The endometrial response to sequential and continuous combined oestrogen-progestogen replacement therapy

Objectives 1. To determine the prevalence of endometrial hyperplasia in pos tmenopausal women taking standard proprietary regimens of sequential oestro gen/progestogen; 2. to determine the effects of nine months treatment with an oral continuous combined regimen of 2 mg 17 beta -oestradiol and 1 mg no rethisterone acetate (Kliofem [Kliogest outside the UK]; Novo Nordisk, Denm ark) on endometrial histology in postmenopausal women. Design An open, prospective study in postmenopausal women. Setting Fifty-four menopause clinics in the UK. Participants 2028 postmenopausal women: 1312 (Group A) taking sequential oe strogen-progestogen hormone replacement therapy (HRT), and 716(Group B) not taking HRT, were recruited. In Group A, 388 women took preparations contai ning 10 days of progestogen, 921 had 12 days, and 3 had 13 days per cycle. Methods Endometrial aspiration biopsies were taken towards the end of a thr ee-month run-in period (Group A) or at study entry (Group B), before admini stration of the continuous combined HRT regimen. Biopsies were repeated at the end of the nine month treatment period. Main outcome measure Endometrial histology. Results Initial endometrial biopsy data were available for 1106 women in Gr oup A, who by the time of endometrial investigation had been taking HRT for a median duration of 2.56 years (5th to 95th centiles: 0.77 to 8.49 years) . Data were available for 661 untreated women, who had no bleeding and had not taken HRT within the last year (Group B). Complex hyperplasia was found in 59 women (5.3%), and atypical hyperplasia in a further eight (0.7%) in Group A. In Group B there were no cases with complex hyperplasia, but one w oman showed atypical hyperplasia (0.2%). At the end of the nine months of c ontinuous combined therapy there was no case of hyperplasia among 1196 biop sies (upper 95% confidence limit of risk 0.31%) in women completing the stu dy. Within this Group all of the women with complex hyperplasia arising dur ing previous sequential HRT and who completed the study (n = 38) reverted t o normal endometrial patterns, There was no case of endometrial carcinoma d uring the study. Conclusions Despite taking standard regimens of sequential HRT containing a t least 10 days of progestogen, there was a 5.3% prevalence of complex endo metrial hyperplasia, and a 0.7% prevalence of atypical hyperplasia. However , continuous combined HRT (Kliofem) containing daily progestogen is not ass ociated with an increased risk of hyperplasia and will convert the endometr ium to normal in those with complex hyperplasia arising during previous seq uential HRT.