{"paper_id":"d9ac5884-3623-4ff3-91c5-406f5111aa0a","body_text":"Original Article\nJ Gynecol Oncol Vol. 19, No. 4:256-260, December 2008  DOI:10.3802/jgo.2008.19.4.256\n256\nThe effect of adjuvant hormonal therapy on the \nendometrium and ovary of breast cancer patients\nHo Sung Kim, Yong T ark Jeon, Yong Beom Kim\nDepartment of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam, Korea\nObjective: To investigate the effect of adjuvant hormonal therapy on the endometrium and ovary of breast cancer \npatients. \nMethods: A retrospective review was performed on the 207 patients who had taken tamoxifen or anastrozole, as \nadjuvant hormonal therapy after breast cancer surgery between January 2003 and December 2006. Gynecologic \nsurveillance constituted of ultrasonographic exam of the endometrial thickness and ovarian cyst formation. The \npatients were classified into three groups and analyzed; premenopausal/postmenopausal women receiving tamoxifen \nand women receiving anastrozole.\nResults: Mean duration of follow up?was 20.6±6.6 months. There was no difference of mean endometrial thickness \nbefore hormonal therapy among the three groups (p=0.327). In women receiving tamoxifen, the endometrium was \ncontinuously thickened in proportion to the duration of the therapy irrespective of menopausal status while it \nremained unchanged in women receiving anastrozole (p＜0.05). Endometrial biopsies were performed in 28 patients \nreceiving tamoxifen. The most common histologic finding was proliferative endometrium in premenopausal women \n(7/21) and atrophic endometrium in postmenopausal women (6/7). There was no case of endometrial cancer in both \ngroups. Ovarian cyst was found in 32 women and the most were developed in premenopausal women receiving \ntamoxifen (30/32). All of them showed benign nature on transvaginal ultrasonographic findings.\nConclusion: Women undergoing adjuvant hormonal therapy after breast cancer surgery exhibited changes in the \nendometrium and ovary. However most changes were not a serious problem in this study and frequent gynecologic \nsurveillance in these patients needs further investigation.\nKey Words: Breast cancer, Tamoxifen, Anastrozole, Endometrium\nReceived October 27, 2008, Revised November 17, 2008,\nAccepted November 18, 2008\nAddress reprint requests to Yong Beom Kim\nDepatrment of Obstertics and Gynecology, Seoul National University\nBundang Hospital, 300, Gumi-dong, Bundang-gu, Seongnam 463-707,\nKorea\nTel: 82-31-787-7253, Fax: 82-31-787-4054\nE-mail: ybkimlh@snubh.org\nINTRODUCTION\n  Breast cancer is the most common cancer in women that is a \nmajor cause of morbidity and mortality, with more than 1 mil-\nlion new cases and 410,000 deaths reported worldwide each \nyear.\n1,2 The primary aim of treatment for early or advanced \nbreast cancer is to maximize therapeutic effect and prevent re-\ncurrence through primary surgery followed by adjuvant ther-\napy including chemotherapy, irradiation, or hormonal therapy. \nIn recent decades, tamoxifen, the selective estrogen receptor \nmodulator, has been the standard regimen of adjuvant hormo-\nnal therapy for estrogen receptor (ER) positive breast cancer \nin both pre- and post-menopausal women. Although tamox-\nifen is an ER antagonist in breast cancer, which reduces the \nbreast cancer recurrence rate and mortality rate,\n3 it also acts as \nan ER agonist in other tissue such as the endometrium and \novary. This agonist effect can stimulate proliferation, which \nincreases the risk of polyps, hyperplasia, endometrial cancer, \nand ovarian cyst formation.\n4-7\n  Aromatase inhibitors (AIs) such as anastrozole have been \nfound to be at least as effective as tamoxifen in the treatment \nof postmenopausal women suffering from ER-positive breast \ncancer.\n8,9 Estrogen ablative therapy with anastrozole may not \nonly be effective in the treatment of breast cancer, but may al-\nso be beneficial in reducing the risk of other estrogen-depend-\nent diseases.\n  The aim of this study was to investigate the effect of tamox-\nifen and anastrozole on the endometrium and ovary in women \nundergoing adjuvant hormonal therapy after breast cancer \nsurgery.\nMATERIALS AND METHODS \n  Between January 2003 and December 2006, 207 women \n\nGynecologic changes with tamoxifen or anastrozole\n257\nFig. 1. Changes of endometrial thickness during adjuvant hormonal \ntherapy after breast cancer surgery (p＜0.05).\nCharacteristics\nTa moxi f e n us e r\nArimidex user\n(group 3) p valuePremenopause\n(group 1)\nPostmenopause\n(group 2)\nNumber of patients\nAge (year)\nDuration of follow up (month)\nEndometrial thickness (mm)\n155\n41.7±5.6\n20.9±7.8\n  3.72±1.92\n32\n56.1±7.8\n19.9±6.7\n  3.45±1.09\n20\n53.0±7.4\n20.1±5.6\n  3.06±0.24\n-\n-\nNS\nNS\nNS: not significant\nTa b l e  1 . Patient’s characteristics\nwith ER-positive, primary breast cancer, who were receiving \nadjuvant tamoxifen or anastrozole treatment more than one \nyear after surgery were included in this study. These women \nwere identified by retrospective review of their medical re-\ncords and classified into three groups; 155 premenopausal \nwomen receiving tamoxifen (group 1), 32 postmenopausal \nwomen receiving tamoxifen (group 2), and 20 post-\nmenopausal women receiving anastrozole (group 3). All pre-\nmenopausal women received adjuvant chemotherapy before \ntamoxifen therapy. Tamoxifen was administered 20 mg/day \nand anastrozole was administered 1.0 mg/day. The post-\nmenopausal status was defined as an amenorrhea duration of \nmore than 1 year or serum FSH (follicular stimulating hor-\nmone) levels of ＞40 mIU/ml before primary surgery. \nEndometrial and ovarian evaluation was performed by \nTransvaginal Ultrasonography (TU) before the start of hor-\nmonal therapy and the changes were periodically measured by \nTU at an interval of 6 or 12 months. All patients underwent \nTU assessment of the endometrial lining by measuring the \nmaximum thickness from the outermost limits of endo-\nmetrial-myometrial juncture. A double-layered endometrial \nstripe subsequently measuring more than 5 mm at a periodic \ncheckup was considered abnormal and an endometrial biopsy \nwas performed. Ovarian cysts were identified as sonolucen-\ncies in the ovary with a diameter of ＞30 mm in all women. \n  All statistical analyses were performed using SPSS 15.0 for \nWindows. Comparative analyses were performed with \nKruskal Wallis test, Mann-Whitney U-test, Chi-square test \nand Fisher's exact test. Continuous variables were presented \nas mean and standard deviation. Only p-values ＜0.05 were \nconsidered significant.\nRESULTS \n  The mean age of the three groups was 41.7±5.6, 56.1±7.8, \nand 53.3±7.4 years, respectively. The mean duration of fol-\nlow-up was 20.6±6.6 months (range, 12 to 36). There was no \ndifference of mean endometrial thickness before hormonal \ntherapy among the three groups (3.72±1.92 vs. 3.45±1.09 vs. \n3.06±0.24 mm, Table 1). \n  The endometrial thickness was continuously increased in \nproportion to the duration of receiving tamoxifen from 3.72± \n1.92 and 3.45±1.09 at baseline to 4.35±2.50 and 4.26±2.15 \nafter 1 year, to 4.89±2.73 and 4.54±1.77 after 2 years, and to \n5.50±3.07 and 5.33±2.94 after 3 years in group 1 and group \n2, respectively, while it remained ＜5 mm in group 3 treated \nwith anastrozole for 3 years (p＜0.05) (Fig. 1).\n  Endometrial biopsies were performed for 28 women receiv-\ning tamoxifen in whom endometrial pathology suspected; in \ngroup 1 (21 women, 13.5%) and group 2 (7 women, 21.9%). \nOf the 21 women in group 1 undergoing endometrial biopsy, \nendometrial polyps were found in 6 cases, proliferative endo-\nmetrium in 7 cases, submucosal myoma in 1 case, simple hy-\nperplasia in 1 case, and atrophic endometrium in 6 cases. Of \nthe 7 women in the group 2, endometrial polyp was found in \n1 case and atrophic endometrium in 6 cases. The most com-\nmon histologic finding was proliferative endometrium in \ngroup 1 (7/21 cases, 33.3%) and atrophic endometrium in \ngroup 2 (6/7 cases, 85.7%). There was no cases of endo-\nmetrial cancer in both groups (Table 2). \n  Ovarian cyst was found by transvaginal ultrasonography \nduring follow up in 30 women (19.4%) of group 1, 2 women \n(6.3%) of group 2, and 1 woman (5.0%) of group 3. All the \ncysts were 30-60 mm in size and unilocular or bilocular in \nshape without any solid portions. Further evaluation such as \nlaparoscopic biopsy was not performed because the ovarian \ncysts had a benign nature on ultrasonography in all cases.\n\nJ Gynecol Oncol Vol. 19, No. 4:256-260, 2008 Ho Sung Kim, et al.\n258\nHistology Premenopause \n(group1, n=155)\nPostmenopause \n(group 2, n=32)\nEndometrial polyp\nProliferative endometrium\nSubmucosal myoma\nSimple hyperplasia\nAtrophic endometrium\nTotal\n6\n7\n1\n1\n6\n21 (13.5%)\n1\n0\n0\n0\n6\n7 (21.9%)\nTable 2. Histopathologic outcomes of endometrial biopsies in ta-\nmoxifen users\nDISCUSSION\n  Treatment for women with early and advanced breast cancer \nare strongly related to the presence of ER-positive and/or \nPR-positive tumors, which indicates that the estrogen stim-\nulates tumor growth, and that hormonal therapy may be effec-\ntive in preventing disease progression. Until recently, tamox-\nifen, which acts by blocking estrogen stimulation, has been \nknown to be an effective adjuvant therapy for breast cancer in \npre- and post-menopausal patients with ER-positive breast \ncancer. However, it is now widely accepted that an AIs should \nbe the treatment of choice for postmenopausal women in the \nadvanced breast cancer setting.\n10\n  A trial of AIs as first-line therapy for postmenopausal wom-\nen with hormone receptor positive advanced breast cancer \nhave shown anastrozole to be at least equivalent to tamoxifen \nin efficacy and tolerability.\n9 Multiple phase III trials of AIs for \nthe treatment of advanced breast cancer have demonstrated \nthat letrozole, anastrozole, and exemestane are superior to \nmegestrol as second-line endocrine therapy after failure with \ntamoxifen.\n11-15\n  Unlike tamoxifen, which prevents estrogen binding to its \ncognate receptor at the DNA level, AIs prevent the formation \nof estrogen.\n16 Therefore, they do not have the mixed agonistic \n/antagonistic properties inherent in tamoxifen, and it is \nthought that the inhibitors may overcome tamoxifen resistance.\n  Tamoxifen has an effect on the endometrium that varies with \nthe serum estradiol (E2) concentration in that it will function \nas an estrogen agonist only in postmenopausal women.\n17-20 \nAn increased risk of endometrial carcinoma has been de-\nscribed, specifically in postmenopausal women, and the risk \nincreases with cumulative dose and duration of tamoxifen \ntreatment.\n6,21-25\n  Cheng et al. compared the endometrial findings of pre- and \npost-menopausal women receiving tamoxifen therapy with \nabnormal bleeding.\n26 No differences were detected in mean \nendometrial thickness, uterine size, and histopathologic find-\nings in premenopausal patients, regardless of tamoxifen \ningestion. In addition, in premenopausal women using ta-\nmoxifen in a chemoprevention trial, who had elevated serum \nlevels of E2 because of ovarian stimulation, the endometrial \nthickness was not increased, suggesting an antiestrogenic ef-\nfect of tamoxifen on the endometrium in an estrogen-rich \nenvironment.\n27 Although data in the literature are scarce and \nlonger follow-up is needed, initial studies show no adverse ef-\nfect of tamoxifen on the endometrium in premenopausal \nwomen.\n  In a chemoprevention trial by Chang et al, endometrial carci-\nnoma has been reported in women who were premenopausal \nat the start of tamoxifen and who became amenorrheic during \nlong-term tamoxifen treatment with proved low serum estro-\ngen levels. Ultrasonography of the endometrium in those \nwomen on tamoxifen showed an increased endometrial \nthickness.\n27 Only in women with a low serum level of E2, ta-\nmoxifen is associated with increased endometrial thickness \nand increased uterine size on ultrasound, and increased fre-\nquency of endometrial pathology.\n4,27\n  Tamoxifen can stimulate proliferation of the endometrium, \nwhich increases the risk of polyps, hyperplasia, and endo-\nmetrial cancer by 2- to 4-fold, compared with patients not re-\nceiving tamoxifen.\n6,21-24,28-31 It has been reported that 10% of \ntamoxifen-treated patients will develop tamoxifen-induced \nendometrial pathology within 5 years, leading to operative \nintention.\n32 Although endometrial cancer was not detected in \nour data, the change of endometrium in the pre- and \npost-menopausal women receiving tamoxifen was in accord-\nance with these reports.\n  In a randomized study (ATAC study) which compared ad-\njuvant anastrozole with tamoxifen in the treatment of meno-\npausal patients with ER positive breast cancer, a lower preva-\nlence of endometrial cancer was found.\n33 The results of the \nATAC endometrial sub-protocol, initiated in order to estab-\nlish the background prevalence of endometrial pathology and \nfinalized to prospectively assess the incidence of endometrial \nchanges following the start of anastrozole therapy, have been \nrecently published.\n34,35 Sixty nine patients were assessable af-\nter 24 months of therapy with anastrozole and there was no \nchange in the median endometrial thickness compared with \nthe baseline. However, the emerging rate of endometrial path-\nology did not differ significantly between the patients treated \nwith anastrozole (8.7%) and tamoxifen (17.9%). Similarly, \nwe showed changes from the baseline endometrial thickness \nafter 3 years in women treated with tamoxifen, whereas endo-\nmetrial thickening did not change in postmenopausal women \ntreated with anastrozole. \n  The mechanism of action of tamoxifen in stimulating the de-\nvelopment of ovarian cysts is not yet fully known. It is believed \nthat tamoxifen competes with estrogen receptors, leading to a \ndecline in circulating estrogen levels and thus increasing the \nlevel of gonadotropin releasing hormone, which stimulates \nthe pituitary gonadotropins.\n36 Chronic treatment with tamox-\nifen in pre-menopausal women with primary breast cancer \nhas been reported to cause an increase in ovarian estrogen \nsynthesis.\n37,38 Powles et al.39 demonstrated in a placebo-con-\ntrolled tamoxifen chemoprevention trial in 1,054 healthy pre- \nand post-menopausal women, a significantly increased risk of \n\nGynecologic changes with tamoxifen or anastrozole\n259\novarian cysts in pre-menopausal women who had received ta-\nmoxifen for ＞3 months. We found ovarian cyst in 19.4% of \npre-menopausal women using tamoxifen in this study. \nChristensen et al. reported that among the overall population \nof 428 gynecologically healthy women, 29 (7%, ages 16-43) \nwere found to have ovarian cysts.\n40\n  In this study, there were significant changes of endometrial \nthickness and ovarian cyst formation in women undergoing \nadjuvant hormonal therapy after breast cancer surgery. When \ncompared with anastrozole, tamoxifen led to much thicker \nendometrium after 3 years of medication. Additionally, pre- \nmenopausal tamoxifen users had a higher proportion of ovar-\nian cyst formation than others. Therefore we conclude that all \nbreast cancer patients being treated with hormones should be \nunder close gynecological and ultrasonographic surveillance. \nGynecologists must be familiar with this side effect of hormo-\nnal therapy to avoid unnecessary invasive studies.\nREFERENCES \n1. Parkin DM, Bray F , Ferlay J, Pisani P . 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