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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. References

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 ≤ 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 ≤ 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.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. References

Transvaginal ultrasonography has been extensively used in the investigation and evaluation of endometrial thickness among postmenopausal breast cancer patients receiving tamoxifen treatment1–27. However, there is no definitive conclusion regarding the effectiveness of this diagnostic procedure.

Many studies have shown a constant trend of thickening endometrial echogenic line using transvaginal ultrasonography in women presenting with postmenopausal breast cancer treated with tamoxifen1–13,22,23,27. Other investigators have claimed that transvaginal ultrasonography is of limited value in the assessment of the endometrium of such women, because it gives a false reading of a positive finding of thick endometrium8,14–21,24–26.

If postmenopausal tamoxifen exposure does cause an increase in endometrial thickness, its discontinuation should result in a reduction in endometrial thickness, as detected by transvaginal ultrasonography. We performed a prospective study comparing endometrial thickness in postmenopausal breast cancer patients measured by transvaginal ultrasonography at various intervals after stopping tamoxifen treatment, with the last measurement taken before the discontinuation of tamoxifen.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. References

From 1 September 1989, all postmenopausal patients with breast cancer who were under medical supervision in the authors' institutions were followed in the gynaecological outpatient clinic utilising an investigative protocol. The study was fully approved by the institutional and Israeli Health Ministry Helsinki Committees. Informed consent was obtained from each patient after the nature of the study was fully explained.

Among other periodic routine examinations, the patient's evaluation included repeated endometrial assessments by transvaginal ultrasonography. These were also performed after stopping tamoxifen treatment. According to our protocol, the ultrasonographic evaluations were performed every six months for the first two years of follow up, and every 12 months thereafter. After tamoxifen treatment was discontinued, the transvaginal ultrasonography studies were performed every six months.

Initially, transvaginal ultrasound was performed using a 5.0 mHz Aloka system (Aloka, Tokyo, Japan), and for the last three years, a 128 XP10 Ultrasound system with a 5 to 7 mHz EV7 high-resolution endovaginal transducer (Accuson, Mountain-View, CA). The women were examined in the lithotomy position with an empty bladder. The women were evaluated prospectively by repeated transvaginal ultrasonography studies, which were all performed by the same investigator.

The uterus was scanned both sagittally and coronally to determine regularity of the endometrium. Anteroposterior measurements of endometrial thickness and regularity were obtained from a long axis view between the outermost edges of the line separating the hyperechogenic endometrium from the myometrium. The maximum width was recorded.

In this study we compared the median interquartile ranges of endometrial thickness, as measured by transvaginal ultrasonography, as well as the frequency of endometrial thickness of ≤ 5 mm in the last ultrasonographic study before (baseline of the study) and at various intervals following discontinuation of tamoxifen. As the women in the study had transvaginal ultrasonography evaluations at different intervals, we divided the data into five intervals of six months, for a total of 30 months following cessation of tamoxifen treatment.

Overall, 58 postmenopausal tamoxifen-treated women were prospectively followed, and all are included in the study. All women were treated with 20–30 mg tamoxifen daily (ABIC Ltd, Chemical and Pharmaceutical Industries, Netanya, Israel). Individual plots of ultrasonographic endometrial thickness against duration of time since discontinuation of tamoxifen treatment was used to correlate transvaginal ultrasonography endometrial thickness in each of the 58 women.

Statistical analysis was performed using the sign rank test, and P < 0.05 was considered statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. References

The mean (SD) age of the women at the first transvaginal ultrasonography assessment was 62.4 years (8.4). The mean (SD) age at menopause was 48.6 years (5.2) and duration of breast disease at the last transvaginal ultrasonography study before tamoxifen discontinuation was 60.6 months (39.7). Indications for tamoxifen discontinuation in the women are described in Table 1.

Table 1.  Indications for tamoxifen discontinuation in the study patients (n= 58). Values are given as n (%).
IndicationWomen affected
≤ 5 years tamoxifen treatment27 (46.6)
> 5 years tamoxifen therapy12 (20.7)
Appearance of metastases17 (29.3)
Fatty liver degeneration1 (1.7)
Visual disturbances1 (1.7)

Distribution of endometrial thickness measured by transvaginal ultrasonography and of the frequency of endometrial thickness of ≤5 mm in the 58 postmenopausal breast cancer patients in the last ultrasonographic study performed before and at different intervals following discontinuation of tamoxifen, are reported in Table 2. The average time (SD) between the last scan before stopping tamoxifen and the scan after stopping tamoxifen was 3.6 months (2.8).

Table 2.  Distribution of endometrial thickness measured by transvaginal ultrasonography and of the frequency of endometrial thickness of ≤ 5 mm in 58 postmenopausal breast cancer patients in the last ultrasonographic study before discontinuation of tamoxifen and at different intervals following its discontinuation. Values are given as n, n (%) or mean [SD]. TVS = transvaginal ultrasonography; TAM = tamoxifen treatment.
Timing of TVS study (months)No. of womenNo. of TVS studiesNo. of women with endometrialthickness ≤ 5 mmTime elapsed since discontinuation of TAM (months)Endometrial thickness (mm)
  1. *P= 0.0002.

  2. Interquartile range.

Before discontinuation of TAM585815 (25.9)7.75 [7]*
1–6444522 (50)3.8 [1.3]5.2 [4.2]*
7–12363920 (55.6)9.4 [1.6]5.0 [5.9]
13–18232414 (60.9)15.7 [1.6]4.75 [3.5]
19–2416169 (56.3)21.2 [1.3]4.8 [5.5]
25–3012127 (58.3)27.5 [1.7]5.0 [3.0]

There was a significant reduction in the median thickness of the endometrium within six months after stopping tamoxifen, from 7.75 mm in the last ultrasonographic study performed before tamoxifen discontinuation down to 5.2 mm (P= 0.0002). There were no further reductions in endometrial thickness, however, it remained constantly low in subsequent ultrasonographic studies which were performed at various times up to 30 months following cessation of tamoxifen treatment. While taking tamoxifen, only 25.9% of the women had endometrial measurements of ≤ 5 mm. This proportion doubled in the first six months after the discontinuation of tamoxifen treatment. Figure 1 shows the individual plots of endometrial thickness, as measured by transvaginal ultrasonography, against duration of time since stopping tamoxifen.

image

Figure 1. Individual plots of ultrasonographic endometrial thickness against duration of time since discontinuation of tamoxifen treatment (n= 58).

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. References

In many studies performed in women suffering from postmenopausal breast cancer and treated with tamoxifen, transvaginal ultrasonography has shown that many of these women have an ‘endometrial’ line > 5 mm1–5. Transvaginal endometrial thickness was found to be significantly greater in asymptomatic women treated with tamoxifen for breast cancer than in similar nontreated women2,3,9 or healthy postmenopausal women4,9. Most of the tamoxifen-treated women had a transvaginal ultrasonography endometrial echo of > 5 mm1–4,9.

Exacoustos et al.9 have shown the most definitive results: All women with endometrial pathologies had a transvaginal ultrasonography endometrial thickness of > 5 mm. An endometrial thickness of 10 mm was always associated with endometrial hyperplasia or endometrial polyps. Other investigators have also found transvaginal ultrasonography to be effective in detecting endometrial abnormalities in postmenopausal tamoxifen-treated women1,22,23,27.

However, other investigators have claimed that transvaginal ultrasonography is of limited value in the evaluation of the endometrium of these women8–14,15,17–20,24–26. A false positive sonographic appearance of thick endometrium and discrepancies between the sonographic and histologic findings were described in such women. This may also be attributed to stromal oedema caused by tamoxifen8,17, which appears as a thick mid-uterine structure resembling a thickened endometrium with no histological evidence of endometrial neoplasm15,18,19 or as subendometrial sonolucencies in adjacent myometrial tissue17.

In an attempt to resolve these conflicting results, and with the assumption that tamoxifen has a direct effect on the endometrium, we prospectively evaluated the measurements of endometrial thickness by transvaginal ultrasonography and compared its median value in the last ultrasonographic study performed before and at various intervals following discontinuation of tamoxifen treatment. This comparison was performed in order to evaluate whether there is a significant reduction in endometrial thickness, as measured by transvaginal ultrasonography, following discontinuation of tamoxifen treatment in postmenopausal breast cancer patients.

We have found a significant reduction in the median thickness of the endometrium within six months after stopping tamoxifen, from 7.75 mm in the last ultrasonographic study performed before tamoxifen discontinuation down to 5.2 mm (P= 0.0002). There were no further reductions in endometrial thickness, however, it remained constantly low in subsequent ultrasonographic studies which were performed at various intervals up to 30 months following tamoxifen cessation (Table 2, Fig. 1). While taking tamoxifen only 25.9% of the women had endometrial measurements of ≤ 5 mm, a proportion that doubled in the first six months after stopping treatment. The frequency of endometrial thickness of ≤ 5 mm, that was found after stopping tamoxifen, is comparable to the endometrial thickness reported in postmenopausal breast cancer patients who did not receive tamoxifen treatment2,3,9.

Our findings are extremely important when using ultrasonography to assess the endometrium in postmenopausal breast cancer patients following discontinuation of tamoxifen treatment. Detecting a transvaginal ultrasonography endometrial echo thicker than that recorded before discontinuation of tamoxifen, or detecting a rise in endometrial thickness following tamoxifen discontinuation, should alert the clinician to the possible existence of endometrial pathology. We believe that the significant decrease of endometrial thickness observed by transvaginal ultrasonography following discontinuation of tamoxifen treatment in postmenopausal breast cancer patients supports the assumption that the endometrial changes observed in these women may be attributable to tamoxifen. However, it is not possible to conclude whether these changes represent changes in the endometrium itself, or in subendometrial tissue or in both.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. References
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