Elsevier

The Lancet

Volume 353, Issue 9167, 29 May 1999, Pages 1824-1828
The Lancet

Articles
Low-potency oestrogen and risk of endometrial cancer: a case-control study

https://doi.org/10.1016/S0140-6736(98)10233-7Get rights and content

Summary

Background

Urogenital symptoms are common among postmenopausal women. Such symptoms may be alleviated by low-potency oestrogen formulations administered orally or vaginally. Although low-potency oestrogen formulations are assumed to have few, if any, adverse effects on the endometrium, risk of endometrial neoplasia has not been quantified.

Methods

In a nationwide population-based case-control study in Sweden of endometrial cancer among postmenopausal women, we obtained detailed information on hormone replacement from 789 cases of endometrial cancer and 3368 population controls. In a histopathological review, 80 cases were reclassified as having endometrial atypical hyperplasia. Odds ratios and 95% CI were calculated with unconditional logistic regression.

Findings

After multivariate adjustment, oral use of oestriol 1–2 mg daily increased the relative risk of endometrial cancer and endometrial atypical hyperplasia: the odds ratios for at least 5 years of use compared with never use were 3·0 (95% CI 2·0–4·4) and 8·3 (4·0–17·4), respectively. The association was stronger for well-differentiated cancers and those with limited invasion. The excess relative risk was lost rapidly after cessation of treatment. Only weak associations were observed between vaginal application of low-potency oestrogen formulations and relative risk of endometrial neoplasia.

Interpretation

Oral, but not vaginal, treatment with lowpotency oestrogen formulations increases the relative risk of endometrial neoplasia. Thus close surveillance of patients is needed, and addition of a progestagen should be considered.

Introduction

Early symptoms of oestrogen deficiency after the menopause are mainly systemic, dominated by vasomotor instability (eg, hot flushes and night sweats).1 Among older postmenopausal women, local symptoms due to atrophy of the vaginal and urethral epithelium may predominate.2 Although medium-potency oestrogens, mainly oestradiol and conjugated oestrogen, clearly alleviate these symptoms,1, 2 benefits may be achieved by the use of low-potency oestrogen formulations administered orally (oestriol) or intravaginal (oestriol, dienoestrol, or oestradiol in very low doses).3, 4, 5, 6 Therefore, prescription of such formulations is common in several countries, particularly in Europe.

Is treatment with low-potency oestrogen formulations based on good scientific evidence? An excess risk of endometrial cancer after use of the more potent oestrogens is well established, although this increase in risk may be reduced or prevented by addition of progestagens.7 By contrast, the risk of endometrial cancer among users of low-potency oestrogen formulations has never been adequately quantified in epidemiological studies. If, as is generally assumed,4, 6, 8, 9, 10, 11 such compounds provide symptomatic relief without adverse endometrial effects, more widespread use might be justified. We addressed these issues because low-potency oestrogen formulations have been used estensively in Sweden and we had access to detailed information on hormone replacement within a large nationwide epidemiological study on endometrial cancer.

Section snippets

Participants

This population-based case-control study was carried out among women aged 50–74 years, born in Sweden and resident there between Jan 1, 1994, and Dec 31, 1995. We restricted our study to postmenopausal women who had not undergone hysterectomy or had a previous diagnosis of endometrial or breast cancer. Women eligible as cases had newly diagnosed and histopathologically confirmed endometrial cancer during the study period. They were identified through the six regional cancer registries covering

Results

The characteristics of the study participants are summarised in table 1. The differences between endometrial cancer cases and controls in age at menopause, parity, age at last birth, body-mass index, use of oral contraceptives, and smoking reflected established epidemiological associations. Among the 648 cases of adenocarcinoma, 241 (37%) were classified as well differentiated, 286 (44%) as moderately differentiated, and 121 (19%) as poorly differentiated; no or little endometrial invasion was

Discussion

We found evidence of an increased relative risk of endometrial cancer in postmenopausal women who had used oral oestriol. The relative risk increased with duration of use and was highest for well-differentiated and least invasive tumours. An even greater excess increase in relative risk was noted for endometrial atypical hyperplasia, a premalignant or early malignant lesion that may be difficult to distinguish unambiguously from invasive cancer, as shown by the histopathology review in this and

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