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

BMJ 2002; 325 doi: (Published 03 August 2002) Cite this as: BMJ 2002;325:239
  1. Michael Wells (m.wells{at}, professora,
  2. David W Sturdee, consultantb,
  3. David H Barlow, professorc,
  4. Lian G Ulrich, consultantd,
  5. Karen O'Brien, clinical research consultante,
  6. Michael J Campbell, professorf,
  7. MartinP Vessey, professorg,
  8. AnthonyJ Bragg, medical directore,
  9. for the UK Continuous Combined Hormone Replacement Therapy Study Investigators.
  1. aAcademic Unit of Pathology, Section of Oncology and Pathology, Division of Genomic Medicine, University of Sheffield Medical School, Sheffield S10 2RX
  2. bDepartment of Obstetrics and Gynaecology, Solihull Hospital, Solihull B91 2JL
  3. cUniversity of Oxford, John Radcliffe Hospital, Oxford OX3 9DU
  4. dDepartment of Obstetrics and Gynaecology, Copenhagen County Hospital Gentofte, 2900 Hellerup, Denmark
  5. eMedical Department, Novo Nordisk, Crawley RH11 9RT
  6. fSchool of Health and Related Research, Community Sciences Centre, Northern General Hospital, Sheffield S5 7AU
  7. gDepartment of Public Health, Institute of Health Sciences, Oxford OX3 7LF
  1. Correspondence to: M Wells
  • Accepted 3 December 2002


Objective: To determine effects of five years of treatment with an oral continuous combined regimen of 2 mg 17β-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 17β-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.


  • Editorialby Archer

  • Funding This study was sponsored by and carried out in collaboration with Novo Nordisk, Denmark, and Novo Nordisk, UK.

  • Competing interests MW, DWS, DHB, LGU, MJC, and MPV have been paid by Novo Nordisk as members of the Kliofem steering committee. MW held a research consultancy with Novo Nordisk with respect to hormone replacement therapy. WLGU owns shares in Novo Nordisk and other pharmaceutical companies.

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