Best Practice & Research Clinical Obstetrics and Gynaecology 23 (2009) 595607

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Obstetrics and Gynaecology
journal homepage: www.elsevier.com/locate/bpobgyn

Abnormal uterine and post-menopausal bleeding in the

acute gynaecology unit
Tommaso Bignardi, MD, Associate Lecturer a, *, Thierry Van den Bosch, MD b,
George Condous, MRCOG, FRANZCOG, Associate Professor a
a

Acute Gynaecology, Early Pregnancy and Advanced Endosurgery Unit, Nepean Centre for Perinatal Care, Nepean Clinical School,
University of Sydney, Nepean Hospital Penrith, Sydney, Australia
Department of Obstetrics and Gynaecology, University Hospitals Leuven, Belgium

Keywords:
abnormal uterine bleeding
post-menopausal bleeding
transvaginal ultrasound
endometrial biopsy
focal endometrial lesions
diffuse endometrial lesions

Abnormal uterine bleeding is one of the most common presentations in the acute gynaecology unit. The general principles of
emergency care, including assessment of haemodynamic state,
symptomatic relief as well as determination of underlying aetiology, apply to these women. We review different strategies in the
diagnosis and investigation of abnormal uterine bleeding in both
pre- and post-menopausal women. Transvaginal ultrasound (TVS)
with colour Doppler is the cornerstone of initial management. TVS,
in experienced hands, can reliably exclude the most common
intra-cavitary pathologies including endometrial polyps and
submucosal broids. Their exclusion, in pre-menopausal women,
aids in the diagnosis of dysfunctional uterine bleeding. In postmenopausal women, the endometrial thickness reliably selects
those who need further testing. If a thin and regular endometrium
is visualised, malignancy is most unlikely. To allow for reliable
evaluation of the endometrium, TVS has to be performed before
endometrial sampling. Saline infusion sonohysterography (SIS) is
most valuable in the detection of focal intra-cavitary lesions. TVS
with or without SIS can provide enough information to avoid an
unnecessary hysteroscopy. In this review, we will also discuss an
evidence-based algorithm for the work-up of women with postmenopausal bleeding.
2009 Elsevier Ltd. All rights reserved.

* Corresponding author.
E-mail address: tommaso.bignardi@alice.it (T. Bignardi).
1521-6934/$ see front matter 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bpobgyn.2009.05.001

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Abnormal uterine bleeding (AUB) accounts for up to 70% of all gynaecological consultations in the
peri- and post-menopausal years.1 Approximately 10% of women with post-menopausal bleeding have
endometrial cancer. However, it is of note that, approximately 12% of endometrial cancers are diagnosed before the menopause.2
For many years, dilatation and curettage (D&C) had been the method of choice for the diagnosis and
subsequent management of endometrial pathology in women with AUB.3 However, D&C necessitates
a general anaesthetic and has a limited accuracy, especially in case of focal lesions.4,5 Endometrial
malignancy may be missed by D&C with a false negative rate ranging from 2% to 11%.5,6 Although the
prevalence of endometrial cancer in women with post-menopausal bleeding is 310%, no organic cause
is found in the majority of cases.7 Thus, in the modern practice, D&C must not be used routinely as
a stand-alone test for women with post-menopausal bleeding.
In recent decades, several ofce-based methods for the diagnosis of uterine pathology have been
developed including transvaginal ultrasound (TVS), diagnostic hysteroscopy, endometrial biopsy,
colour Doppler imaging and saline infusion sonohysterography (SIS). The aim of these tests is to offer
an equivalent, or higher diagnostic accuracy in the case of focal lesions, compared with D&C, without
the need for a general anaesthesia.
The aim of this article is to evaluate the use of different strategies for the diagnostic evaluation of
AUB and post-menopausal bleeding. The value of ultrasound alone or in combination with different
diagnostic tools, is discussed. A diagnostic algorithm is proposed as well.
Ultrasound imaging of the uterus
The evaluation of the thickness and of the echogenicity of the endometrium on TVS reects
histological changes in the uterus. The knowledge of the normal physiological appearances of the
uterus on TVS during a womans life (normal menstrual cycle, postpartum and post-menopause) will
improve the diagnosis of uterine pathology. Quantitative ultrasound features (e.g., endometrial
thickness measurements), as well as qualitative features (e.g., the presence of enhanced vascularity),
have been studied.
The endometrium constantly changes throughout the menstrual cycle. This premise is essential
when evaluating this dynamic structure ultrasonographically. In the proliferative phase, increased
oestrogen secreted by the ovaries stimulates endometrial proliferation. This cyclic endometrial transformation is reected on ultrasound by changes in thickness and echogenic texture of the endometrium.8 The echogenicity of the endometrium is compared with the ultrasonographic reection of the
myometrium. During the proliferative phase, the endometrial thickness increases progressively while
the echogenicity of the endometrium remains low. The typical (leaf-like) three-layer pattern of the
proliferative endometrium consists of three hyperechogenic lines divided by two hypoechogenic areas
(Fig. 1). After ovulation, progesterone is produced by the corpus luteum. The combined reaction to

Fig. 1. The total (double layer) endometrial thickness is measured at its thickest part in the longitudinal plane. The surrounding
more echolucent layer (or halo) is considered to be the inner myometrium and is not included. When the endometrial layers are
separated by intracavity uid, both layers are measured and the sum recorded.

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oestrogen and progesterone activity leads to the secretory changes of the endometrium. The total
endometrial thickness is xed at about its pre-ovulatory level of 56 mm, but the glands and the vessels
continue to grow. This results in progressive tortuosity of the glands and intensied coiling of the spiral
vessels within the endometrium. In the late secretory phase, the stromal cells become large and polyhedrical producing a compact sturdy stroma. The sub-epithelial capillaries and spiral vessels become
increasingly engorged, and by day 2122 of the cycle oedema of the endometrial stroma due to increased
capillary permeability becomes the predominant morphological feature.
Using colour or power Doppler imaging, blood ow within the myometrium and endometrium can
be visualised. The uterine, arcuate, and part of the radial arteries can be visualised by most ultrasound
machines, provided that the appropriate settings are used. Higher-level machines allow visualisation of
vascularity inside the endometrium, especially in the secretory phase of menstrual cycle. The presence
of a distinct and localised vascular pedicle running from the myometrium into the endometrial lining is
to be considered abnormal. Timmerman et al. demonstrated that the presence of a pedicle artery is
highly suggestive for the presence of an endometrial polyp9 (Fig. 2).
AUB before menopause
The aetiology of acute abnormal genital tract bleeding encompasses a wide range of disorders that
can be secondary to benign changes of the female genital tract, such as infection, endocrinological
disorders, malignancies and systemic illness. Although the majority of abnormal bleeding comes from
the uterus, a careful physical examination will rule out vulvar, vaginal and cervical pathology. Possible
uterine causes of abnormal bleeding are listed in Table 1. Pregnancy-related causes of acute vaginal
bleeding will not be covered in this article.
As a rule, acute AUB in the pre-menopausal woman requires an assessment of haemodynamic state,
symptomatic relief as well as determination of underlying aetiology. A urinary pregnancy test is
mandatory in all women of reproductive age who present with acute vaginal bleeding, regardless of
their last menstrual period. Having ruled out pregnancy, then appropriate history, clinical examination,
including vital signs as well as TVS are all important in the assessment of such women. If a woman is
haemodynamically compromised then rapid resuscitation with intravascular crystalloid or colloid
expansion is mandatory in order to stabilise the clinical state as well arranging an evaluation of haemoglobin and haematocrit. It may be appropriate on occasion to consider blood transfusion; however,
this decision needs to be made in the context of the age of the woman, her clinical state and the
potential benets/risk associated with using blood products. Clinical speculum examination is
essential to exclude any lower genital tract abnormality that may be the cause for the presentation, for

Fig. 2. The pedicle artery sign in case of an endometrial polyp.

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Table 1
Common causes of abnormal bleeding of uterine origin.
Benign Uterine
Atrophic endometrium
Leiomyomas
Endometrial polyps
Adenomyosis
Intrauterine devices
Endometritis
Endocrine (thyroid disease, polycystic ovaries)
Anovulatory bleeding
Exogenous hormones (oral contraceptives, progestin-only contraceptives, hormone replacement therapy, tamoxifen)
Malignancies
Endometrial hyperplasia
Endometrial cancer
Endometrial stimulation by estrogen-producing ovarian neoplasm
Metastatic disease (leukemia, gastrointestinal cancers)
Systemic
Coagulopathies
Liver disease
Sepsis
Pregnancy
Viable intrauterine pregnancy
Spontaneous miscarriage (complete, incomplete or missed)
Ectopic pregnancy
Complication of pregnancy termination
Gestational trophoblastic disease

example, vaginal laceration/trauma, cervical polyp, cervical ectropion and cervical carcinoma. Having
taken a thorough history and established that the woman is clinically stable, TVS is the diagnostic tool
of choice to evaluate the endometrial cavity.
Cervical cytology to rule out cervical disease is essential in the evaluation of AUB. However, the
value of cervical cytology in the diagnosis of endometrial disease is limited. In a study on 128
consecutive women with post-menopausal bleeding, the presence of endometrial cells on cervical
smear had a positive predictive value for endometrial cancer of only 17%.10 The presence of atypical
endometrial cells was associated with endometrial malignancy in half of the cases. On the other hand,
in patients with even advanced disease, cervical cytology smears alone will detect endometrial cancer
in only 2555% of patients.11 Cervical cytology may give a hint as to possible endometrial disease, but
the absence of endometrial cells on cervical cytology does not rule out endometrial cancer.
TVS performs very well in the conrmation or exclusion of focal intra-cavitary pathologies,
including endometrial polyps or submucosal broids.12 In the absence of focal endometrial pathology,
the endometrium needs to be evaluated in terms of its thickness as well as its appearance. In contrast to
the post-menopausal population, where the endometrial thickness cut-off <4 mm is the gold standard
on which to base management, no specic endometrial thickness is agreed upon in pre-menopausal
women. It is the age of the pre-menopausal woman and not the endometrial thickness which determines subsequent management. If a woman is <40 years and there is no focal endometrial pathology,
she does not need to have an endometrial biopsy to exclude global endometrial pathology. However, if
the woman is 40 years and there is no focal endometrial pathology, then she does need to have an
endometrial biopsy to exclude global endometrial pathologies such as endometrial hyperplasia (with
or without atypia) or endometrial carcinoma.13 Remember that 12% of all endometrial cancers occur in
pre-menopausal women, whereas only 1% occurs in women <40 years.2
In most pre-menopausal women, the cause of the bleeding will be attributed to dysfunctional
uterine bleeding or idiopathic menorrhagia.14 This is a diagnosis of exclusion. Having determined the
underlying cause of the AUB, it is sometimes necessary to reduce or even halt the bleeding pharmacologically. This is to control symptoms and prevent or reduce secondary anaemia. This can be done
with one or a combination of non-steroidal anti-inammatory agents, for example, mefanamic acid

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500 mg three times a day orally, anti-brinolytics, for instance, oral or intravenous tranexamic acid 1 g
four times a day, as well as oral progestagens. Local delivery of progestagens via intrauterine devices,
seems to be particularly effective and potentially avoids the systemic side effects of the oral route.15
Imaging methods can only be used to conrm or refute an anatomical abnormality, for example,
submucosal myoma, endometrial polyp or adenomyosis. These might or might not be the cause of the
presenting complaint. In the Dueholms review on diagnostic modalities for the investigation of uterine
abnormalities2, only two studies had hysterectomy as the gold standard and blinded examiners.16,17 In
one, magnetic resonance imaging (MRI) was found to be superior to TVS, SIS and hysteroscopy for the
evaluation of the degree of protrusion of submucosal myomas into the cavity, also known as grading of
the myoma.16 SIS improves the sensitivity and the specicity of TVS for the detection of uterine
pathology in pre-menopausal women, with a reported failure rate of 48%, usually caused by cervical
stenosis (Fig. 3). Endometrial cancer is a relatively uncommon cause of bleeding before menopause.
Even if there is no consensus about which imaging modality represents the most efcient way of
managing post-menopausal women with abnormal bleeding, we believe TVS, and/or SIS if needed,
continues to represent a simple, cheap and accurate rst-line investigation for this group of women.

Post-menopausal bleeding
As a rule, acute and severe post-menopausal bleeding is relatively uncommon. Most women who
present with post-menopausal bleeding have minor symptoms and, as a rule, present to an elective
gynaecology clinic. Notwithstanding this, if a woman presents to an acute gynaecological setting, the
same principles of management apply as in the pre-menopausal population, that is, an assessment of
haemodynamic state, symptomatic relief as well as determination of underlying aetiology. Appropriate
history, clinical examination, including vital signs as well as TVS, are all important in the work-up of
such women. If, in the unlikely event, a post-menopausal woman is haemodynamically compromised
then rapid resuscitation is needed in order to stabilise the clinical state. It may be appropriate to
arrange haemoglobin and haematocrit; and, on occasion, blood transfusion may be considered. Clinical
speculum examination is mandatory to exclude any lower genital tract abnormality that may be the
cause for the presentation, for example, cervical polyp, cervical ectropion and cervical carcinoma.
Having taken a thorough history and established that the woman is clinically stable, TVS is the diagnostic tool of choice to evaluate the endometrial cavity.

Fig. 3. Simple endometrial hyperplasia at saline-infusion sonohysterography (SIS). At SIS is visible the polypoid prole of the
endometrium.

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An endometrial thickness of <4.0 mm in both the Italian and Nordic multicentre studies correlated
well with the absence of endometrial cancer, that is, an atrophic endometrium.1820 According to
Epstein and Valentin, if the endometrial thickness is <5 mm and there is no focal endometrial
pathology, women can be managed expectantly.21 The advice should be to perform an endometrial
biopsy if the woman re-bleeds or the endometrial thickness is thickened at the follow-up scan.
In a meta-analysis of nine studies by Tabor et al., 3483 women without endometrial cancer and 330
women with endometrial cancer were included.6 The median endometrial thickness in women with
and without endometrial cancer was calculated for each participating centre. The median endometrial
thickness in symptomatic women without endometrial cancer who did not use hormone replacement
therapy (HRT) ranged from 2 mm to 6.4 mm. The median endometrial thickness in women with
endometrial cancer was 3.7 times that in unaffected women at the same centre (Fig. 4). The detection
rate was 96% (95% condence interval: 9498) for a 50% false-positive rate.
Smith-Bindman et al. included data of 35 studies in their meta-analysis representing 5892 women.2
Using a threshold of 5 mm, the sensitivity for the diagnosis of endometrial cancer was 96% (95% CI 94
98) with a specicity of 61% (95% CI 5963) (Table 2). According to those meta-analyses, about 4% of
endometrial cancers will be missed using a threshold for endometrial thickness of 45 mm. To evaluate
endometrial cancer cases notwithstanding a thin endometrium of less than 5 mm, in Leuven we
performed a retrospective study on 187 consecutive patients with endometrial cancer, conrming that
malignancy is extremely rare in cases of an appropriately measured thin and regular endometrium.22
Ultrasound features of the post-menopausal endometrium are due to oestrogen deprivation, which
in turn results in a thin and atrophic endometrium. The endometrial tissue, however, remains
responsive to endogenous (e.g., oestrogen secreting tumours such as a granulosa cell tumour) as well as
exogenous oestrogen stimulation (e.g., oestrogen supplementation or oestro-progestogen replacement
therapy). On ultrasonography, endometrial cancer is associated with a thickened endometrium caused
by the growth of tumour tissue and/or concomitant hyperplasia.18,19 The measurement of endometrial
thickness on TVS in post-menopausal women is the cornerstone of management. Cut-offs for the
endometrial thickness of <4 mm or <5 mm have been prospectively validated.

Fig. 4. Symptomatic women with endometrial cancer: endometrial thickness in multiples of the unaffected median for women of
the same centre and menopausal status (Ann Tabor et al., 2002).

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Table 2
Sensitivity and specicity for endometrial disease and cancer using different endometrial thickness TVS measurements to dene
an abnormal result (adapted from Smith-Bindman et al., 1998).
Threshold (mm)

Endometrial disease
Sensitivity % (95% CI)

Specicity % (95% CI)

Sensitivity % (95% CI)

Specicity % (95% CI)

3
4
5
6

98
91
92
87

62
69
81
82

100
96
96
95

38
53
61
55

(94100)
(8993)
(9093)
(8589)

Cancer

(5371)
(6771)
(7983)
(8084)

(89100)
(9398)
(9498)
(9297)

(3245)
(5155)
(5963)
(5357)

If the endometrial thickness is 5 mm, Epstein and Valentin recommend SIS and endometrial biopsy.
If focal endometrial pathology is demonstrated, then the woman should be scheduled for operative
hysteroscopy.5 If the SIS however is negative, then an endometrial biopsy needs to be taken to exclude
diffuse endometrial pathologies including endometrial hyperplasia, with or without atypia, and even
endometrial cancer. Epstein et al. found that if the endometrial thickness was <7.0 mm and the SIS was
negative, then outpatient Pipelle endometrial sampling performed as well as formal D&C under general
anaesthetic. Conversely, if the endometrial thickness was 7.0 mm and the SIS was negative, then formal
D&C under general anaesthetic was superior to outpatient Pipelle endometrial sampling.5
The issue of the effect of endometrial sampling on the ultrasound features of the endometrium is
addressed in a prospective series of 99 women with AUB.23 At rst, all women underwent TVS for
measurement of the endometrial thickness and for evaluating of endometrial sonographic features.
Thereafter, a Pipelle endometrial biopsy was taken. Finally, TVS was repeated. The endometrial thickness
measurements were signicantly affected by Pipelle sampling as was the quality of the other ultrasound
features. We therefore advocate performing ultrasound before proceeding with endometrial sampling.
Ofce endometrial sampling is a rapid, safe and convenient way of obtaining an endometrial
specimen for histological diagnosis of intrauterine pathology and it is well accepted by the majority of
patients. As in traditional D&C, it remains a blind procedure, and there is concern about non-representative samples. We evaluated the value of Pipelle endometrial sampling in 148 consecutive patients
with post-menopausal bleeding.24 The Pipelle sampling was performed after ultrasound evaluation by
another examiner. Hysteroscopy and curettage was used as reference test. The diagnostic value of
Pipelle sampling in both benign and malignant endometrial disease in our series is given in Table 3.
Clark et al. performed a systematic review on the accuracy of outpatient endometrial biopsy in the
diagnosis of endometrial cancer.25 A negative test result of ofce endometrial sampling is much less
accurate than a positive test result: for the Pipelle device, the positive likelihood ratio (LR) was 64.6
(22.3187.1) and the negative likelihood ratio (LR) 0.1 (0.040.28) (Table 4).
Devices other than the Pipelle sampler have been used to biopsy the endometrium or to sample
endometrial cells. We compared the Endopap device that collects endometrial cells for cytological
analysis, with the Pipelle sampler in 106 consecutive postmenopausal women with AUB.26 The
reference test was hysteroscopy with curettage or hysterectomy. Endopap showed a lower specicity
for endometrial disease and one cancer case was missed. Our data tend to favour Pipelle against
Endopap as a diagnostic tool for endometrial disease.
Dijkhuizen and co-workers performed a meta-analysis on the diagnostic accuracy of different sampling
devices.27 They conclude that endometrial biopsy with the Pipelle is superior to other techniques in the
detection of endometrial carcinoma and atypical hyperplasia. The detection rate for endometrial carcinoma of Pipelle was 99.6% and 91% in post-menopausal and pre-menopausal women, respectively.

Table 3
Accuracy of ofce Pipelle sampling in the detection of endometrial disease (Van den Bosch et al., 1995).

Disease
Carcinoma

Sensitivity %

Specicity %

PPV %

NPV %

44.6
100.0

98.5
99.1

96.1
85.7

69.0
100.0

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Table 4
Pooled estimates of pre-test probability, likelihood ratio and post-test probability for TVS measurement of endometrial thickness
in predicting endometrial disease (hyperplasia and/or carcinoma) (adapted from: Gupta et al., 2002).
Cut-off level
for abnormality

Test result

Pre-test probability % (95% CI)

Likelihood ratio % (95% CI)

Post-test probability % (95% CI)

< 3 mm

Positive
Negative
Positive
Negative
Positive
Negative

26.0
26.0
26.0
26.0
26.0
26.0

2.5
0.03
2.17
0.07
2.62
0.15

46.7
1.0
43.3
2.4
47.9
5.0

< 4 mm
< 5 mm

(25.027.0)
(25.027.0)
(25.027.0)
(25.027.0)
(25.027.0)
(25.027.0)

(1.953.2)
(0.00.4)
(1.732.73)
(0.040.11)
(2.033.38)
(0.090.27)

(39.454.0)
(0.012.9)
(36.646.7)
(1.33.9)
(40.455.6)
(2.99.1)

Women on HRT
As a rule of thumb, if a woman is on a continuous combined HRT, then she can be scanned at any
time during the month. The endometrial thickness cut-offs, as previously described, can be applied to
these women who are on bleed-free preparations.28 However, if a woman is on a cyclical HRT, then she
should have her TVS immediately post a withdrawal bleed. Under these circumstances, the same cutoff rules can also be applied.29

Women with endometrial polyps on scan

Endometrial polyps can cause uterine bleeding or remain asymptomatic. The signicance of the
incidental nding of polyps in a conspicuous number of asymptomatic post-menopausal women
remains unsettled. Since the vast majority of endometrial polyps is benign, a systematic removal of all
incidentally diagnosed polyps may not be appropriate. Malignancy has been reported in 0.10.8% of
asymptomatic polyps30,31, and in 2.2% of symptomatic polyps.31 In a recent Italian retrospective study
on asymptomatic endometrial polyps, the diameter of the polyps was the only variable signicantly
associated with abnormal histology at multivariate analysis.31
Therefore, expectant management may be defendable in case of the incidental nding of a small
polyp in an asymptomatic woman providing the clinician is condent of the womans compliance. The
patient must be informed to come back in case of bleeding, and a follow-up ultrasound within 3
months after her rst visit may be advisable.

Women on tamoxifen
Tamoxifen (TMX) is a selective oestrogen receptor modulator (SERM) and is used in the prevention
and treatment of breast cancer. The hormonal activity of a SERM depends on the target tissue: TMX acts
mainly as an anti-oestrogen in breast tissue, but has a weak oestrogenic activity on the endometrium.
The possible role of TMX in inducing endometrial disease became evident in the early 1990s. According
to the literature, there is a two-to-three-fold increase in the incidence of endometrial carcinoma in
TMX users.32 TMX induces stromal changes in the endometrium: it thickens with a Swiss-cheese like
pattern caused by multiple intra-endometrial cysts of varying size (Fig. 5). Following cessation of TMX
use, the endometrium tends to return to normal. This TMX-induced thickening of the endometrium
results in a poor positive predictive value of TVS in the detection of malignant and benign endometrial
lesions. To distinguish between an empty cavity with a cystic appearance of the subepithelial layer of
the endometrium and true lesions inside the uterine cavity, SIS or hysteroscopy are recommended in
case of a thickened endometrium at TVS in symptomatic TMX users.28,33 In asymptomatic women,
routine ultrasound surveillance is probably not useful because of its low specicity.34 Berlie`re and coworkers showed that the risk of atypical lesions during TMX therapy was signicantly higher in women
who had endometrial lesions before starting TMX treatment.35 They advocate endometrial assessment
before starting the TMX and careful follow-up in all high-risk patients with initial lesions.

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Fig. 5. Swiss-cheese like pattern of the endometrium at TVS in a woman taking tamoxifen.

To summarise, no single test has been proven to yield a high diagnostic accuracy for all uterine
pathology including focal intra-cavitary lesions, endometrial hyperplasia and endometrial cancer.
Different diagnostic algorithms have been proposed combining two or more available tests.
Proposal of a diagnostic algorithm for the work-up of women with post-menopausal bleeding
Most gynaecologists are practising alone, without the permanent help of a nurse or an assistant.
Therefore, it can be assumed they would favour TVS or ofce sampling over SIS or hysteroscopy as
initial diagnostic tests.
In Fig. 6, we have developed an algorithm for the work-up of women with post-menopausal
bleeding. In this algorithm, we propose to start with a TVS with colour Doppler imaging. This choice is
based on the fact that the measurement of the total endometrial thickness on scan is reliable and cost
effective in triaging at-risk women for endometrial disease. Moreover, TVS is associated with only little
or no discomfort. Most ultrasound machines in modern practice are also equipped with colour
Doppler; this was included as part of the rst-line examination. Colour Doppler evaluation does not
prolong the overall ultrasound examination signicantly and it also offers additional information as to
the presence or absence of a pedicle artery inside the endometrium.
The choice of an endometrial thickness cut-off value remains a matter of dispute. The threshold for
endometrial thickness below which further investigation may not be required depends on the pre-test
risk for endometrial disease, on the acceptability of the post-test risk and on the womans compliance
to appropriate follow-up. The lower the cut-off value, the less diseased cases will be missed, but the
more unnecessary additional investigations will be performed36 (Table 4). In our proposed diagnostic
algorithm, we used a cut-off of 4 mm.
Relying on strict criteria, a thin and regular endometrial line virtually excludes endometrial carcinoma. If the endometrium is 4 mm or less (and in the absence of a pedicle artery sign), endometrial
disease is most unlikely. The woman can be reassured and advised to come back in case of recurrent
bleeding. The recurrence rate after a rst episode of post-menopausal bleeding managed expectantly is
low. However, women with recurrent bleeding have a considerable risk of carcinoma; up to 8% in
a recent follow-up study.37 A distinct vascular pedicle is rarely demonstrated by colour Doppler in
a thin endometrium.
If the endometrium is thicker (>4 mm) and colour Doppler shows a clear vascular pedicle, a focal
intra-cavity lesion is most probable. This patient can be directly referred for operative hysteroscopy. As
focal malignancy may be restricted to the stalk of its polyp, any focal lesion has to be removed under
hysteroscopic guidance to ascertain the completeness of the resection.

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Ultrasound
&
Color Doppler

ET 4mm

ET > 4mm

ET > 4mm

ET not clearly visualised

OR
pedicle uncertain

Follow-up

Pipelle

Operative
hysteroscopy

SIS

Normal

Insufficient
tissue

Disease

Focallesion

Follow-up

SIS

Treat

Operative
hysteroscopy

Focallesion

No focal lesion

Operative
hysteroscopy

Hysteroscopy

&
pedicle NEG

&
pedicle NEG

&
pedicle POS

No focallesion

uncertain

ET 4mm

ET > 4mm

uncertain

Follow-up

Pipelle

Hysteroscopy

Normal

Insufficient
tissue

Disease

Follow-up

Hysteroscopy

Treat

Hysteroscopy

Fig. 6. Proposal of an algorithm for the work-up of postmenopausal bleeding. ET endometrial thickness, SIS saline-infusion
sonohysterography.

If the endometrium is thick (>4 mm) without internal vessels, more diffuse endometrial pathology
may be present. In these cases, we propose a Pipelle sampling immediately after TVS. A thickened
irregular endometrium with multiple and irregular vessels is suspicious for malignancy and the result
of the endometrial sampling has to be awaited before proceeding with any other test. The models
proposed in the previous section may be used to predict the likelihood of malignancy based on TVS and
Pipelle sampling. In case of a high probability of malignancy, the pathologist may be asked to examine
the endometrial biopsy with some priority and an earlier appointment may be proposed to the patient.
The patient will be further managed according to the histology result of the Pipelle biopsy. If the
endometrial histology is normal (e.g., proliferative endometrium and secretory changes), the patient
can be reassured and told at her return visit to come back in case of recurrent bleeding. If the
pathologist reports endometrial hyperplasia without atypia, medical therapy can be initiated. In case of
atypical hyperplasia, however, most gynaecologists will propose a hysterectomy because of its
malignant potential.38 Medical therapy is only an option in well-selected cases of atypical hyperplasia,
after extensive patients information and providing a rigorous follow-up including repeat endometrial
sampling. If Pipelle sampling yields a malignant diagnosis, the patient will be treated accordingly.
If, despite a thickened endometrium on scan, the Pipelle sampling failed to yield tissue, a focal intracavitary lesion needs to be excluded and a SIS should be performed at rst visit. Likewise, if the
pathologist reports insufcient or atrophic tissue, notwithstanding a thick endometrium at ultrasound,
we would propose to proceed with a SIS at the time of the return visit in order to exclude a focal lesion.
Incomplete visualisation of the endometrium, an ill-dened endometrium as well as suspicion of
focal lesions on scan should be considered abnormal. If the endometrium cannot be assessed over the
whole length of the uterine cavity, or the echogenicity of the endometrium is not homogeneous or the
presence of a pedicle artery is uncertain at colour Doppler examination, we propose to proceed with
a SIS. If a focal lesion is diagnosed at SIS, the patient can be given an appointment for an operative

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hysteroscopy. If no focal lesion is seen at SIS and if the endometrium is thin, the patient can be reassured and told to come back in case of recurrent bleeding. If the endometrium is thicker than 4 mm, we
propose to perform a Pipelle endometrial sampling.
As discussed previously, any recent sampling of the endometrium can also make the measurement
of the endometrial thickness unreliable.
In all cases where TVS with Doppler and SIS do not provide conclusive information or in case of
conicting results between the TVS/SIS ndings and histology, a diagnostic hysteroscopy is indicated.
It should be stressed once again that if the rst investigation(s) did not demonstrate any serious
pathology, the woman must be advised to come back in case of recurrent postmenopausal bleeding.
Gull and co-workers demonstrated in a longitudinal study after initial negative evaluation, that all
cases of endometrial cancer during follow-up had recurrent bleeding.39 All cases of endometrial cancer
occurred in those women who had an initial endometrial thickness exceeding 4 mm. Atypical hyperplasia was found in 7.1% during follow-up in women with an initial endometrium 4 mm.

Conclusions
A systematic approach to women with either AUB in the pre-menopause age or post-menopausal
bleeding is essential in their diagnostic work-up. The general principles of emergency care including
assessment of haemodynamic state, symptomatic relief as well as determination of underlying aetiology, apply to these women presenting to an acute gynaecology setting. TVS with or without SIS forms
the basis for exclusion of focal endometrial pathologies, whilst outpatient Pipelle endometrial biopsy is
essential to rule out diffuse endometrial diseases.

Practice points
 AUB, in terms of pre-menopausal menstrual disorders and post-menopausal bleeding, is
a common presentation in the acute gynaecology clinic. Acute AUB requires an assessment of
haemodynamic state, symptomatic relief as well as determination of underlying aetiology.
 Approximately 310% of women with post-menopausal bleeding have endometrial cancer.
 As much as 12% of endometrial cancers are diagnosed before the menopause.
 Imaging methods can only be used to conrm or refute an anatomical abnormality, for
example, submucosal myoma, endometrial polyp or adenomyosis. These might or might not
be the cause of the bleeding. TVS, and/or SIS if needed, are a simple, cheap and accurate rstline investigation.
 Measurement of endometrial thickness is a simple and accurate method for estimating the
risk of endometrial malignancy in post-menopause, endometrial thickness <4 mm indicating
low risk. If the endometrium is thin, the woman can be reassured and advised to come back in
case of recurrent bleeding.
 If the endometrium is thicker (>4 mm) and colour Doppler shows a clear vascular pedicle,
a focal intra-cavitary lesion is most probable. SIS may improve the visualisation of focal
lesions.
 If the endometrium is thick (>4 mm) without internal vessels, more diffuse endometrial
pathology may be present. In these cases, an endometrial biopsy is mandatory to exclude
malignancy.
 Pipelle is accurate in the diagnosis of endometrial hyperplasia and endometrial malignancy.
However, most focal lesions such as polyps will be missed by the endometrial sampling alone.
 If the endometrium is not clearly visible at ultrasound examination, further diagnostic tests,
that is, hysteroscopy, are indicated.
 The combined use of ultrasound and ofce endometrial sampling in a single visit setting is
a feasible and reliable approach for the work-up of AUB.

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Research agenda
 The clinical signicance of focal intrauterine lesions at ultrasound examination in asymptomatic women.
 The evaluation of the value of three-dimensional (3D) ultrasound in the diagnosis of endometrial disease.
 The implementation of saline- or gel-infusion sonography in general practice, to improve the
detection of focal intra-cavity lesions.

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