Rapid responses are electronic comments to the editor. They enable our users
to debate issues raised in articles published on bmj.com. A rapid response
is first posted online. If you need the URL (web address) of an individual
response, simply click on the response headline and copy the URL from the
browser window. A proportion of responses will, after editing, be published
online and in the print journal as letters, which are indexed in PubMed.
Rapid responses are not indexed in PubMed and they are not journal articles.
The BMJ reserves the right to remove responses which are being
wilfully misrepresented as published articles or when it is brought to our
attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not
including references and author details. We will no longer post responses
that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
New study does not show that HRT use causes ovarian cancer:
The epidemiological study by the Collaborative Group on Epidemiological Studies of Ovarian Cancer discussed the cause-effect relationship between HRT use and ovarian cancer in their recent report1. However their reasons for suggesting a strong causal relationship are very weak. In using women recruited from prospective studies, there is a temporal relationship because HRT use preceded development of ovarian cancer, which is supportive of a causal relationship.
The study alludes to a dose-response relationship by stating that ovarian cancer risk is greatest in current users of hormone therapy, falls after use ceases and varies by tumour type as strong evidence. The dose-response relationship was assessed by duration of use and the risk after HRT was stopped. The study neither reported on the relationship of increases in dosage of the different HRT’s and risk of ovarian cancer nor did it address the risk with increasing duration of use within each dose level. At best this factor is a very weak factor for causality.
Observational epidemiological research, whether prospective or retrospective, requires other powerful factors when a cause-effect relationship is evaluated. For example, after statistical significance of an association, the strength of association between HRT use and incidence of ovarian cancer should be strong. While a 53% increase in relative risk (RR 1.53) sounds high when the incidences of ovarian cancer are compared between HRT users and never-users, this increase is very small in the context of epidemiological studies because they do not directly measure causality because of inherent weaknesses like bias and confounding. In epidemiological studies that have stood the test of time, the magnitude of increases in the relative risk is much more robust. For example, the increase in mortality from lung cancer in smokers compared to non-smokers was 810% (RR = 9.1)2 and the increase in mortality from laryngeal cancer in smokers compared to non-smokers was 1900% (RR 20)3
Moreover, in the only epidemiological study that could directly establish a cause-effect relationship, a randomized controlled trial which recruited 16608 women, there were no significant differences in the incidences of ovarian cancer between HRT users and non-users up to 5 years of use4.
Secondly an important factor that supports a cause-effect relationship is biologic credibility. Why should HRT increase the risk of ovarian cancer? Why does the contraceptive pill, with stronger similar hormones reduce the risk of ovarian cancer5? At present there is no plausible biologic hypothesis.
Thirdly, the most persuasive evidence to support a judgement of a cause-effect relationship between HRT use and ovarian cancer incidence arises when a number of studies conducted by different investigators at various times using alternative methodology in a variety of geographic or cultural settings and among different populations all show similar results. This centralised analysis was established because there was no consensus among epidemiological studies about the association of HRT use and ovarian cancer incidence. Unfortunately this study cannot be compared with these other studies as it was not primary research, but an amalgamation of previous research, for central analysis. Therefore the inconsistencies persist.
When observational studies and randomized controlled trials have different results, most experts give more weight to the results of the randomized controlled trial. This interpretation should be passed on to the wider audience, which includes women who use HRT and who are worried about compromising their future health.
When we accept the results of the only randomized study which does not show that HRT use causes ovarian cancer, and this exhaustive centralised analysis of observational data which also does not support that HRT use causes ovarian cancer, it will become easier to help women reach a decision about their health as it pertains to HRT.
There is some merit in considering that HRT might have a role in the late stages of carcinogenesis. If HRT shows the cancer earlier because of its promoting role in late carcinogenesis, then we would expect earlier diagnosis of more cancer, which can be an advantage, than later diagnosis because HRT has not been involved in late carcinogenesis.
1. Collaborative Group on Epidemiological Studies of Ovarian Cancer. Menopausal hormonal use and ovarian cancer Risk: individual participant meta-analysis of 52 epidemiological studies. Lancet Online February 13, 2015.
2. Doll R and Hill AB. A study of the aetiology of the carcinoma of the lung. Br Med J, 1952: 1271, 2.
3. U.S. D.H.H.S. The Health consequences of smoking: Cancer. A Report of the Surgeon-General. Rockville, MD: Office of Smoking and Health, 1982.
4. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288: 321–33.
5. Collaborative Group on Epidemiological Studies of Ovarian Cancer. Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls. 2008; 371: 303–314.
Re: Short term use of HRT increases risk of ovarian cancer, analysis finds
New study does not show that HRT use causes ovarian cancer:
The epidemiological study by the Collaborative Group on Epidemiological Studies of Ovarian Cancer discussed the cause-effect relationship between HRT use and ovarian cancer in their recent report1. However their reasons for suggesting a strong causal relationship are very weak. In using women recruited from prospective studies, there is a temporal relationship because HRT use preceded development of ovarian cancer, which is supportive of a causal relationship.
The study alludes to a dose-response relationship by stating that ovarian cancer risk is greatest in current users of hormone therapy, falls after use ceases and varies by tumour type as strong evidence. The dose-response relationship was assessed by duration of use and the risk after HRT was stopped. The study neither reported on the relationship of increases in dosage of the different HRT’s and risk of ovarian cancer nor did it address the risk with increasing duration of use within each dose level. At best this factor is a very weak factor for causality.
Observational epidemiological research, whether prospective or retrospective, requires other powerful factors when a cause-effect relationship is evaluated. For example, after statistical significance of an association, the strength of association between HRT use and incidence of ovarian cancer should be strong. While a 53% increase in relative risk (RR 1.53) sounds high when the incidences of ovarian cancer are compared between HRT users and never-users, this increase is very small in the context of epidemiological studies because they do not directly measure causality because of inherent weaknesses like bias and confounding. In epidemiological studies that have stood the test of time, the magnitude of increases in the relative risk is much more robust. For example, the increase in mortality from lung cancer in smokers compared to non-smokers was 810% (RR = 9.1)2 and the increase in mortality from laryngeal cancer in smokers compared to non-smokers was 1900% (RR 20)3
Moreover, in the only epidemiological study that could directly establish a cause-effect relationship, a randomized controlled trial which recruited 16608 women, there were no significant differences in the incidences of ovarian cancer between HRT users and non-users up to 5 years of use4.
Secondly an important factor that supports a cause-effect relationship is biologic credibility. Why should HRT increase the risk of ovarian cancer? Why does the contraceptive pill, with stronger similar hormones reduce the risk of ovarian cancer5? At present there is no plausible biologic hypothesis.
Thirdly, the most persuasive evidence to support a judgement of a cause-effect relationship between HRT use and ovarian cancer incidence arises when a number of studies conducted by different investigators at various times using alternative methodology in a variety of geographic or cultural settings and among different populations all show similar results. This centralised analysis was established because there was no consensus among epidemiological studies about the association of HRT use and ovarian cancer incidence. Unfortunately this study cannot be compared with these other studies as it was not primary research, but an amalgamation of previous research, for central analysis. Therefore the inconsistencies persist.
When observational studies and randomized controlled trials have different results, most experts give more weight to the results of the randomized controlled trial. This interpretation should be passed on to the wider audience, which includes women who use HRT and who are worried about compromising their future health.
When we accept the results of the only randomized study which does not show that HRT use causes ovarian cancer, and this exhaustive centralised analysis of observational data which also does not support that HRT use causes ovarian cancer, it will become easier to help women reach a decision about their health as it pertains to HRT.
There is some merit in considering that HRT might have a role in the late stages of carcinogenesis. If HRT shows the cancer earlier because of its promoting role in late carcinogenesis, then we would expect earlier diagnosis of more cancer, which can be an advantage, than later diagnosis because HRT has not been involved in late carcinogenesis.
1. Collaborative Group on Epidemiological Studies of Ovarian Cancer. Menopausal hormonal use and ovarian cancer Risk: individual participant meta-analysis of 52 epidemiological studies. Lancet Online February 13, 2015.
2. Doll R and Hill AB. A study of the aetiology of the carcinoma of the lung. Br Med J, 1952: 1271, 2.
3. U.S. D.H.H.S. The Health consequences of smoking: Cancer. A Report of the Surgeon-General. Rockville, MD: Office of Smoking and Health, 1982.
4. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288: 321–33.
5. Collaborative Group on Epidemiological Studies of Ovarian Cancer. Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls. 2008; 371: 303–314.
Competing interests: No competing interests