Correspondence to: Dr M. C. Breijer, Department of Obstetrics and Gynecology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands (e-mail: firstname.lastname@example.org)
Measurement of endometrial thickness is an important tool in the assessment of women with postmenopausal bleeding, but the role of endometrial thickness measurement by ultrasound in asymptomatic women is unclear. The aims of this study were to determine: (1) the normal endometrial thickness measured by ultrasonography, (2) the prevalence of serious endometrial pathology and (3) the sensitivity and specificity of endometrial thickness measurement by transvaginal ultrasonography (TVS) for diagnosing premalignant and malignant endometrial disease in asymptomatic postmenopausal women.
A MEDLINE and EMBASE search (from inception to January 2011) was performed. Articles reporting on endometrial thickness measurement in the diagnosis of endometrial carcinoma and atypical hyperplasia in asymptomatic postmenopausal women not using hormone replacement therapy (HRT) were selected. Endometrial thickness and the prevalence of endometrial (pre)malignancies were recorded. If possible, 2 × 2 tables were extracted.
Thirty-two studies reporting on 11 100 women were included. The estimated mean endometrial thickness was 2.9 mm (95% CI, 2.6–3.3 mm). The pooled estimated prevalences of endometrial carcinoma and atypical endometrial hyperplasia were 0.62% (95% CI, 0.42–0.82%) and 0.59% (95% CI, 0.22–0.96%), respectively. Summary estimates for sensitivity and specificity of TVS endometrial thickness measurement in the prediction of endometrial carcinoma were 0.83 (95% CI, 0.19–1.00) and 0.72 (95% CI, 0.23–0.95) for a 5-mm cut-off and 0.33 (95% CI, 0.04–0.85) and 0.94 (95% CI, 0.92–0.96) for a 6-mm cut-off.
The results from this systematic review do not justify the use of endometrial thickness as a screening test for endometrial carcinoma and atypical endometrial hyperplasia in asymptomatic postmenopausal women not using HRT.
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Endometrial carcinoma is the most common malignancy of the female genital tract in developed countries and presents with postmenopausal bleeding in more than 95% of cases[1, 2]. In patients with postmenopausal bleeding, sonographic measurement of endometrial thickness is the first test to determine whether further investigations are needed to rule out malignancy. Guidelines recommend a cut-off value of 4 or 5 mm by transvaginal ultrasonography (TVS), below which endometrial cancer is unlikely[4-7]. When the endometrial thickness is below this cut-off, the probability of endometrial carcinoma is below 1%. In contrast to the clear guidelines on the management of women with postmenopausal bleeding, clinicians are faced with uncertainty when endometrial thickness is measured in asymptomatic postmenopausal women. Symptom-free women may undergo TVS for other indications, such as vaginal prolapse or abdominal complaints. Inevitably, the endometrium is then visualized and a thickened endometrium may incidentally be observed. It is not known how best to manage such patients in whom a thick endometrium is observed incidentally.
Based on a decision analysis in a theoretical cohort, Smith-Bindman et al. concluded that in asymptomatic postmenopausal women with an endometrial thickness of ≥ 11 mm an endometrial biopsy should be performed. They argued that women with an endometrial thickness above this threshold have a malignancy risk of 6.7%, which is comparable with the risk in patients with postmenopausal bleeding and an endometrial thickness of > 5 mm (7.3%), the latter being the widely accepted threshold for performing a biopsy in symptomatic patients.
Apart from the debate on the accuracy of endometrial thickness measurement in asymptomatic postmenopausal women, its potential value also depends on the prevalence of the disease searched for, i.e. endometrial carcinoma and/or its precursors. Since in asymptomatic women the prevalence of endometrial carcinoma is lower than in symptomatic women, the cut-off of endometrial thickness for abnormality in these women should be higher.
To address the abovementioned dilemmas, we reviewed the literature on asymptomatic postmenopausal women not using hormone replacement therapy (HRT). The aims of this review were to address in asymptomatic postmenopausal women: (1) normal endometrial thickness as measured with sonography, (2) the prevalence of serious endometrial pathology and (3) the sensitivity and specificity of endometrial thickness measurement by TVS for diagnosing premalignant and malignant endometrial disease.
Identification of studies
We performed an electronic search in January 2011 in MEDLINE (from 1948) and EMBASE (from 1980) to identify articles reporting on endometrial thickness and/or endometrial carcinoma and hyperplasia in asymptomatic postmenopausal women. We used the following keywords: postmenopausal, asymptomatic, screening, endometrial, thickness, ultrasound, hyperplasia and carcinoma. The complete search syntax is reported in Appendix S1 online. Language restrictions were not applied. Abstracts or articles written in languages other than English were read by a member of the team with sufficient knowledge of the language; if there was no team member available, the article was translated by a native speaker. References of selected studies were searched for articles not identified by the electronic searches, and this process was repeated for any further relevant studies found. No review protocol was registered.
Selection of studies and data abstraction
Two independent reviewers (M.B., J.P.) screened the electronic search results by reading titles and/or abstracts. Studies that were restricted to patients with postmenopausal bleeding or women using HRT or tamoxifen were excluded. Titles and abstracts were assessed to identify eligible studies. Subsequently, these articles were evaluated in full text for each of the three objectives independently for the final study selection. Any disagreements were resolved by consensus. In case of persistent disagreement, the judgment of a third reviewer (A.T.) was decisive.
If multiple publications reported analyses on the same dataset, only the largest study was included. If a dataset was split into different subgroups and the subgroups were reported separately in multiple publications, we combined the results of these publications. We used the quality assessment of diagnostic accuracy studies (QUADAS) checklist to assess the methodological quality of included studies (Appendix S2 online).
To evaluate normal endometrial thickness in asymptomatic postmenopausal women, we searched for studies that (1) reported a mean endometrial thickness with a measure of variance and (2) described a standardized approach to measurement of endometrial thickness by TVS. Mean endometrial thickness as well as SD, standard error or 95% CI were recorded for each included study. A pooled estimate of mean endometrial thickness was then calculated using inverse variance weighting in a random-effects model.
Prevalence of endometrial (pre)malignancies
To assess the prevalence of (pre)malignant lesions of the endometrium in asymptomatic postmenopausal women, we included studies that reported on any form of endometrial verification in the total population of asymptomatic postmenopausal women not using HRT. The endometrium could be assessed by histology (hysterectomy, dilatation and curettage, hysteroscopy with biopsy, endometrial biopsy) or by cytology. Studies in which there was partial verification (histological verification only in a subgroup based on a previous test, e.g. endometrial thickness above a cut-off level or patients positive on progesterone challenge test) were excluded. The method of verification, the number of women with atypical endometrial hyperplasia and the number of women with endometrial carcinoma were recorded for each selected study. The prevalence of endometrial carcinoma and atypical endometrial hyperplasia was then calculated for each study, and a weighted pooled estimate was derived.
Diagnostic accuracy of endometrial thickness for endometrial (pre)malignancy
Finally, to estimate the diagnostic accuracy of endometrial thickness for (pre)malignancy of the endometrium, we selected studies that reported on both endometrial thickness measurement and endometrial histological verification in asymptomatic postmenopausal women. Information required to construct a 2 × 2 table for each reported endometrial thickness cut-off value was recorded for each selected study. Three different outcomes were considered: benign (including atrophy, endometrial polyps and endometrial hyperplasia without atypia), atypical endometrial hyperplasia and endometrial carcinoma.
The data from the 2 × 2 tables were used to calculate sensitivity and specificity, as well as positive and negative predictive values for each study. If the study reported on multiple thresholds, we included 2 × 2 tables for all reported thresholds. Subsequently, summary point estimates for sensitivity and specificity were generated for each reported endometrial cut-off value using a bivariate random effects approach, for endometrial carcinoma, atypical endometrial hyperplasia and these two diagnoses combined in one group.
Our search resulted in 503 citations; another 31 studies were identified through reference searches. There were 95 studies eligible for inclusion based on title and abstract. After assessment of the full text articles, 63 studies were discarded (Figure 1). As a result, a set of 32 relevant studies was available to answer our three questions: 10 studies could be used for question 1 (estimating normal endometrial thickness); 15 studies could be used for question 2 (prevalence of endometrial malignancy and premalignancy) and 20 studies could be used for question 3 (diagnostic accuracy of TVS for these endometrial diseases).
Assessment of methodological quality
Study quality was considered generally good when eight of the 14 QUADAS items were met, with over 70% of the included studies fulfilling this criterion (Figure 2). Studies scored poorly on the items regarding blinded interpretation of the reference test and description of withdrawals. In five of the 32 studies, almost the entire QUADAS checklist was scored as not applicable because, for example, no endometrial thickness measurement (index test) or no endometrial verification (reference test) was reported. Absence of the index or reference test automatically led to problems in completing the QUADAS checklist. For these five studies it was impossible to answer some questions of the QUADAS checklist with ‘yes’, ‘no’ or ‘unclear’, and these items were scored ‘not applicable’.
We found 10 studies that reported on endometrial thickness measurement with a measure of variance in asymptomatic women not using HRT[11-20]. The 10 studies that were assessed for inclusion had been conducted in nine different countries. One study was published in German; the other nine were published in English. In total, these 10 studies reported on 3049 women, with a median sample size of 207 (range, 97–1182). Mean endometrial thickness in the 10 studies varied from 2.1 to 5.7 mm. The pooled estimate of the mean endometrial thickness was 3.2 mm (95% CI, 2.8–3.6 mm). There was one outlier, with a mean endometrial thickness of 5.7 mm, compared with the other studies; Güven et al. reported a thicker endometrium. Mean body mass index (BMI) in this study was 29.5 kg/m2. In contrast, mean BMI in the other included studies ranged from 22.4 to 25.6 kg/m2. The purpose of the study by Güven et al. was to correlate BMI to endometrial thickness, which could potentially have led to inclusion bias. We therefore excluded this study from the meta-analysis for endometrial thickness.
The remaining nine studies reported on 2952 women, with a median sample size of 259 (Table 1). The pooled estimate of the mean endometrial thickness was 2.9 mm (95% CI, 2.6–3.3 mm) (Figure 3). Statistical heterogeneity between studies (I2) was 28%.
Table 1. Characteristics of studies included in meta-analysis for mean endometrial thickness measured by transvaginal ultrasound in asymptomatic postmenopausal women without hormone replacement therapy
In 28 studies a histological diagnosis of the endometrium (endometrial verification) was obtained. We excluded 13 from further analysis, as they had only partial endometrial verification (verification in a subgroup of patients selected by a previous test, e.g. endometrial thickness or progesterone challenge test). The 15 remaining studies had been performed in nine different countries[13, 14, 21-33]. Thirteen studies were published in English, one in Portuguese and one in Italian. Together, these studies described a total of 3595 women (Table 2). The median sample size was 145 (range, 30–883). The prevalence of endometrial carcinoma varied between 0 and 2.1%, the prevalence of atypical endometrial hyperplasia varied between 0 and 3.5% and the prevalence of combined (pre)malignancy varied between 0 and 4.3%. The pooled estimated prevalence of endometrial carcinoma was 0.62% (95% CI, 0.42–0.82%), of endometrial hyperplasia it was 0.59% (95% CI, 0.22–0.96%) and of combined (pre)malignancies it was 1.21% (95% CI, 0.63–1.79%).
Table 2. Characteristics of studies included in meta-analysis for assessment of prevalence of endometrial (pre)malignancies in asymptomatic postmenopausal women not using hormone replacement therapy
Prevalence of (pre)malignancy (%)
Only first author of each study is given. AEH, atypical endometrial hyperplasia; D&C, dilatation and curettage; EBK, endometrial biopsy, Karman; EBN, endometrial biopsy, Novak curette; EBNS, endometrial biopsy not specified; EBP, endometrial biopsy, Pipelle; EBS, endometrial biopsy, Semm's cannula; EES, endocyte endometrial sampler; Hyst, hysteroscopy; NR, not reported; SC, softcyto.
Diagnostic accuracy of endometrial thickness for endometrial (pre)malignancy
There were 20 studies that reported on the endometrial thickness cut-off value and histological or cytological endometrial verification[11-16, 23, 26, 29, 31, 32, 34-42]. These studies were performed in 13 different countries. Sixteen studies were published in English, one in Italian, one in Spanish, one in Portuguese and one in German. In total, these 20 studies described 6974 women, with a median sample size of 209 (range, 47–1926) (Table 3). In 13 studies partial verification was performed, whereas in the other seven studies endometrial verification was performed in all women. In 5198 out of 6974 women an endometrial sample was obtained. Endometrial carcinoma was found in 32 and atypical endometrial hyperplasia in 21 women.
Table 3. Characteristics of studies included for estimation of sensitivity and specificity of endometrial thickness as measured by transvaginal ultrasound with regard to premalignant or malignant endometrium in asymptomatic postmenopausal women without hormone replacement therapy
Eight different endometrial thickness cut-off values were reported in the 20 studies. Sensitivity, specificity, negative predictive value and positive predictive value for the detection of endometrial carcinoma for each reported endometrial thickness cut-off value are reported in Table S1 online. Positive predictive values varied between 0 and 0.2 and negative predictive value, if it was possible to ascertain, was 1. For the reported endometrial thickness cut-offs of 4, 5 and 6 mm we were able to calculate a summary sensitivity and specificity for the detection of endometrial carcinoma. The remaining five cut-offs were reported by one single study, so for these cut-offs we were unable to calculate summary sensitivity and specificity. The summary estimate of the sensitivity for the different cut-offs varied between 0.00 and 0.83. The summary estimate of the specificity for the different cut-offs varied between 0.72 and 0.94 (Table 4). For the summary estimates of sensitivity and specificity as well as for the reported sensitivity and specificity, the 95% CIs were very wide, indicating the high uncertainty surrounding these estimates.
Table 4. Summary estimates of sensitivity and specificity with regard to endometrial carcinoma for different transvaginal ultrasound-derived endometrial thickness cut-off values*
Sensitivity (95% CI)
Specificity (95% CI)
Reported number is included in cut-off, i.e. cut-off of 5 mm means endometrial thickness ≥ 5 mm.
NE, not possible to estimate.
Diagnosis of atypical endometrial hyperplasia
Six different endometrial thickness cut-off values were reported in 13 studies. The other seven studies did not report on an endometrial thickness cut-off for atypical endometrial hyperplasia. Sensitivity, specificity, negative predictive value and positive predictive value for the detection of atypical endometrial hyperplasia for each reported endometrial thickness cut-off value are reported in Table S2 online. There were no cut-off values for which multiple studies reported sufficient data to calculate both sensitivity and specificity. Therefore, we were unable to calculate summary estimates of sensitivity and specificity for the different cut-off values for atypical endometrial hyperplasia. With regard to atypical endometrial hyperplasia, the range of sensitivity was 0.00–1.00 and the range of specificity was 0.63–0.95.
Diagnosis of combined (pre)malignancy
For this combined analysis, studies were included if they reported on both endometrial carcinoma and atypical endometrial hyperplasia. All 20 studies reported on endometrial carcinoma and 13 studies reported on atypical endometrial hyperplasia as well. Six different endometrial cut-off values were reported. Sensitivity, specificity, negative predictive value and positive predictive value for the detection of endometrial (pre)malignancy for each reported endometrial thickness cut-off value are reported in Table S3 online. As for atypical endometrial hyperplasia, there were no cut-off values for which multiple studies reported sufficient data to calculate both sensitivity and specificity. Therefore, we were unable to calculate summary estimates of sensitivity and specificity for the different cut-off values for the combined outcome of (pre)malignancy. With regard to the combined diagnosis of premalignant and malignant endometrium, the range of sensitivity was 0.17–1.0 and the range of specificity was 0.63–0.95.
Our review shows that in a population of postmenopausal women without postmenopausal bleeding and not using HRT, the mean endometrial thickness is 2.9 mm and the prevalences of endometrial carcinoma and atypical endometrial hyperplasia are 0.62 and 0.59%, respectively. Positive predictive values for the three outcomes (endometrial carcinoma, atypical endometrial hyperplasia and both combined) for all reported endometrial thickness cut-offs were between 0 and 0.2. The negative predictive value of TVS was between 0.98 and 1.0 at all endometrial thickness cut-offs and for all three disease outcomes. However, the utility of a negative test in an asymptomatic postmenopausal population is limited because the absolute risk of disease is already low, as demonstrated in this review (prevalence of endometrial carcinoma 0.62% and atypical endometrial hyperplasia 0.59%). This contrasts with symptomatic postmenopausal women, in whom the pre-testing risk of endometrial cancer or atypical hyperplasia varies between 5 and 20%[43, 44]. Thus, TVS is only of value in postmenopausal women with vaginal bleeding because a clinically substantial reduction in the estimated probability of disease may be achieved by the observation of a normal endometrial thickness on TVS. This reduction is typically from around 10% to below 1% for endometrial carcinoma, a probability threshold where firstly, the majority of clinicians recommend reassurance and no need for further evaluation of the endometrium, and secondly, post-TVS probability is demonstrated to be equivalent to the prevalence in the asymptomatic postmenopausal female population[4-7].
The strength of our analysis is the complete overview of data combining endometrial thickness, endometrial carcinoma and atypical endometrial hyperplasia in asymptomatic postmenopausal women not using HRT. We describe mean endometrial thickness and the prevalence of endometrial (pre)malignancies in these women. Furthermore, we assessed the diagnostic accuracy of endometrial thickness measurements in this population. Efforts were made to identify all available publications on this subject and we used the most appropriate technique to summarize the sensitivity and specificity, to come to better estimates than the formerly applied summary receiver–operating characteristics curve (sROC) technique for meta-regression in diagnostic meta-analysis[10, 45-47]. To our knowledge, there is no previously published review or meta-analysis on this subject.
A limitation of our study is that despite the thousands of women included in our analysis, the estimates of sensitivity and specificity are very imprecise, especially those of sensitivity. Another limitation could be a bias because of the quality of the included studies. We tried to minimize this bias by performing quality assessment and applying strict criteria for inclusion of studies in the meta-analysis.
In a decision analysis performed by Smith-Bindman et al., an endometrial thickness cut-off of 11 mm for an incidentally measured increased endometrial thickness in an asymptomatic woman was proposed. In this decision analysis the risk of malignancy in a woman below the threshold is extremely low and the risk of malignancy above the threshold varies between 2.2 and 9.3%. In contrast to this analysis, which was a decision analysis in a theoretical cohort, we analyzed observational data. Unfortunately, we had insufficient data from the published studies to calculate an optimal threshold for endometrial thickness based on the sensitivity and specificity reported in the different studies. Because of the low prevalence of the disease, the 95% CI for the summary estimates of sensitivity are very wide, indicating a high degree of inaccuracy.
The use of TVS is not limited to women with postmenopausal bleeding. The portability and improved resolution of TVS have contributed to the ubiquity of the test in routine gynecological practice. Postmenopausal women undergo TVS for a variety of gynecological indications (e.g. pelvic pain, suspicion of a pelvic mass, uterine prolapse). During TVS for such non-bleeding indications, images of the endometrium are frequently obtained and a thickened endometrium may be observed. This situation of an apparently incidental finding of an abnormal endometrium will be familiar to all practicing sonologists. Faced with such a TVS finding, it is difficult for the physician to decide on the right management and this usually results in a decision to undertake further, more invasive testing with endometrial sampling and/or hysteroscopy, in keeping with current guidelines for postmenopausal bleeding. Therefore, the findings of this review, describing normative values for endometrial thickness, determining serious disease prevalence and estimating diagnostic accuracy at various TVS thresholds, in this non-bleeding postmenopausal population are clinically important. Our review has shown that the average TVS-derived endometrial thickness is 2.9 mm. However, the significance of an endometrial thickness beyond 4 mm is not the same as for a symptomatic postmenopausal bleeding population, and extrapolating protocols from postmenopausal bleeding to an asymptomatic population is not justifiable in view of the low overall disease prevalence and poor performance of TVS in detecting serious endometrial disease at all cut-offs.
Because the prevalence of the target disease in an unselected postmenopausal population without bleeding symptoms and not using HRT is very low, and endometrial thickness measurement in this population cannot achieve a sufficiently high sensitivity to provide additional reassurance to women with a negative test or achieve a sufficiently high specificity to justify further invasive testing in women with a positive test, endometrial thickness measurement has no value in this population. Furthermore, there is no evidence that patients in whom endometrial cancer was discovered while asymptomatic have a prognostic advantage over postmenopausal endometrial cancer patients who visited their gynecologist immediately after bleeding had occurred. Thus, the results from this systematic review do not justify the use of endometrial thickness as a screening test for endometrial carcinoma and atypical endometrial hyperplasia in any asymptomatic postmenopausal woman not using HRT. Hence, the need for further diagnostic evaluation of the endometrium should be made by the clinician on an individual patient basis taking into account clinical signs (e.g. abnormal findings at physical examination, pelvic pain, distension, urinary and bowel complaints), risk factors for endometrial disease (e.g. abnormal BMI, medical comorbidities, family history) and patient preference[49-54].
Supporting Information On The Internet
The following supporting information may be found in the online version of this article:
Appendix S1 Search strategy for MEDLINE and EMBASE
Appendix S2 Quality assessment of diagnostic accuracy studies (QUADAS) checklist
Tables S1–S3 Sensitivity, specificity and positive and negative predictive values of endometrial thickness as measured by transvaginal ultrasound, in detection of endometrial carcinoma (Table S1), atypical endometrial hyperplasia (Table S2) and endometrial malignancy/premalignancy (Table S3). Studies are grouped by reported cut-off value.