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DGReview

No Higher Risk of Endometrial Cancer Seen With Long-Term Combined Hormone Replacement Therapy

There is no increased risk of endometrial cancer among women following long-term use of continuous combined oestrogen-progestogen hormone replacement therapy.

A five-year trial with continuous hormone replacement therapy (HRT) containing oestradiol 2 mg and norethisterone 1 mg daily, found no association with endometrial hyperplasia or malignancy.

Dr. Michael Wells and colleagues at University of Sheffield Medical School, Sheffield, and collaborating clinicians across Britain, found that among women who had complex hyperplasia during previous sequential or unopposed HRT regimens, the endometrium returned to normal during treatment with continuous combined HRT.

Continuous combined HRT use is on the rise, the clinicians note, and this regimen avoids the cyclical problems associated with sequential therapy for most women. It provides protection of the endometrium, along with amenorrhoea, and this means compliance among women is higher.

In one of the largest long-term studies of its kind, the clinicians at 31 menopause clinics enrolled 534 postmenopausal women. All of the women had an intact uterus, and 364 had taken sequential HRT, 164 had not used HRT and 10 had taken oestrogen-only HRT.

All of the women were placed on a course of continuous combined HRT for nine months, and then invited to take part in a long-term study. Endometrial aspiration biopsies were taken before the women started the continuous combined regimen, after nine, 24 and 36 months, and then at the end of five years among the 345 who remained in the study.

Dr. Wells and colleagues found no cases of endometrial hyperplasia or malignancy detected at biopsy, and 69 percent of the women had an endometrium classified as atrophic or inaccessible on completion of the study, or when they withdrew earlier.

Before the study began, complex hyperplasia was found among 21 of the women: 20 had taken sequential hormone replacement therapy before the study, and one had taken unopposed oestrogen. After nine months of continuous combined HRT, the endometrium had reverted to normal.

The findings of normal histology, together with the reversion of hyperplasia without cytological abnormality, suggest that continuous daily progestogen in such regimens provides greater protection of the endometrium. It also provides reassurance that long term treatment does not harm the endometrium.

Despite their positive findings, Dr. Wells and colleagues conclude that even longer studies are needed. "A trend towards the use of continuous combined hormone replacement therapies that include low doses of oestrogens--for example, 1 mg oestradiol or its equivalent--and different combinations of hormones means that the safety of such regimens needs to be evaluated continually."
BMJ 2002: 325:239-42.

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