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Background: Endometrial polyps are the most common endometrial pathology described in association with postmenopausal tamoxifen exposure. Up to 3% of these polyps may show malignant changes. However, to the authors' knowledge no one has described any risk factor for the development of this pathology in postmenopausal patients with breast carcinoma treated with tamoxifen. OBJECTIVE. The objective of this study was to evaluate whether risk factors can be identified for the development of endometrial polyps in postmenopausal patients with breast carcinoma treated with tamoxifen., Methods: The authors reviewed the medical records of 54 postmenopausal patients with breast carcinoma in whom endometrial polyps were resected by hysteroscopy after at least 6 months of tamoxifen treatment (Group I). Demographic characteristics, health habits, risk factors for endometrial carcinoma, and clinical factors related to the primary breast disease were examined. The results were compared with those obtained from 210 similar patients in whom hysteroscopy did not reveal any endometrial pathology (Group II)., Results: Age at menopause was significantly older, duration of breast disease was significantly longer, and body weight was significantly heavier among Group I patients compared with Group II patients (P = 0.0162, P = 0.0026, and P = 0.0364, respectively). Endometrial thickness, measured by transvaginal ultrasonography, was significantly thicker in Group I patients (16.3 +/- 7.2 mm) compared with that detected in Group II patients (11.8 +/- 6.3; P = 0.0001)., Conclusions: Various factors, such as older age at menopause, longer duration of breast disease, heavier weight, and thicker endometrium may contribute to the prediction of increased risk of development of endometrial polyps in postmenopausal patients with breast carcinoma treated with tamoxifen., (Copyright 2001 American Cancer Society.)

Clinical data indicate that tamoxifen (TAM) therapy may cause an increased risk of endometrial pathology in postmenopausal but not in premenopausal women. Molecular mechanisms of the uterotrophic activity of TAM have not been clearly established nor its relevance to apoptosis in endometrial cells. The present study was implemented to evaluate the apoptotic effect of TAM on primary endometrial cell cultures in the presence or absence of steroid hormones (SHs). A total of 14 primary endometrial cell cultures were established and maintained both with and without SHs. Cell cultures were treated for 24 h with either 20 microM TAM or 10 nM estradiol. Apoptotic cells presented in a pre-G1 peak and the expression of bcl-2 were studied using flow cytometry. All endometrial cell cultures maintained in a SH-containing environment, except one, responded to TAM by a significant increase (P = 0.03) in the pre-G1 cell fraction, indicating a proapoptotic effect. A significant (P = 0.03) reduction in the pre-G1 peak equivalent to an antiapoptotic response was observed in 6 of 13 cell cultures maintained in a SH-deficient environment. In 4 of 10 cell cultures evaluated in both media, the pre-G1 population was medium dependent. In 8 of 10 cultures evaluated for Bcl2 levels, no trend was found in either media, but a dependency on SH content was observed. Comparison between effects of TAM and estradiol demonstrated identical trends, regardless of the menstrual phase or SH content in cell environments. These results suggest that TAM acts as an estrogen agonist on endometrial tissue in both environments. We conclude that TAM modulates apoptotic pathways in primary endometrial cell cultures. The SH content in the cell environment influences the apoptotic effect of TAM and determines the propensity for a cell to undergo apoptosis or, on the contrary, to resist apoptotic death in response to TAM treatment. This is in concordance with the observed clinical risk of endometrial pathologies in postmenopausal versus premenopausal women.

Objective: To assess whether there is a decrease in endometrial thickness following discontinuation of tamoxifen treatment as measured by ultrasound., Design: Prospective study., Setting: Department of Obstetrics and Gynaecology, Sapir Medical Centre, Kfar-Saba, Israel., Population: Fifty-eight postmenopausal women with breast cancer who were treated with tamoxifen., Methods: Transvaginal ultrasonographic measurements of endometrial thickness., Main Outcome Measures: Evaluation of the changes of endometrial thickness and the frequency the endometrium reached a thickness of < or = 5 mm at different time intervals after stopping tamoxifen treatment., Results: There was a significant decrease in median thickness of the endometrium, within six months after stopping tamoxifen, from 7.75 mm measured at the last ultrasonographic study performed before tamoxifen discontinuation down to 5.2 mm (P = 0.002). There were no further reductions in endometrial thickness, and it remained constantly low in subsequent ultrasonographic studies which were performed at various times up to 30 months following the discontinuation of tamoxifen treatment. While taking tamoxifen, only 25-9% of the women had an endometrial thickness of < or = 5 mm. This proportion doubled in their first six months after stopping., Conclusions: Median thickness of endometrial thickness significantly reduced within six months following tamoxifen discontinuation, and remained constantly low thereafter. This finding may support use of ultrasonographic imaging for the measurement of tamoxifen's effect on the endometrium of postmenopausal breast cancer patients.

Purpose of Investigation: 1) To assess whether endometrial specimens obtained from removed uteri might show an increase in endometrial pathologies which had been previously diagnosed by hysteroscopy in postmenopausal breast cancer tamoxifen-treated patients. 2) To assess whether hysteroscopy is an efficient method of detecting endometrial pathologies in such patients., Methods: The findings of two consecutive pathological evaluations in 18 postmenopausal breast cancer tamoxifen-treated patients, performed 11.2+/-11.2 months apart, were compared. The first specimen was collected by hysteroscopy and the second was obtained following hysterectomy., Results: The most significant changes observed were three new cancers diagnosed at hysterectomy, one of which was poorly-differentiated. In the first (hysteroscopy) samplings, one patient had atrophic endometrium, a second patient had endometrial proliferation and a third patient had a benign endometrial polyp. Overall, 55.6% of the study patients had various endometrial pathologies in the first sampling, while 83.3% had endometrial pathologies in the second sampling. However, this difference was not statistically significant., Conclusion: 1) Endometrial histologic evaluations, performed on removed uteri 11.2+/-11.2 months following previous endometrial samplings of postmenopausal breast cancer tamoxifen-treated patients, showed a non-significant risk of developing overall endometrial pathologies. 2) Hysteroscopy may have missed some endometrial pathologies which were diagnosed later on in specimens obtained by hysterectomy.

To evaluate possible predicting factors for endometrial cancer in postmenopausal breast cancer patients with tamoxifen treatment, we compared various clinical features between 12 postmenopausal breast cancer tamoxifen-treated patients with endometrial cancer and a control group of 261 otherwise similar patients without this endometrial pathology. These comparisons were based on a long-term prospective follow-up. Several clinical factors such as longer duration of breast disease, older patient age, lower frequency of chemotherapy administration, and higher frequency of postmenopausal bleeding were found among the tamoxifen-treated patients with endometrial cancers, and were significantly different when compared to the control group. Only eight (66.7%) had postmenopausal bleeding, and a preoperative diagnosis of endometrial cancer was made in only six (50.0%). When considering postmenopausal bleeding as a marker for endometrial cancer in the study patients, sensitivity was 67% and specificity was 98%.

Background: Endometrial polyps are the most common endometrial pathology described in association with postmenopausal tamoxifen exposure. It is generally accepted that the occurrence of malignancy in endometrial polyps among healthy women is up to 0.5%. However, no one has yet described the incidence of this malignant transformation among postmenopausal breast cancer tamoxifen-treated patients. Objective. The aim of this study was to study the exact rate of malignant changes in endometrial polyps recovered from postmenopausal breast cancer tamoxifen-treated patients., Methods: We reviewed the pathological results and medical records of all postmenopausal breast cancer patients in whom endometrial polyps were recovered following at least 6 months of tamoxifen treatment in our institute. We also looked for the rate of malignant changes in polyps recovered from all healthy postmenopausal controls with endometrial polyps in our institute during the period of the study., Results: Two (3.0%) of 67 endometrial polyps recovered from postmenopausal breast cancer tamoxifen-treated patients revealed malignant features. None of the clinical variables tested, including risk factors for endometrial cancer, was significantly different between the groups. In the controls only 5 (0.48%) of 1034 polyps were malignant., Conclusion: Up to 3.0% of endometrial polyps recovered from postmenopausal breast cancer tamoxifen-treated patients may show malignant changes. This rate is higher than that found in our controls as well as that reported in the general female population., (Copyright 1999 Academic Press.)

Objective: The aim of this study was to evaluate changes in transvaginal ultrasonographic endometrial thickness with increased duration of tamoxifen treatment in postmenopausal breast cancer patients., Material and Methods: In this prospective study we evaluated the changes (mean +/- SD) of endometrial thickness measured by transvaginal ultrasonography in 181 postmenopausal breast cancer patients, according to the duration of tamoxifen treatment. According to our protocol, the ultrasonographic evaluations were performed every 6 months for the first 2 years of the follow-up and every 12 months thereafter. Two such subsequent ultrasonographic evaluations were performed in 181 patients following 35.1 +/- 41.7 months of tamoxifen treatment, three studies in 127 patients following 44.7 +/- 47.98 months of treatment, four studies in 75 following 54.2 +/- 61.7 months of treatment, five studies in 51 patients following 65.3 +/- 74.4 months of treatment, and six studies in 27 patients following 79.5 +/- 98.8 months of treatment., Results: The measured endometrial thickness detected varied from 8.84 +/- 4.66 to 10.61 +/- 12.35 mm. There were no significant changes in mean +/- SD of endometrial thickness following various durations of tamoxifen treatment., Conclusions: Extension of duration of tamoxifen treatment in postmenopausal breast cancer patients up to 79.48 +/- 98.79 consecutive months does not cause a significant increase in transvaginal ultrasonographic endometrial thickness., (Copyright 1999 Academic Press.)

The present study evaluates the potential beneficial effect of co-treatment with LHRH-agonist in resolving premenopausal tamoxifen's induced supraphysiological serum 17beta estradiol levels and persistent ovarian cysts. Ultrasonographic and serum hormonal evaluations were performed before, during, and following three consecutive injections of long acting LHRH-agonist administered to 14 premenopausal breast cancer patients treated with tamoxifen, who had supraphysiological serum 17beta estradiol levels and simultaneous persistent ovarian cysts. Within 3 weeks of the first LHRH-agonist injection, all patients had menopausal serum estradiol levels. Ovarian cysts completely disappeared within 2 months following the first injection. Following the discontinuation of LHRH-agonist co-treatment, serum estradiol levels remained in physiological levels and the ovaries remained a normal size in 64.3% of the patients for 13.3 +/- 11.5 months. 28.6% of the patients had a gradual reappearance of high serum estradiol levels and of ovarian cysts, and were, therefore, treated with a second course of LHRH-agonist. Following the second course, serum estradiol levels remained in physiological levels and the ovaries remained a normal size for 8-15 months. It is concluded that short duration of co-treatment with long acting LHRH-agonist administered to premenopausal breast cancer patients treated with tamoxifen, successfully resolved the tamoxifen-induced supraphysiological serum 17beta estradiol levels and the ovarian cysts.

Aims: To evaluate whether endometrial pathology is more likely to be diagnosed in gynaecologically symptomatic rather than in gynaecologically asymptomatic postmenopausal breast cancer patients with tamoxifen treatment; and to evaluate the possible influence of various clinical factors on the incidence of endometrial pathology., Methods: Endometrial histological findings, transvaginal ultrasonographic endometrial thickness, demographic characteristics, health habits, and risk factors for endometrial cancer were compared between 14 gynaecologically symptomatic (group I) and 224 gynaecologically asymptomatic (group II) postmenopausal breast cancer patients with tamoxifen treatment., Results: Overall, 28.6% of the study population had endometrial pathology. The incidence of overall positive endometrial histological findings was significantly higher in group I than in group II (92.9% v 24.6%, p < 0.0001). Atrophic endometrium was more common in group II than in group I (75.3% v 7.1%, p < 0.0001). Most other endometrial pathology was significantly more common in group I than in group II (endometrial hyperplasia, 35.7% v 5.6%, p < 0.0001; endometrial polyps, 35.7% v 13.4%, p < 0.0111; endometrial carcinoma, 21.5% v 0.9%, p < 0.0001). Endometrial pathology appeared considerably later in the gynaecologically asymptomatic patients than in gynaecologically symptomatic patients (p = 0.0002). Vaginal bleeding or spotting occurred exclusively in group I. The incidence of endometrial pathology in the entire study population was consistent with that reported elsewhere, and higher than that reported for healthy postmenopausal women., Conclusions: Endometrial pathology is more likely to be diagnosed in gynaecologically symptomatic postmenopausal breast cancer patients with tamoxifen treatment, and after a shorter duration of time, than in gynaecologically asymptomatic patients.

To assess whether a higher cumulative tamoxifen dose is associated with increased incidence of various types of endometrial pathologies, we compared cumulative dose of tamoxifen treatment as well as demographic characteristics, risk factors for endometrial cancer, transvaginal ultrasonographic endometrial thickness, and various treatments for the primary breast cancer between 159 postmenopausal breast cancer tamoxifen-treated patients without endometrial pathologies (group I) and 67 similar patients with endometrial pathologies (group II). A similar comparison was made between group I patients and similar patients with proliferative endometrium (group IIa), with endometrial hyperplasia (group IIb), with endometrial polyps (group IIc), and with endometrial cancer (group IId). Overall cumulative tamoxifen dose was significantly higher in group II as compared to group I (27.4+/-33.4 and 17.4+/-20.2, respectively; P<0.0252). Transvaginal ultrasonographic endometrial thickness was significantly higher in group II than in group I patients (16.3+/-11.3 mm and 12.1+/-6.3 mm, respectively; P<0.0147). The frequency of diabetes mellitus, of previous postmenopausal bleeding, and of previous exposure to hormone replacement therapy was significantly higher in group II than in group I patients (P<0.001, P<0.0001 and P<0.001, respectively). There were no significant differences in all parameters tested between group I, group IIa, group IIb, group IIc, and group IId. However, there was an obvious trend for higher cumulative tamoxifen dose in patients with benign endometrial pathologies as compared to those without endometrial pathologies or to those with endometrial cancer (Group I = 17.4+/-20.2 g, group IIa = 22.5+/-18.5 g, group IIb = 28.1+/-20.3 g, group IIc = 31.4+/-42.7 g and group IId = 10.4+/-12.6 g). Endometrial pathologies, except for endometrial cancer, are associated with a high cumulative dose of tamoxifen in postmenopausal breast cancer patients.

Aim: Tamoxifen is the antihormonal treatment of choice for premenopausal breast cancer patients with advanced breast disease. Its premenopausal administration has been shown to induce supraphysiological 17beta-estradiol serum levels and to be associated with the presence of persistent, bilateral functional ovarian cysts. However, these abnormalities have not yet been compared to controls. In this study we evaluated the possibility that the above hormonal and/or ovarian abnormalities are more frequent among premenopausal breast cancer patients treated with tamoxifen than among similar nontreated patients, and thus they may be attributed to tamoxifen effect., Methods: We evaluated serum hormone levels of 17beta-estradiol, follicular-stimulating hormone, luteinizing hormone, and progesterone, the presence of ovarian cysts, and various demographic and clinical characteristics in 20 premenopausal breast cancer patients treated with tamoxifen (study group) and compared them to those observed in 12 similar nontreated patients (control group)., Results: Ovarian cysts were found in 80% of the study patients and only in 8.3% of the control patients (P = 0.001). The incidence of oligomenorrhea was nearly significantly higher in the study than in the control group (50 and 16.7%, respectively; P = 0.0651). Various serum hormone levels tested were not found to be significantly different between the two groups, except for 17beta-estradiol serum levels as detected on days 14 and 21 of the menstrual cycle, which were significantly higher among the study than in the control patients. (Day 14 serum estradiol: 757.7 +/- 372.0 pg/mL versus 206.5 +/- 275.0 pg/mL, P = 0.0012. Day 21 serum estradiol: 300.0 +/- 134.5 pg/mL versus 96.5 +/- 71.5 pg/mL, P = 0.0008.), Conclusions: Tamoxifen treatment increases the incidence of ovarian cysts and the significantly higher 17beta-estradiol serum levels in premenopausal breast cancer patients., (Copyright 1999 Academic Press.)

Histological findings of endometrial specimens collected by hysteroscopy from 261 postmenopausal breast cancer patients with tamoxifen treatment (group I) and from endometrial specimens obtained following hysterectomy from 40 similar patients (group II) were compared. This comparison was performed in order to assess whether endometrial pathologies are more frequently diagnosed in specimens collected by hysterectomy than by those collected during hysteroscopy in such patients. Overall positive endometrial histological findings were significantly more common in group II patients than in group I patients (82.5 and 24.5%, respectively; p < 0.0001). Atrophic endometrium was significantly more common in group I patients than in group II patients (75.5 and 15.0%, respectively; p < 0.0001). All other different endometrial pathologies, except for proliferative endometrium, were significantly more common in group II patients than in group I patients (endometrial hyperplasia = 17.5 and 4.2%, respectively; p < 0.0003; endometrial polyps = 30.0 and 11. 5%, respectively; p < 0.006; endometrial polyps with hyperplasia = 17.5 and 4.2%, respectively; p < 0.0003; endometrial carcinoma = 15. 0 and 0.4%, respectively; p < 0.0001). These findings suggest that in postmenopausal breast cancer patients treated with tamoxifen, the frequency of various endometrial histological findings and of overall positive endometrial histological findings were significantly higher in specimens collected by hysterectomy than in specimens obtained by hysteroscopy.

In order to assess possible ovarian cell potential for interaction with tamoxifen, thus demonstrating possible effects of this agent on the development of ovarian pathologies through growth stimulation and cell proliferation, we measured estrogen receptors (ER) and progesterone receptors (PR) by immunohistochemical method in 16 benign ovarian tumors removed from 11 postmenopausal breast cancer patients treated with tamoxifen (study group). The results were compared with those measured in 7 similar ovarian tumors obtained from 5 similar patients without tamoxifen treatment (control group I), and in 9 similar tumors removed from 9 age-matched postmenopausal women (control group II). There were no significant differences with regard to ER or PR expression between the study group and control group I and II (ER = 18.75, 0.0 and 11%, respectively; PR = 43.75, 28.5 and 44%, respectively; p = NS). There were also no significant statistical differences between the three groups when subdividing the ovarian pathologies according to different histological types. From the results obtained in this study, it seems that tamoxifen probably does not have any direct influence on the ovaries of menopausal breast cancer patients.

Tamoxifen administration to postmenopausal women has been described as being associated with various endometrial and other gynecological pathologies. However, different coexisting gynecological pathologies in such patients have not yet been described. In the present study, we assessed the histopathological conditions diagnosed in endometrium, myometrium, and ovaries of 28 postmenopausal breast cancer patients who were treated with tamoxifen (study group) and compared the findings to those obtained from 14 similar patients without tamoxifen treatment (control group I) and from 28 age-matched healthy postmenopausal controls (control group II). All specimens were removed by total abdominal hysterectomy and bilateral salpingo-oophorectomy for various indications. The overall incidence of two or more different coexisting gynecological pathologies was significantly higher among the study group (92.9%) than in control group I or in control group II (42.9 and 50%, respectively; p = 0. 0001). There was no significant statistical difference between the control groups. Overall endometrial (and endometrial-like) origin of pathological conditions was significantly more common in the study group (92.6%) than in control group I (50%; p = 0.00072) and control group II (32.1%; p = 0.0000), while there was no significant difference between the latter two groups. These findings suggest that there might be an association between postmenopausal tamoxifen exposure and the development of such different coexisting or specific single gynecological pathologies originating from the endometrium.

Transvaginal ultrasonography is an effective diagnostic procedure, and thus, it can reasonably be used to determine which asymptomatic, postmenopausal breast cancer patient with tamoxifen treatment will require endometrial sampling. Overall, it seems that the contribution of pulsed Doppler flow in the diagnosis of endometrial pathologies in such patients is nonconclusive. It is suggested that sonohysterography is a useful diagnostic tool for the assessment of specific endometrial pathologies, especially of space-occupying lesions in the endometrial cavity, in such patients.

Adenomyosis is an ectopic endometrial tissue located in the myometrium. It has been reported to develop at a higher rate among postmenopausal breast cancer patients on tamoxifen (TAM) treatment than in untreated patients. It has also been reported to be stimulated by estrogen. Assessing receptor levels in adenomyotic tissue may indicate the adenomyotic cell's potential to interact with TAM. In the present study the estrogen receptor (ER) and progesterone receptor (PR) were analyzed by an immunohistochemical technique in adenomyotic and the corresponding endometrial tissues of 14 postmenopausal breast cancer patients treated with TAM and in 15 healthy postmenopausal patients who served as controls. All TAM-treated patients had normal postmenopausal serum estradiol levels. Overall the ER and PR contents in adenomyotic tissue (42.9 and 71.4%) and in the endometriotic tissue (64.3 and 78.6%) obtained from the study patients were similar to those obtained from the control group (adenomyosis, ER and PR = 46.7 and 86.7%; endometrium, ER and PR = 40 and 73.3%; p = NS). In the study group, the ER content was lower in the adenomyotic (42.9%) than in the endometriotic tissue (64.3%). No correlation was found between the duration of TAM therapy, the TAM dosage level or the ER or PR content in the adenomyotic or endometrial tissues. The finding of a relatively low ER content in the adenomyotic tissue than in the endometriotic tissue in postmenopausal TAM-treated patients without endogenous estrogens, similar to that observed in healthy premenopausal women, may be attributed to the estrogen-like effect of TAM.

Assessment of receptor levels in tamoxifen-exposed endometrial pathologies may indicate endometrial cells potential for interaction with tamoxifen. To assess this assumption, we analyzed estrogen receptor (ER) and progesterone receptor (PR) expression by an immunohistochemical technique in endometrial specimens with benign hyperplasia, benign polyps, and carcinoma obtained from postmenopausal breast cancer patients treated with tamoxifen (study group) and from age-matched healthy postmenopausal women treated with estrogen replacement therapy (control group I) and not treated with estrogen replacement therapy (control group II). Overall gland and stromal ER expression of benign endometrial hyperplasia and of benign endometrial polyps was significantly higher in control groups I and II than that obtained from the study group (endometrial hyperplasia: P = 0.0274 and 0.00093, respectively, and P = 0.00003 and 0.00001, respectively; benign endometrial polyps: P = 0.02889 and 0.00596, respectively; and P = 0.00228 and 0.00005, respectively), while there were no differences between the two control groups. Overall gland and stromal PR expression was nearly similar in all the three groups (P = NS). There was no correlation between the length of tamoxifen treatment and the presence of ER and PR in various endometrial pathologies in the tamoxifen-treated patients. The significantly lower ER expression in most benign endometrial pathologies obtained from postmenopausal tamoxifen treated patients may further support the weak estrogen-like effect of tamoxifen on the endometrium in the menopause.

Postmenopausal breast cancer patients who were treated with tamoxifen and progestogens showed a uniform decidual reaction of the endometrium. It is well established that progestogens antagonize the estrogen effect on the endometrium by reducing its receptors in the endometrium. To assess in vivo such a possible effect of progestogens on endometrium primarily exposed to tamoxifen, we analyzed estrogen and progesterone receptors (ER, PR) on endometrial specimens showing decidualization from nine postmenopausal breast cancer patients on tamoxifen and progestogen treatment and on endometrial polyps with areas of decidualization from two other similar patients. ER was weakly detected in the endometrial glands of four (36.4%) patients and in the endometrial stroma of one (9.1%) patient. PR was detected in the endometrial gland of only one (9.1%) patient. No PR was detected in the endometrial stroma. There was no correlation between the length of tamoxifen treatment, the tamoxifen dosage, or the length of progestogen treatment and the ER or PR content, although progestogens were administered for more than 3 consecutive months in all patients. This relatively very low ER and PR content may be attributed to the antagonistic effect of progestogens on the "priming" estrogen-like effect of tamoxifen on the endometrium.

A prospective study was performed to assess the efficacy of sonohysterography (SHG) in identifying endometrial pathologies among asymptomatic, postmenopausal breast cancer patients treated with tamoxifen. In this study the uterine cavity of 68 such patients with endometrial thickness of > or = 8 mm was prospectively evaluated by SHG. Forty-six (67.6%) patients in whom SHG did not identify any findings in the uterine cavity (negative group) were followed by diagnostic hysteroscopy. Another 22 (32.4%) who were identified by SHG to have abnormal endometrial findings, such as an echogenic or polypoid mass (positive group), were followed by operative hysteroscopy and by postoperative SHG. In the positive group the basal transvaginal sonogram revealed an endometrial echogenic mass in only 10 (45.5%). In the remaining 12 (54.5%) patients, the transvaginal sonogram identified only thick endometrium. In these latter 12 patients, histological assessment confirmed endometrial polyps in 8 (66.7%) and fibroid in 1 (8.3%). Four (18.2%) patients in the positive group had no histological endometrial pathology. Two (50%) of them had a uterine septum as diagnosed during hysteroscopy, in one (25%) operative hysteroscopy failed to resect the endometrial polyp, and in another (25%) there was a false-positive SHG diagnosis. Overall, SHG accurately diagnosed endometrial and/or other intrauterine pathology in 95.5% of these patients. In the 46 patients with "negative" basal SHG features, diagnostic hysteroscopy confirmed this diagnosis. Thus, there was no SHG false-negative diagnosis. Comparing the results of the basal SHG with those of operative hysteroscopy and/or the histopathological findings in the positive group, the sensitivity of SHG was 1.0, the specificity 0.0, positive predictive value 95.5%, and negative predictive value 0.0. It is suggested that SHG is a useful diagnostic tool for the assessment of specific endometrial pathologies in asymptomatic postmenopausal breast cancer patients treated with tamoxifen who were diagnosed by transvaginal sonography to have thick endometrium.

Background: Postmenopausal breast cancer patients treated with tamoxifen have been found to have a high incidence of ovarian tumors. Transvaginal ultrasonography is an accurate and reliable method for measuring ovarian size. The purpose of this study was to establish normal values for basal ovarian volume in postmenopausal tamoxifen-treated patients and compare them with those established for healthy, postmenopausal women in the same population with no exposure to hormone treatment., Methods: In a prospective open pilot study, the ovaries of 65 postmenopausal breast cancer patients treated for at least 6 months with tamoxifen were measured by transvaginal ultrasonography. From the same population, 311 healthy postmenopausal women with no exposure to hormone therapy were examined and served as controls. After matching for menopausal age, ovarian volume was compared between groups., Results: Mean ovarian volume of postmenopausal tamoxifen-treated patients was persistently low through the menopause, whereas the mean ovarian volume of the controls was large, gradually decreasing up to the 10th menopausal year (8.6 +/- 2.3 and 2.8 +/- 2.1 cm3, respectively). Mean ovarian volume of the tamoxifen-treated patients was significantly lower than that of the controls during the initial menopausal years., Conclusions: An ovarian volume that is considered within normal range for a specific menopausal age in a healthy postmenopausal woman is abnormal for a postmenopausal tamoxifen-treated patient.

In an attempt to assess the hypothesis that different endometrial sites may respond differently to tamoxifen exposure in postmenopausal women, hysteroscopic selected endometrial histology was investigated in 175 postmenopausal breast cancer patients who received continuous treatment with tamoxifen, and in 27 similar patients not treated with tamoxifen who served as controls. In the tamoxifen-treated patients 14 (8.0%) developed endometrial polyps. Of 14 patients, 8 (57.2%) each displayed atrophic endometrium in the same histologic specimen, 5 (35.7%) each had coexisting simple hyperplasia, and 1 (7.1%) other had complex hyperplasia. Another 21 (12.0%) developed simple or complex hyperplasia. The endometrial hyperplasia coexisted with atrophic endometrium in all these patients. All these lesions were selectively identified by hysteroscopic examination prior to the endometrial biopsy. In the control group 3 (11.0%) had simple hyperplasia and 2 (7.4%) had endometrial polyps. The above results support the hypothesis that the endometrium of postmenopausal breast cancer patients on tamoxifen treatment may possess different responses to tamoxifen exposure.

Pathologic evaluation for adenomyosis in uterine specimens as well as demographic characteristics, health habits and risk factors for endometrial cancer were compared in 28 postmenopausal breast cancer patients with tamoxifen (TAM) treatment and in 11 similar patients without TAM treatment in order to determine the association between postmenopausal TAM exposure and the frequency of adenomyosis. The same comparison was also made between TAM-treated patients with adenomyosis and TAM-treated patients without adenomyosis. Adenomyosis was histologically diagnosed in 53.6% TAM-treated patients and in 18.2% non-TAM patients. Overall, there were no significant statistical differences in all parameters tested between the 2 groups, as well as between the TAM-treated patients with adenomyosis and the TAM-treated patients without adenomyosis. It can be concluded that adenomyosis was significantly more common among postmenopausal breast cancer patients who were treated with TAM as compared to similar patients without TAM treatment (p = 0.0186). This significant high rate of adenomyosis may be attributed to the continuous and unopposed exposure to TAM. It is, however, impossible to predict which postmenopausal breast cancer patient will develop adenomyosis after treatment with TAM.

Various endometrial lesions were more frequent among asymptomatic postmenopausal breast cancer patients who were treated with tamoxifen for > 48 consecutive months (30.8%) when compared with similar patients who were treated for 6-24 months or for 25-48 months (20.8% and 12.5%, respectively). However, this difference was not statistically significant. There were also no significant differences in the frequency of the various endometrial lesions between these three groups, although endometrial polyps were more frequently found among those treated for > 48 months. Overall, 20.7% of the 164 tamoxifen-treated patients in the study had an endometrial pathology. It can be concluded that there is a slight tendency among those postmenopausal patients who have been treated for > 48 consecutive months to have a higher frequency of endometrial lesions.

From September 1, 1989, to November 30, 1994, 175 menopausal breast cancer patients treated with tamoxifen were followed at the authors' institutions. During this period. 16 (9.1%) underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy, for various indications. Of these, 10 (62.5%) had either uni- or bilateral ovarian tumors. The analysis of surgical findings showed an incidence of 5.7% (10/175) ovarian tumors among all the patients. In 2 (20%), the ovarian masses displayed enlargement over a relatively short period while on treatment. In 5 (50%) patients, the findings were bilateral. All tumors were detectable by ultrasonography, except four serous cystadenomas found in 3 women. The mean duration of tamoxifen treatment was 36.6 +/- 24.9 (range 9-86) months. The rate of 5.7% for ovarian tumors, in this selected group of patients, is four to five times higher than that reported for similar pathologic conditions detected by general screening with ultrasonographic scans among nonselected, asymptomatic, and untreated postmenopausal women. Two possibilities should be considered in the development of ovarian tumors coinciding with tamoxifen treatment; (1) women with breast malignancy are prone to develop benign or malignant ovarian tumors in relation to genetic factors, regardless of tamoxifen treatment; and (2) tamoxifen may stimulate enlargement of such tumors and may even cause them.

In order to assess endometrial reaction to the combined treatment of tamoxifen and progestogens in asymptomatic postmenopausal breast cancer patients, we evaluated all such patients by vaginal ultrasonography and by histological examination of endometrial samplings. All patients were initially treated with tamoxifen, and progestogens were then added when metastases became evident. Of 12 patients included in the study, eight (66.66%) showed evidence of strong endometrial stromal decidualization, while three (25%) had decidual reactions in endometrial polyps. Overall, 11 (91.66%) of the patients had decidual reactions, and all were treated with progestogens for > or = 3 consecutive months. One patient, treated with progestogens for 1 months, had an inactive endometrium. All but three had thickened endometria (> 10 mm) on ultrasonographic evaluation. These data show that postmenopausal breast cancer patients who received progestogens for < or = 3 months, and who concomitantly took tamoxifen, had a uniform decidual reaction in all uteri.

Between September 1, 1989 and October 31, 1994, 173 postmenopausal breast cancer women on tamoxifen treatment were followed up in the authors' institutions. During this period, 14 (8.1%) underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy for various indications. Eight (57.1%) were found to have adenomyosis, of whom one had a large fundal adenomyotic lump and the other seven patients had two to four small microscopic foci of adenomyosis. In this study, the rate of adenomyosis described among those postmenopausal breast cancer patients treated with tamoxifen is nearly three to four times higher than the rate reported in the literature for pre- and postmenopausal women. There is no previous reported increased incidence of adenomyosis in postmenopausal breast cancer patients treated with tamoxifen. Thus, it is suggested that the prolonged and unopposed estrogen-like stimulation by tamoxifen may play a causal role rather than be a casual factor in the development of this pathologic entity.

Tamoxifen is widely used as adjuvant therapy for postmenopausal breast cancer patients with positive estrogen receptors. Data on a possible association of endometrial pathologies with tamoxifen treatment have been accumulating. In this review, we examine the current literature and include our own experience with this occurrence. We recommend close supervision of these patients.

We present the first case of ovarian endometrioid carcinoma and endometriosis in a postmenopausal patient who was treated with tamoxifen for breast cancer. The association with prolonged unopposed estrogen-like stimulation with tamoxifen as a possible factor in the development of ovarian endometrioid carcinoma is discussed.

Adjuvant tamoxifen therapy for breast cancer patients has been found to be associated with various endometrial pathologic conditions, including endometrial cancer. This preliminary case control study evaluated whether prolonged and continuous exposure to tamoxifen in the menopause may aggravate existing endometrial pathologies. Two vaginal ultrasound evaluations of endometrial thickness and histologic findings of two endometrial biopsies, performed 18 months apart, were evaluated for 25 asymptomatic, postmenopausal breast cancer patients who were continuously treated with tamoxifen. In the first endometrial biopsy, 4 patients (16.0%) were found to have endometrial pathologies: 2 patients had proliferative endometrium, 1 had hyperplastic endometrium, and 1 had an endometrial polyp. In the second endometrial biopsy, none of these patients showed any endometrial pathologies. Another patient (4.0%) with no endometrial pathology in the first visit had endometrial hyperplasia in the second visit. None of the patients developed endometrial cancer, and generally there was no increase in ultrasonographically-measured endometrial widths. The results of this preliminary study may suggest that there is no increased risk of development of endometrial pathologies during an additional 18 months of continuous tamoxifen therapy nor is there aggravation of already existing endometrial pathologies.

A prospective pilot study was conducted to evaluate the usefulness of uterine artery blood flow in the detection of various pathologic endometrial conditions in 39 asymptomatic postmenopausal breast cancer patients who were treated with tamoxifen. No specific pattern was seen for the uterine artery pulsatility index values in the tamoxifen-treated patients that could be related to any specific endometrial lesions, nor were any specific changes observed in the pulsatility index value with increasing severity of the pathologic endometrial conditions. Similarly, no correlation was found between ultrasonographically measured endometrial widths and uterine artery pulsatility index values. Thus, although pulsed Doppler flow ultrasonography has been shown previously to be effective in the detection of uterine cancer in non-tamoxifen-treated post-menopausal patients, it probably does not contribute to the assessment of endometrial lesions in post-menopausal breast cancer patients treated with tamoxifen.

Pre-menopausal tamoxifen treatment causes hyperoestrogen production and ovarian cyst formation. Two pre-menopausal breast cancer patients who were treated with tamoxifen developed both permanent supraphysiological oestrogen concentration and ovarian cysts. Serum oestrogen decreased to post-menopausal concentrations and ovarian cysts completely resolved during and following simultaneous treatment with tamoxifen and gonadotrophin-releasing hormone agonist (GnRHa). In pre-menopausal breast cancer patients, GnRHa may prevent possible side-effects of tamoxifen, such as ovarian cysts and supraphysiological oestrogen production.

Endometrial thickness, as evaluated by vaginal ultrasonography, and endometrial histologic findings, as well as demographic characteristics, health habits, and risk factors for endometrial cancer, were compared between 93 asymptomatic postmenopausal breast cancer patients who had been on tamoxifen treatment and 20 patients who had not. The mean ultrasonographic endometrial thickness in the women on tamoxifen treatment was 13.1 +/- 10.4 mm, which was significantly thicker than the 4.0 +/- 3.2 mm found in the nontreated women (P = 0.001). The frequency of endometrial pathological findings was remarkably high (35.5%) among the tamoxifen-treated patients, compared with nontreated patients (20.0%), with a P value of 0.058 and an odd ratio of 4.6. Thus, it is suggested that the remarkably high prevalence of pathological endometrial changes was due to the continuous and unopposed exposure of the endometrium to tamoxifen.

To the best of our knowledge, this is the first report of in vivo endometrial estrogen and progesterone receptor induction as a result of tamoxifen exposure in a postmenopausal breast cancer patient. The following observations, that the postmenopausal endometrium is sensitive to tamoxifen, that this agent can act as an estrogen-like substance, and that it may cause proliferation of the endometrium in the absence of progestin, may explain the endometrial decidual changes described herein as a protective mechanism against possible neoplastic endometrial changes.

Objective: To evaluate whether risk factors, other than tamoxifen, can be identified for the development of endometrial pathologies in postmenopausal breast cancer patients treated with tamoxifen., Design: A cross-sectional study., Setting: Department of Obstetrics and Gynaecology and Oncology Clinic, Sapir Medical Center, Kfar Saba, Israel., Subjects: 77 asymptomatic postmenopausal women, treated with tamoxifen for breast cancer. Of these, 55 had no endometrial tissue and 22 had endometrial tissue obtained by biopsy., Main Outcome Measures: Demographic characteristics, health habits, risk factors, vaginal ultrasonographic evaluations of endometrial thickness and texture, and histologic evaluations of endometrial biopsies., Results: Overall, there was a high rate (29%) of endometrial pathological change among the 77 asymptomatic postmenopausal women. There were no significant statistical differences in the features tested between the two groups., Conclusion: It is impossible to predict which postmenopausal women will develop pathological endometrial changes after treatment with tamoxifen and thus a routine periodic endometrial sampling-follow up is suggested for all postmenopausal women being treated with this agent.

We present the first case of heterologous mixed mesodermal tumor that developed 9 years following tamoxifen therapy in a climacteric woman with no previous pelvic irradiation and was initially treated by total abdominal hysterectomy and bilateral salpingo-oophorectomy. She continued tamoxifen therapy for 2 years, following the initial treatment, until the diagnosis of a recurrent tumor by laparotomy. The patient died of the disease 5 months subsequent to the second surgery. The association of prolonged unopposed estrogenic stimulation, with tamoxifen as a possible etiologic factor in the development of endometrial sarcomas, is discussed.

Seventy-two asymptomatic, postmenopausal women treated with tamoxifen for breast cancer were studied prospectively with vaginal ultrasonography, followed by endometrial sampling. Seventy-one patients demonstrated an endometrial echo of more than 5 mm, and one displayed an endometrial echo of less than 5 mm. No patient with an endometrial echo of less than 5 mm displayed any endometrial pathology. Different endometrial pathologic conditions were found when the endometrial echo was over 5 mm. When classifying those patients whose ultrasonic endometrial widths were wider than 5 mm, on the basis of different endometrial histologic findings, no obvious correlation was found between the various pathologic endometrial findings and endometrial thickness. Thus, a "thicker" endometrial sonographic image did not necessarily correlate with pathologic endometrial findings. When ultrasonic endometrial thickness of 5 mm was considered the upper limit of normal, the sensitivity of ultrasonography in correlating to positive histologic findings was 91% and the specificity was 96%. These findings suggest that there is good correlation between endometrial width measured by ultrasonographic assessment and histologic findings.