Published: December 1999

Endometrial Cancer and Low Potency Oestrogen

Prescriber Update 19: 23-25
December 1999

Medsafe Editorial Team

A recent population-based case-control study in postmenopausal women found an increase in risk of endometrial cancer with hormone replacement therapy using oral oestriol 1-2mg daily. The relative risk increased with duration of use, by 8% per year, and rapidly declined on discontinuation. The same study found only a marginal increase in risk with vaginal oestrogens, with an annual increase in relative risk of 2% (not statistically significant).
If vaginal atrophy is the only indication for hormone replacement therapy, it is worth recommending vaginal treatment as possibly a safer alternative.

The risk of endometrial cancer is increased using oral low potency oestrogen

A recent study1 has found an increase in risk of endometrial cancer with oral low potency oestrogen (eg. Ovestin) used as hormone replacement therapy, but only a marginally significant increase in risk was noted with vaginal oestrogens. Oestriol is regarded as a low potency oestrogen and was not thought to promote endometrial proliferation.

The population-based case-control study included women aged 50-74 years who were resident in Sweden during 1994 and 1995 and had been born in that country. Cases had newly diagnosed endometrial cancers and they were identified through the cancer registry. Controls were selected randomly from the study population. For the purposes of the study, the original histological specimens were retrieved and reviewed by a single pathologist who did not know which women had used hormones. Data on usage of hormones were collected by means of a questionnaire.

The risk with vaginal oestrogens is smaller

An increase in risk of endometrial cancer and atypical hyperplasia was found with use of oral oestriol 1-2mg daily. The risks increased with duration of use so that for  5 years or more use, the relative risk of endometrial cancer was 3.0 (95% confidence interval 2.0-4.4), and for atypical hyperplasia it was 8.3 (4.0-17.4). The relative risk of endometrial cancer increased by 8% each year. The overall relative risk of endometrial cancer associated with recent use (< 1 year previously) of oral oestriol was 2.4 (1.8-3.0). Women taking oral oestriol were more likely than non-users to have low-grade well-differentiated cancers. After discontinuation the risk of endometrial cancer in past users of oestriol rapidly fell to the background level. The increase in risk with use of vaginal oestrogens was of borderline significance and the annual increase in relative risk was 2%.

This is the first adequate quantification of the risk of endometrial cancer in post-menopausal women taking low potency oestrogens. Standard potency oestrogens unopposed by progestogen have been found to be associated with a relative risk of endometrial cancer of a similar magnitude to that found with oestriol.2-4 However, because of differences in study design, diagnostic techniques and data analysis, it is not possible to obtain an indication of the difference in risk of endometrial cancer with standard and low potency oestrogens by simple comparison of relative risks between studies.

Vaginal oestrogen an alternative for urogenital symptoms of menopause

The results of this Swedish study suggest that if the reason for hormone replacement in menopause is urogenital symptoms alone, vaginal oestrogen may be a safer option than systemic therapy. Vaginal treatment is worth recommending if atrophy is the only indication. If a low potency oestrogen is taken orally, cyclic use of a progestogen should be considered.

  1. Weiderpass E, Baron JA, Adami H-O, et al. Low potency oestrogen and risk of endometrial cancer: a case-control study. Lancet 1999;353:1824-28.
  2. Beresford SAA, Weiss NS, Voigt LF, McKnight B. Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestagen therapy in postmenopausal women. Lancet 1997;349:458-61.
  3. Pike MC, Peters RK, Cozen W, et al. Estrogen-progestin replacement therapy and endometrial cancer. J Nat Can Inst 1997;89:1110-6.
  4. Hormone replacement therapy and breast cancer, endometrial cancer and venous thromboembolism. Prescriber Update No.16, Apr 1998, p.10-15.