{"paper_id":"b391ba9d-1df2-45b1-9347-238dc27fd51c","body_text":"Submit Manuscript | http://medcraveonline.com\nIntroduction\nMost women (90%) with endometrial cancer develop symptomatic \nvaginal bleeding or discharge, and this is often what prompts them to \nseek gynecologic care. 1 The American College of Obstetricians and \nGynecologists (ACOG) recommends endometrial tissue sampling \nin any woman with abnormal uterine bleeding who is older than 45 \nyears, or in younger patients who have failed medical management, \nhave persistent abnormal uterine bleeding, or have unopposed \nestrogen exposure, such as in obesity or polycystic ovary syndrome. 2 \nThere is currently a large body of evidence to guide gynecologists \nin the treatment of women found to have endometrial hyperplasia \nor cancer on biopsy or curettage. 3–5 However, there is little to no \nevidence to guide clinicians in the interpretation of non-hyperplastic, \nnon-neoplastic endometrial sampling findings, which may result in \ndelayed diagnosis in those patients with a false negative result.\nOne of these seemingly benign results is atrophy of the \nendometrium, which occurs as a consequence of the prolonged \nabsence of endogenous or exogenous estrogenic stimulation. This \nis a physiologic occurrence in postmenopausal women, and is the \nmost common cause of postmenopausal vaginal bleeding.6 Pathology \nspecimens show a thin mucosa, a decrease in the number of glands \nand volume of stroma, and absence of nuclear stratification, mitotic \nactivity, and secretory products. 7,8 Atrophic endometrial glands are \nalso encountered in biopsy specimens of premenopausal patients \nin the setting of exogenous hormone use. Hormone preparations \ncontaining both estrogen and progestin typically result in weak or \npoorly developed secretory endometrium. Progestin-only compounds \nresult in atrophic glands with minimal or absent mitotic activity, \nbut unlike endometrium devoid of hormonal stimulation, there is \nalso evidence of stromal expansion and pseudodecidualization. The \nintensity of the histological response will depend upon the potency, \ndosage, and duration of use of the progestin but this response is \nsimilar whether the progestin is delivered via tablets, injections, or an \nintrauterine device.9–11\nWhile atrophic glands are characteristic of premenopausal \npatients taking exogenous hormones, atrophy in any other setting in a \npremenopausal woman is an unexpected finding and its significance \nis not well understood. The minority of uterine cancers can arise \nin a background of atrophy. These cancers are usually estrogen-\nindependent, less differentiated, and associated with a poorer \nprognosis than estrogen-dependent tumors. Although endometrial \ncancer is most commonly encountered in postmenopausal patients, \n8.5-14.2% are diagnosed in premenopausal women.12\nThere are no studies to date that evaluate the risk of malignancy \nin young women with endometrial atrophy on sampling, and little \ndata exist to direct clinical management in this setting. Few studies \nhave even defined the prevalence of atrophic endometrium in young \nwomen. In one small study of 230 premenopausal women with \nirregular uterine bleeding who underwent endometrial sampling, 8.7% \nwere found to have atrophy.13 In another study of 12,949 endometrial \nbiopsies performed in patients undergoing infertility workup, 2.4% \nrevealed atrophy.14 The objective of this study was to determine the \nprevalence and clinical significance of endometrial sampling showing \natrophy among women younger than 50 years of age. \nObstet Gynecol Int J. 2015;3(3):323‒327. 323\n©2015 Brunette et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which \npermits unrestricted use, distribution, and build upon your work non-commercially.\nSignificance of atrophy on endometrial sampling in \nwomen younger than fifty years of age\nVolume 3 Issue 3 - 2015\nLaurie Brunette,1,2 Lirona Katzir,1,2 Malaika \nAmneus,1,2 Chisa Aoyama,3,4 Christine H \nHolschneider1,2 \n1Department of Obstetrics and Gynecology, Olive View-UCLA \nMedical Center, USA\n2Department of Obstetrics and Gynecology, David Geffen \nSchool of Medicine at UCLA, USA\n3Department of Pathology and Laboratory Medicine, Olive \nView-UCLA Medical Center, USA\n4Department of Pathology and Laboratory Medicine, David \nGeffen School of Medicine at UCLA, USA\nCorrespondence: Christine H Holschneider, Olive \nView-UCLA Medical Center, Department of Obstetrics and \nGynecology, 14445 Olive View Drive, Sylmar, CA 91342, Room \n6D-116, T el 818-364-3222, Fax 818-364-3255, \nEmail: \nReceived: October 29, 2015 | Published: December 1, 2015\nAbstract\nObjective: To determine the prevalence and significance of endometrial sampling showing \natrophy among women younger than 50 years. \nStudy design:  Retrospective study of consecutive endometrial sampling results among \nwomen younger than 50 years collected over 2 years. Data were abstracted on patient \ndemographics and clinico-pathological factors. \nResults: Among 2,034 eligible women, 96 had atrophy (prevalence 4.7% [95% CI: 3.8-\n5.6%]). The corresponding endometrial echo complex was 6.4±3.6 mm on transvaginal \nultrasound. 93% of patients had a clinical history compatible with endometrial atrophy, \nincluding use of progestin-containing hormones, menopause, or a thin endometrial echo \ncomplex on ultrasound; 7% of patients with abnormal uterine bleeding had ultrasound \nfindings inconsistent with endometrial atrophy, such as an intracavitary lesion or an \nunevaluable or thickened (>14mm) endometrial echo complex. One patient was found to \nhave a uterine malignancy. \nConclusion: Nearly 5% of women younger than 50 years of age had endometrial atrophy. \nOf those, 1% had an underlying malignancy. If a premenopausal woman is not on progestin \nor combination hormone therapy and ultrasound findings are inconsistent with atrophy, \nan endometrial sampling result showing atrophy cannot reliably rule out malignancy. \nWe recommend that this subset of patients undergo further testing before malignancy is \nexcluded. \nKeywords: endometrial atrophy, abnormal uterine bleeding, endometrial sampling, \nuterine malignancy, premenopausal, endometrial echo complex\nObstetrics & Gynecology International Journal \nResearch Article\n Open Access\n\n\nSignificance of atrophy on endometrial sampling in women younger than fifty years of age\n324\nCopyright:\n©2015 Brunette et al.\nCitation: Brunette L, Katzir L, Amneus M, et al. Significance of atrophy on endometrial sampling in women younger than fifty years of age. Obstet Gynecol Int J. \n2015;3(3):323‒327. DOI: 10.15406/ogij.2015.03.00082\nMaterials and methods\nA retrospective study of women younger than 50 years of age with \natrophy on endometrial sampling was conducted at Olive View-UCLA \nMedical Center, a university-affiliated public safety net hospital. \nIRB approval was obtained from the Olive View-UCLA Education \nand Research Institute. The pathology database was searched for \nconsecutive endometrial sampling specimens collected between \nJanuary 1, 2009 and December 31, 2010 from women less than 50 \nyears of age. Amongst these, the subset that showed endometrial \natrophy on pathology was identified. Patients with a previous history \nof endometrial cancer were excluded. Medical records were reviewed \nto determine the following for each patient at the time of sampling: age, \nethnicity, body mass index, gravity, parity, menopausal status, medical \ncomorbidities, personal and family history of cancer, abnormal uterine \nbleeding patterns, exogenous hormone use, indication for sampling, \npelvic ultrasound findings, and all previous and subsequent uterine \nor endometrial pathology results. The ultrasound that was performed \nclosest to the date of sampling was included, regardless of whether \nit occurred before or after the endometrial sampling. However, since \nultrasonographic findings of the endometrium are strongly influenced \nby hormonal factors, data were included in the analysis of the \nendometrial echo complex thickness only if there was no intercurrent \nchange in hormonal medications between the two procedures. \nPathology was assessed for evidence of hormone effect. All slides \nwere re-reviewed by the study pathologist if the original pathology \nreport was equivocal or did not comment on hormone effect. \nThe prevalence of endometrial samplings showing atrophy among \nwomen younger than 50 years of age was calculated. The t-test or \none-way ANOV A were used for paramentric variables and the Mann-\nWhitney U or Kruskal-Wallis test were used for non-parametric \ntesting of continuous variables as indicated. The Chi-square test was \nused for categorical variables. All tests were two-sided and a p-value \nof <0.05 was considered significant.\nResults\nOver the two-year study period, 2,034 women younger than \n50 years of age underwent endometrial sampling with 96 of these \nwomen showing atrophic endometrium on pathology. This resulted \nin a prevalence of endometrial atrophy of 4.7% (95% CI: 3.8-\n5.6%) in this age group. The majority of pathology specimens, 92, \nwere from an office endometrial sampling and four were from an \nendometrial curettage. Figure 1 summarizes the study cohort. Twenty-\nthree patients were postmenopausal at the time of sampling. Of the \n73 premenopausal patients, 44 were using exogenous hormones. \nThirty-four were on a progestin-only regimen and 10 were taking a \ncombination of estrogen and progestin. The indications for hormone \nuse in these patients included a history of endometrial hyperplasia \n(n=20), irregular bleeding without a history of hyperplasia (n=21), \nhormonal contraception (n=2), and management of vasomotor \nsymptoms (n=1). In 40 (91%) of the 44 patients on hormones, the \nendometrial sampling specimen showed definite evidence of atrophy \nwith hormone effect based on original pathology reports and re-\nreview by our study pathologist. One patient had a sample that was \nsuboptimal to evaluate for hormone effect, and three patients who \nreported exogenous hormone use at the time of biopsy did not have \nany evidence of hormone effect on pathology. \nThe demographics of all patients with atrophy on endometrial \nsampling are shown in Table 1 and are divided by menopausal \nstatus and use of exogenous progestins. Not surprisingly, the \naverage age among the postmenopausal patients was higher than \nin either premenopausal group. However, the difference in age \nremained statistically significant (p<0.001) when comparing only the \npremenopausal patients on progestins to those not on any hormones, \nas did the median gravity (p=0.005) and parity (p=0.015). The other \ndemographic factors of the premenopausal patients on progestins \ndid not differ significantly from the premenopausal patients not \ntaking hormones. For all of these 29 premenopausal patients not \non progestin or combination therapy, the indication for endometrial \nsampling was abnormal uterine bleeding. Outcomes post-atrophic \nindex biopsy was as follows: four patients underwent hysterectomy \nfor persistent bleeding, one of whom had a malignancy. One patient \nhad a polypectomy with benign final pathology. Seventeen patients \nexperienced resolution of their symptoms. Five of these patients had \nsubsequent endometrial sampling for persistent abnormal uterine \nbleeding, and all specimens showed either persistent atrophy or \nweakly proliferative endometrium. Seven patients did not follow up \nafter undergoing initial endometrial sampling.\nFigure 1: Study Cohort.\nFigure 1 Study cohort.\n\n\nSignificance of atrophy on endometrial sampling in women younger than fifty years of age\n325\nCopyright:\n©2015 Brunette et al.\nCitation: Brunette L, Katzir L, Amneus M, et al. Significance of atrophy on endometrial sampling in women younger than fifty years of age. Obstet Gynecol Int J. \n2015;3(3):323‒327. DOI: 10.15406/ogij.2015.03.00082\nT able 1 Patient demographics by menopausal state and exogenous progestin or combination hormone use\nCharacteristic\nPremenopausal (n=73)\nPNo Hormones Progestin±Estrogen Postmenopausal\n(n=29) (n=44) (n=23)\nAge (y) 43.7±6.2 37.7±7.7 46.2±3.9 < 0.001\nGravity 4 [2,5] 2 [0,3] 3 [2,4] 0.011\nParity 3 [2,4] 2 [0,3] 3 [2,3] 0.032\nBMI (kg/m2) 32.2±8.5 33.0±7.1 31.3±9.4 0.802\nRace or Ethnicity\nHispanic 23 (79.3) 32 (72.7) 12 (52.2) 0.246\nWhite 1 (3.4) 7 (15.9) 4 (17.4)\nAfrican American 2 (6.9) 1 (2.3) 3 (13.0)\nAsian 3 (10.3) 2 (4.5) 2 (8.7)\nOther 0 (0) 2 (4.5) 2 (8.7)\nComorbidities\nDiabetes Mellitus 0 (0) 5 (11.4) 3 (13.0) 0.147\nHypertension 4 (13.7) 9 (20.5) 6 (26.0) 0.537\nThyroid Disease 2 (6.9) 3 (6.8) 1 (4.3) 0.911\nPersonal History of Cancer 2 (6.9) 2 (4.5) 1 (4.3) 0.886\nFamily History of Cancer 7 (24.1) 5 (11.4) 4 (17.4) 0.356\nBMI, body mass index Data are n (%), median (interquartile \nrange [25%tile, 75%tile]), or mean±standard deviation unless \notherwise specified Seventy-one of the 96 patients underwent \ntransvaginal ultrasound. Twenty-three premenopausal patients \nwere on exogenous progestins alone or in combination at the time \nof endometrial sampling but not at the time of their ultrasound, \nand they were excluded from the ultrasound analysis. The mean \nendometrial echo complex thickness for all patients with atrophy of \nthe endometrium and no other intrauterine pathology was 6.4±3.6mm. \nAmong those patients (Figure 1), there was no significant difference \n(p=0.97) in the mean endometrial echo complex thickness between \npostmenopausal patients (6.2±2.8mm), premenopausal patients on \nprogestins with or without estrogen (6.5±4.4mm) and premenopausal \npatients who were not taking exogenous progestins (6.5±3.9mm). \nOf the 96 women identified who were younger than 50 years of \nage and had atrophy on endometrial sampling, 89 (93%) experienced \nresolution of their bleeding or had a clinical history compatible with \nendometrial atrophy, such as the use of exogenous progestins or \ncombination hormone therapy, postmenopausal state, or an ultrasound \nshowing no intracavitary lesions and an endometrial echo complex \nthickness measuring within 2 standard deviations of the mean for \nthis cohort (≤14mm). The remaining seven premenopausal patients \nwho were not taking exogenous progestins had ultrasound findings \ninconsistent with atrophy, such as an intracavitary lesion (n=4), an \nendometrial echo complex thickness >14mm (n=2), or an unevaluable \nendometrial echo complex due to a large uterine mass (n=1).\nOne (14%) of these seven patients was found to have a uterine \ncarcinosarcoma. The patient was a 30 year-old African-American \nfemale who presented with abnormal vaginal bleeding. During her \ninitial consult, a pelvic ultrasound revealed a 14cm uterus with a \nthickened endometrial echo complex of 29mm and a heterogeneous \nlower uterine segment. An endometrial biopsy performed on the same \nday revealed atrophy. She was thus managed with hormonal medication \nwith initial improvement of her bleeding until she returned 7 months \nlater with a 22 cm uterus, pain, severe anemia and lymphadenopathy. \nShe underwent surgical management and was diagnosed with stage IV \ncarcinosarcoma on final pathology. \nDiscussion\nIn our study, nearly 5% of women under 50 years of age who \nunderwent endometrial sampling had atrophy. For the majority \nof patients (67 out of 96) an atrophic endometrium was consistent \nwith clinical history, as they were either postmenopausal or using \nexogenous progestin or combination hormone therapy. The 29 \npatients who were premenopausal and not taking progestins or \ncombination therapy all underwent endometrial sampling for a history \nof abnormal uterine bleeding. On average, they were older and had \na higher gravity and parity compared to the group using hormone \ntherapy. These differences are most likely attributable to the high \nproportion of patients in the progestin or combination hormone group \nwho underwent endometrial sampling for a history of endometrial \nhyperplasia (45%) and may have associated infertility or are delaying \npregnancy until after resolution of their hyperplasia. \nOf the 29 premenopausal patients not taking progestins or \ncombination therapy, seven were identified in whom an atrophic \nendometrium was inconsistent with clinical and ultrasound findings. \nThese included all patients with a thickened endometrial echo complex \n(>14mm), an unevaluable endometrial echo complex, or an intracavity \nlesion. Of these patients, one (14%) was found to have a malignancy. \nThis constellation of clinical factors may place a patient into a higher \nrisk category where the reliability of an atrophic endometrial sampling \nresult may be limited at excluding a uterine malignancy. \n\nSignificance of atrophy on endometrial sampling in women younger than fifty years of age\n326\nCopyright:\n©2015 Brunette et al.\nCitation: Brunette L, Katzir L, Amneus M, et al. Significance of atrophy on endometrial sampling in women younger than fifty years of age. Obstet Gynecol Int J. \n2015;3(3):323‒327. DOI: 10.15406/ogij.2015.03.00082\nMultiple studies have explored the relationship between \npreoperative endometrial sampling results and final pathology after \nhysterectomy.8–11 Endometrial biopsies have been shown to have a \nhigh overall accuracy in the diagnosis of endometrial cancer, with \na sensitivity of 99.6% in postmenopausal women, but only 91% in \npremenopausal women.15,16 In addition, the diagnosis is more likely to \nbe missed if the cancer is localized to an endometrial polyp or occupies \nless than 50% of the endometrium. 17 Clark et al. 18 found that an \nendometrial biopsy result showing cancer was more accurate at ruling \nin disease than a negative test result was at ruling it out, with a post \ntest probability of 81.7% for a positive result and 0.9% for a negative \nresult.18 Bansal et al reported that the overall ability of preoperative \nendometrial sampling to detect a malignancy was significantly lower \nfor non-endometrioid histologies with 75% accuracy for uterine \npapillary serous and clear cell carcinomas, 59% for carcinosarcoma, \nand 52% for other sarcomas. 19 Sany et al. 20 described a correlation \nbetween underlying histology and the ability to make an accurate \ndiagnosis based on preoperative endometrial sampling (endometroid \ncarcinoma 78%, non-endometrioid carcinoma 67%, carcinosarcoma \n90%, and sarcoma 40%). 20 Given the possibility of false negative \nresults with endometrial sampling, ACOG recommends further testing \nto rule out endometrial pathology in the setting of persistent abnormal \nuterine bleeding with benign pathology. 2 As malignancies of non-\nendometrioid histology can arise in a background of atrophy and have \na higher incidence of being misdiagnosed on endometrial sampling, \nwe propose that women younger than 50 years of age with atrophy on \nendometrial sampling but with clinical and ultrasonographic findings \ninconsistent with this result be considered at higher risk of having \nan underlying malignancy and additional testing should be initiated \nwithout further delay.\nWhile transvaginal ultrasound evaluation of the endometrial \necho complex thickness using 4mm as the cutoff is valuable in \npostmenopausal women at excluding endometrial hyperplasia \nand cancer, it is not reliable in premenopausal women. 2 Normal \nendometrial echo complex thickness varies based on the patient’s \nmenstrual cycle typically ranging from 3-5mm at the end of menses \nto approximately 12-14mm in the secretory phase. 21,22 Based \non correlative data of endometrial echo complex thickness and \nhistopathology in premenopausal women with abnormal uterine \nbleeding published by Ozdemir et al. 23 the average endometrial echo \ncomplex in premenopausal women with atrophy was 4.6±2.5mm.23 In \nour cohort, the respective mean endometrial echo complex thickness \nfor all patients with atrophy and no intracavitary pathology was \n6.4±3.6mm. This finding was consistent for all patients with atrophy \nregardless of menopausal status or any use of exogenous progestins or \ncombination hormone therapy. Based on the above, we used a cutoff \nfor an endometrial echo complex measurement at which the thickness \nshould be considered incompatible with atrophy of 14mm, which is \ngreater than 2 standard deviations above the mean. \nWe also propose for further study clinical risk stratification for \nwomen younger than 50 years of age with atrophy on endometrial \nsampling (Table 2) that may help guide clinical management in \naddition to the integration of other risk factors, such as obesity or \nfamily history.\nIn summary, atrophy is observed in nearly 5% of women \nundergoing endometrial sampling under age 50. Of these, 1% had \nan underlying malignancy. On transvaginal ultrasound, the mean \nendometrial echo complex for patients with atrophy under age 50 is \n6.4±3.6mm, regardless of menopausal state and hormone use. With \nonly one case of malignancy observed, it is beyond the scope of this \nstudy to determine the true incidence of cancer in this population. \nHowever, in the setting of abnormal uterine bleeding in this population, \nwe propose to stratify patients into a higher or lower risk category \nbased on menopausal status, exogenous progestin or combination \nhormone use and ultrasound findings. If a premenopausal woman \nis not on progestin or combination hormone therapy and ultrasound \nfindings are inconsistent with atrophy, an endometrial sampling result \nshowing atrophy cannot reliably rule out malignancy. We recommend \nthat this subset of patients undergo further testing before malignancy \nis excluded.\nT able 2 Proposed cancer risk stratification for women younger than 50 years of age with atrophy on endometrial sampling\nRisk stratification Clinical characteristics\nLow Risk\nPostmenopausal or\nTaking exogenous progestins (alone or in combination) or\nPelvic ultrasound findings consistent with atrophic endometrium\nEndometrial echo complex (≤14mm) and\nNo intracavitary lesions\nHigh Risk\nPremenopausal and\nNo exogenous progestin use and\nPelvic ultrasound findings inconsistent with atrophic endometrium\nThickened endometrial echo complex (>14mm) and/or\nUnevaluable endometrial echo complex and/or\nIntracavitary lesion\n\nSignificance of atrophy on endometrial sampling in women younger than fifty years of age\n327\nCopyright:\n©2015 Brunette et al.\nCitation: Brunette L, Katzir L, Amneus M, et al. Significance of atrophy on endometrial sampling in women younger than fifty years of age. Obstet Gynecol Int J. \n2015;3(3):323‒327. DOI: 10.15406/ogij.2015.03.00082\nAcknowledgments \nPresented in part at the Western Association of Gynecologic \nOncologists Annual Meeting; Huntington Beach, CA; June 27-30, \n2012 and the 67th Annual Obstetrical and Gynecological Assembly of \nSouthernCalifornia; Los Angeles, CA; April 13-14, 2012. \nConflicts of interest \nThe authors declare there is no conflict of interests.\nReferences\n1. American College of Obstetricians and Gynecologists. ACOG practice \nbulletin, clinical management guidelines for obstetrician-gynecologists, \nnumber 65, August 2005: management of endometrial cancer. Obstet \nGynecol. 2005;106(2):413–425.\n2. Committee on Practice Bulletins-Gynecology. Practice bulletin no. 128: \ndiagnosis of abnormal uterine bleeding in reproductive-aged women. \nObstet Gynecol. 2012;120(1):197–206.\n3. Gültekin M, Diribaş K, Dursun P, et al. Current management of \nendometrial hyperplasia and endometrial intraepithelial neoplasia (EIN). \nEur J Gynaecol Oncol. 2009;30(4):396–401.\n4. Gallos ID, Shehmar M, Thangaratinam S, et al. Oral progestogens \nvs levonorgestrel-releasing intrauterine system for endometrial \nhyperplasia: a systematic review and metaanalysis. Am J Obstet Gynecol. \n2010;203(6):547.e1–547.e10.\n5. Greer BE, Koh WJ, Abu-Rustum N, et al. Uterine Neoplasms. \nClinical Practice Guidelines in Oncology. J Natl Compr Canc Netw . \n2009;7(5):498–531.\n6. Karlsson B, Granberg S, Wikland M, et al. Transvaginal ultrasonography \nof the endometrium in women with postmenopausal bleeding--a Nordic \nmulticenter study. Am J Obstet Gynecol. 1995;172(5):1488–1494.\n7. Zaino RJ. Endometrial atrophy. Interpretation of endometrial biopsies and \ncurettings. Philadelphia, USA: Lipincott-Raven; 1996. \n8. Kurman RJ. Morphology of Inactive and Atrophic Endometrium. \nBlaustein’s Pathology of the Female Genital Tract. 5th edn. New York, \nUSA: Springer-Verlag; 2002.\n9. McCluggage WG. My approach to the interpretation of endometrial \nbiopsies and curettings. J Clin Pathol. 2006;59(8):801–812.\n10. Moyer DL, Felix JC. The effects of progesterone and progestins on \nendometrial proliferation. Contraception. 1998;57(6):399–403.\n11. Rizkalla HF, Higgins M, Kelehan P, et al. Pathological findings associated \nwith the presence of a mirena intrauterine system at hysterectomy. Int J \nGynecol Pathol. 2008;27(1):74–78.\n12. Felix AS, Weissfeld JL, Stone RA, et al. Factors associated with Type I and \nType II endometrial cancer. Cancer Causes Control. 2010;21(11):1851–\n1856.\n13. Zlatkov V , Radeva V , Cholakova G, et al. Assessment of irregular \nuterine bleeding in premenopausal women. Akush Ginekol (Sofiia). \n2002;41(5):33–35.\n14. Sahmay S, Oral E, Saridogan E, et al. Endometrial biopsy findings \nin infertility: analysis of 12,949 cases. Int J Fertil Menopausal  Stud. \n1995;40(6):316–321.\n15. ACOG Committee on Practice Bulletins--Gynecology. American College \nof Obstetricians and Gynecologists. ACOG practice bulletin: management \nof anovulatory bleeding. Int J Gynaecol Obstet. 2001;72(3):263–71.\n16. Dijkhuizen FP, Mol BW, Br ölmann HA, et al. 2000;The accuracy of \nendometrial sampling in the diagnosis of patients with endometrial \ncarcinoma and hyperplasia: a meta-analysis. Cancer. 89(8):1765–1772.\n17. Guido RS, Kanbour-Shakir A, Rulin MC, et al. Pipelle endometrial \nsampling. Sensitivity in the detection of endometrial cancer. J Reprod \nMed. 1995;40(8):553–555.\n18. Clark TJ, Mann CH, Shah N, et al. Accuracy of outpatient endometrial \nbiopsy in the diagnosis of endometrial cancer: a systematic quantitative \nreview. BJOG. 2002;109(3):313–321.\n19. Bansal N, Herzog TJ, Burke W, et al. The utility of preoperative \nendometrial sampling for the detection of uterine sarcomas. Gynecol \nOncol. 2008;110(1):43–48.\n20. Sany O, Singh K, Jha S. Correlation between preoperative endometrial \nsampling and final endometrial cancer histology. Eur J Gynaecol Oncol . \n2012;33(2):142–144.\n21. American College of Obstetricians and Gynecologists. ACOG Committee \nOpinion No. 426: The role of transvaginal ultrasonography in the \nevaluation of postmenopausal bleeding. Obstet Gynecol. 2009;113(2 Pt \n1):462–464.\n22. Thomas M VVB. Gynecologic Ultrasound. 10th edn. Philadelphia, USA: \nLippincott Williams & Wilkins; 2008.\n23. Ozdemir S, Celik C, Gezginç K, et al. Evaluation of endometrial thickness \nwith transvaginal ultrasonography and histopathology in premenopausal \nwomen with abnormal vaginal bleeding. Arch Gynecol Obstet . \n2010;282(4):395–399.","source_license":"CC0","license_restricted":false}