Does hormone replacement therapy (HRT) cause breast cancer? An application of causal principles to three studies.

BACKGROUND: Based principally on findings in three studies, the Collaborative Reanalysis (CR), the Women's Health Initiative (WHI), and the Million Women Study, it is claimed that hormone replacement therapy (HRT) is an established cause of breast cancer. The authors have previously reviewed those studies (Parts 1-4). The WHI findings were first published in 2002, following which the use of HRT rapidly declined. A correspondingly rapid decline in the incidence of breast cancer has been reported, and attributed to the drop in the use of HRT. The evidence, however, is conflicting. METHODS: Using generally accepted causal criteria, in this article (Part 5) the authors evaluate reported trends in the incidence of breast cancer. RESULTS: The evidence to suggest a correlated decline in the incidence of breast cancer following a decline in the use of HRT has not adequately satisfied the criteria of time order, detection bias, confounding, statistical stability and strength of association, internal consistency, and external consistency; biological plausibility is difficult to assess. CONCLUSIONS: Based on the observed trends in the incidence of breast cancer following the decline in HRT use, the ecological evidence is too limited either to support or refute the possibility that HRT causes breast cancer.

Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies. Part 4: the Million Women Study.

BACKGROUND: Based principally on findings in three studies, the collaborative reanalysis (CR), the Women's Health Initiative (WHI) and the Million Women Study (MWS), it is claimed that hormone replacement therapy (HRT) with estrogen plus progestogen (E+P) is now an established cause of breast cancer; the CR and MWS investigators claim that unopposed estrogen therapy (ET) also increases the risk, but to a lesser degree than does E+P. The authors have previously reviewed the findings in the CR and WHI (Parts 1-3). OBJECTIVE: To evaluate the evidence for causality in the MWS. METHODS: Using generally accepted causal criteria, in this article (Part 4) the authors evaluate the findings in the MWS for E+P and for ET. RESULTS: Despite the massive size of the MWS the findings for E+P and for ET did not adequately satisfy the criteria of time order, information bias, detection bias, confounding, statistical stability and strength of association, duration-response, internal consistency, external consistency or biological plausibility. Had detection bias resulted in the identification in women aged 50-55 years of 0.3 additional cases of breast cancer in ET users per 1000 per year, or 1.2 in E+P users, it would have nullified the apparent risks reported. CONCLUSION: HRT may or may not increase the risk of breast cancer, but the MWS did not establish that it does.

Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies: part 3. The Women's Health Initiative: unopposed estrogen.

BACKGROUND: Studies from the Women's Health Initiative have reported an increased risk of breast cancer in users of estrogen plus progestogen. Among users of estrogen alone an increased risk was not observed. OBJECTIVE: To evaluate the evidence for unopposed estrogen. METHODS: In a related article (Part 2) the authors apply generally accepted causal criteria to the findings for estrogen plus progestogen. Here (Part 3) the authors apply the criteria to the findings for unopposed estrogen, as reported in a clinical trial, and in combined data from the trial and an observational study. RESULTS: In the clinical trial, after 7.1 years of follow-up the relative risk (RR) of invasive breast cancer for women assigned to estrogen was 0.77 in an 'intention-to-treat' analysis (95% CI 0.59-1.01) and 0.67 (95% CI 0.47-0.97) in an 'as treated' analysis; after 10.7 years the risk reduction persisted. Time order was correctly specified; detection bias was minimal; in the 'as treated' analysis confounding was unlikely; duration-response and internal consistency could be evaluated only to a limited extent because of scanty data; the findings were discordant with increased risks observed in the Collaborative Reanalysis and the Million Women Study; biological plausibility could not be assessed. In the combined analysis, among women who had previously used estrogen soon after the menopause there was no clear evidence of either a reduction or an increase in the risk of breast cancer among women assigned to estrogen during the trial, or among women who were using estrogen in the observational study when follow-up commenced. The combined analysis did not satisfy the criteria of time order, bias, confounding, statistical stability and strength of association, duration-response, and internal consistency; biological plausibility could not be assessed. CONCLUSIONS: The evidence from the clinical trial suggests that unopposed estrogen does not increase the risk of breast cancer, and may even reduce it. The latter possibility, however, is based on statistically borderline evidence.

Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies: part 2. The Women's Health Initiative: estrogen plus progestogen.

BACKGROUND: Based principally on findings in three studies, the Collaborative Reanalysis (CR), the Women's Health Initiative (WHI), and the Million Women Study (MWS), it is claimed that combined hormone replacement therapy (HRT) with estrogen plus progestogen is now an established cause of breast cancer. For unopposed estrogen therapy the evidence in the three studies is conflicting: the CR and MWS have reported increased risks in estrogen users, while the WHI has not. The authors have previously reviewed the findings in the CR (Part 1). OBJECTIVE: To evaluate the evidence for causality in the WHI studies. METHODS: Using generally accepted causal criteria, in this paper (Part 2) the authors evaluate the findings in the WHI for estrogen plus progestogen; in a related paper (Part 3) the authors evaluate the findings for unopposed estrogen. An evaluation of the MWS (Part 4), and of trends in breast cancer incidence following publication of the WHI findings in 2002 (Part 5) will follow. RESULTS: For estrogen plus progestogen the findings did not adequately satisfy the criteria of bias, confounding, statistical stability and strength of association, duration-response, internal consistency, external consistency or biological plausibility. CONCLUSION: HRT with estrogen plus progestogen may or may not increase the risk of breast cancer, but the WHI did not establish that it does.

Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies: Part 1. The Collaborative Reanalysis.

BACKGROUND Concern that hormone replacement therapy (HRT) may cause breast cancer has existed since the time it was introduced, and based on evidence in three studies, the Collaborative Reanalysis (CR), the Women's Health Initiative (WHI) and the Million Women Study (MWS), it is claimed that causality is now established. OBJECTIVE To evaluate the evidence for causality in the three studies. Methods Using generally accepted causal criteria, in this paper the authors begin with an evaluation of the CR. Analogous evaluations of the WHI and MWS will follow. RESULTS The findings in the CR did not adequately satisfy the criteria of time order, bias, confounding, statistical stability and strength of association, dose/duration-response, internal consistency, external consistency or biological plausibility. CONCLUSION HRT may or may not increase the risk of breast cancer, but the CR did not establish that it does.

Venous thromboembolism and cyproterone acetate in men with prostate cancer: a study using the General Practice Research Database.

OBJECTIVE: To evaluate the risk of venous thromboembolism (VTE) associated with the use of cyproterone acetate (CPA) amongst men with prostate cancer. PATIENTS AND METHODS: Using data from the General Practice Research Database, cases of VTE were identified amongst men with prostate cancer. Four controls with no evidence of a VTE were selected for each case. The time from diagnosis of prostate cancer to first hormonal treatment, and from first hormonal treatment to VTE, was compared for different treatments. Adjusted risk estimates for VTE were derived from further analysis using a nested case-control study design amongst all men with advanced prostate cancer, qualified by evidence of hormonal treatment. RESULTS: The time between diagnosis and first treatment was significantly shorter for men first treated with CPA than for men first treated with a luteinizing hormone releasing hormone (LHRH) analogue (adjusted hazard ratio 1.33, 95% confidence interval, CI, 1.06-1.67). When the first treatment was CPA, the treatment-free period after diagnosis was significantly shorter for men who later had a VTE than for those who did not. The case-control study yielded an adjusted risk estimate for VTE amongst CPA users that was significantly higher than amongst men who were prescribed an LHRH analogue or who had had an orchidectomy (adjusted odds ratio 5.23, 95% CI 3.12-8.79). CONCLUSION: There was a greater risk of VTE associated with CPA, which might be due to differences in disease severity between users of different products. The clinical significance of this finding is unclear.

Incidence of clinically diagnosed systemic lupus erythematosus 1992-1998 using the UK General Practice Research Database.

PURPOSE: To determine the age- and sex-specific incidence rates of systemic lupus erythematosus (SLE) in the population of the General Practice Research Database (GPRD) between 1.1.1992 and 31.12.1998. METHODS: We searched the GPRD for incident cases of clinically diagnosed SLE with supporting evidence of diagnosis in their medical record. Cases must have had at least 3 years of data in their record prior to date of first diagnosis. We calculated the annual and age- and sex-specific incidence rates of SLE. RESULTS: We identified 390 incident cases of SLE yielding an incidence rate (IR) of 3.02/100 000/year (CI(95) 2.72, 3.32). There were 41 males (IR 0.65/100 000/year (CI(95) 0.45, 0.85)) and 349 females (IR 5.30/100 000/year (CI(95) 4.75, 5.86)). The median age at diagnosis for males and females was 54 and 46 years, respectively, and the peak incidence rates were amongst women aged 30-69 years. The incidence rate ratio for females to males was 8.15 (CI(95) 5.9, 11.6). CONCLUSIONS: This is the first UK-wide study of the incidence of SLE. The results of this study are consistent with previous smaller studies conducted in Nottingham and Birmingham. Although recording of symptoms of SLE is not complete in the GPRD, we conclude that incident cases can be successfully identified because generally there is supporting evidence of diagnosis in medical record.

Hormone replacement therapy and risk of acute myocardial infarction : a review of the literature.

Many animal studies and studies on intermediate clinical endpoints have shown hormone replacement therapy (HRT) to be associated with both favourable and unfavourable cardiovascular effects. We reviewed the literature regarding HRT and the distinct endpoint of acute myocardial infarction (AMI) in peri- and postmenopausal women. Searches of the MEDLINE and EMBASE databases were conducted. Fifty papers were identified as eligible for inclusion: eight randomised controlled trials, 18 cohort studies, 23 case-control studies and one case-control and cohort study. The single large primary prevention randomised controlled trial on HRT and the risk of AMI in generally healthy women (Women's Health Initiative trial) reported a small yet significantly increased risk of AMI in postmenopausal women receiving combined HRT. This contrasts with a large number of observational studies that suggested a protective effect, although in many of these studies the results were not statistically significant. Inconclusive evidence on the effect of duration of use does not support the notion that a possible protective association is causal. Detection bias and residual confounding are alternative explanations for the associations observed in the randomised controlled trial and observational studies. No studies on groups of women with existing cardiovascular disease or with diabetes mellitus, including the only large secondary prevention trial (Heart and Estrogen/Progestin Replacement Study), reported a significant change in AMI risk between HRT users and non-users. There is insufficient evidence to suggest that HRT is associated with a change in the risk of AMI in the majority of women. However, certain subgroups of women with specific genetic polymorphisms may be more susceptible to a change in the risk of AMI with HRT use.

Tibolone and endometrial cancer: a cohort and nested case-control study in the UK.

OBJECTIVE: Case series and spontaneous reports of endometrial cancer have raised the question as to whether the use of tibolone (introduced into the UK in 1991) is associated with an increased risk of endometrial cancer. This study set out to evaluate whether tibolone use is associated with an increased risk of endometrial cancer. METHODS: Age-adjusted incidence rate ratios (IRRs) of endometrial cancer were calculated for tibolone use compared with the use of other hormone replacement therapy (HRT). Separate sets of controls, matched for age and general practice, were compared with cases, all nested within a cohort of HRT users identified from the UK General Practice Research Database (GPRD). Conditional logistic regression analysis, adjusted for potential confounders, was used to study the association between tibolone use and the risk of endometrial cancer. RESULTS: 4995 women used tibolone as their first HRT product; 10 783 (4.3%) of the users of combined HRT had changed to tibolone at some time during the study period. Amongst women whose HRT began with tibolone, the age-adjusted IRR relative to those who started with combined sequential HRT was 1.83 (95% CI 1.19, 2.82). The nested case-control study comprised 162 cases, each matched to two sets of 972 controls. There were 43 tibolone-exposed subjects, 28 of whom had used other HRT before or after tibolone. The adjusted odds ratio of the risk of endometrial cancer in women who had ever used tibolone, compared with users of combined sequential HRT, was 1.54 (95% CI 1.03, 2.32) in the age-matched set and 1.58 (95% CI 1.01, 2.47) in the practice-matched set. Sensitivity analyses did not decrease the risk estimates found. DISCUSSION: Tibolone may be associated with an increased risk of endometrial cancer compared with conventional forms of HRT, but our data are fragile. Residual bias and uncontrolled confounding cannot be excluded, and follow-up time is insufficient to draw any firm conclusions with respect to the endometrial safety of tibolone.

Incidence, prevalence and management of lower urinary tract symptoms in men in the UK.

OBJECTIVE: To describe the incidence, prevalence and management of lower urinary tract symptoms (LUTS), suggestive of benign prostatic hyperplasia, reported in UK general practice. PATIENTS AND METHODS: All clinical information relating to LUTS and its treatment was assessed for men aged > or = 45 years and registered on the UK General Practice Research Database (GPRD) at some time between 1992 and 2001. Incidence and prevalence were derived from the GPRD population. Secular trends in the management of LUTS were examined from prescribing rates and the intervals between first symptoms, first treatment and surgery or catheterization. RESULTS: The incidence of reported LUTS showed a strong linear increase with age. The prevalence increased from 3.5% for men aged 45-49 years to > 30% for men aged > 85 years. Between 1992 and 2000 there was a five-fold increase in the proportion of time with LUTS when men were receiving medical treatment. This was accompanied by a progressive decrease in the intervals between first symptoms and first drug treatment, and a significant increase in the intervals from first symptoms or first treatment to surgery or catheterization. Treated men received surgery or catheterization significantly later than those receiving no drug treatment. CONCLUSION: There has been a significant increase in the use of medical therapy for LUTS over the last decade. The accompanying postponement of surgery/catheterization is likely to be a result, at least in part, of successful earlier medical treatment and the treatment of a greater proportion of symptomatic men.

No risk of drug-associated liver injury with alpha1-adrenoreceptor blocking agents in men with BPH: results from an observational study using the GPRD.

PURPOSE: To compare the risk of liver injury in men treated with alpha1-blockers against that in a similar non-exposed population. METHODS: Using a study population registered on the UK General Practice Research Database (GPRD) we performed (a) a retrospective cohort analysis amongst men with lower urinary tract symptoms (LUTS) indicative of benign prostatic hypertrophy (BPH) comparing the incidence of liver injury in men exposed to alpha1-blockers with the incidence in those not exposed, and (b) two nested case-control studies looking at risk factors associated with the development of liver injury compared with age- or practice-matched controls. RESULTS: Amongst 45,851 men with LUTS/BPH, 9666 were exposed to an alpha1-blocker and 154 were identified with drug-induced/idiopathic liver injury. The crude incidence of liver injury in men with LUTS/BPH exposed to an alpha1-blocker was not statistically significantly different from that in the unexposed population (13.9 vs. 11.0 cases per 10,000 exposed years: incidence rate ratio (IRR) 1.28 [95% confidence interval (CI): 0.64, 2.31]). In the case-control analyses, the adjusted odds ratio (OR) of liver injury associated with exposure to alpha1-blockers compared with no use was not statistically significant (age-matched OR 0.92 [95%CI: 0.43, 1.97]; practice-matched OR 0.98 [95%CI: 0.45, 2.16]). Our analyses confirmed an association between liver injury and alcohol consumption as well as exposure to various classes of drugs known to be potentially hepatotoxic. CONCLUSIONS: This study could not offer any evidence to support an association between exposure to alpha1-blockers and liver injury in men with LUTS/BPH.

Ischemic stroke in young women: a nested case-control study using the UK General Practice Research Database.

BACKGROUND AND PURPOSE: Estimates of the incidence of ischemic stroke in young women vary widely from 0.9 to 8.9 per 100,000 per year. This study was conducted to determine the incidence and risk factors for ischemic stroke in young women in the UK. METHODS: Women aged 15 to 49 with a first diagnosis and supporting evidence of ischemic stroke between January 1, 1992, and December 31, 1998, were identified from the UK General Practice Research Database. Age-specific incidence rates were calculated and a nested case-control study was conducted with up to 6 controls randomly selected and matched to each case by year of birth and general practice. Crude and adjusted odds ratios (ORs) were calculated using conditional logistic regression. RESULTS: The incidence of ischemic stroke was 3.56/100 000 per year. Factors associated with an increased risk were heart disease (OR, 10.5), heavy alcohol consumption (OR, 8.5), previous venous thromboembolism (OR, 6.2), treated diabetes mellitus (OR, 4.7), hypertension (OR, 4.6), migraine (OR, 2.3), and use of combined oral contraceptives (OR, 2.3). Light alcohol consumption was found to be protective (OR, 0.17). CONCLUSIONS: The crude incidence rate was lower than previously reported for the USA and Europe but higher than that reported for the UK Oxford Region. This could be because of an under-representation of mild cases or because of a true lower incidence in the UK compared with the USA and the rest of Europe. The results of the case-control study are consistent with previous studies of ischemic stroke in young women.

Drug or symptom-induced depression in men treated with alpha 1-blockers for benign prostatic hyperplasia? A nested case-control study.

PURPOSE: Regulatory authorities have raised concern that alpha 1-blockers, prescribed predominantly for benign prostatic hyperplasia (BPH), may be associated with an increased risk of depression. The aim was to assess the risk of depression with alpha 1-blockers independently of that associated with symptoms being treated and concurrent illness. METHODS: Using a study population registered on the UK General Practice Research Database, and taking a prescription for an antidepressant as a proxy for clinical depression, we performed: (a) cohort analyses comparing the incidence of depression in current users of alpha 1-blockers versus non-users, and in men with BPH versus those without. (b) A nested case-control analysis looking at the association between depression and alpha 1-blocker exposure, accounting for the presence of BPH and other illness. RESULTS: In the cohort analyses, risk of depression was significantly higher in men with BPH compared to those without (IRR 2.17, 2.12-2.22), but was not significantly different for men exposed to alpha 1-blockers versus those unexposed when adjusted for the presence of BPH. Cases of depression were more likely to have pre-existing BPH (crude OR 2.09, 2.02-2.15) than controls. After adjusting for concurrent illness (using number of GP visits as a proxy) and the presence of BPH (adjusted OR 1.38, 1.33-1.43), there was no association with depression for exposure to any alpha 1-blocker (adjusted OR 1.03, 0.90-1.18). CONCLUSIONS: This study did not suggest that the prescribing of alpha 1-blockers increases the risk of being depressed. The association highlighted by spontaneous reporting systems appears to be explained by confounding by concurrent disease.