Effect on endometrium of long term treatment with continuous combined oestrogen-progestogen replacement therapy: follow up study

Abstract

Objective To determine effects of five years of treatment with an oral continuous combined regimen of 2 mg 17 -oestradiol and 1 mg norethisterone acetate on endometrial histology in postmenopausal women. Design Follow up study in postmenopausal women. Setting 31 menopause clinics in the United Kingdom. Participants 534 postmenopausal women, all with an intact uterus, who had completed nine months of treatment with oral continuous combined 2 mg 17 -oestradiol and 1 mg norethisterone acetate agreed to take part in a long term follow up study. Women were assigned to different groups on the basis of the treatment status immediately before entering the original study: 360 women had taken sequential oestrogen-progestogen hormone replacement therapy, 164 had taken no hormone replacement therapy, and 10 had taken unopposed oestrogen therapy. Methods Endometrial aspiration specimens were taken before the women started the continuous combined regimen, after 9 and 24-36 months, and at the end of the five year treatment period or on withdrawal from the study. Main outcome measure Results of endometrial histology. Results The duration of treatment with continuous combined hormone replacement therapy was 4.4 (range 1.1-5.9) years. Data on endometrial specimens were available for 526 women after nine months of treatment, 465 women after 24-36 months of treatment, and 398 women who completed the five years treatment (345 women) or were withdrawn between the two latter visits for biopsies (53 women). No cases of endometrial hyperplasia or malignancy were detected at biopsy; 69% of women had an endometrium classified as atrophic or unassessable on completion of the study or withdrawal from it. Before the continuous combined therapy was started, complex hyperplasia was detected in 21 women who had taken sequential hormone replacement therapy before the study and in one who had taken unopposed oestrogen. All of these women had normal results on histological examination of endometrial tissue after nine months of treatment with continuous combined hormone replacement therapy, and hyperplasia did not recur after up to five years of treatment. Conclusions Long term treatment (for up to five years) with continuous combined hormone replacement therapy containing oestradiol 2 mg and norethisterone 1 mg daily was associated with neither endometrial hyperplasia nor malignancy. In women who had complex hyperplasia during previous sequential or unopposed regimens, the endometrium returned to normal during treatment with continuous combined hormone replacement therapy. These findings provide reassurance about the long term safety of this continuous combined regimen in terms of the endometrium.

Endometrial Cancer in Postmenopausal Women Using Estradiol–Progestin Therapy

“…The use of continuous combined estradiol-progestin therapy may eliminate some premalignant endometrial changes. 36 This may further be substantiated by our findings that the risk of endometrial cancer already started to reduce during the first 3 years of continuous estradiol-progestin therapy use.…”

Ultra-low-dose continuous combined estradiol and norethisterone acetate: improved bleeding profile in postmenopausal women

“…Progestins reduce the incidence of endometrial cancer in postmenopausal women using estrogen, by inhibiting the proliferation of the endometrium and maintaining a progestogenic or atrophic state 7,34,35 . Endometrial biopsies and histologic assessments were not performed routinely in this study.…”

The Rise and Fall of Menopausal Hormone Therapy

“…In another review, EPT with continuous combined or cyclic progestin used for 10 or more days per cycle carried no increased risk (7). In a more recent prospective observational study, treatment with up to 5 years of continuous combined estradiol (2 mg) plus norethisterone (1 mg) daily was not associated with endometrial hyperplasia, and preexisting hyperplasia reverted to normal in HT-treated women (98).…”