is an Assistant Professor, Department of Radiology, University of
Washington Medical Center, Seattle, WA.
Some of the material contained in this article was presented
in part at the Society of Radiologists in Ultrasound Meeting,
October 2007, Chicago,IL,and the Society of Uroradiology Meeting,
February 2008, Rancho Mirage, CA.
Postmenopausal bleeding (PMB) refers to any bleeding other than
the expected bleeding that occurs with sequential hormones in
postmenopausal women. It is a common problem that affects 1 in 10
postmenopausal women older than 55 years.
Approximately 70% of all gynecological consultations in
perimenopausal and postmenopausal women are for PMB.
Abnormal perimenopausal or postmenopausal bleeding is associated
with endometrial carcinoma in approximately 10% of cases, and PMB
is considered to be caused by endometrial neoplasia until proven
Approximately 90% of women with endometrial carcinoma present with
In 18% to 40% of women, benign focal lesions, such as endometrial
polyps and fibroids, are common. Although PMB is most commonly due
to other conditions, it is essential to exclude endometrial
carcinoma. Thus, accepted practice in the United States includes
further evaluation to exclude endometrial carcinoma in women with
Formerly, dilatation and curettage (D&C) was the principal
means of investigation for PMB. But D&C has now been replaced
by newer methods of investigation, incuding outpatient endometrial
biopsy, transvaginal ultrasound (TVUS), and hysteroscopy. However,
there is still uncertainty about the most accurate, acceptable, and
efficient diagnostic approach.
Definition of postmenopausal bleeding
is defined by the World Health Organization as the permanent
cessation of menstruation resulting from the loss of ovarian
follicular activity. From a symptomatic perspective, PMB is vaginal
bleeding following a woman's last menstrual cycle, which is
considered an episode of bleeding ≥12 months after her last period.
It may be difficult to assess abnormal bleeding in women who are
using hormone replacement therapy (HRT).
is the term used to describe breakthrough bleeding occurring in
women on HRT. Therefore, assessment depends on the type of regimen.
For sequential HRT regimens, abnormal bleeding may be heavy or
prolonged at the end of or after the progestogen phase or may occur
at any time (breakthrough bleeding). Continuous combined regimens
induce amenorrhea and, therefore, avoid cyclical bleeding.
According to Ettinger et al,
however, nearly half of women on continuous combined HRT regimens
will experience bleeding at some time, usually within the first 6
months of treatment. Bleeding on continuous combined HRT regimens
should be evaluated if it occurs after the first 6 months of
treatment or if it occurs after amenorrhea has been
Etiology of postmenopausal bleeding
Various causes of postmenopausal bleeding are listed in Table 1
and include endometrial atrophy (approximately 75% of cases),
submucosal fibroids, endometrial polyps, endometrial hyperplasia,
endometrial carcinoma (approximately 10%), and estrogen withdrawal.
Patients with atrophic endometritis usually have been
postmenopausal for >10 years. Treatment of atrophic endometritis
is topical or systemic estrogens. Curettage has also been known to
be curative for an atrophic endometrium.
Endocervical polyps are more common than ectocervical polyps.
Endometrial hyperplasia is the result of unopposed estrogens on the
endometrium and is commonly encountered in perimenopausal women. It
is an abnormal proliferation of endometrial stroma and glands and
represents a spectrum of endometrial changes that range from
glandular atypia to frank neoplasia. As suggested by Kurman et al,
up to one third of endometrial carcinoma is thought to be preceded
by hyperplasia. Endometrial carcinoma is the most common
gynecologic malignancy and the fourth most frequent site of
malignancy in females in North America and Europe. Risk factors
include obesity, unopposed estrogens, polycystic ovarian syndrome,
and nulliparity. The common presenting symptom is postmenopausal
bleeding or abnormal uterine bleeding in the premenopausal patient.
Though a majority of the patients will be postmenopausal,
approximately 20% of the patients will be premenopausal and will
present with irregular bleeding.
Diagnostic tools available and choice of study
Since endometrial carcinoma is an important differential
diagnosis for postmenopausal bleeding, the standard of care is
further evaluation of any PMB. Various investigations available for
evaluation of the endometrium are TVUS, saline infusion
sonohysterography (SIS), D&C, hysteroscopy, and endometrial
biopsy. So the question is, which test is to be done first? That
depends on the accuracy, safety, comfort, efficiency, and
availability of each modality. The sensitivity, specificity, and
adverse events associated with TVUS, hysteroscopy, and endometrial
biopsy are shown in Table 2.
A definitive diagnosis in PMB is made by histology.
Historically, endometrial samples have been obtained by D&C.
This involves curetting the walls of the uterine cavity in a
systematic fashion. However, the technique is blind, and it covers
as much as 60% of the cavity but may miss polyps as they recoil
from the passing curette.
In a series by Grimes et al,
endometrial lesions were overlooked in up to 10% of cases in which
D&C was the only procedure used. Also, D&C must be
performed as an inpatient procedure, which makes it a costly
procedure and increases the risks associated with the use of
general anesthesia. Outpatient endometrial sampling devices, such
as the Pipelle endometrial sampler (Unimar, Inc., Wilton, CT), have
a narrow bore (typically with an external diameter of approximately
3 mm) and sample the endometrium by aspiration. There are a variety
of different samplers available, such as the Novak (Cooper
Surgical, Trumbull, CT), the Kevorkian curette (Cooper Surgical),
and the Vabra aspirator (Berkeley Medevices, Richmond, CA), but no
systematic comparisons have been made between them. All methods of
sampling the endometrium will miss some cancers.
Unlike directed biopsy, the sample by these devices is obtained
blind and as little as 4% of the cavity is sampled. Also, polypoid
lesions may not be sampled or removed by these devices. Guido et al
evaluated the sensitivity of the Pipelle endometrial suction
curette in the detection of endometrial carcinoma in patients with
known endometrial cancer. They enrolled 65 patients with known
endometrial cancer who were undergoing hysterectomy as part of a
formal staging procedure. Endometrial biopsies were performed prior
to each surgical procedure, and the biopsy results were compared
with the hysterectomy specimen. They found that Pipelle biopsy was
adequate for analysis in 63 of 65 patients (97%). When the cancer
was localized to <25% of the surface, however, 7 cases were
missed; when cancer was localized to <50% of the surface, 11
cases were missed; and when cancer involved >50% of the surface,
no cases were missed. They concluded that Pipelle endometrial
suction curette is an effective office device for evaluating
patients at risk of endometrial cancer but that tumors localized to
a polyp or small area of endometrium may go undetected.
The authors also noted that D&C had a greater complication
rate, but the diagnostic accuracies of the 2 techniques were
The main disadvantage of the use of the Pipelle is the
relatively high proportion of inadequate samples, particularly
among postmenopausal women. Dijkhuizen et al
conducted a meta-analysis by examining 39 studies that included
8000 patients who underwent endometrial biopsy and compared results
with those from D&C, hysteroscopy, or hysterectomy. The authors
found that the detection rate for malignancy was higher in
postmenopausal women. The Pipelle device proved to be the best
sampling tool, with cancer detection rates of >99% for
postmenopausal women and 81% sensitivity in detecting complex
Pelvic ultrasound can be used to evaluate the uterus and
endometrium. In the absence of visible abnormalities (eg,
fibroids), endometrial thickness (ET) and homogeneity have been
used as markers for endometrial pathology. Details of ultrasound
and sonohysterography in postmenopausal bleeding are mentioned
The guidelines for evaluation of PMB suggested by the Society of
Radiologists in Ultrasound (SRU) consensus panel
are limited since there have been no full-fledged
cost-effectiveness analysis and no large-scale randomized
controlled trials have compared the effectiveness of ultrasound or
biopsy. The SRU panelists stated that, in their opinion, either
TVUS or office biopsy can be used as the initial test in the
evaluation of women with PMB. The panelists agreed that SIS or
hysteroscopy was appropriate when a focal abnormality is suspected
on TVUS. One advantage of hysteroscopy is that it permits biopsy of
a focal mass.
Imaging of normal and abnormal endometrium in
Standards for ultrasound
Transabdominal ultrasound (Figure 1) alone is not sufficient to
assess the uterus due to the suboptimal resolution of the uterus
and endometrium. However, a transabdominal ultrasound should be
performed so that large masses or fluid collections are not missed.
A transabdominal ultrasound should be followed by a TVUS (Figure
1). The uterus and adnexae are evaluated by long- and short-axis
views (Figure 2). This should include assessment of the cervix. The
endometrium is evaluated on both the long- and short-axis views
through the uterus; however, the endometrium is measured on the
long-axis view (Figure 2). The entire endometrium should be
evaluated to avoid missing focal lesions. The thickest measurement
of the endometrium in the midline is reported (Figure 3). Any focal
abnormalities should be noted and their appearance and location
described (Figures 4 and 5). Any vascularity within the focal
lesion should also be noted. Polyps may be broad-based and sessile
or pedunculated with a central stalk of vascularity on color
Fluid within the endometrium is not included in the measurement. In
cases of endometrial fluid, ET is the sum of the thickness of the 2
endometrial layers (Figure 6). Non-visualized endometrium should
not be considered as a normal endometrium. The nonvisualization of
the endometrium could be due to large fibroids displacing the
endometrium (Figure 7) or endometrial carcinoma infiltrating the
myo metrium (Figure 8).
Two separate studies by Briley et al
and Karlsson et al
have suggested that nonvisualized endometrium or poorly seen
endometrium should be biopsied.
Imaging of normal and abnormal endometrium
The endometrium in a postmenopausal patient should be thin and
homogenous. There is controversy regarding the cutoff value of ET
that should be considered normal. Some investigators have found
that the ET decreases with age
; however, others believe that there is no statistically
significant change during menopause.
Warming et al
reported the results of their study that followed 1182 asymptomatic
patients between 45- and 83-years-old without HRT. They noted that
when using transvaginal endometrium measurement, the normal range
of ET was correlated with years since menopause (YSM). For women
with <5 YSM, the mean ET was significantly greater than for
women >5 YSM. Furthermore, the mean ET decreased in the first 5
YSM, whereas it remained almost unchanged from 5 to 13 YSM, only to
increase slightly during the rest of the postmenopausal years.
In general, a double-layer thickness <5 mm without focal
thickening excludes significant disease.
Homogenous endometrium measuring ≤5 mm is considered within the
normal range with or without HRT.
Several studies have established that the ET generally does not
exceed 4 or 5 mm in a normal postmenopausal woman.
However, there is considerable confusion as to which measurement
should be used as a cutoff to trigger further investigations. In a
study by Gull et al,
the prevalence of endometrial carcinoma in patients with ET of
<5 mm was 0.6%. A meta-analysis study by Smith-Bindman
found that with the use of a cutoff of 5 mm, 96% of endometrial
carcinomas would be detected in postmenopausal patients with
bleeding. When this threshold was changed to 4 mm, it did not alter
the sensitivity for cancer detection (sensitivity 96%); however, it
increased the false-positive rate from 9% to 30%.
They also found that TVUS was better at detecting cancer than it
was at detecting polyps or hyperplasia. By using a 5-mm threshold,
96% of women with cancer had an abnormal ultrasound result, whereas
92% of women with endometrial disease had an abnormal ultrasound.
In a prospective study by Granberg et al
of 1110 women with PMB, endometrial pathology was found most
frequently when the ET was >8 mm, and no endometrial cancers
were detected in women with ET <4 mm. Similarly, an evaluation
of 419 women with PMB by Garuti et al
assessed the sensitivity of 2 ET thresholds: 4 mm and 8 mm. The
authors reported a diagnostic sensitivity of 95.1% and a
specificity of 54.8% with the use of the 4-mm cutoff, and 83.8%
sensitivity and 81.3% specificity when the 8-mm cutoff was used.
Using a maximum of 5-mm ET to exclude carcinoma, a study by Briley
of 182 women with PMB found no cases of carcinoma; however, 3
patients had hyperplasia. According to Levine et al,
the variation in what is considered the upper limit of normal ET
seems to be correlated with the body-mass index and type of HRT,
with higher values in heavier women and in those taking
combinations of estrogen and progesterone. Another study by Gull et
reported a 0.6% prevalence of endometrial cancer in women with PMB
and ET <4 mm. This prevalence increased to 19% in women with an
ET <5 mm. The authors concluded that endometrial biopsy is not
required in women with an ET <4 mm. Several studies also suggest
that an ET >15 mm is highly suggestive of endometrial carcinoma,
although on sonograms polyps can present as an endometrium >15
mm thick. Other authors suggest that a minimum sonographically
measured ET of 6 mm should be utilized to reduce the number of
Some other markers have been reported as suggestive of
malignancy, including collection of fluid in the endometrial cavity
and irregularity of the myometrial-endometrial interface. In 1995,
Weigel et al
suggested that adding assessment of the endometrium for
homogeneity, presence of a central echo, and echogenicity would be
most useful in diagnosing cancers in women whose ET is in the
''gray area'' of 4 to 10 mm. Another prospective trial by Fistonic
found a 100% sensitivity for irregular myometrial-endometrial
interface in predicting endometrial carcinoma. Doppler imaging has
been reported to increase the sensitivity and specificity of
sonography in detecting endometrial pathology. In a prospective
study of 60 women with PMB, Amit et al
reported a sensitivity of 86% and specificity of 89% for pulsed
Doppler (pulsatility index point cutoff, 1.0). Sheth et al,
however, evaluated pulsed Doppler in postmenopausal women with
thickened endometria and found that low-impedance arterial flow did
not differ significantly between benign and malignant lesions.
Errors in TVUS
Even in the most experienced hands, TVUS may provide inaccurate
results. According to Fleischer,
errors arise from improper measurement, single linear measurement,
and distortion by fibroids. The most common error is improper
measurement of the endometrium. The shape of the endometrium is not
purely geometric, and measurements of its width rather than its
anteroposterior 2-layer thickness can result in overestimation of
its thickness. The echotexture of the endometrium should be
carefully assessed. Any echogenic mass that disrupts the smooth
texture with or without punctate cystic areas may signify the
presence of a polyp (Figure 9).
Since the shape of the endometrium is not geometric, the thickness
of the endometrium may vary in the fundus and the body. Also, focal
lesions may make the endometrium thicker focally. According to
Karlsson et al,
readers of ultrasonograms also vary in their interpretations, with
a difference of almost 1.5 mm seen in a study among sonographers.
Submucosal (Figure 10) and intramural fibroids may distort the
endometrium, making it difficult to measure thickness in the
anteroposterior plane. According to Levine et al,
the endometrium also varies with the cycle in patients on cyclic
estrogen and progesterone with a difference of up to 3 mm.
Saline infusion sonohysterography
Saline infusion sonohysterography is a diagnostic technique
consisting of an intrauterine infusion of saline solution by means
of a catheter with an inflating balloon positioned in the cervical
canal. The expansion of the uterine cavity is directly observed
through TVUS. Saline infusion sonohysterography allows reliable
differentiation between focal and diffuse endometrial and
According to Farquhar et al,
SIS is primarily indicated in symptomatic and asymptomatic patients
who have an irregular endometrial appearance on TVUS when
endometrial lesions (such as polyps [Figure 11], submucosal
fibroids, and focal endometrial hyperplasia) are suspected. Saline
infusion sonohysterography can be performed safely and easily as an
outpatient procedure, and anesthesia is not needed. The detection
rates for focal abnormalities are comparable with those of
The SRU consensus panel favored SIS when a focal endometrial
abnormality is suspected on the TVUS to confirm that a focal
abnormality is indeed present and to better determine the nature of
the focal abnormality.
According to Goldstein et al,
SIS may also be helpful when a thickened endometrium has been
identified on the sonogram to allow more efficient triaging of
patients. Saline infusion sonohysterography will show whether the
abnormality is diffuse (in which case a biopsy or D&C would be
the next step) or focal (in which case hysteroscopy would be the
next step). Saline infusion sonohysterography is also helpful if
there is a discrepancy between the findings on the TVUS and biopsy.
Saline infusion sonohysterography is also more sensitive than TVUS
or biopsy in detecting focal endometrial abnormalities.
In a multicenter study investigating the utility of SIS, Bree et
reported polyps in 47% and endometrial hyperplasia in 4% of women
with PMB. In a recent study, Neele et al
found that nearly 35% of asymptomatic postmenopausal women had
endometrial abnormalities detected with SIS.
Issues related to tamoxifen and HRT
Tamoxifen is a selective estrogen receptor modulator that is
commonly used as an adjuvant therapy in the treatment of breast
cancer. It binds to the estrogen receptor and acts as both estrogen
antagonist and agonist, depending on the target organ.
Tamoxifen has been shown to help prevent the original breast cancer
from recurring after breast surgery while also hindering the
development of new cancers in the opposite breast.
It is well known that tamoxifen use increases the risk of
developing endometrial carcinoma.
In a study by Cuzick et al,
women taking tamoxifen were 2.4 times more likely to have
endometrial carcinoma than women who were not taking the drug. This
risk also increased with increasing duration of use (relative risk
2.0 times for 2 to 5 years and 6.9 times for >5 years).
In a patient on tamoxifen, TVUS shows a thickened endometrium
with a characteristic appearance of tiny cystic areas (Figure 12).
Goldstein et al
suggested that these changes actually represented small
subendometrial anechoic areas in the proximal myometrium; however,
others maintain that these changes are actually in the endometrium.
Using histopathologic analysis, McGonigle et al
concluded that endometrial cystic atrophy may be responsible for
these benign changes.
Estrogens had been used as a monotherapy to relieve
postmenopausal women's complaints since the 1940s. Estrogen has a
proliferative effect on the endometrium glands as well as on
stroma. The proliferative activity of the endometrium is preserved
Although shortly after the appearance of postmenopausal HRT a
cause-and-effect relationship between estrogens and endometrial
carcinoma was suspected, it could be proven until 1974.
In 1961 hat scientists proved the capacity of progesterone to
counteract the proliferative effect of estrogen on the endometrium.
Since 1975, the use of combined preparations has grown; estrogen
monotherapy is now used only under limited circumstances.
Progesterone, administered to counteract the effect of estrogen,
can also counteract endogenous estrogen and thus decrease the risk
of endometrial carcinoma below the original level. According to
Erkkola et al,
during postmenopausal sequential HRT, time-dependent appearance of
endometrial hyperplasia can be expected, which poses an increased
risk for the development of endometrial carcinoma, since the
prevention of osteoporosis requires 10 years of treatment.
Therefore, sequential treatment is indicated in the frame of
short-term palliative therapy to relieve complaints.
Postmenopausal bleeding is a common problem, with endometrial
carcinoma being an important differential diagnosis. At present,
endometrial sampling is the gold standard for the diagnosis of
endometrial carcinoma; however, endometrial sampling is an invasive
procedure. Ultrasound can be used for noninvasive assessment of the
endometrium. However, further evaluation of PMB depends on the
expertise available at a particular institution and