The effects of norethisterone on endometrial abnormalities identified by transvaginal ultrasound screening of healthy post-menopausal women on tamoxifen or placebo

Abstract

Summary Tamoxifen (tam) is used extensively for treatment of patients with breast cancer and is being evaluated for chemoprevention in healthy women. It has, however, been reported to increase the risk of endometrial cancer in post-menopausal women, probably by an oestrogenic effect on the endometrium. It also causes endometrial cysts and polyps. The aims of this study were to identify the incidence of endometrial thickening, polyps and cysts by transvaginal ultrasound (TVUS) screening of a population of post-menopausal healthy women in the Royal Marsden tamoxifen chemoprevention trial and to evaluate the possible benefit from the use of intermittent norethisterone (NE) in women with persistent changes. Since 1990, we have undertaken regular TVUS, using an endovaginal B mode probe, of the 463 postmenopausal women in the trial randomized to tam (20 mg day-') or placebo (plac), without breaking the randomization code. Endometrial thickening (ET) was defined as .8 mm at the widest point across the myometrial cavity in the longitudinal plane, including any stromal changes. Cystic changes were defined as more than one hypoechogenic area > 1 mm. Polyps were identified using saline hydrosonography. Oral NE (2.5 mg day-1) was used for 21 days out of 28 for three consecutive cycles by women with persistent endometrium . 8 mm, including cystic and polypoid changes. TVUS was repeated after the three courses to evaluate any change caused by NE and endometrial biopsies, including hysteroscopy, was performed on those women with persistent abnormalities. A persistent ET . 8 mm was identified in 56 (24%) of the 235 women on tamoxifen compared with only 5 (2%) of 228 women on placebo (P <0.0005). Stromal changes, including cysts, were detected in 36 (15%) and polyps in 26 (11%) of the women on tamoxifen compared with only two (<1%) of the women on placebo (P << 0.0005). After 3 months of cyclical norethisterone, 39 of 47 women (83%) on tamoxifen had persistent ultrasound changes. However, 45 (96%) had a progesterone withdrawal bleed. Hysteroscopy was performed in 39 women on tamoxifen (28 endometrial biopsy, 15 polypectomy), five of whom had histological evidence of a proliferative endometrium and a further three had an atypical hyperplastic endometrium (one of whom had a focus of invasive carcinoma). The cysts and polyps which were detected in women on tam could not be reversed by NE and were presumably stromal and not of malignant risk. However, 96% of the women had withdrawal NE bleeding, indicating an oestrogenically primed endometrium which could be a mechanism for an increased risk of endometrial cancer. Further studies are required to ascertain whether a progestin would protect against this risk. As in other studies, these results indicate that any increased risk of endometrial cancer caused by tamoxifen is low, and that TVUS screening is probably not justified for asymptomatic women on tamoxifen. Group, 1992). Based on these findings, it is now widely used and many millions of women have had, or are now receiving, such ...

The effects of tamoxifen on proliferation and steroid receptor expression in postmenopausal endometrium

“…Despite the upregulation of the expression of PR in tamoxifen exposed endometrium, clinical studies have not yet shown a beneficial effect of systemic progestins on the prevention of tamoxifen induced endometrial proliferation, 11 28 29 although withdrawal bleeding has been described. 29 In a recent randomised trial, a levonorgestrel releasing intrauterine device resulted in an 85% stromal decidualisation of tamoxifen primed endometrium, although endometrial ultrasonographic appearance and thickness remained unchanged and an excess of bleeding appeared in the treatment group. 30 Only data from a large prospective trial can answer the question of the efficacy of progestin treatment in the prevention of endometrial cancers and polyps in longterm tamoxifen users.…”

Postmenopausal Evaluation and Risk Reduction With Lasofoxifene (PEARL) trial

“…13,14 By contrast, increases in endometrial thickness associated with tamoxifen and estrogen use have been associated with hyperplasia. 8,15 A comprehensive assessment of endpoints associated with pelvic organ prolapse/urinary incontinence was a central component of the lasofoxifene clinical development program. Validated measures of anatomical pelvic prolapse and urinary incontinence showed no evidence of any effect of lasofoxifene on these endpoints.…”

Long-term effects of the levonorgestrel-releasing intrauterine system on serum lipids and the endometrium in breast cancer patients taking tamoxifen

“…The use of systemic progestogens does not reverse the development of these lesions and causes side-effects. In addition, the effect of systemic progestogen on the recurrence of breast cancer is not known 21,22 . In our study, we have aimed to prevent or reverse these endometrial changes by using local progestogen, which produces a much higher concentration of levonorgestrel in the uterine cavity than in the circulation, and the wanted treatment effect is essentially local and not systemic 23,24 .…”

“…These results are similar to the results of another study 11 . After insertion of the LNG-IUS, one would expect endometrial thinning, but, as local progestogen affects the stroma, this does not happen 22,23 .…”