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Hormone replacement therapy (HRT) increases the risk of ovarian cancer, reported eight newspapers (19 April 2007). The newspapers were generally accurate in their reports of a large, well-conducted cohort study, the findings of which are likely to be reliable. However, the numbers of deaths attributed to HRT are estimates only.

Use of hormone replacement therapy (HRT) increases the risk of ovarian cancer, reported eight newspapers (19 April 2007) (1-10). All the newspapers report that between 1991 and 2005, use of HRT has led to 1300 additional ovarian cancer cases and 1000 additional deaths in the UK.
The reports were based on a large, well-conducted cohort study of 948,576 postmenopausal women, investigating the link between HRT use and incidence of and death from ovarian cancer (11). The authors concluded that current HRT users are at increased risk of developing and dying from ovarian cancer compared with never users, although there was no increased risk for past users. They estimated that over five years HRT use resulted in one extra case of ovarian cancer in every 2500 users, and one extra death from malignancy in every 3300 users.
The newspapers were largely accurate in their reports of the study. All newspapers correctly pointed out that the increased risk of ovarian cancer is not maintained if HRT is no longer used. The authors' conclusion that women who use HRT are at increased risk of ovarian cancer is likely to be reliable; however, it should be noted that the reports of 1000 deaths after HRT treatment are based on estimates only.

Evaluation of the evidence base for the effects of HRT on ovarian cancer

Where does the evidence come from?

The research was carried out by the Million Women Study Collaborators, led by Professor Beral from the Cancer Research UK Epidemiology Unit, Oxford. Funding was provided by Cancer Research UK, the NHS Breast Screening Programme, and the Medical Research Council.

What were the authors' objectives?

To assess the effect of HRT use on women's risks of developing or dying from ovarian cancer.

What was the nature of the evidence?

This large cohort study was part of the UK Million Women Study, and involved 948,576 postmenopausal women who did not have previous cancer (other than non-melanoma skin cancer) or bilateral oophorectomy.

What were the factors of interest?

Information on HRT use and other social and demographic factors were obtained at recruitment (1996-2001) using a questionnaire. A second questionnaire was sent to participants about three years after recruitment to update information on use of HRT and other factors. The main outcomes of interest were rates of incident and fatal malignant ovarian cancer, provided by the National Health Service Central Registers. Women were followed up for an average of 5.3 years for incidence of ovarian cancer, and 6.9 years for death.

The incidence of ovarian cancer and death from ovarian cancer was compared between current, past and never users of HRT. Other variables that might affect results, such as age, hysterectomy status, area of residence, socioeconomic group, time since menopause, parity, body-mass index, alcohol consumption, and use of oral contraceptives were taken into account in the analyses. Because updated information from the second questionnaire was not available for all participants, a sensitivity analyses was carried out to assess the effects of this potentially out of date information on results.

What were the findings?

At the time of last contact, 30% of women were currently using HRT and 50% had never used it. 2273 incident ovarian cancers and 1591 deaths from malignancy were recorded during the study period. Current users of HRT were 1.2 times more likely to develop ovarian cancer and 1.23 times more likely to die from ovarian cancer than those who had never used HRT. These findings were statistically significant, and showed little variation when potentially confounding variables were taken into account or when sensitivity analyses were carried out. For current users of HRT, incidence of ovarian cancer also significantly increased with duration of use, but did not differ according to type of HRT or method of administration. Past users of HRT were not at increased risk of ovarian cancer.

Standardised incidence and mortality rates for ovarian cancer in women who had never used HRT were 2.2 and 1.3 per 1000 respectively; and in current users they were 2.6 and 1.6 per 1000. If the differences in ovarian cancer between never and current users can be attributed to HRT, these results imply that over a 5 year period, HRT use resulted in one extra case of ovarian cancer in every 2500 users of HRT, and one extra death from malignancy in every 3300 users.

What were the authors' conclusions?

Women who use HRT are at an increased risk of both developing and dying from ovarian cancer. Since 1991, use of HRT has led to 1300 additional ovarian cancers and 1000 additional deaths from malignancy in the UK.

How reliable are the conclusions?

This was a large, well-conducted cohort study. Data for HRT use relied on self-report questionnaires and in some cases may have been out of date. However, sensitivity analyses were conducted to assess the effects of any potentially out of date information on results. Information on HRT use was recorded before a diagnosis of cancer was made, and cancer data was coded before it was supplied to study investigators, which will have helped to reduce bias. Given the design of the study, only an association and not a definitive causal link between HRT and ovarian cancer risk can be demonstrated. However, groups were largely similar at baseline, and measures were taken to control for and investigate several variables that could potentially affect results. Consequently, the authors' conclusion regarding the use of HRT and increased risk of ovarian cancer is likely to be reliable; however, it should be noted that the numbers of incident and fatal ovarian cancers attributed to HRT use are estimates only.

Systematic reviews

Information staff at CRD searched for systematic reviews relevant to this topic. Systematic reviews are valuable sources of evidence as they locate, appraise and synthesize all available evidence on a particular topic.

There were no related systematic reviews identified on the Cochrane Database of Systematic Reviews (CDSR), however there was one on the Database of Abstracts of Reviews of Effects (DARE)(12).

References and resources

1. HRT is linked to more than 1,000 ovarian cancer deaths. Daily Mail, 19 April 2007, p9.

2. HRT 'raises risk of ovarian cancer'. The Daily Telegraph, 19 April 2007, p1.

3. HRT 'raises risk of ovarian cancer', claim scientists. The Daily Telegraph, 19 April 2007, p6.

4. HRT linked to 1000 deaths from cancer. The Guardian, 19 April 2007, p1-2.

5. 1000 HRT women killed by cancer: massive study claims deadly link. The Sun, 19 April 2007, p27.

6. 1000 cancer deaths may be linked to HRT. Daily Mirror, 19 April 2007, p24.

7. New cancer warning for women: shock revelation as 1,000 die after HRT treatment. Daily Express, 19 April 2007, p1,4.

8. HRT alert after more than 1000 women die. The Times, 19 April 2007, p1-2.

9. It remains the treatment of choice. The Times, 19 April 2007, p2.

10. Women undergoing HRT face increased risk of getting cancer. The Independent, 19 April 2007, p11.

11. Beral V, Million Women Study Collaborators. Ovarian cancer and hormone replacement therapy in the Million Women Study. The Lancet Early Online Publication 19 April 2007 DOI:10.1016/S0140-6736(07)60534-0.

12. Garg P P, Kerlikowske K, Subak L, Grady D. Hormone replacement therapy and the risk of epithelial ovarian carcinoma: a meta-analysis. Obstetrics and Gynecology 1998;92(3):472-479. [DARE Abstract]