Regimens
For many women, 3 to 6 months of symptomatic relief
from leiomyomas does not allow them to avoid surgery
but does afford them the opportunity to prepare them-
selves optimally for an operation. Therefore, the concept
of adding additional therapy to minimize the side effects
of prolonged therapy was developed, the so-called add-
back regimens.304-306 The goal of add-back regimens was to
achieve a window of therapeutic efficacy during which side
effects would be lessened or eliminated, yet no regrowth of
the myomas would occur.
Studies have utilized one of two treatment strategies:
simultaneous and sequential administration. With simulta-
neous treatment regimens, both the GnRH-agonist and the
add-back regimens are started at the same time. In sequen-
tial treatment regimens, the GnRH-agonist is given alone
for up to 6 months before steroid hormone treatment is
added reducing a period of hypoestrogenism before steroid
add-back therapy is started. Studies have suggested that
sequential treatment is superior for therapeutic efficacy in
the treatment of fibroids.305
Innovative GnRH-Agonist Add-Back Therapies
The estrogen receptor antagonists, tamoxifen and raloxi-
fene, have been used in randomized prospective 6-month
studies in a simultaneous add-back study design with the
GnRH agonist.307,308 Results were conflicting. No change in
myoma size was noted when 20 mg of tamoxifen was used;308
whereas, when 60 mg of tamoxifen was used a reduction in
myoma size, but not symptoms, was noted.307 Studies using
raloxifene (60 mg/day) therapy in postmenopausal women
with leiomyomas were able to cause a reduction in size.309
Tibolone, a synthetic steroid, has been used as a single agent
for menopausal HRT for its combination of estrogenic and
progestational actions in the same molecule.310 This medi-
cation has been studied in premenopausal women receiving
GnRH-agonists for the treatment of myomas.311 There was
no inhibition of uterine shrinkage with tibolone, and patients
showed preservation of bone density as well as symptomatic
improvement. Thus, tibolone may be used as a single-agent
add-back in the future.312 Ipriflavone, an isoflavone that is
a weak estrogen modulator, has been studied in add-back
regimens.313 Although originally studied to determine its
effect on bone, it appears effective in slowing bone loss and
decreasing symptoms without impeding the volume reduc-
tion of GnRH-agonist therapy.
GnRH-Antagonists
GnRH-antagonists have also been studied in the treatment
of uterine leiomyomas.314-317 The lack of flare effect and
rapid onset of action give them an advantage over GnRH-
agonists. Although they are not Food and Drug Administra-
tion (FDA)-approved for this indication, they have several
significant advantages over GnRH-agonists. However, in the
United States, these agents are marketed for use of ovula-
tion induction and long-term preparations are not available.
This could make treatment of fibroids cumbersome.

Progesterone Modulators
Clinical data regarding the efficacy of progesterone mod-
ulators has conformed the importance of progesterone in
myoma biology. A concern of paramount importance while
using progesterone receptor modulators (PRMs) is the poten-
tial of increased risk of endometrial hyperplasia or cancer.
Pathologists have however shown a unique histological pat-
tern in patients on these medications.318 These PRM-asso-
ciated endometrial changes do not have typical molecular
signatures of malignant progression,319 however, long-term
data is still lacking.
Mifepristone (RU486) is a steroidal derivative of nor-
ethindrone, which acts primarily as an antiprogestin. It
has, in high doses (50 mg/day), shown reduction in myoma
size comparable to GnRH-agonists.319 Thus, the clinical
benefit was equivalent to that seen with GnRH-agonists,
yet follicular levels of estradiol were maintained to sup-
port bone mass and provide symptomatic relief. Identical
results were found with a reduction in dose to 25 mg/day;
however, with a 5 mg/day dose, although acyclicity was
maintained, volume reduction was reduced to 30%.319-325
More recent studies suggest that doses of 5 and 10 mg
produce volume reduction equivalent to those elicited by
the higher doses, but produced amenorrhea in only 60% to
65% of women but did result in decreased menstrual blood
loss.320,324 Nonetheless, this provides significant symptom-
atic improvement. Mifepristone has mild side effects com-
pared with GnRH-agonists. Adverse effects included mild
and infrequent hot flashes in approximately 20% of patients
during the first month of treatment only with higher doses;
however, more persistent symptoms appeared in another
study. Mifepristone is not approved for use by the United
States FDA. A major impediment to off-label use is that the
current available dose of RU486 is not appropriate (200 mg
once for pregnancy termination versus 5 to 10 mg/day for
fibroid treatment for 6 months).326
Ulipristal acetate, another PRM, was recently compared
with placebo at 5 or 10 mg once daily for 13 weeks in a ran-
domized control trial.327 The medication resulted in resolu-
tion of heavy menstrual bleeding and significant reduction in
fibroid volume, in women with uteri of less than 16 weeks
gestational size.327 There were also no findings of endome-
trial hyperplasia with its use. In another noninferiority trial,
ulipristal was compared to GnRH-agonists, at 5 or 10 mg
a day for 13 weeks.328 Both arms had comparable rates of
resolution of heavy menstrual bleeding, however, ulipristal
resulted in less myoma size reduction compared to GnRH-
agonist but a more rapid induction of amenorrhea.328 Data
from the supplementary appendix of these studies suggests
that PRMs provide more prolonged volume reduction after
treatment is discontinued compared to GnRH agonists.328
Endometrial biopsies from women on ulipristal revealed
a carryover effect of this medication after 3 months of
therapy that lasted up to 6 months.327 Women with symp-
tomatic fibroids thus may have the option of a unique inter-
mittent therapy with this medication.329 Like Mifepristone
however, the available FDA approved formulation (30 mg
tablet) makes off-label use for fibroids problematic.
Other PRMs are being studied for the treatment of uter-
ine leiomyomas.330 These drugs appear to have efficacy sim-
ilar to mifepristone but decreased side effects and increased
specificity when interacting with the progesterone receptor.
CHAPTER 27  Benign Uterine Diseases 595
Aromatase Inhibitors
Aromatase inhibitors have shown to decrease symptoms
from fibroids and shrinkage in size when given to women
that were pre- or peri-menopausal.331-334 A randomized trial
compared letrozole at 2.5 mg/day to triptorelin (3.75 mg/
month) for 12 weeks in 70 women with a single fibroid
≥5 cm size. A statistically significant volume reduction in
myoma size was noted in the letrozole group vs. the trip-
torelin arm (45% versus 33%).334 Serum hormone levels
were also significantly reduced in the triptorelin arm vs. the
letrozole group.334 Extensive data regarding the safety, effi-
cacy, and cost-effectiveness of this class of medications as
medical therapy for uterine fibroids is still lacking.
Serum Estrogen Receptor Modulators
Selective estrogen-receptor modulators (SERMs), which
exhibit tissue-specific agonist or antagonist activity, appear
to work better in animal models of myomas than in clinical
trials. Studies have examined both tamoxifen and raloxifene.
Clomiphene has not been studied and has been reported to
cause growth of a myoma in a single case report.335 Despite
promising results in animal models,336,337 clinical studies
have had less impressive results.309 However, in premeno-
pausal women, raloxifene alone or when combined with
GnRH agonists demonstrated little efficacy despite use at
three times the conventional dose.307,338
Androgens
Danazol, an androgenic steroid most commonly used for the
medical treatment of endometriosis, can be used to induce
amenorrhea in order to control anemia due to fibroid-related
heavy menstrual bleeding. A second androgenic steroid,
gestrinone, has been shown to cause volume reduction and
amenorrhea in women with myomas.339 A great advantage
of this drug is that, after it is discontinued, there is a carry-
over effect like those of PRMs; in one study, 89% of the
women maintained a decreased uterine volume 18 months
after cessation of therapy.339 Unfortunately, gestrinone is
not available in the United States. However, androgenic side
effects including acne, hirsutism, and irreversible deepening
of the voice have limited its clinical use.
Growth Factor-Directed Treatments
Particular factors which appear to be relevant to leiomyoma
biology include the angiogenic factor basic fibroblast growth
factor (bFGF), the fibrotic growth factor transforming
growth factor-beta (TGF-β), and insulin-like growth fac-
tors I and II (IGF I and II), which mediate the effects of
growth hormone (GH).1,122 These molecules, as well as
other growth factors, are likely to be targets for leiomyoma
treatment in the future.
GH-Directed and IGF-Directed Therapy
Both growth hormone (GH) and the IGFs appear to have
metabolical effects on uterine leiomyomas and the sur-
rounding myometrium.164 Because women with acromeg-
aly (an excess of growth hormone) have a high incidence
of leiomyomas, researchers decided to test the hypoth-
esis that interfering with the growth hormone axis might
work as a treatment for leiomyomas.167 Lanreotide (a
long-acting somatostatin analogue) has been used in seven
premenopausal women with uterine myomas in a pilot
596 PART 2  Pathophysiology and Therapy
study in Italy.340 Over the 3 months of treatment, both
uterine volume and the volume of the largest leiomyoma
were significantly reduced by 24% and 42%, respectively.
Three months following the discontinuation of therapy
there was some regrowth, but a significant reduction in
uterine volume persisted at 17% and 29%, respectively.
Levels of estradiol were not affected by this treatment,
though both plasma GH and IGF-I levels were signifi-
cantly reduced and additional pathological modulators
may be effective.341
Anti-Angiogenic Therapies
There is significant evidence that the angiogenic factor
bFGF and its type I receptor are important in the patho-
genesis of leiomyoma-related bleeding.104,105 In a variety
of systems, interferons (INF) IFN-α or INF-β antagonize
the effects of bFGF and have proven clinically useful in the
treatment of a variety of vascular tumors. In vitro studies of
leiomyomas demonstrate that IFN-α is an effective inhibitor
of serum-stimulated and bFGF-stimulated DNA synthesis
in both leiomyoma and normal myometrial cells, as well as
in endometrial cells.103 A case report also raises the possibil-
ity that IFNs may provide effective treatment for fibroids.
A premenopausal woman who was treated with IFN-α for
hepatitis C was noted to have significant shrinkage of a leio-
myoma after 7 months of interferon therapy.342 Tranilast
[N-(3′4′-dimethoxycinnamonyl) anthranilic acid (N-5′)], a
drug currently used in the treatment of a variety of allergic
conditions, has been shown in vitro to decrease leiomyoma
cellular proliferation by arresting cells at the transition from
G0 to G1 phase.343 While it acts as an angiogenesis inhibitor,
it also works as a mast-cell stabilizer and a fibrosis inhibitor,
which may have relevance for leiomyomas.343
Current research also involves work on the role of reti-
noic acid,344,345 Vitamin D,346,347 and green tea compo-
nents348 in preventing fibroid formation.
Adenomyosis
Adenomyosis, formerly termed endometriosis interna, is
another benign uterine disease characterized by the pres-
ence of ectopic endometrial glands and stroma within the
myometrium (Fig. 27.3). Furthermore, the surrounding
myometrium is usually altered to produce hypertrophy.
Disease ranges from grossly visible nodules termed ade-
nomyomas, which can clinically resemble leiomyomas, to
disease that is only detectable by microscopy. Definitions
vary for the abnormal presence of gland within the stroma,
with most settling on a definition of glands found one to
three low-power fields from the endomyometrial junction.
Clearly, differences in definition will lead to differences in
perceived rates.
Classically, an adenomyotic uterus is termed boggy,
globular, and symmetrically enlarged. However, this disease
coexists with many other uterine conditions. One study
has argued that adenomyosis is not indeed a true disease
but a variant of the norm as women had similar symptoms
for hysterectomy with and without adenomyosis.349 Most
women in this study were perimenopausal which could have
been a major selection bias.
Adenomyosis can affect around 20% to 65% of women,350
though the accuracy of these numbers can be questioned
FIGURE 27.3  A T2-weighted fast-spin echo (FSE) image of the ade-
nomyotic uterus. Adenomyosis is characterized by proliferation of
glandular elements of the uterus so that bright (white) areas similar
in intensity to the endometrial cavity are seen deep into the uterine
wall. The uterine walls can be asymmetric in this disease, and in this
image the posterior wall is markedly thicker than the anterior wall.
Thickening of the junctional zone, another characteristic of adeno-
myosis is not seen in this image.
since diagnosis can only be made with certainty by micro-
scopic examination of the uterus typically after a hyster-
ectomy. In another series of hysterectomies, adenomyosis
appears in about one quarter of all uterine specimens but
is no more likely to coexist with symptomatic leiomyomas
(23.3%) than with endometrial cancer (28.2%) or ovarian
cancer (28.1%).351
Unlike leiomyomas, adenomyosis is associated with
increasing parity.351-356 It is estimated that at least 80% of
women with this disorder are parous. However, this may be
a confounding variable since women with a history of multi-
ple pregnancies may simply have had more indications and/
or inclination to proceed to hysterectomy during which the
diagnosis could be made. Studies that suggest the presence
of adenomyosis with imaging modalities rather than histopa-
thology have suggested the presence of this disease process
in adolescents as well.357,358 The California Teachers Study
noted clinical differences in women with endometriosis
and adenomyosis.354 Women with adenomyosis were older,
had higher parity, early menarche, shorter menstrual cycles
and were more obese compared to women with endome-
triosis.354 Another study compared women with presence
of fibroids and adenomyosis to women with fibroids only.359
Women with both fibroids and adenomyosis had more pelvic
pain and dysmenorrhea, higher parity, a history of previous
uterine surgery and had more clinical depression compared
to women with fibroids only.359 Women with histopathol-
ogy proven adenomyosis were more likely to have a his-
tory of previous uterine surgery in several reports.355,359,360
Data regarding smoking as a risk factor for adenomyosis is
controversial.353,356

Clinically, adenomyosis has similarities to leiomyomas
in that its peak incidence is in women ages 40 to 50 years
old with approximately 60% of women reporting abnormal
uterine bleeding, chiefly heavy menstrual bleeding. Abnor-
mal distribution of thick and dilated vessels in the endome-
trium, particularly in the secretory phase of the menstrual
cycle, is one explanation for heavy menstrual flow in such
women.361,362 Dysmenorrhea is the other frequent symp-
tom of adenomyosis, occurring in approximately one quarter
of all cases.350 Dysmenorrhea has been correlated with deep
penetration and/or a high density of endometrial glands
within the myometrium.363 Abnormal uterine bleeding in
the presence of adenomyosis is now classified as FIGO class
AUB-A type of bleeding (see the section on abnormal bleed-
ing later in this chapter).364
The most widely quoted hypothesis regarding the patho-
genesis of adenomyosis is that invasion of the myometrium
by the endometrium induces hypertrophy and hyperplasia
of the myometrium. Proponents of this theory often quote
the association of parity with adenomyosis to suggest that
disruption of the layers of the uterus at the time of preg-
nancy and cesarean delivery may predispose to this condi-
tion. However, experimental evidence indicates instead
that adenomyosis can be metaplastic process or a devel-
opmental defect. First, adenomyosis has been diagnosed
in a woman with Rokitansky-Kuster-Hauser syndrome,
who lacked eutopic endometrium.365 Additionally, stud-
ies comparing the molecular expression of growth factors
show distinct differences between ectopic and eutopic
endometrium.89,366-369 Factors that appear common to the
pathogenesis of leiomyomas and adenomyosis include angio-
genic factors such as bFGF, fibrotic factors including GM-
CSF, the gonadotropin receptor LH, and resident immune
cells.89,368,370-374 The efficacy of some conventional and
investigational therapies may be mediated through these
systems.375,376
Gonadal steroid hormones also play a role in patho-
physiology of adenomyosis. Adenomyotic implants express
higher aromatase and estrone sulfatase activity,377,378 and
also have polymorphisms in estrogen receptors (ER).379
In  vitro studies have shown normalization of aroma-
tase activity by gonadotropin releasing hormone agonists
(GnRH) and danazol, but there is lack of data to show
these effects in vivo.375,377 The role of estrogen and ER in
adenomyotic implants is further supported by the fact that
endometrial hyperplasia was more prevalent in women with
adenomyosis in one report.380 A murine model of adeno-
myosis also supports this, as early tamoxifen exposure in
these mice lead to development of adenomyosis and abnor-
mal myometrium.381
Interestingly, another murine model of adenomyosis has
been developed by placing a graft of pituitary tissue in a
uterine horn.382,383 Prolactin appears to be the key patho-
genic agent in this model: the mice have elevated levels of
plasma prolactin, and administration of bromocriptine pre-
vents the development of adenomyosis.382,384 In this model,
there does appear to be endometrial cell invasion due to
degeneration of myometrial cells.383 Indirect exposure of
the uterus due to hyperprolactinemia secondary to selective
serotonin reuptake inhibitor (SSRI) medications can also
induce adenomyosis.385 This theory is further strengthened
by recent work that showed both clinical depression and
CHAPTER 27  Benign Uterine Diseases 597
antidepressant use to be increased in women with adeno-
myosis.359 A second model using the FORKO (follitropin
receptor knockout mouse) suggests that the rising levels of
FSH seen with aging may also play an important pathogenic
role in this disease.386
Although definitive diagnosis of adenomyosis requires
histology, imaging techniques are increasingly able to sug-
gest the appropriate diagnosis. Both transvaginal ultrasonog-
raphy (TVS) and magnetic resonance imaging (MRI) are
used for this purpose. MRI is a better imaging modality for
adenomyosis but is expensive. It can also differentiate very
well, between an adenomyoma and a fibroid.387 TVS is a
less expensive imaging technique but is known to be opera-
tor dependent. A review of 23 articles comparing sensitivity
and specificity MRI and TVS revealed both techniques to
have similar sensitivity (0.72 for TVS and 0.77 for MRI)
and specificity (0.81 for TVS and 0.89 for MRI).388 Com-
puted tomography has no role in diagnosis of adenomyo-
sis389 and needle biopsy should be reserved for cases where
malignancy needs to be ruled out.390
The only definitive treatment for adenomyosis is total
hysterectomy. GnRH-agonist treatment has been shown to
produce amenorrhea, a transient decrease in uterine size
and even in the ability to conceive.391-393 Other medical
therapies include use of levonorgestrel-releasing intrauter-
ine device,394-397 and a single case report of danazol con-
taining intrauterine device.398 Unfortunately, resumption
of pretreatment uterine size and recurrence of symptoms
are usually documented within 6 months of cessation of
therapy.396
Data regarding conservative surgery (if adenomyoma
present) are scarce. Adenomyomectomy has been reported
to improve symptoms of adenomyosis,399,400 and one study
reports conservative surgery and GnRH medical therapy
following treatment to be superior to surgery alone.401
Other reported techniques include endomyometrial abla-
tion and laparoscopic myometrial electrocoagulation which
appear to decrease symptoms in more than half of patients
with 3 years of follow-up data.402,403
Both UAE and MRgFUS have been reported for the
treatment of adenomyosis. UAE can achieve success rates
of approximately 50% over a 36-month follow-up.404 In a
recent report after a median follow-up of 58 months around
18% women ended with a hysterectomy, however, 73%
of women were completely asymptomatic.405 For MRg-
FUS, the largest study to date included 20 patients with a
6-month follow-up and indicated safe and effective MRg-
FUS therapy in all subjects enrolled.406 Another MRgFUS
case reports a spontaneous pregnancy with full term deliv-
ery after treatment.407 Ultrasound-guided high-intensity
focused ultrasound ablation has also been studied in one
report.297 Seventy eight patients with adenomyosis were
enrolled and after a mean follow-up of 24 months around
90% of the patients had complete relief of symptoms.297
As imaging techniques get better, adenomyosis is being
diagnosed with increasing frequency in women of reproduc-
tive age. Data on these women is limited to small case series.
Indirect evidence shows a link between adenomyosis and
infertility,408 however, there is no direct link.409 Increased
risk of preterm birth and preterm premature rupture of
membranes in women with adenomyosis (diagnosed with
TVS or MRI) was noted in one epidemiological study.410
598 PART 2  Pathophysiology and Therapy

The most frequent symptom in women with endometrial

Endometrial Polyps
Endometrial polyps, as their name suggests, arise from the
endometrial layer of the uterus. They are characterized by
glandular proliferation surrounding a central core of promi-
nent blood vessels in the stroma. Polyps are associated with
abnormal uterine bleeding, particularly spotting and irregu-
lar bleeding, but the underlying mechanism has not been
articulated. Several mechanisms are thought to play a role in
development of endometrial polyps. These include overex-
pression of endometrial aromatase activity,411,412 monoclo-
nal endometrial hyperplasia,413 genetic factors, particularly
cytogenetic rearrangements of chromosome 6p,12q and
7q,414,415 and alterations in endometrial levels of matrix
metalloproteinases and cytokines.416 Recent work has also
shown the role of increased TGF-β, VEGF,417 and bcl-2418 in
the pathogenesis of endometrial polyps. Historically polyps
have been known to have estrogen receptors, though cur-
rent literature suggests the presence of both estrogen and
progesterone receptors (ER and PR).419,420 It is suggested
that both estrogen and progesterone contribute to the elon-
gation of endometrial glands, stroma, and blood vessels to
give them a characteristic appearance.421 Progestins also
have an antiproliferative function on polyps422 as do andro-
gens, however, data suggest that testosterone does not sub-
stitute for progestational activity for endometrial polyps.423
The estimated prevalence of polyps varies widely from
7.8% to 34.9% depending on the definition and diagnostic
modality used.424-427 The reported prevalence of polyps is as
low as 0.9% in women less than 30 years old,425 and increases
with age. Risk factors for development of endometrial polyps
include obesity,428,429 hypertension,428 diabetes,428,430 and
advancing age, especially postmenopausal status.428 At least
one paper has challenged these classical risk factors and has
shown only age to be statistically significant risk factor.431
Tamoxifen use in postmenopausal women can lead to
development of polyps in around 2% to 36% of women.432
Tamoxifen induced polyps may be large in number and
size and also show unique molecular alterations.432-435 The
levonorgestrel loaded IUD has shown to reduce tamoxifen
induced polyp development in patients being treated for
breast cancer when followed for a year.436 Data regarding
a relationship between endometrial polyps and postmeno-
pausal hormone therapy are contradictory.425,437-440
polyps is abnormal uterine bleeding (AUB-P) in the updated
Federation Internationale de Gynecologie et d’Obstetrique
(FIGO) classification441 and is reported in 50% of symp-
tomatic cases.442 Conversely of women who have abnormal
bleeding, approximately 30% have evidence of endometrial
polyps.443 Although abnormal bleeding is the most common
clinical representation most polyps may remain symptom
free and are an incidental finding on imaging.444 The size,
number, and location of polyps do not correlate with clinical
symptomatology.445
Most polyps are benign and malignant transformation
can occur in 0% to 12.9% of polyps.446-448 Microsatellite
instability has been noted in patients with multiple pol-
yps or polyps with hyperplasia.449 A recent meta-analysis
revealed that the prevalence of malignant polyps was higher
in postmenopausal women compared to women in their
reproductive years (5.42% versus 1.7%) and that malig-
nant polyps were more likely to bleed than non-malignant
ones.450 Risk factors associated with malignant endome-
trial polyps include an age greater than 60 years, polyp size
greater than 1.5 cm in length, menopausal status, and abnor-
mal bleeding.432,451,452
Endometrial polyps are still diagnosed following dila-
tion and curettage (D&C) or hysterectomy, though new
methods of diagnosis and treatment are being utilized
more frequently.453 Increasingly, the use of saline-infusion
sonography (SIS), also termed sonohysterograms, or less
commonly, office hysteroscopy diagnose polyps (Fig. 27.4).
Polyps can also be diagnosed by hysterosalpingogram if the
uterine cavity is also visualized. Newer 3-D ultrasound
probes provide more accurate visualization between the
endometrium and myometrium at the fundus and the cor-
nual angles, hence improving the diagnostic accuracy com-
pared to standard ultrasound.454 A recent review reported
a similar performance of transvaginal ultrasound (TVS),
saline infusion sonography and hysteroscopy for detection
of endometrial polyps.455 Both hysteroscopy and SIS give a
better sense of the endometrial cavity than TVS, however,
SIS has an added advantage of providing the examiner with
information regarding the adnexa and myometrium as well.
Medical management of polyps has limited role. There
is some data regarding prevention of polyp formation in
women being treated for breast cancer with tamoxifen,

A B C
FIGURE 27.4  Comparison of imaging modalities for diagnosis of endometrial polyps. A, A sagittal view of a retroverted uterus obtained by a
transvaginal ultrasound. A thickened endometrial stripe is appreciated, though the thickness is not well defined. B, A saline-infusion sonogram
of the same patient. After infusion of saline into the endometrial cavity, the endometrial polyp is visualized protruding into the endometrial
cavity and a thin endometrium is seen. C, A photograph taken during hysteroscopy reveals a well-defined polyp in the endometrial cavity.
Polyps tend to blood vessels that are not as coarse as seen in submucosal fibroids and they have softer edges. (Images courtesy of Dr. Mary
Frates, Department of Radiology, Brigham and Women’s Hospital and Harvard Medical School, Boston.)

its use is limited to research protocols only.436 Observing
asymptomatic polyps can be an option in low risk individu-
als. When left untreated, asymptomatic polyps can regress
spontaneously. In one trial, 27% of lesions resolved within
1 year of follow-up in premenopausal patients.456 Pol-
yps with mean length of 1.5 cm or more were less likely
to resolve.456 Other studies have shown complete resolu-
tion of polyps less than 1 cm.426,457 The majority of cases of
endometrial polyps are however, treated with hysteroscopic
resection or hysteroscopically-guided D&C rather than the
traditional D&C. Visualization and direct removal with
this technique is reported to be more effective in reducing
recurrence rates.458 It has been reported that the volume of
menstrual loss in women that underwent polypectomy did
not differ from women who did not undergo polypectomy,
but intermenstrual bleeding was significantly improved by
polypectomy.459
There are little data on the effects of polyps on infer-
tility. There are many theories of how polyps can effect
implantation. These include mechanical obstruction hinder-
ing ostium function and affecting sperm migration460 and
decreased endometrial receptivity due to cytokines and
cellular adhesion molecules.461-464 The only randomized
trial showed an improvement of pregnancy rates after pol-
ypectomy in women undergoing intrauterine insemination
(IUI).465 Other retrospective data have shown no differ-
ence in pregnancy rates, especially if the polyp was less than
1.5 cm in length.466,467 In light of conflicting data, expert
opinion recommends removal of polyps when diagnosed
prior to in vitro fertilization (IVF) treatment. When lesions
are seen during stimulation the treatment decision is made
best on an individual basis.468
Abnormal Uterine Bleeding
Abnormal uterine bleeding (AUB) affects up to one third
of reproductive age women and can occur in conjunction
with the pathological processes we have discussed or in
their absence. AUB also accounts for around one third of
all outpatient gynecological visits.469 In the United States,
AUB (previously called dysfunctional uterine bleeding) is
commonly equated with anovulatory bleeding, whereas in
Europe it is a diagnosis of exclusion of excessive bleeding
not due to demonstrable pelvic disease, complications of
pregnancy, or systemic disease. Heavy menstrual bleeding
(HMB) may occur in 10% to 30% of women and in up to
50% of women in the perimenopause.470,471 However, the
self-reporting of menstrual regularity and flow is highly
variable. Change in pattern of flow is probably the most
important sign of pathology. HMB is the type of abnormal
bleeding frequently associated with benign uterine pathol-
ogy, including leiomyomata and adenomyosis. Fragile, large
thin-walled vessels and an aglandular endometrium appear
to underlie the menorrhagia associated with some submu-
cous myomas.472 These vessels may arise from abnormali-
ties in angiogenesis associated with growth factors released
by myomata (e.g., basic fibroblast growth factor, vascular
endothelial growth factor).1
There has been a recent push towards changing and stan-
dardizing terminology for AUB as confused terminology has
made research collaborations and interpretation of clinical
trials difficult.473,474 Terms like menorrhagia, metrorrhagia,
CHAPTER 27  Benign Uterine Diseases 599
and dysfunctional uterine bleeding should be abolished.474 To
standardize communication, FIGO created a universal clas-
sification of causes of abnormal uterine bleeding for women
in their reproductive years.364,475-477 The “PALM-COEIN”
nomenclature has four categories that are defined by struc-
tural criteria. These are: PALM; bleeding due to Polyps,
Adenomyosis, Leiomyomas, and Malignancy or hyperplasia.
The other four are unrelated to structural abnormalities and
include: COEIN; bleeding due to Coagulopathy, Ovulatory
disorders, Endometrial causes, Iatrogenic and pathologies
Not classified. It is hoped that this classification system
should facilitate collaborations to study AUB, however, the
ease of use has to be demonstrated. The four structural
causes of AUB, excluding bleeding due to malignancy have
been discussed in the chapter. Previously classified true dys-
functional uterine bleeding equates to the four nonstruc-
tural causes of bleeding in the FIGO classification.
Around 13% of women with HMB have some form of
coagulopathic disorder.478 Systemic disease as a cause of
HMB should be suspected in adolescents where coagulopa-
thies including thrombocytopenia, von Willebrand disease,
or other coagulopathies may be the underlying cause.479
Ovulatory disorders include both ovulatory and anovula-
tory dysfunction leading to AUB. Anovulatory dysfunctional
uterine bleeding is characterized by irregular and prolonged
bleeding secondary to disturbances in the hypothalamic-
pituitary-ovarian axis. It is most common in the extremes
of reproductive life480 and in association with polycystic
ovary syndrome. The unopposed action of estrogen on the
uterus, resulting in dilated veins and the lack of suppression
of spiral arteriole development, may represent the under-
lying pathophysiology.470,471,481 Large, thin walled tortuous
vessels can be demonstrated on the surface of the hyper-
plastic endometrium. Unopposed estrogen reduces vascular
tone either through direct effects of estrogen on vascular
smooth muscle cells or increased production of nitric oxide,
leading to vasodilatation. The endometrium often breaks
down unevenly in these circumstances. Scattered patches of
thrombotic foci and necrotic degeneration are found adja-
cent to abnormally proliferated endometrium.
Ovulatory dysfunctional uterine bleeding is character-
ized by regular episodes of heavy menstrual flow, usually
with the heaviest loss during the first 3 days of menstrua-
tion. Though many ovulatory disorders can be traced back
to endocrinopathies, the underlying abnormality appears to
be defects in processes that regulate loss of blood during
menstruation, primarily angiogenesis, vasoconstriction, and
hemostasis. In contrast to anovulatory dysfunctional uterine
bleeding, the surface vessels of the endometrium appear to
be grossly normal and only minor abnormalities have been
described in endometrial and myometrial veins like venule
ectasia.1
Endometrial causes of AUB are similar in pathogenesis to
ovulatory disorders. In HMB the local endometrial hemo-
stasis process is disrupted. This can be due to deficient
production of vasoconstrictors like endothelin-1 and pros-
taglandin F2α, increased production of vasodilators such
as prostaglandin E2 and prostacyclin, and excessive break-
down of clot in the endometrium by abnormal production
of plasminogen activator.482-484 In addition, vascular smooth
muscle cell proliferation is reduced in the spiral arterioles
in the midsecretory and late secretory stages in women
600 PART 2  Pathophysiology and Therapy
with menorrhagia, possibly contributing to vessel instability.
Endometrial bleeding associated factor (EBAF) (a.k.a. TGF-
β4) a member of the TGF-β family of growth factors sup-
presses production of collagen and promotes expression of
collagenolytic and elastinolytic enzymes by antagonizing the
normal signaling pathway activated by TGF-β growth fac-
tors. Abnormal expression of EBAF, which in a normal cycle
occurs only in the late secretory and menstrual phases, has
been reported in the endometrium of women with HMB.86
Angiopoietin 1 & 2 (Ang-1 and Ang-2) may also be involved
in the pathogenesis of HMB. Ang-1 promotes vascular mat-
uration, while Ang-2 destabilizes vessels and initiates neo-
vascularization.485 An altered ratio of Ang-1 to Ang-2 in the
endometrium due to down-regulation of Ang-1 expression
is also associated with HMB.485,486
AUB due to iatrogenic causes (AUB-I) usually include
the use of exogenous steroid therapy in form of combined
estrogen and progestin pill, patch or ring, and levonorgestrel-
releasing intrauterine device. The not classified category
(AUB-N) includes a number of entities that do not fall into
any group, for example AUB due to uterine arteriovenous
malformation. Furthermore, this category has been left for
new entities that may cause AUB that have not yet been
discovered. It is important to note that a woman can have
AUB due to more than one cause, for example a woman
with HMB due to submucosal fibroid (AUB-L) can also
have concomitant anovulation if she has PCOS and would
have AUB-O type of bleeding as well.
These pathophysiological mechanisms proposed to
underlie dysfunctional uterine bleeding are targets for novel
therapeutic interventions (Fig. 27.5). The use of nonhor-
monal oral anti-fibrinolytic medication called tranexamic
Ovary
Intermittent ovulation
Fluctuation in
estrogen and
progesterone
Reduced Dilated
spiral surface
FIGURE 27.5  Ovarian and uterine mech- arteries vessels
anisms underlying breakthrough bleed-
ing. A schematic drawing detailing the
interaction between ovarian steroids
and local endometrial factors leading
to abnormal uterine bleeding. MMPs,
matrix metalloproteinases.
acid has shown a 66% response rate for HMB487 and has
shown to be extremely helpful in patients with AUB.488,489
While tranexamic acid has been widely used internationally
for many years, its recent FDA approval is leading to increas-
ing use in the United States. Other options would include
the use of antiprogestins or selective progesterone receptor
modulators to suppress endometrial growth and stabilize
the endometrial vasculature; MMP inhibitors to prevent
extracellular matrix catabolism, including the matrix of
the vessel walls; and non-steroidal anti-inflammatory drugs
(NSAIDs) or selective cyclooxygenase-2 (COX-2) inhibi-
tors to suppress prostanoid synthesis. Even though their use
is not novel, combined estrogen and progestin formulation
in form of patch, ring or pill, cyclical oral progestins, pro-
gestin-releasing intrauterine devices, are still unfortunately
being used as the primary therapy for such patients.490-493
Surgical destruction or removal of endometrium via endo-
metrial ablation with newer nonresectoscopic, operator
friendly devices has shown impressive success rates239,494,495
and are also shown to be safe.496 Hysterectomy is a defini-
tive but less desirable option for AUB patients that are not
concerned about fertility preservation.
Intrauterine Adhesions
The formation of intracavitary synechiae in an organ that
routinely undergoes sloughing and regrowth without scar-
ring is not well understood.497 The clinical literature con-
sistently reports that pregnancy frequently precedes the
formation of intrauterine adhesions. The relationship
between intrauterine adhesions and pregnancy is thought
to be the result of defects in the regeneration of the
Endometrium
Vessels Stroma Epithelial
compartment
Abnormal Altered
Increased
angiogenesis hemostasis
MMPs
Prolonged
bleeding
Increased Deficient microvascular
microvascular basement membrane
density
Microvascular fragility
Breakthrough bleeding

endometrium after delivery, especially the area underly-
ing the placenta. The placental site takes up to 6 weeks to
repair with the thrombosed vessels and superficial necrotic
tissue exfoliated as growing endometrium undermines the
area. Trauma to the regenerating endometrium involved in
restoring stroma and epithelium at this site, for example as
a consequence of curettage performed 1 to 4 weeks after
delivery and may result in a permanent scar with adhesions.
This is considered the primary reason for intrauterine adhe-
sions in the industrialized world. A review of 1856 women
with intrauterine adhesions revealed 67% had undergone
D&C for spontaneous or induced abortion and 22% had a
postpartum D&C.498 In another study, women were either
randomized to nonsurgical treatment or D&C after incom-
plete abortion. Of the women that underwent D&C, 7.7%
had some form of intrauterine adhesions compared to no
adhesions in the nonsurgical group.499 Curettage in the first
48 hours postpartum seems to cause fewer adhesions than
when they are done later than that.500 Not only D&C, but
any sort of intrauterine instrumentation can lead to devel-
opment of intrauterine synechiae. The average incidence
of adhesion formation after hysteroscopic myomectomy
for example has been reported around 10% at second look
hysteroscopy after surgery.501 In another study the rate of
adhesion formation was noted at 6.7% after uterine sep-
tum take down, 31.3% after myoma resection, and as high
as 45.5% after multiple myoma resection.502 Even though
there is need for larger randomized trials there is some
evidence that highlights the use of adhesion barriers after
hysteroscopic procedures.503,504 The role of infection after
abortion or delivery in formation of uterine synanche is con-
troversial.505,506 A comparison of uterine cavities of women
that delivered via cesarean with and without endometritis
at the time, did not show any differences when it came to
intrauterine adhesions.507
In the developing world, infection of the endometrium
particularly with mycobacterium tuberculi is an important
cause of uterine synanche. With the human immunodefi-
ciency virus-acquired immune deficiency syndrome (HIV-
AIDS) epidemic and ease of air travel, genital tuberculosis
should not be considered a threat to the developing world
only. It is also important to note that most African stud-
ies have still attributed the major cause for intrauterine
adhesions to be previous cavitary instrumentation.508-510
Estimated prevalence of genital tuberculosis varies widely
between 2% to 25% in infertile women, depending on diag-
nostic criteria used and the geographical location.511,512
Tuberculous adhesions can be in as high as 35% of women
with the infection513 and have a poor prognosis for future
fertility.498,514 A characteristic pipe stem or beaded appear-
ance on hysterosalpingogram and culture with acid fast
stains on endometrial biopsy is helpful but, both tests have
poor sensitivity. Newer tests like interferon-gamma release
assays are more useful currently.515
Women with intrauterine adhesions may have no symp-
toms or a variety of menstrual disorders including hypomen-
orrhea, oligomenorrhea, amenorrhea, dysmenorrhea, and
very rarely heavy menstrual bleeding.498 Infertility, amenor-
rhea, and hypomenorrhea are the most common presenting
complaints with infertility rates reported as high as 43%.498
A number of classification systems have been proposed for
women with intrauterine adhesions.516 All systems require
CHAPTER 27  Benign Uterine Diseases 601
a thorough evaluation of the endometrial cavity to note the
consistency, extent, and location of the adhesions. There
is paucity of data from comparison of these classification
systems.516
Hysterosalpingography is performed to view the cavity,
and hysteroscopy reveals the intrauterine lesions. Ultraso-
nography, sonohysterography, and magnetic resonance517,518
imaging can also be valuable in certain cases (Fig. 27.6). One
group compared hysterosalpingography, sonohysterography,
and transvaginal ultrasonography in patients with infertility
and found both hysterosalpingography and sonohysterog-
raphy imaging to have similar sensitivities of around 75%
in detecting intrauterine adhesions. There was very limited
use of transvaginal sonography in detection of synechiae in
this study.519 The gold standard for diagnosis of intrauterine
adhesions is by diagnostic hysteroscopy.520
There is no consensus regarding the optimal methods to
treat and prevent intrauterine adhesions. Since asymptom-
atic adhesions do not interfere with a woman’s general well
being, expectant management in such women has lead to
resumption of regular menses in 1 to 7 years in up to 78% of
women in one report.498 There is no role of medical therapy
for treatment of intrauterine adhesions. Before wide spread
use of hysteroscope, blind D&C was used. Schenker and
Margalioth reported an 84% rate of resumption of normal
menses in women after D&C. Fifty one percent of these
women conceived and 55% had term deliveries.498 Surgical
removal of adhesions hysteroscopically with blunt dissec-
tion, scissors, electrocautery, or laser ablation is now rec-
ommended. Return of normal menses after hysteroscopic
resection varies between 92% to 96%.521 The primary goal
of surgery is to restore normal volume and shape of the
uterine cavity.521 In the nonindustrialized part of the world
where hysteroscopic resection may not be feasible, there
have been reports to show D&C to be equivalent to hys-
teroscopic resection, which is reassuring.510 Post operative
management is focused upon reducing the risk of reforma-
tion of adhesions, the rate of which can be as high as one
in three women with mild to moderate and two in three
women with severe adhesions.516,522-525 Insertion of an
intrauterine device or balloon catheter after lysis of adhe-
sions is commonly employed to prevent recurrence.526
FIGURE 27.6  A sagittal view of an anteverted uterus obtained dur-
ing saline-infusion sonography. An adhesion can be appreciated in
this patient with a history of dilation and curettage (D&C) to treat a
first trimester pregnancy loss.
602 PART 2  Pathophysiology and Therapy
Stimulation of endometrial proliferation with exogenous
estrogens alone or in combination with a progestin has been
advocated although there is debate as to the efficacy of this
treatment as well as the administration of antibiotics and
anti-inflammatory steroids.
Successful pregnancy rates after hysteroscopic resection
of adhesion can be up to 63%,521 with issues of placentation
being most serious complication of pregnancy. Of 696 births
reported in a recent review,52117 pregnancies had placenta
accreta. Preterm delivery rate was 40% to 50% in this group
of patients.521
Dysmenorrhea
Primary dysmenorrhea, menstrual pain not associated with
recognizable pelvic disease, is due to intrinsic uterine dys-
function. Occurring only in ovulatory cycles, the symptoms
of dysmenorrhea usually commence a few hours before
the onset of the menstrual flow. Pain is greatest when the
endometrium is shedding rapidly, approximately 12 hours
after flow begins. The diagnosis of primary dysmenorrhea
is established when secondary causes of dysmenorrhea are
ruled out and based on medical history and normal findings
on pelvic and rectovaginal examination and imaging.
The prevalence of dysmenorrhea in women varies
between 50% to 90% in most studies.527-536 Under 30 years
old, smoking, irregular or heavy menstrual flow, body mass
index (BMI) less than 20 kg/m2, menarche before age 12,
history of sexual assault, and a strong family history of dys-
menorrhea are a few of the many risk factors known for
primary dysmenorrhea.537,538
The painful cramps of dysmenorrhea are associated with
uterine contractions; in women with dysmenorrhea, uter-
ine contractile activity is heightened during menses, and
basal myometrial tone and amplitude of contractions are
increased.539 During intense contractions, there is a reduc-
tion in blood flow to the endometrium suggesting that isch-
emia, in part, causes the pain of dysmenorrhea. There is also
evidence from Doppler studies to show higher resistance
in uterine vessels in women with primary dysmenorrhea,
which can reduce blood flow to the endometrium.540,541
The uterine contractions are prompted by prostaglandins,
which are potent uterotonic agents both in vitro and in vivo
acting through cell surface prostaglandin receptors.542 Pros-
tanoids may also directly sensitize uterine pain fibers. The
notion that prostanoids are central to the pathogenesis of
dysmenorrhea is supported by the observations that eico-
sanoids, most prominently prostaglandin F2-alpha (PGF2α),
are found in high concentrations in menstrual fluid and that
PGF2α levels are higher in the endometrium and menstrual
fluid of women complaining of dysmenorrhea than in women
with pain-free menses.543 This high concentration of pros-
taglandins has been shown not only in the endometrium but
also in saliva of women during attacks of menstrual migraine
associated with dysmenorrhea.544 More recently patients
with primary dysmenorrhea have also been hypothesized to
have endothelial dysfunction.545
Treatment of primary dysmenorrhea is individualized
to each patient’s severity of symptoms. All drugs effective
in inhibiting prostaglandin synthesis, including the potent
nonsteroidal anti-inflammatory drugs (NSAIDs) ibupro-
fen, naproxen, and mefenamic acid alleviate symptoms of
dysmenorrhea.546 A Cochrane database review included 73
randomized trials to compare NSAID therapy to placebo
and paracetamol. NSAIDs were significantly more effective
in reducing pain symptoms compared to placebo or acet-
aminophen.547 A combination of NSAID and paracetamol
may also be helpful in relieving pain of primary dysmen-
orrhea.548 Choosing an appropriate NSAID for treatment
may be difficult. It is not clear whether some NSAIDs work
better than others.547 Some studies suggest that fenamates
(class that includes mefenamic acid, flufenamic acid, tolfen-
amic acid, etc.) may have better pain relieving propensities
than phenylpropionic acid derivatives (class that includes
ibuprofen and naproxen).549,550 Though there may not be
sufficient data to prove the superiority of medications from
the fenamates class, a reasonable option would be to start
with NSAIDs from phenylpropionic acid derivative group
and move onto fenamate class of medications if insufficient
relief is noted.
Combined oral contraceptive pills (OCPs) are second
line medications after NSAIDs for relief of pain from pri-
mary dysmenorrhea. No randomized trials have compared
the efficacy of NSAIDs with OCPs. A systematic review
compared OCPs to placebo and evaluated 10 randomized
trials. A treatment benefit with OCPs was noted (pooled
OR 2.99, 95% CI 1.76-5.07).551 Continuous rather than
cyclical administration of OCPs has shown more success in
treating patients with primary dysmenorrhea.552,553 Con-
traceptive ring users have similar results to OCP users for
dysmenorrhea,554 where as contraceptive patches have not
shown comparable results to OCPs.555 The use of levonor­
gestrel releasing intrauterine device for primary dysmen-
orrhea has been limited to case reports.556 Commonly if
treatment with NSAIDs is not successful after 3 months,
OCPs are tried for another 3 months. If no relief is noted,
reasons for secondary dysmenorrhea should be explored.
A long list of complementary and alternative medicines
has been used for treatment of primary dysmenorrhea. Most
of them have shown similar efficacy to the conventional
nonsteroidal anti-inflammatory medications. Heat applied
to the lower abdomen,557,558 aerobic exercise,559 yoga,560,561
acupuncture,562 aromatic essential oil massage,563 and the
use of far infrared emitting belts564 are one of the few non-
pharmacological agents tested for dysmenorrhea in random-
ized clinical trials and have shown promising results. Data
on diet supplements are limited to a few small studies. A
low fat vegetarian diet,565 diet rich in dairy,566 omega-3 fatty
acids,567 and vitamin E supplementation568,569 have been
effective in pain management from primary dysmenorrhea.
Newer medications that include calcium antagonists like
nifedipine are also effective because they prevent uterine
contraction.570-572 Magnesium573 and glyceryl trinitrate574
have also been used for primary dysmenorrhea. In addi-
tion to prostanoids, other uterotonic substances including
lipoxygenase products, vasopressin, and oxytocin may have
a role in dysmenorrhea. Thus, antagonists of the V1 receptor
and oxytocin receptor have a therapeutic effect in dysmen-
orrheic subjects. Reductions in nitric oxide (NO), which
relaxes uterine smooth muscle, may also contribute to the
intensified contractions associated with dysmenorrhea.575
The complete reference list can be found on the companion
Expert Consult Web site at www.expertconsult.com.

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