Misrepresentation of the risk of ovarian cancer among women using menopausal hormones. Spurious findings in a meta-analysis.

BACKGROUND: Based on a meta-analysis of 52 studies, and principally on a meta-analysis of 17 follow-up studies, it has been claimed that current-or-recent use (last use <5 years previously) of menopausal hormones causes ovarian cancer, even if the duration of use was <5 years, and that women aged about 50 years who use hormones for >5 years have about one extra case per 1000 users, and one extra fatal case per 1700 users. OBJECTIVE: To evaluate the validity of the evidence. METHODS: Generally accepted epidemiological principles of causation were applied to the evidence. FINDINGS: The study base included hysterectomised women, an unknown proportion of whom were oophorectomised, and not at risk for ovarian cancer. The findings did not satisfy the criteria of time order, bias, confounding, strength of association, dose-response, duration-response, consistency, and biological plausibility. CONCLUSIONS: The meta-analysis did not establish that current-or-recent use of menopausal hormones causes ovarian cancer. The strong likelihood is that early symptoms of as yet undiagnosed ovarian cancer "caused" current-or-recent short-duration hormone use, not the reverse. The representation of the number of extra cases, and fatal cases, among hormone users was misleading and alarmist.

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.

Risk of venous thromboembolism among users of oral contraceptives: a review of two recently published studies.

BACKGROUND: Two recent studies, a cohort study from Denmark, and a case-control study from The Netherlands, have reported increased risks of venous thromboembolism (VTE) among users of oral contraceptives (OCs) containing desogestrel, gestodene, drospirenone and cyproterone, relative to the use of levonorgestrel. CRITIQUE: In the Danish study the comparisons were not valid. (1) VTE risk is highest soon after commencement of OC use, and duration of use was underestimated for levonorgestrel users, but not for drospirenone users; for the remaining compounds duration was only slightly underestimated. The underestimation for levonorgestrel resulted in systematic overestimation of the relative risks for the compared OCs. (2) Duration was also incorrectly estimated: only the duration of current use, not duration of all episodes of use was relevant to VTE risk. (3) Confounding was not adequately controlled. In The Netherlands study the comparisons were not valid. (1) The relative risk for drospirenone versus levonorgestrel was not statistically significant. (2) Extensive publicity had been given to the risk of VTE among users of desogestrel, gestodene, drospirenone and cyproterone: information bias and detection bias were therefore likely. (3) Inadequate allowance was made for duration of use. (4) The combination of two different control groups, both of them likely to have been biased, into a single category was not valid. CONCLUSION: The best evidence continues to suggest that the increased risk of VTE in OC users is a class effect, dependent on the estrogen dose and duration of use, and independent of the progestogen used.

Risk of breast cancer during hormone replacement therapy: mechanisms.

Regarding estrogen replacement therapy, two main mechanisms have to be considered for it to be discussed as a potential carcinogen in the breast, and also considering the World Health Organization definition of estrogens and estrogen/progestogen combinations as "carcinogenic": (i) the proliferative/apoptotic effects on already pre-existing estrogen-sensitive cancer cells and (ii) the production of possible genotoxic estrogen metabolites. By addition of the progestogen component, as is usual in non-hysterectomized women, both mechanisms can lead to an increased risk compared to estrogenonly therapy. The detailed mechanisms underlying the development of the benign breast epithelial cell into clinically relevant breast cancer cells are very complicated. Based on these mechanisms, the following simplified summary of the main steps explains that: (i) an increased risk cannot be excluded, (ii) especially when estrogens are combined with progestogens, but (iii) there are differences between the preparations used in therapy; (iv) the risk seems to be very rare, needing very special cellular and extracellular conditions, (v) and could even be decreased in special situations of estrogen therapy. It is concluded that when critically reviewed, an increased risk of breast cancer during hormone replacement therapy cannot be excluded in very rare cases. Definitive mechanistic evidence for a possible causal relationship with carcinogenesis still remains open.

Cervical human papillomavirus (HPV) infection and HPV type 16 antibodies in South African women.

There is a high incidence of cervical cancer in South African women. No large studies to assess human papillomavirus virus (HPV) infection or HPV type 16 (HPV-16) exposure have occurred in the region, a requirement for policy making with regards to HPV screening and the introduction of vaccines. Control women (n = 1,003) enrolled in a case control study of hormonal contraceptives and cervical cancer were tested for 27 cervical HPV types by reverse line blot analysis. The seroprevalence of HPV-16 immunoglobulin G (IgG) and IgA antibodies was assessed by a virus-like particle-based enzyme-linked immunoassay of 908 and 904 control women, respectively, and of 474 women with cervical cancer. The cervical HPV prevalence was 26.1%. The HPV-16 IgG seroprevalence was 44.4% and the HPV-16 IgA seroprevalence was 28.7% in control women, and these levels were significantly higher (61.8% and 52.7%, respectively) for women with cervical cancer (odds ratio [OR], 2.1 and 2.8, respectively). The cervical HPV prevalence showed an association with cervical disease, and the HPV-16 IgG prevalence decreased while the HPV-16 IgA prevalence increased with increasing age (P < 0.05). The prevalence of oncogenic HPV types (including HPV-16) decreased with age, whereas nononcogenic HPV types showed limited association with age. Multivariate analysis revealed cervical HPV infection to be associated with herpes simplex virus type 2 infection (OR, 1.7) and increasing years of education (OR, 1.9). HPV-16 IgG antibodies were inversely associated with current smoking status (OR, 0.6), and the presence of HPV-16 IgA antibodies was inversely associated with the use of alcohol (OR, 2.1) and inversely associated with the use of oral contraceptives (OR, 0.6). High levels of exposure to HPV, and particularly HPV-16, were evident in this population. The apparent increase of serum HPV-16 IgA with increasing age requires further investigation.

Cervical human papillomavirus (HPV) infection in South African women: implications for HPV screening and vaccine strategies.

The prevalence of cervical human papillomavirus (HPV) in South African women (n = 1,073) increased from 20.4% (173/848) in women with normal cytology to 41.7% (48/115) in women with atypical squamous cells of undetermined significance, 70.2% (40/57) in women with low-grade squamous intraepithelial lesions, and 83% (44/53) in women with high-grade squamous intraepithelial lesions (HSILs). HPV types 16 and 35 were the dominant types in women with HSILs but not in women in the other categories.

Papanicolaou smears induce partial immunity against sexually transmitted viral infections.

BACKGROUND: In a case-control study of hormonal contraceptives and invasive cervical cancer, an unexpected finding was a substantial decline in the prevalence of high-risk human papillomavirus (HPV) infection according to the lifetime number of Pap smears received. Here we assess the risk of 3 sexually transmitted viral infections -- herpes simplex virus 2 (HSV2), HPV, and human immunodeficiency virus (HIV) 1 and 2 -- in relation to the lifetime receipt of Pap smears. METHODS: Stored sera taken from 1540 controls were tested for HSV2 and HIV; cervical scrapings were tested for HPV. Confounder-adjusted odds ratios for the lifetime receipt of Pap smears were estimated, relative to never having had a Papanicolau test. RESULTS: For ever-receipt of a Papanicolau test, the odds ratios for HSV2 and HPV were 0.7 (95% confidence interval = 0.5-0.9) and 0.5 (0.3-0.7), respectively, and there were dose-response trends according to the lifetime number of Pap smears received (test for trend P = 0.02 and 0.04, respectively). For HSV2 the odds ratios according to last receipt declined from 0.8 for 10 or more years previously to 0.4 for <1 year previously (trend P = 0.002). For HPV the ORs were 0.4 (0.3-0.7) for last receipt 5-9 years previously and 0.5 (0.4-0.8) for less than 5 years previously; for HIV the odds ratio for last receipt less than 5 years previously was 0.4 (0.3-0.9). For HSV2 and HIV the crude odds ratio estimates were systematically lower than the adjusted estimates, and residual confounding cannot be ruled out. In particular, the true number of sexual partners may have been under-reported, and there was no information on the sexual activity of the male partners, or on other health behaviors of the women or their partners. CONCLUSION: We hypothesize that Pap smears may provoke a short-term immune response against sexually transmitted viral infections.