CLINICAL OBSTETRICS AND GYNECOLOGY
Volume 48, Number 2, 258–273
The Evaluation
of Abnormal
Uterine Bleeding
HARRY HATASAKA, MD
Department of Reproductive Endocrinology, University of Utah,
Salt Lake City, Utah
Introduction
Abnormal uterine bleeding (AUB) can arise
from a bewildering number of sources
(Table 1). Prior to menopause, 20% of gyne-
cology visits and approximately one fourth
of gynecologic procedures are done for
AUB. The primary goal of the clinical eval-
uation of AUB is to establish a specific
diagnosis in the most efficient and least in-
vasive manner possible. History and physical
examination provide the foundation and di-
rection on which the course of the evaluation
begins. However, a contemporary, safe, and
comprehensive evaluation most often also
relies on diagnostic procedures, which will
be the focus of this chapter.
Abnormal uterine bleeding will be con-
sidered to arise from 1 of 4 broad etiologic
categories. First are pregnancy-related etiol-
ogies (such as abortion, ectopic, and trophoblas-
tic disease as well as puerperal complications
such as retained products of conception and
endomyometritis). Second is AUB arising
Correspondence: Harry Hatasaka, MD, Department of
Reproductive Endocrinology, University of Utah, 30 N
1900 E, Room 2B200, Salt Lake City, UT 84108. E-mail:
Catherine.Lowe@hsc.utah.edu
CLINICAL OBSTETRICS AND GYNECOLOGY
258

2005, Lippincott Williams & Wilkins
from the endocrine-mediated sequelae of
anovulation. Third is AUB resulting from
disorders of coagulation. Finally, the fourth
category of AUB involves a direct anatomic
(structural) source of uterine pathology
(including benign and cancerous or precan-
cerous lesions).
This chapter will review current informa-
tion to guide the selection and use of the
prevailing diagnostic procedures aimed at
establishing or excluding structural sources
of AUB during the reproductive years. Al-
though thoughtful selective use of these
diagnostic techniques may be critical to estab-
lish a diagnosis efficiently, comprehensive
evaluation for nonstructural sources of
AUB is a necessary prerequisite. It is not un-
common to encounter more than 1 source of
AUB concomitantly. A systematic approach
toward evaluating AUB will be presented
followed by an analysis of the use of diag-
nostic procedures for differentiating ana-
tomic causes.
Differential Diagnosis
The probability of encountering some of the
pathogenic causes of AUB changes across
/ VOLUME 48 / NUMBER 2 / JUNE 2005
 Evaluation of Abnormal Uterine Bleeding
TABLE 1. Some Conditions Causing AUB
in Reproductive Age Women
Pregnancy complications
Anovulation associated
Submucous fibroids
Endometrial polyps
Medication related
Endometrial hyperplasia
Endometrial cancer
Infection associated
Coagulation abnormalities
Müllerian abnormalities
IUD complications
IUD, intrauterine device.
the reproductive time span. For example,
incidences of most structural lesions causing
AUB such as leiomyomata, polyps, endome-
trial carcinoma, and adenomyosis rise with
chronologic age. Conversely, pregnancy com-
plications as a source of AUB become less
frequent in proportion to the diminished in-
cidence of pregnancy across the reproduc-
tive age. Other conditions that result in
AUB tend to be more consistently encoun-
tered throughout the time frame such as
infections, medication-induced AUB, and
anovulation. The steady incidence of anov-
ulation as a source of AUB is mainly due
to the wide variety of underlying etiologies
such as polycystic ovary syndrome (PCOS),
endocrinopathies such as hyperprolactine-
mia and thyroid disease, anorexia nervosa,
central nervous system (CNS) lesions, as
well as impending premature ovarian failure.
Anovulatory bleeding and hormonal medi-
cation use represent the most common sour-
ces of noncyclic uterine bleeding in this age
group.
Some other common female anatomic
lesions, including pelvic/intrauterine adhe-
sions and endometriosis, have not been de-
finitively associated with AUB. However,
other conditions causing AUB are present
at birth but may not come to medical atten-
tion until after adolescence, such as bleeding
diatheses including the statistically most
common von Willebrand disease. This con-
dition as well as adult onset congenital adre-
259
nal hyperplasia and congenital uterine mal-
formations may not be unmasked until
women discontinue oral contraceptives that
had been initiated to control AUB during
adolescence.
At the perimenopausal extreme of repro-
ductive age, as ovarian function wanes, an-
ovulatory AUB is anticipated. The danger of
evaluating AUB during this phase is in mak-
ing the assumption that AUB is due solely to
intermittent ovulation while a more threaten-
ing concomitant pathology such as neo-
plasms and even pregnancy complications
may be present (Table 2). This trap is made
all the more easy to fall into because there is
no consistent expected uterine bleeding pat-
tern that can be considered normal during
perimenopause. Although about 70% of
perimenopausal women exhibit reduced fre-
quency and/or quantity of uterine bleeding,
18% tend to manifest increased frequency
and/or quantity of bleeding, whereas only
12% cease bleeding acutely.1 Moreover, other
structural lesions causing AUB such as fib-
roids and polyps are at their peak prevalence
during perimenopause so that anovulation
must be considered a diagnosis of exclusion.
HISTORY
Although medical history is not specific
enough to make a firm diagnosis for AUB,
some questions assist in further narrowing
the diagnostic possibilities. Questions plac-
ing the bleeding in context of a woman’s other
health considerations (age, weight, previous
menstrual patterns, medical problems, etc.)
are most valuable in diagnosis. Further-
more, consistent questioning about each
of the broad categories of AUB (preg-
nancy complications, bleeding diathesis,
TABLE 2. Common Pathology Causing
AUB in Perimenopausal Women
Anovulation associated
Focal uterine lesions (fibroids, polyps, adenomyosis)
Diffuse uterine lesions (endometrial hyperplasia and
cancer, diffuse adenomyosis)
260 Hatasaka
anovulation, and structural lesions) helps to
avoid omitting important history.
Pregnancy
Knowing the usual menstrual cycling pat-
tern, the timing of the last menstrual period,
and the possibility of exposure to pregnancy
should be initial questions. With a sudden
change from a regular menstrual history to
AUB, pregnancy-related AUB is an immedi-
ate possibility.
Coagulation Abnormalities
When there is a bleeding diathesis, menor-
rhagia with prolongation of flow is a com-
mon presentation. Coagulation abnormali-
ties are suspected even further when a fam-
ily history of bleeding diatheses can be
elicited or when the patient gives a history
of frequent epistaxis, frequent bleeding of
the mucous membranes (eg, with a tooth-
brush), and excessive bleeding with previ-
ous surgery.
Anovulation
Predictable cyclic menses, especially with
premenstrual molimina suggestive of pro-
gesterone secretion, provide over a 95%
probability that a woman is ovulating.
Conversely, anovulatory bleeding is typi-
cally noncyclic with an unpredictable pattern
ranging from prolonged bouts of spotting to
outright hemorrhage. In comparison to an
ectopic pregnancy, anovulatory bleeding is
characteristically painless. When anovula-
tion is suspected, disease and medication-
specific questioning for the most common
causes of anovulation such as PCOS, thy-
roid disease, hyperprolactinemia, and eating
disorders is appropriate.
A history of passing clots has important
clinical implications. Whereas an intact clot-
ting cascade can be deduced, clotting is nev-
ertheless a pathologic sign that generally
indicates menorrhagia with attendant risk
of anemia. Passing clots (especially .1.1
inches in diameter) has been correlated with
blood loss .80 mL during menses.2 The
mechanism of intrauterine clot formation
appears to involve disequilibrium between
the delicate balance of normal uterine hemo-
stasis. Normally, the endometrium possesses
high fibrinolytic activity that promotes liq-
uefaction of shed endometrium including
the endometrial clots that have provided
menstrual hemostasis. This process exhausts
the fibrolytic proteins, which can no longer
be measured in normal menstrual fluid.
When uterine bleeding is excessive, the lack
of fibrinolytic activity may result in clot for-
mation. Teleologically, intracavitary clot for-
mation offers a source of internal pressure
and also stimulates uterine cramping and
contractility in an attempt to stem excessive
bleeding.
Structural
Chronic intermenstrual bleeding superim-
posed upon normal menstrual cycling is
often associated with uterine structural
lesions. This contrasts to bleeding diatheses
that typically manifest as excessive but cy-
clic bleeding. Women with certain Müllerian
abnormalities such as noncommunicating
uterine horns and blind vaginal pouches as-
sociated with longitudinal vaginal septums
may give a history of normal menstrual cy-
cling but associated progressive cyclic pain
due to increasing hematometra and/or hem-
atocolpos collections. In other young women
with Müllerian anomalies, intermenstrual
spotting may be superimposed upon regular
cycles as menstrual effluvium is slowly re-
leased from sequestered sites that have a
patent outflow tract.
The bleeding pattern for women with
focal structural lesions such as fibroids and
polyps is not specific, as these lesions may
present with menorrhagia and/or metrorrha-
gia. Metrorrhagia tends to be more common
with intracavitary lesions, whereas menor-
rhagia is associated with intramural or
partially submucosal lesions. The AUB
associated with diffuse uterine lesions
(hyperplasia and endometrial carcinoma) also
tends to be unpredictable because bleeding
from these lesions is generally superimposed
upon long-term anovulatory patterns of AUB.
 Evaluation of Abnormal Uterine Bleeding
PHYSICAL EXAMINATION
A systematic approach to the physical exam-
ination is crucial to conduct a safe, efficient,
and yet comprehensive initial evaluation.
After hemodynamic stability is established,
the next priority is to establish that the ab-
normal bleeding is truly uterine. This can
be difficult when bleeding is not active at
the time of the examination because of the
enormous diversity of potential nonuterine
sites that can cause vaginal bleeding. These
include traumatic, inflammatory, infectious,
hormonal, and neoplastic lesions of the der-
matologic system and virtually all compo-
nents of the gastrointestinal (GI), genitouri-
nary (GU), and reproductive tracts. Once
these possibilities have been considered,
the same framework used in history taking
(pregnancy complications, coagulopathies,
anovulation, and structural lesions) is useful
in directing the remainder of the physical
examination.
Visual examination of the cervix can of-
ten immediately confirm a uterine source of
bleeding. The uterine contour, size, firmness,
mobility, position, and tenderness can sug-
gest the presence of fibroids, adenomyosis,
other pelvic neoplasms, pregnancy, Müller-
ian anomalies, and infections. Likewise, ad-
nexal examination may help distinguish
masses, ectopic pregnancy, polycystic ova-
ries, and pelvic inflammatory disease (PID).
Pregnancy
Uterine size, shape, color, and consistency
incorporated into Chadwick and Hegar
signs may help predict the presence of
AUB from a pregnancy complication. In
the circumstance of spontaneous abortion,
cervical dilation and the presence or absence
of products of conception at the ostium de-
fine the category of abortion.
Coagulopathy
Physical findings to corroborate bleeding
abnormalities such as von Willebrand dis-
ease and idiopathic thrombocytopenic pur-
pura (ITP) include bruising and petechiae
of the mucous membranes.
261
Anovulation
Important physical examination checkpoints
include examination for stigmata of syn-
dromes and systemic diseases that can cause
AUB via anovulation such as PCOS, anorexia,
Cushing syndrome, and hyperprolactinemia.
The uterine examination is remarkable in
these conditions only for the lack of detect-
able abnormalities.
Structural
The obvious presence of 2 cervices, a uterine
fundal notch, longitudinal vaginal septae, or
hematocolpos help establish the presence of
Müllerian abnormalities. An enlarged uterus
with irregular contours usually indicates the
presence of leiomyomata. This is especially
true when uterine sounding exceeds the 8
cm upper limit of normal even in a multipa-
rous woman. Unless prolapsing at the cervi-
cal ostium, physical examination cannot re-
veal uterine polyps. On the other hand,
adenomyosis is suspected, particularly in
multiparous women with menorrhagia,
when there is an enlarged, moderately ten-
der, and soft to boggy uterus. Attention to
the parametria during bimanual examination
is essential for diagnosis and staging in the
case of cervical carcinoma. Moreover, recto-
vaginal examination may prove especially
helpful in confirming structural lesions that
may be causing AUB.
LABORATORY
The history and physical largely determine
which laboratory tests will be most perti-
nent. Measures of blood volume (hemoglo-
bin, hematocrit) are usually indicated initially
to help assess hemodynamic stability and
acuity or chronicity of the patient’s condi-
tion. Cervical cytology is also essential
to help ascertain the presence of cervical
neoplasia as a potential source of AUB. Al-
so, upper uterine lesions can sometimes be
distinguished from cervical lesions by expe-
rienced cytopathologists. Cultures should be
considered especially when history suggests
sexually transmitted disease (STD) risk. As
with the history and physical, systematic
262 Hatasaka
screening is achieved by again bearing in
mind the major groups of disorders that
cause AUB.
Pregnancy
Ectopic and other pregnancy abnormalities
must always be considered or they are easily
overlooked. Rapid screening with a serum
human chorionic gonadotropin (hCG) con-
centration is highly reliable and quickly fo-
cuses the investigation.
Coagulopathy
When coagulopathy is suspected, screening
using a complete blood count (CBC) with
platelet determination and more specific
tests for von Willebrand such as ristocetin
cofactor and factor VIII may be considered.
Bleeding times and prothrombin and partial
thromboplastin times are generally less
helpful for screening (see chapter on coagu-
lation abnormalities).
Anovulation
If history indicates that anovulation is a pos-
sible proximate cause for AUB, then exam-
ining the presumptive tests for ovulation,
such as basal body temperatures, luteinizing
hormone (LH) measurements, or mid-luteal
progesterone assessments, supports the di-
agnosis. Once anovulation is diagnosed,
more specific investigation may require screen-
ing measurements of thyroid-stimulating
hormone (TSH), prolactin, follicle-stimulating
hormone (FSH), estradiol, and 17-hydroxy-
progesterone, depending upon the condi-
tions suspected. Because anovulatory AUB
is considered a diagnosis of exclusion, when
hormonal therapy fails to control AUB, uter-
ine structural lesions must be considered.
Structural
When anatomic uterine lesions are found in
women with AUB, the mere presence of the
lesions does not assure that they are the
source of the AUB. Therefore, a compre-
hensive investigation of all possible causes
is important in each case of AUB. Re-
sponse to treatment may ultimately be re-
quired to help confirm a structural source
of AUB. For example, for a woman with leio-
myomata who is also suspected of being
anovulatory, a medical trial [such as with
oral contraceptive pills (OCPs)] may be pru-
dent prior to moving directly to hystero-
scopic myomectomy. The OCPs should help
regulate anovulatory AUB but generally
have little effect on bleeding from offending
fibroids.
With the introduction of numerous tech-
nological advances in recent decades, it
has become challenging for clinicians to se-
lect the most appropriate diagnostic imaging
procedures to detect and characterize struc-
tural lesions of the uterus. The selection of a
test must balance the test characteristics with
efficiency, risk, availability, available exper-
tise, discomfort, and expense.
Overview of Structural
Lesions Causing Abnormal
Uterine Bleeding and Their
Diagnostic Procedures
THE STRUCTURAL LESIONS
Among the many anatomic lesions that
cause AUB, some of the more common ones
causing the greatest diagnostic dilemmas are
discussed individually. Although there is
some crossover, structural lesions causing
AUB can be categorized as either focal (fib-
roids, polyps, adenomyomas) or diffuse (en-
dometrial atrophy, hyperplasia or cancer,
and diffuse adenomyosis) (Table 3). In the
following section, the commonly used diag-
nostic tests for these anatomic causes of
AUB will be reviewed.
Uterine Leiomyomata
Leiomyomata can be a source of AUB start-
ing even in the early reproductive years. Al-
though transvaginal ultrasonography (TVUS),
magnetic resonance imaging (MRI), and
 Evaluation of Abnormal Uterine Bleeding
TABLE 3. Potential Structural Causes of
Abnormal Uterine Bleeding
(excluding pregnancy-related,
hormone-mediated, and
coagulation abnormalities)
Uterine leiomyomata
Uterine polyps
Endometrial hyperplasia or endometrial carcinoma
Uterine cancers
Adenomyosis
Infectious: endometritis, pyometrium, PID,
tuberculous
Foreign objects (intrauterine device)
Trauma (uterine rupture, uterine perforations,
lacerations)
Müllerian abnormalities
Atrophic endometrium
Asherman syndrome with partial occlusion of the
outflow tract
Vascular (arteriovenous malformations)
computed tomography (CT) offer precise
size and location mapping for fibroids, the
delineation of intracavitary-intramural to-
pography is best done by sonohysterography
(SHG). Even direct visualization by hystero-
scopy does not afford this information.
When only the ‘‘tip of the iceberg’’ of a fi-
broid is visible at hysteroscopy, it remains
uncertain how much of the mass remains
hidden from view without the help of imag-
ing methods. Submucosal leiomyomata are
the most likely to present with AUB fol-
lowed by intramural leiomyomata. With
leiomyomata, the most important role of di-
agnostic testing is to help the surgeon devise
the safest treatment plan.
There is often uncertainty when rounded
intracavitary masses are visualized radiolog-
ically as to whether they may be a polyp,
leiomyomata, or clots. Often, pedunculated
leiomyomata demonstrate continuity with
the myometrium, whereas polyps do not.
Color flow Doppler can sometimes also
provide a clue because leiomyomata generally
have no distinct feeding vessel. Their vascu-
larity is diffuse, or they may exhibit periph-
eral flow around their rims. Polyps generally
have single feeding vessels, whereas cancer-
ous masses may have multiple feeding ves-
263
sels. Noncavitary leiomyomata can be imaged
most accurately using MRI if other less costly
modalities are inadequate for treatment
planning. Some interventional radiologists
feel that a leiomyoma demonstrating low
signal intensity on T2-weighted MRI images
indicates a vascular leiomyoma that is more
likely to respond to treatment by uterine
artery embolization.
Imaging characteristics of uterine masses
using current techniques are insufficiently
specific to differentiate benign from malig-
nant uterine masses such as sarcomas unless
invasion has occurred.
Uterine Polyps
By menopause, polyps are the most preva-
lent focal uterine lesion. Polyps also repre-
sent the most common cause of endometrial
thickening, so they may present sonograph-
ically as either a focal or a diffuse lesion.
This makes differentiation from hyperplasia
and cancer of the endometrium problematic
by TVUS alone.3 Sonohysterography is a
more reliable means of detecting polyps
than TVUS.4 Historic risk factors for polyps
overlap those for endometrial hyperplasia.
There is a continuum of increasing inci-
dence starting from adolescence.
Although not completely consistent,
polyps tend to demonstrate homogeneous
echogenicity with clear-cut borders and a
narrow stalk that often exhibits a single ves-
sel source by Doppler examination. Such a
Doppler finding also excludes the presence
of an inanimate mass such as a blood clot.
The polyp usually crosses the midline and
is contained within the endometrial stripe
when TVUS is used. Polyps are easily missed
by endometrial biopsy and even TVUS.
Sonohysterography and hysteroscopy prom-
ise the best sensitivities in detecting uterine
polyps. Adenocarcinomas can arise within
a polyp or sometimes present directly as pol-
yps. Because radiographic techniques are in-
sufficiently specific to distinguish malignant
from nonmalignant tissue, polyps should be
removed when found in postmenopausal
women.
264 Hatasaka
Endometrial Hyperplasia and Carcinoma
Approximately 5% to 10% of all postmeno-
pausal women with AUB will prove to have
endometrial carcinoma. However, in premeno-
pausal women, the prevalence is largely de-
termined by their risk factors. Abnormal
uterine bleeding is also the most common
presenting symptom for women with endo-
metrial hyperplasia. The diffuse lesions may
be screened for by endometrial imaging pro-
cedures, but firm diagnosis relies on tissue
confirmation. This can be accomplished by
several sampling devices or by formal dila-
tion and curettage (D&C). However, the
gold standard to establish and stage these
diffuse lesions is complete histologic evalu-
ation of a hysterectomy specimen.
Adenomyosis
Adenomyosis is a presumptive anatomic
cause of AUB, particularly menorrhagia in
multiparous women. Definitive proof of a
role for adenomyosis in AUB is lacking;
however, correlation has been repeatedly
reported from observational studies. The
peak age of diagnosis of adenomyosis is
during the fifth decade of life. Diagnosis
has been problematic as the lesions (benign
endometrial glands and stroma with asso-
ciated myometrial hypertrophy) can be
multifocal, diffuse, or nodular and are by
definition embedded in the myometrium
out of the reach of detection by hysterosal-
pingogram (HSG) or hysteroscopy. Random
myometrial biopsy is impractical and insen-
sitive. Diagnosis has historically relied upon
histologic examination of hysterectomy
specimens because initial radiologic techni-
ques lacked sensitivity. Today, sonography
and MRI are the main imaging methods that
have useful predictive values for diagnosing
adenomyosis.5
Leiomyomata tend to have well-defined
margins due to the pseudocapsules of com-
pressed myometrium. In contrast, focal
condensations of adenomyosis termed
‘‘adenomyomas’’ tend to be intertwined in
the myometrium, causing their surgical
removal to be difficult and their margins
to be poorly defined. The consistency of
adenomyomas is typically soft so that they
do not displace myometrium and therefore
rarely present as subserosal or submucous
masses.
Unfortunately, expertise in the radiologic
diagnosis of adenomyosis is not yet widely
available due to the challenging nature of
interpreting both sonograms and MRI im-
ages. With TVUS, sensitivities and specific-
ities in research situations have been
reported as high as 89% and 96%, respec-
tively. A number of subtle signs such as
heterogeneous, hypoechoic areas with ill-
defined margins in an elliptical form help
make the diagnosis. Unfortunately, the fea-
tures used to suggest adenomyosis are not
generally capable of being interpreted from
static images and therefore require real-time
evaluation.
Consensus criteria for diagnosing adeno-
myosis by both TVUS and MRI have not
been defined due in large measure to the
subtleties and variation of the available ra-
diologic signs. Interpretation is made even
more difficult by the frequent and confound-
ing coexistence of other diffuse and focal
uterine lesions such as endometrial hyper-
plasia and leiomyomata.
Standard T2-weighted MRI images
provide reproducibility yet still require spe-
cialized expertise to interpret. Limited avail-
ability of subspecialty radiologists, together
with the expense, narrows the indications to
obtain an MRI for the indication of sus-
pected adenomyosis. Nonetheless, when
the information is critical to obtain, expert
radiologists have reported diagnostic accu-
racy using MRI for adenomyosis to be in
the range of 85% to 90%. One study per-
forming a direct comparison between
TVUS and MRI for making a diagnosis of
adenomyosis found that MRI accurately di-
agnosed the condition in 88% of the cases
compared to 53% by TVUS.6
If definitive hysterectomy is planned for
AUB, there is little need to image specif-
ically for adenomyosis as long as cancer
has been adequately ruled out. However,
 Evaluation of Abnormal Uterine Bleeding
when conservative uterine-sparing surgery
is planned for a woman with focal uterine
lesions, then presurgical imaging to differ-
entiate adenomyosis from leiomyomata
may be justified. When imaging reveals a
high level of suspicion that adenomyosis
may be present rather than fibroids alone,
this knowledge will be beneficial for patient
risk counseling and surgical preparation.
Another potential indication for imaging
for adenomyosis is when endometrial abla-
tion is contemplated. If adenomyosis is
found to be physically distant from the
endometrial-myometrial margin where tis-
sue destruction cannot be achieved, then
endometrial ablation is often unsuccessful
in treating AUB.7
Atrophic Endometrium
Atrophic endometrium is the most common
cause of postmenopausal AUB.8 It may also
be a source of AUB in reproductive-aged
women using hormonal contraceptives and
in women with anorexia or premature ovar-
ian failure. Women with atrophic endometrium
as a cause of AUB tend to have a history of
irregular spotting. Diagnosis requires the
finding of scant tissue by biopsy with the
presence of benign proliferative histology.
In some circumstances, sonography may
supplant the need for endometrial biopsy
to make the diagnosis of atrophic endometrium
as the source of AUB. An endometrial thick-
ness (ET) measurement of ,4 mm by
TVUS suggests endometrial atrophy. How-
ever, if the ET exceeds 4 mm or if the texture
is heterogeneous, then TVUS is inadequate
and biopsy is required for diagnosis.
THE DIAGNOSTIC PROCEDURES
Innovative diagnostic techniques such as
color-flow Doppler and 3-dimensional ultra-
sonography have been developed. At this
time, however, more investigation into their
optimal roles will be needed. Each of the
commonly used diagnostic procedures for
AUB is reviewed here regarding the data
concerning their accuracy, as well as practi-
cal matters and their potential roles.
265
Endometrial Biopsy
Only about 60% of the endometrial cavity is
curetted in a D&C, leaving room for missed
diagnoses. In particular, most focal lesions
(polyps and fibroids) are missed by D&C
in postmenopausal women with AUB.9
However, for the diagnosis of diffuse lesions
(endometrial hyperplasia or carcinoma), the
accuracy of outpatient endometrial biopsy
has proven to be similar to the more invasive
and costly D&C.
A review of the studies containing infor-
mation regarding the accuracy of endome-
trial sampling using 18 different devices
from 1966 to 1999, identified 39 informative
studies involving 7914 women.10 The stud-
ies included combinations of menopausal
and/or perimenopausal women. Either sub-
sequent formal D&C or hysterectomy was
used as a reference compared with office en-
dometrial biopsy. Diagnostic accuracy was
better in menopausal women. Yet overall, ac-
curacy was good in all women, especially
with the use of the Pipelle brand of curette,
where sensitivity for endometrial carcinoma
was 99.6% and specificity was 91%. Sensi-
tivity for atypical hyperplasia was 81% with
a specificity exceeding 98%.
A similar systematic review involving
1013 patients from 11 primary studies using
6 different commercial clinic biopsy instru-
ments identified good accuracy for a biopsy
to identify endometrial cancer if the speci-
men was adequate for evaluation.11 The
combined failure rate for obtaining an ade-
quate specimen was 7%, and biopsy failure
was more common in menopausal women.
Endometrial biopsy results were also com-
pared with the reference standards D&C
or hysterectomy. When a biopsy was posi-
tive for cancer, the postbiopsy probability
of endometrial cancer was 81.7% (95% con-
fidence interval [CI] 59.7–92.9). The pooled
probability that a negative biopsy missed
an endometrial cancer was 0.9% (95% CI:
0.4–2.4). Overall, a positive result was accu-
rate in the diagnosis of endometrial cancer,
whereas a negative result was not. There-
fore, if an endometrial biopsy is negative
266 Hatasaka
in a situation where AUB continues, or if a bi-
opsy cannot be obtained, then further more
aggressive diagnostic efforts are warranted.
Transvaginal Ultrasound
Besides endometrial sampling, transvaginal
ultrasound has also been used to screen for
endometrial hyperplasia and carcinoma.
There are no pathognomonic sonographic
characteristics that correlate completely
with histology, so comprehensive tissue
diagnosis remains the gold standard. In gen-
eral, along with endometrial thickening, the
sonographic characteristics of hyperechoge-
nicity and heterogeneous texture represent
higher risks for cancer than other patterns.
An enlarged uterus, fluid within the cavity,
increased blood flow, and an irregular inter-
face of the endometrium and myometrium
also suggest cancer.
Also bear in mind that the larger the vol-
ume of an intrauterine mass, the worse the
histologic severity the lesion tends to have.
Another general rule is that as a woman’s
age increases, so does her risk of endometrial
cancer given the same ET. Therefore, ET
measurements stand to predict risk for endo-
metrial cancer in postmenopausal women
more accurately than in premenopausal
women. Indeed, TVUS has demonstrated
good accuracy for detecting endometrial
carcinoma in postmenopausal women.
A systematic analysis of 35 studies of
TVUS among 5892 women with postmeno-
pausal bleeding found prevalence rates of
13% for endometrial cancer and 40% for hy-
perplasia and/or polyps.12 Pooled results fo-
cused only on ET and not other sonographic
characteristics of the endometrial lesions.
Mean (±SD) ET measurements were 4
(±1) mm for normal histology, 10 (±3) mm
for polyps, 14 (±4) mm with hyperplasia,
and 20 (±6) mm with carcinoma. The bal-
ance between sensitivity and specificity is
dependent on the ET threshold used to de-
fine abnormal. If 3 mm was used, sensitivity
and specificity were 98% and 38%, respec-
tively; but if 5 mm was used, the test char-
acteristics were 92% and 81%; and if 10 mm
was designated as abnormal, 66% and 79%.
Another way to state the risk of endometrial
cancer in a postmenopausal woman with
AUB, is that the risk of cancer approximates
7.3% if the ET exceeds 5 mm and is ,0.07%
if the ET is #5 mm.13
Measurements of ET have been shown
to be highly reproducible to both intra-
and interobserver measurement.14 Neverthe-
less, ET measurements in premenopausal
women have not been shown to predict
the presence of endometrial hyperplasia or
carcinoma reliably as they have in peri- or
postmenopausal women. Even so, it is logi-
cal that the persistent noncyclical finding of
ETs in excess of approximately 11 mm
should trigger concern in premenopausal
women, especially in those with risk factors
for endometrial carcinoma.4 Risk factors
include extended duration of AUB, chronic
anovulation, estrogen exposure, nulliparity,
diabetes, obesity, hypertension, and tamoxi-
fen use.
Despite the relative shortcomings for the
use of TVUS in defining diffuse endometrial
lesions in premenopausal women with AUB,
a strength of TVUS is in detecting and char-
acterizing focal anatomic lesions of the
uterus.
Sonohysterography
Sonohysterography (SHG) is also known by
a number of other names including hystero-
sonography, saline infusion sonography,
hydrosonography, and saline contrast hystero-
sonography. It is more expensive and
invasive than TVUS and transabdominal
ultrasonography due to the infusion of ster-
ile saline into the uterine cavity during trans-
vaginal sonography. Another disadvantage
is that optimally it must be done in the
proliferative phase after the menses so that
menstrual tissue does not give false-positive
results and so that thick secretory endome-
trium is less likely to conceal focal lesions.
There is potential advantage in separating
and clarifying the relationships of anatomic
lesions in and around the endometrial–
myometrial junction. The size and myometrial
 Evaluation of Abnormal Uterine Bleeding
depth of fibroids can be ascertained to assist
in surgical removal. Sonohysterography also
may allow the ability to visualize mobility of
intracavitary lesions such as adhesions and
polyps within the liquid media. This is not
possible with simple sonography due to
compression of the structures within the
cavity. Performing and interpreting sonohys-
terography takes special training, as outlined
by the American College of Obstetrics and
Gynecology (ACOG).15
In an attempt to delineate potential
advantages and disadvantages of using SHG
for the diagnosis of AUB, a meta-analysis
of pre- and postmenopausal women with
AUB was performed.16 From 1992 to
2002, 24 publications that collectively to-
taled 2278 SHG procedures were analyzed.
Sonohysterography was successfully com-
pleted in 95% of the premenopausal women
and 87% of the postmenopausal patients.
Sixteen of these studies had complete veri-
fication of the results using hysteroscopy
or hysterectomy as the gold standard refer-
ence (877 women). From among the 16
studies, pooled sensitivity for the success-
ful SHGs was 95% (95% CI: 0.93–0.97),
whereas the specificity was 88% (95% CI:
0.85–0.92). Five cases were complicated
by vasovagal episodes and 2 by urinary tract
infections. Sonohysterography was twice as
reliable for detecting submucosal fibroids as
it was for detecting polyps in this study.
Although accurate for identifying focal
lesions, SHG does not necessarily add to
the value of TVUS for the diagnosis of dif-
fuse lesions such as hyperplasia and cancer.
Therefore, in postmenopausal women with
AUB where the exclusion of cancer is more
pressing than evaluating focal intracavitary
lesions, SHG may not be the best choice
for an initial diagnostic test.
One study showed that SHG confirmed
the presence of masses in 84% of 214 con-
secutive cases of suspected intracavitary
lesions.17 However, sonohysterography is
incapable of reliably diagnosing specific his-
tology. Therefore, its role is primarily to dif-
ferentiate focal from diffuse disease and sec-
267
ondarily to characterize focal lesions by
size, number, location, and relationship to
the endometrial–myometrial interface. Rein-
hold and Khalili have suggested 3 circum-
stances where SHG is recommended assum-
ing indeterminate TVUS and endometrial
biopsy have been performed already: 1)
thickened endometrium in the face of a non-
diagnostic biopsy; 2) indeterminate TVUS;
and 3) negative TVUS and biopsy findings
but persistent bleeding.
Hysterosalpingography
Hysterosalpingography (HSG) can reliably
identify intracavitary masses. Occasionally,
subtle HSG findings can suggest a specific
pathology. For example, when present, en-
dometrial cancer tends to demonstrate irreg-
ular masses that are broad based. Another
clue for endometrial cancer is limited uterine
distensibility by contrast fluid during an
HSG. However, disadvantages of HSG in-
clude the inability to consistently identify
diffuse lesions, the sites of attachment of
intracavitary masses, intramural or subser-
osal lesions, and the relative invasiveness
(pain and radiation exposure) of the proce-
dure. In addition, there is a risk that intraca-
vitary blood clots associated with AUB will
yield false-positive findings. Therefore, a
primary role of hysterosalpingography for
AUB has not been promoted.
Magnetic Resonance Imaging
in the Evaluation of Abnormal
Uterine Bleeding
Currently, although MRI has extremely high
resolution, a role for MRI for diffuse endo-
metrial lesions causing AUB is not well de-
fined, as the number of women studied is
low. This is due in part to the high relative
cost of MRI with no clear benefits yet de-
scribed for the indication of AUB.3 Magnetic
resonance imaging has largely been rele-
gated to a contingency study for assisting in
the diagnosis and management of other pa-
thologies that cause AUB when less expen-
sive procedures have been nondiagnostic.
Magnetic resonance imaging does, however,
268 Hatasaka
have several important supporting roles in
the evaluation of AUB. For instance, when
ultrasonography is inadequate, the utility
of MRI for defining precise locations of
leiomyomata is excellent. Another possible
role for MRI in the evaluation of AUB has
been for detecting adenomyosis where
MRI is more accurate than other methods.
However, obtaining an MRI for adenomyo-
sis will infrequently change clinical man-
agement. Magnetic resonance imaging does
have an important role in defining specific
Müllerian anomalies that are occasional
causes of AUB.
Hysteroscopy
Miniaturization of hysteroscopy equipment
with its attendant patient tolerability and
lower cost has provided new diagnostic
and even therapeutic possibilities in an
office setting. Hysteroscopy has had an
evolving role in the evaluation of AUB.
Direct visualization of intracavitary masses
is an obvious benefit over imaging. How-
ever, the critical unknown is how accurate
hysteroscopy is in diagnosing the diffuse
lesions (endometrial hyperplasia and
carcinoma).
Clark et al addressed this question in a
systematic review of 65 primary studies that
included 26,346 women.18 Visual hystero-
scopic results were compared with tissue di-
agnoses. Tremendous heterogeneity of the
data hampered quantitative interpretation;
however, in qualitative terms, hysteroscopy
is only moderately accurate in diagnosing
diffuse endometrial disease. The technique,
however, is highly accurate for diagnosing
frank carcinoma. Outpatient hysteroscopy
results were as accurate as operating room
procedures. Overall, a very low complication
rate was observed, but 8 women did suffer
major complications. Hysteroscopy could not
be completed in 5% of attempted procedures.
Practical considerations help guide the
appropriate use of hysteroscopy in the eval-
uation of AUB. Given the moderate increase
in invasiveness and the definite increase in
the need for specialized equipment and
training to perform and interpret, hysteros-
copy has not been an obvious primary
screening tool for evaluating AUB. Its main
role has been to verify the intrauterine status
visually and by directed biopsy when the
less invasive measures such as blind biopsy,
sonography, and SHG are inadequate.
The greatest potential advantage of office
hysteroscopy resides in its ability to allow
directed biopsy in addition to direct visual-
ization of lesions. This property compen-
sates for the modest diagnostic capability
of hysteroscopy for diffuse lesions and sur-
passes the accuracy of the blind biopsy tech-
niques. As experience grows, ambulatory
hysteroscopy may one day supplant the cur-
rently popular 2-stage approach that uses
screening TVUS in conjunction with blind
endometrial sampling.
COMPARATIVE ASSESSMENT OF
DIAGNOSTIC PROCEDURES
Given the nature of the lesions reviewed
and the characteristics of the diagnostic pro-
cedures available, it is a challenging task
for clinicians to assemble the information
into an efficient and safe diagnostic plan.
A helpful study toward this end aimed at
assessing relevant test characteristics and
secondary clinical outcomes comes from
the Cochrane Menstrual Disorders and Sub-
fertility Group.4
They examined the test characteristics of
the 3 most commonly used diagnostic tests
for AUB in premenopausal women.4 Trans-
vaginal ultrasonography, sonohysterogra-
phy, and hysteroscopy with biopsy were
compared for their ability to identify cor-
rectly submucosal fibroids, polyps, endome-
trial hyperplasia or carcinoma, or any detect-
able intrauterine pathology verified histolog-
ically by subsequent operative hysteroscopy
or hysterectomy. Sixty-one potential studies
were analyzed, but only 19 met the inclusion
criteria (n = 2917 patients total, of whom
97.5% were premenopausal). The findings
of the review can be summarized according
to the procedure evaluated.
 Evaluation of Abnormal Uterine Bleeding
Transvaginal Ultrasonography
Strengths
1. No complications were recorded from among
11 studies of TVUS
2. Mean procedure time is approximately
8 minutes (SD 1.7)
Weaknesses
1. 2% reported unpleasant pain, 40% reported
slight pain from the procedure
2. TVUS is suboptimal to identify submucosal
leiomyomata
3. Compared to SHG and hysteroscopy, TVUS
has a higher false-negative rate in diagnosing
intrauterine pathology
Sonohysterography
Strengths
1. Mean procedural time was 15 minutes (SD
2.7)
2. Highly accurate and similar to hysteroscopy
in its ability to diagnose intrauterine masses
3. Good (similar to hysteroscopy) in its ability
to diagnose endometrial hyperplasia
Weaknesses
1. From 3 studies that tracked pain, the inci-
dence of moderate to severe pain approximated
12%, whereas 19% to 100% experienced
slight pain from the procedure
2. The combined rate of failing to complete an
SHG procedure was 5% from 633 attempted
procedures among 8 different studies
Office Hysteroscopy With Biopsies
Strengths
• Only 1 case of tubal infection was reported
from 770 procedures; no other serious com-
plications were noted
• Procedure time was only 11 minutes (SD 1.7)
on average
• Highly accurate and similar to SHG in its
ability to diagnose intrauterine masses
• The best test among the 3 to diagnose submu-
cous fibroids, although SHG is also excellent
for this purpose
• Hysteroscopy with biopsies is also good at
detecting endometrial hyperplasia
269
Weaknesses
• Two studies assessed pain with office hysteros-
copy. One study using flexible hysteroscopy19
found that 50 of 130 (38.5%) of patients
reported tolerable (32/130) or barely tolerable
(18/130) pain. Another 25% reported mild
pain during the procedure. The other study20
did not formally assess pain using a pain
scale, but the authors noted that 28 of 793
patients reported that they would not consider
hysteroscopy again in the future due to pain.
Another 1.6% of the procedures could not be
completed due to intolerable discomfort.
Thus, a considerable number (5.1%) of
patients overall found pain from hysteroscopy
to be objectionable. The need for cervical di-
lation for office hysteroscopy and its relation-
ship to pain was not addressed.
• Pain from hysteroscopy compared to SHG
cannot be fairly compared using available in-
formation, as there are no well-designed com-
parison studies using a reference pain scale
• Nulliparous women tend not to tolerate the
procedure as well as multiparas
From this Cochrane data analysis, it can be
surmised that all 3 diagnostic procedures
evaluated (TVUS, SHG, and diagnostic hys-
teroscopy with biopsies) appear to be help-
ful in both predicting the presence of ana-
tomic lesions associated with AUB and in
predicting their absence when they are not
present. However, the authors of the
Cochrane systematic review make the obser-
vation that test accuracy for correlation with
histopathology has been assessed, but accu-
racy is not sufficient to help clinicians man-
age a diagnostic evaluation of AUB. For in-
stance, each diagnostic test has its individual
strengths for detecting specific uterine
lesions, but without prior certainty as to
which lesions may be present, it is not al-
ways possible to select the best initial test.
Nevertheless, a tendency of some authors
has been to recommend some diagnostic
procedures due to their high level of accu-
racy even when the findings may not change
clinical management.
Considerable limitations remain in our
understanding about how best to use the
270 Hatasaka
techniques. Of the 19 studies meeting inclu-
sion criteria in the analysis by the Cochrane
group, only 4 were rated as high-quality
studies. For the studies involving TVUS
and SHG, heterogeneity was quite variable;
therefore, the results for the pooled data can-
not be interpreted with confidence. Interop-
erator assessments for consistency of inter-
pretation of the procedures have not been
reported. Equipment costs and the degree
of specialized training required to achieve
optimal accuracy have not yet been ad-
dressed in a useful manner. Moreover,
large-scale cost-effectiveness analyses and
decision analyses have not been done for
the roles of 1 or combinations of the 3 diag-
nostic procedures or for endometrial biopsy
in the assessment of AUB.
Although not addressed in the Cochrane
review, it is surprising that the studies as-
sessing procedural pain have not shown
a benefit to the use of nonsteroidal anti-
inflammatory drugs (NSAIDs) or paracervi-
cal anesthesia for the pain during the proce-
dures.19 The agents may, however, help
postprocedural discomfort, but this has not
been studied adequately. It will be critical
to know whether the use of the available di-
agnostic procedures will lead to the ability
to replace major surgeries safely with mini-
mally invasive ones.
DIAGNOSTIC STRATEGIES FOR
STRUCTURAL LESIONS
A fundamental responsibility is to identify
potentially life-threatening conditions asso-
ciated with AUB quickly (such as ectopic
pregnancy, severe anemia, and cancers) be-
fore a systematic evaluation for other causes
can be initiated. Although anemia and preg-
nancy can be detected immediately by
serum testing, the elimination of uterine
cancer as a possibility is more problematic.
Imaging procedures can only correlate with
but not make the diagnosis of uterine can-
cers. Definitive diagnosis requires tissue
confirmation; however, routine endometrial
sampling for all women with AUB is im-
practical. Instead, skillful history, physical
examination, and directed laboratory work
will be the most important initial diagnostic
tools. The focus should be on determining
those women with AUB who are at highest
risk of endometrial cancer. During the repro-
ductive time frame, these will typically be
women with chronic anovulation.
The ACOG Practice Committee formu-
lated recommendations regarding when an
endometrial biopsy is indicated in the eval-
uation of anovulatory uterine bleeding based
upon clinical risk.15 Even in adolescents, en-
dometrial biopsy should be considered after
2 to 3 years of anovulatory bleeding, partic-
ularly in obese girls. Biopsy is indicated for
all women suspected of anovulatory bleed-
ing beyond 35 years of age. Women who
do not respond to medical therapy or who
have AUB and other risk factors for endo-
metrial cancer such as unopposed estrogen
therapy or tamoxifen use should be biopsied
at any age. These ACOG recommendations
do not incorporate criteria based upon any
imaging studies.
When acutely threatening conditions
have been ruled out, yet the diagnosis re-
mains in doubt, a comprehensive search
for the underlying cause(s) of AUB may be-
gin. Systematic evaluation of pregnancy, co-
agulation, and malignant sources rely most
heavily on history, physical, serum labs,
Pap testing, and endometrial sampling. His-
torically, AUB superimposed upon ovulatory
cycles is usually from a structural source,
although anatomic lesions can also be pres-
ent coincidentally in anovulatory women.
Structural lesions are best characterized by
imaging techniques.
Although imaging procedures cannot re-
place definitive histologic diagnoses, they
are indispensable for characterizing ana-
tomic abnormalities that can cause AUB.
Before ordering, the goals of a given imag-
ing procedure and its ability to meet the
goals should be carefully thought out. Some
potential goals include the initial detection
of anatomic lesions and the identification
of their likely pathology, prevention of un-
necessary invasive diagnostic procedures,
 Evaluation of Abnormal Uterine Bleeding
and monitoring the progression of lesions.
Another important goal of imaging pro-
cedures is to provide critical adjunctive in-
formation to help guide surgical and other
therapeutic interventions optimally.
Elaborate diagnostic algorithms incorpo-
rating biopsy and imaging procedures were
proposed by an expert panel for the evalua-
tion of postmenopausal bleeding.21 As
opposed to the situation in postmenopausal
women where these experts recommended
a threshold endometrial thickness of
#5 mm to withhold endometrial sampling,
a safe endometrial thickness threshold has
not been substantiated for premenopausal
women. Considerable overlap exists be-
tween hyperplasia, cancer, and ovulatory
endometrial thickness measurements in pre-
menopausal women. Moreover, there are
substantial limitations to our knowledge
about the accuracy, tolerability, cost-
efficiency, and practicality of the available
diagnostic tests for the evaluation of AUB
in premenopausal women. Therefore, a uni-
versal, linear, evidenced-based algorithm in-
corporating imaging procedures for AUB
cannot be assembled.
No one diagnostic test will distinguish all
anatomic lesions that can cause AUB with
high sensitivity and specificity. However,
TVUS being relatively well tolerated repre-
sents the most logical first diagnostic step
when a structural lesion is suspected. It
offers rapid triage to determine the presence
of an anatomic lesion and has the added
advantage of reliably determining whether
a lesion may be diffuse or focal. Even if pre-
vious endometrial sampling was nondiag-
nostic, TVUS may identify diffuse disease,
and it is superior to blind sampling to detect
focal lesions.
Once anatomic lesions have been identi-
fied by examination or imaging, subsequent
evaluation requires individualization. Each
diagnostic procedure including, endometrial
biopsy, HSG, TVUS, diagnostic hysteros-
copy, hysteroscopic-directed biopsies,
MRI/CT, and SHG have their strengths
and weaknesses. The prudent selection of
271
appropriate tests depends upon their ability
to characterize the anatomic lesions most
highly suspected after thorough initial eval-
uation. Other variables that the clinician must
balance include patient preference, available
expertise, local costs and availability, risks,
and discomfort. Ultimately, test selection
should be guided by the underlying principle
that the results are capable of changing the
clinical management of a patient in a mean-
ingful way. Therefore, a clinician must be
knowledgeable about the characteristics of
each potential diagnostic test for each type
of structural lesion.
Summary
The goal of evaluation of AUB is to arrive at
an accurate and clinically useful diagnosis in
the most efficient and cost-effective manner
possible. An algorithmic approach cannot
be universally applied due to the many com-
plex variables involved in the causes of
AUB and the available diagnostic proce-
dures to diagnose the condition. However,
a systematic approach (structured by general
diagnostic categories) throughout the history
and physical and laboratory assessments
affords a comprehensive and efficient evalua-
tion. Clinicians must first carefully rule out
the potentially perilous acute conditions, in-
cluding severe anemia, abnormal pregnancy
states, systemic disease, and other nonuter-
ine sources of AUB. Once anatomic lesions
become the likely underlying cause of the
AUB, the risk of endometrial cancer
becomes the first priority. The later concern
is the primary risk associated with AUB for
postmenopausal women but should also be
the focus of premenopausal women with
risk factors sufficient to trigger concern.
The selection of a diagnostic approach
relies on knowledge of the accuracy, practi-
cality, and availability, patient acceptability,
complication rates, assessment of whether
the results will change management, cost ef-
fectiveness, and the likelihood that a particu-
lar diagnostic test will ultimately improve the
clinical outcome. More research is needed
272 Hatasaka
on the available testing procedures to help us
optimize their utility.
Transvaginal ultrasonography provides a
relatively noninvasive first step with reason-
able sensitivity for both focal and diffuse
lesions causing AUB. Sonohysterography
extends the sensitivity and specificity of
TVUS, and hysteroscopy allows targeted bi-
opsies of both focal lesions and suspected
diffuse lesions.
The roles for diagnostic procedures have
not been clearly defined yet. Given the cur-
rent available information reviewed in this
chapter, individualization and balanced clin-
ical judgment are required to design an op-
timal redundant diagnostic approach to
AUB.
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