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Cancer risk and oral contraception use
- Ana M. Ocana (13 September 2007)
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Validity of findings and interpretation of core results of the Royal College of General Practitioners` oral contraception study are questionable
- Martina Dören, Sabine Schwarz, Henry Völzke. (14 September 2007)
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Flawed RCGP Pill study underestimates cancer risks from use of progestogens and oestrogens.
- Ellen C Grant (16 September 2007)
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General Practitioner’s oral contraceptive study reveals greater; not lesser cancer risks
- Joel Brind (14 December 2007)
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Author's reponse
- Philip C Hannaford, Sivasusbramaniam Selvaraj, Alsion M Elliott, Valerie Angus, Lisa Iversen, Amanda J Lee (21 December 2007)
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Re: Flawed RCGP Pill study underestimates cancer risks from use of progestogens and oestrogens.
- Ellen C Grant (22 January 2008)
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Re: Re: Flawed RCGP Pill study underestimates cancer risks from use of progestogens and oestrogens.
- suzanne l adams (6 March 2008)
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Ana M. Ocana, physician Universidad Nacional Autonoma de Mexico
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This is one of the most relevant studies related to cancer risk and oral contraception use. But in this research is missing the type of progestin used. Maybe this could be another extension to look for. Some progestins have more androgenic, antiandrogenic or progestagenic effects and could act in differently way over susceptible tissues. Competing interests: None declared |
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Martina Dören, Professor of Women´s Health Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, D-12200 Berlin, Germany, Sabine Schwarz, Henry Völzke.
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We feel that the effects of long term use of oral contraceptives (OC) as defined (>8 years) are not adequately discussed in the Royal College of General Practitioners` oral contraception study.1 Public health is at stake if there is an increased risk of any cancer (adjusted relative risk 1.22, 95% confidence interval 1.07 to 1.39), as the authors report for this subgroup which amounts to less than a quarter of the total of users. Long term use of OC is common in many industrialized countries, including the UK and even more so Germany, the latter possibly with both one of the highest prevalences reported for OC use2,3 and, unfortunately, a lack of data about the effects of OC on cancer risks. Health effects due to exposure to OC and later menopausal hormone therapy (MHT) are of increasing public health relevance, given substantial proportions of women using OC since the 60ies, many of whom administer MHT later4. Available epidemiologic evidence suggests at least uncertain5-13, possibly a negative effect due to cumulative exposure to both types of sex steroid therapy14 regarding increased breast cancer risk. Thus, careful assessment of effects of life time exposure to exogenous hormones in countries with long standing availability of both types of hormone therapy, a suggestion brought forward many years ago15, appears ever more necessary to delineate the burden of cancers in women across the life span attributable to these types of exogenous hormones. In general, observational studies are of limited value to assess the risk of pharmaceutical and other treatment strategies. Higher outcome risks in treated than non-treated subjects might not necessarily be causally related with the treatment. Rather, it might be related to patient characteristics that have promoted the decision for a specific treatment. For example, sexual dysfunction commonly observed in men treated with beta-blockers is most probably due to cardiovascular disease that has indicated the drug therapy16. In the study of Hannaford et al. e.g. differences in life style factors may also explain divergent outcomes in women with and without oral contraceptives. In the absence of proper randomisation, the application of propensity scores and instrumental variables (for review see e.g.17) might be powerful tools to distinguish between drug effects and outcomes related to therapy inducing variables. Martina Dören, Professor of Women´s Health and Sabine Schwarz,
Research Fellow
Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin
Hindenburgdamm 30
D-12200 Berlin, Germany
Henry Völzke, Senior Researcher Institute for Community Medicine, SHIP/ Clinical-Epidemiological Research Walther Rathenau Str 48 D-17487 Greifswald, Germany Competing interests: none. References 1. Hannaford PC, Selvaraj S, Elliott AM, Angus V, Iversen L, Lee AJ. Cancer risk among users of oral contraceptives: cohort data from the Royal College of General Practitioner`s oral contraception study. BMJ, doi:10.1136/bmj.39289.649410.55, (published 12 September 2007) 2. Lundberg V, Tolonen H, Stegmayr B, Kuulasmaa K, Asplund K, WHO MONICA Project. Use of oral contraceptives and hormones replacement therapy in the WHO MONICA project. Maturitas 2004;48: 39-49. 3. Schwarz S, Völzke H, Alte D, Hoffmann W, John U, Dören M. Gynaecological health care utilization and use of sex hormones - the Study of Health in Pomerania (SHIP). Hum Reprod 2005;20: 2916-2922. 4. Cogliano V, Grosse Y, Baan R, Straif K, Secreta B, El Ghissassi F. Carcinogenicity of combined oestrogen-progestagen contraceptives and menopausal treatment. Lancet Oncol 2056:552-553. 5. Mills PK, Beeson WL, Phillips RL, Fraser G. Prospective study of exogenous hormones use and breast cancer in Seventh-day Adventists. Cancer 1989;64: 591-597. 6. Stanford JL,. Brinton LA, Hoover RN. Oral contraceptives and breast cancer: results from n expanded case-control study. Br J Cancer 1989;60: 375-381. 7. Schuurman AG, van den Brandt P, Goldbohm RA. Exogenous hormones use and the risk of postmenopausal cancer: results from the Netherlands Cohort Study. Cancer Causes Control 1995;6: 416-424. 8. Stanford JL, Weiss NS, Voigt LF, Daling JR, Habel LA, Rossing MA. Combined estrogen and progestin hormone replacement therapy in relation to risk of breast cancer in middle-aged women. JAMA 1995;274: 137-142. 9. Brinton LA, Brogan DR, Coatzes R, Swanson C, Potischman N, Stanford JL. Breast cancer risk among women under 55 years of age by joint effects of usage of oral contraceptives and hormone replacement therapy. Menopause 1998;5: 145-151. 10. Ursin G, Tsen C-C, Paganini-Hill A, Enger S, Wan PC, Formenti S, et al. Does menopausal hormone replacement therapy interact with known factors to increase risk of breast cancer. J Clin Oncol 2002;20: 699-706. 11. Norman SA, Berlin JA, Weber AL, Strom BL, Daling JR, Weiss LK, et al. Combined effect of oral contraceptive use and hormone replacement therapy on breast cancer risk in postmenopausal women. Cancer Causes Control 2003;14: 933-943. 12. Dumeaux V, Fournier A, Lund E, Clavel-Chapelon F. Previous oral contraceptive use and breast cancer risk according to hormone replacement therapy use among postmenopausal women. Cancer Causes Control 2005;16: 537 -544. 13. Shantakumar S, Terry MB, Paykin A, Teitelbaum SL, Britton JA, Moorman PG, et al. Age and menopausal effects of hormonal birth control and hormone replacement therapy in relation to breast cancer risk. Am J Epidemiol 2007;165:1187-1198. 14. Lund E, Bakken K, Dumeaux V, Andersen V, Kumle M. Hormone replacement therapy and breast cancer in former users of oral contraceptives – The Norwegian Women and Cancer study. Int J Cancer 2007;121:645-648. 15. Committee on the Relationship between Oral Contraceptives and Breast Cancer. Oral Contraceptives and Breast Cancer. Washington, D.C.: National Academy Press, 1991. 16. Böhm M, Baumhäkel M, Probstfield JL, Schmieder R, Yusuf S, Zhao F, et al. Sexual function, satisfaction, and association of erectile dysfunction with cardiovascular disease and risk factors in cardiovascular high-risk patients: substudy of the ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNT Study in ACE-INtolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND). Am Heart J 2007; 154: 94-101. 17. Wunsch H, Linde-Zwirble WT, Angus DC. Methods to adjust for bias and confounding in critical care health services research involving observational data. J Crit Care 2006;21: 1-7. Competing interests: None declared |
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Ellen C Grant, physician and medical gynaecologist Kingston-upon-Thames, KT2 7JU
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Professor Hannaford and colleagues report cancer risks from the Royal College of General Practitioners’ oral contraception study from 1968 to 2004.1 No overall increased risk of cancer was demonstrated but statistically significant trends of increasing risk for cervical cancers and central nervous system and pituitary cancers were found. Previous reports from the RCGP OC study have listed significant increases in breast and cervical cancers and in deaths from breast, cervical, lung and liver cancer in various sub-groups such as longer users. The data now presented seemed to show that pill progestogens and oestrogens decreased the risk of some cancers, especially of the ovaries and uterine body. These cancers are known to be increased when progestogens and/or oestrogens are given as HRT.2-4 Has confusing the effects of the pill and HRT caused important mistakes? The authors acknowledge that misclassification of never users (their control, reference group) would underestimate pill related cancer risks. They assumed never users older than 38 years leaving the study would not subsequently start oral contraception. They seemed to forget that a majority of menopausal women might start HRT. 92% of cancers listed in this study are in women older than 39. Unfortunately, the authors have kept no records of HRT use since 1996 when only 10% of never users and 12% of pill users in the GP study base had used HRT. Over the next 8 years most women originally enrolled in 1968-9 would have reached the menopause and many would have restarted taking progestogens and oestrogens as HRT. 45% of postmenopausal women in the UK recruited into the Million Women Study (MWS) in 1996-2001 had used HRT.2 It is therefore a serious mistake to calculate risks by including any women taking HRT as never users. This type of misclassification must be a main reason for the study’s latest failure even to find an increased risk of breast cancer. The increased risk of endometrial cancer with oestrogen HRT resulted in a switch to progestogen dominant HRT since the 1970s.2 More recently use of combined progestogen/oestrogen HRT has been confirmed to increase the risk of ovarian cancer.3,4 Therefore increasing current HRT use among never users of the pill would contribute to an apparently decreasing risk of ovarian and uterine body cancers in past pill users. Misclassification of never users may also apply to the smaller numbers of younger women with cancer. So-called never users of oral contraceptives may have taken fertility drugs or hormones for reasons other than contraception. This study was partly funded by the Imperial Cancer Research Fund, British Heart Foundation, and by contraceptive pill and HRT manufacturers. The wide-spread publicity given to this flawed report is particularly unfortunate at a time when breast cancer deaths are falling rapidly. This is because large numbers of women have stopped taking HRT since 2004 to avoid the proven increases in breast cancer, strokes, thromboses and heart attacks.5 1 Hannaford P C, Selvaraj S, Elliott AM, Angus V, Iversen L, Lee AJ. Cancer risk among users of oral contraceptives: cohort data from the Royal College of General Practitioner's oral contraception study. BMJ 2007; 0: bmj.39289.649410.55v1 2 Beral V, Bull D, Reeves G: Million Women Study Collaborators. Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet 2005;365:1543-51. 3 Beral V: Million Women Study Collaborators, Bull D, Green J, Reeves G. Ovarian cancer and hormone replacement therapy in the Million Women Study .Lancet. 2007; 369:1703-10. 4 Greiser CM, Greiser EM, Doeren M. Menopausal hormone therapy and risk of ovarian cancer: systematic review and meta-analysis. Human Reproduction Update, pp. 1–11, 2007 5 Colditz G A. Decline in breast cancer incidence due to removal of promoter: combination estrogen plus progestin. Breast Cancer Research 2007, 9:108 doi:10.1186/bcr1736 Competing interests: None declared |
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Joel Brind, Professor Baruch College, City University of New York, New York, NY 10010 USA
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In their recent report of the Royal College of General Practitioner’s oral contraception (OC) study, Hannaford et al.1 conclude that “oral contraception was not associated with an overall increased risk of cancer; indeed it may even produce a net public health gain.” The specific finding underlying this conclusion was “a statistically significant 12% reduction in the risk of any cancer (adjusted relative risk 0.88, 95% confidence interval 0.83-0.94)”. Such a significant protective effect was widely reported in the popular media as reassuring evidence of the safety of OC. However, the report itself provides the evidence to dismiss this significant protective effect as an artifact resulting from the authors’ asymmetrical exclusion criteria. Since some of the women in the study were lost to follow-up for various reasons during the years between 1969 and 1996, it was indeed prudent to exclude participants under age 38 at time of loss to follow-up, since their use of (OC) after that time would be unknown. But inappropriately, the authors chose to exclude only those who were non-users at the time of loss to follow-up, rather than all women in the under 38 age group. They justified this differential exclusion on the basis of the fact that “ever users” would of course remain classifiable as “ever users” regardless of future use, whereas the classification of “never users” under age 38 could never be certain once they were lost to follow-up. Astonishingly, Hannaford et al., in their discussion, reported that they did indeed perform an analysis of the data with both the ever users and never users under 38 at time of loss to follow-up excluded, in order to determine if their differential exclusion of younger never users affected their results. The result of this analysis was: “The adjusted relative risk for any cancer was 0.95 (95% confidence interval 0.88 to 1.02).” Although this result was presented without comment, it clearly demonstrated that their selective exclusion criterion did indeed bias their findings; in fact generating an artifactual significant decrease in the risk of any cancer for ever users v. never users. This author has never seen such a display before, in which the authors of a study prove the distorting effect of their own flawed methodology, yet proceed to use it anyway! Moreover, the demonstration that the biased methodology produced an underestimation in the overall relative risk for cancer implies that all the relative risks presented are therefore underestimated. Even so, certain of the findings are ominous. For example, whereas others have found that the increased risk of breast cancer among current and recent users declines after cessation of OC use and disappears within 10 years2, Hannaford et al. report a significant increase in risk (relative risk 1.27) only beginning 10 years after cessation of use, and rising to a relative risk of 2.45 between 15 and 20 years after cessation of use, and finally declining only after 20 years. Moreover, the significant elevation of risk (relative risk 1.22) for any cancer among those who used OC’s for more than 8 years was matched by the relative risk (1.22) for breast cancer among such users. While the authors note that “less than a quarter of users” in their study had used OC for that long, it is troubling that current patterns of OC use are different; usually for much longer periods. In addition, it is odd that in such a detailed paper, Hannaford et al. failed to present any data on differential risk between women who began OC use before v. after their first full-term pregnancy (FFTP). Such data had apparently been collected in their study, and previous studies have suggested a three-fold greater risk increase among women starting OC use before, rather than after FFTP3. Presumably, most of the women in the Hannaford study began using OC only after FFTP, since the average age at recruitment was 29, and since the study commenced in 1968, only a few years after OC became widely available for use. This provides yet another reason to suspect that the Hannaford results provide substantial underestimates of real risk increases for a large proportion of current users, who often start OC use in their teens and use them for 10 years or more before FFTP. A further finding of an ominous nature in the Hannaford study is the strong association found for “central nervous system or pituitary” cancers. The relative risk for these cancers was found to be 3.23 for ever users v. never users, and it also showed a significant trend of increasing risk, rising from 1.70 for users of under 4 years’ duration, to 5.51 for users of over 8 years’ duration. It is indeed deeply troubling that, despite their demonstrated methodological impropriety, Hannaford et al. still found even greater cancer risks than previously suspected. Hence, their conclusion that “at least in this relatively healthy UK cohort, the cancer benefits associated with oral contraception outweigh the risks.” is nothing short of irresponsible. Respectfully submitted, Joel Brind, Ph.D. Department of Natural Sciences, Baruch College, City University of New York, New York, NY 10010 USA, and Breast Cancer Prevention Institute Poughkeepsie, NY 12601 USA email: joelbrind@yahoo.com References: 1. Hannaford PC, Selvaraj S, Elliott AM, Angus V, Iversen L, Lee AJ. Cancer risk among users of oral contraceptives; cohort data from the Royal College of General Practitioner’s oral contraception study. BMJ ONLINE FIRST 11 Sep 2007; doi:10.1136/bmj.39289.649410.55 2. Collaborative group on hormonal factors in breast cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies. Lancet 1996;347:1713-27. 3. Kahlenborn C, Modugno F, Potter DM, Severs WB. Oral contraceptive use as a risk factor for premenopausal breast cancer: a meta-analysis. Mayo Clin Proc 2006;81:1290-1302. Competing interests: None declared |
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Philip C Hannaford, NHS Grampian Professor of Primary Care University of Aberdeen, AB25 2AY, Sivasusbramaniam Selvaraj, Alsion M Elliott, Valerie Angus, Lisa Iversen, Amanda J Lee
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We thank the various correspondents for their thoughts on our paper. The progestogens in the 61 oral contraceptive brands used by women in our study included norethisterone, ethynodiol, lynestrenol, levonorgestrel, megestrel, norethynodrel and chlormadinone. Most women used more than one product and so it is impossible, even within a dataset as large as ours, to disentangle the specific effects of different progestogens or brands of oral contraceptives on cancer risk. We agree with Professor Doren and colleagues of the importance of studying the long term cancer effects of different periods of use of oral contraceptives and hormone replacement therapy, especially among women who have used both forms of exogenous hormones during their lifetime. That is why we will continue to follow up the RCGP Oral Contraception Study. We also agree that in principle randomised trials provide best evidence of causal relationships in epidemiology, and that this is why randomised trials are the greatly preferred options for studying the efficacy or effectiveness of medications. This methodology, however, has important limitations when trying to study adverse events resulting from drugs. One major limitation is the size of study needed to investigate rare outcomes. For example it has been estimated that a trial to study whether different brands of oral contraceptives vary in their risk of deep vein thrombosis, 300,000 women would need to be recruited into each arm of a trial to detect a doubling of risk between prepartions1. For events that take many years to occur, such as cancer, the methodological challenges become even greater, even if a trial which randomised women to different methods of contraception were deemed acceptable to an ethics committee. For the foreseeable future, we believe we will have to rely on observational studies to inform us about the long-term risks associated with different medications, with, of course, appropriate consideration of the limitations that this approach introduces. It is not clear how propensity scores or instrumental variables might be used to study the relationship between oral contraception and cancer. Dr Grant is concerned that we did not allow for hormone replacement therapy use in the main dataset analysis of our paper. We agree that ideally we should have been able to adjust for this variable (or even better, examine the effect of this exposure after never or ever use of oral contraception). As we explained in our paper, however, we do not have this information for all the women and so could not adjust for it. It is worth noting, however, that, like others2, we have found that ever users of oral contraceptives are more likely to use hormone replacement therapy than never users. As a consequence, any hormone replacement therapy-related effects would tend to be stronger in the ever user group, not the never user group. Professor Brind asks why we did not adjust for age at first full-term pregnancy. We could not do so because our study has never collected this information. When we wrote our paper, we were conscious that no-one knows the absolute truth in science. With this in mind, we were careful to explore our data for important biases which might lead us to reach erroneous conclusions about ‘the truth’. We also chose to present all the relevant results so that the reader could decide for her/himself whether their interpretation of the evidence fits with ours. Professor Brind feels that the results relating to the analysis in which both ever and never users lost to follow before the age of 38 years were excluded (adjusted relative risk 0.95, 95% confidence interval 0.88 to 1.02) demonstrates serious bias and invalidates the main dataset results in which only never users younger than 38 years were excluded (adjusted relative risk 0.88, 95% confidence interval 0.83 to 0.94). We would remind Professor Brind that since the total populations in these two analyses are different, the standardised results from the two analyses should not be compared directly (in the same way that the standardised results from the main and the general practitioner observation dataset should not be compared directly, as indicated in the footnote to table 2). Furthermore, since the standard populations are different there will inevitably be some variation in the point estimates from each analysis. We do not believe that the point estimate of 0.95 from the ‘fully excluded analysis’ is materially different to that of 0.88 from the ‘partially excluded dataset’, although the latter risk estimate is based on more data. Furthermore, the upper 95% confidence interval of the ‘fully excluded’ point estimate was just above unity, at 1.02, suggesting no increased risk of overall cancer risk. We remain happy with our interpretation of the evidence presented in our paper that ‘oral contraception was not associated with an overall increased risk of cancer, indeed it may even produce a net public health gain’. 1. Lewis MA, Spitzer WD, MacRae KD. Authors reply. British Medical Journal 1996, 312, 577-578. 2. Million Women Study Collaborators. Patterns of use of hormone replacement therapy in one million women in Britain, 1996-2000. British Journal of Obstetrics and Gynaecology 2002, 109, 1319-1330. Competing interests: PCH's academic department has recently received payment from Wyeth Pharmaceuticals for a lecture on the role of HRT in clinical practice, Wyeth also manufactures oral contraceptives |
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Ellen C Grant, physician and medical gynaecologist Kingston-upon-Thames, Surrey, KT2 7JU
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Professor Hannaford and colleagues seem unwilling to accept the implications for Pill follow-up studies which choose to include older women, 50% of whom start HRT in their 40s or 50s, as never users of hormones.1,2 In the latest report from the RCGP OC Study up to half of the 715 cancers recorded in never takers might qualify to be added to the 936 cancers recorded in OC takers because of later hormone use. This could increase the risk estimates for all cancers. Breast cancer increase due to any hormone use might then be 2 to 3 fold or more, which in line with their previous results and the results of the latest combined HRT study.3 A small extra 3 to 9% HRT use among past OC users would have little impact on these risk estimates compared with the large effect of 50% of the never OC users starting HRT and therefore joining the hormone user group. When OC use is started at young ages before a first full-time birth an important reason for an increased risk of breast cancer is that a higher percentage of early-age starters continue with taking the pill for more years. The original authors of the RCGP OC Study listed age and parity for the 46,377 women (including 4,900 new takers and 18,800 previous takers) recruited in 1968 and 1969. Only 2.8% of all the women (1,291) started OCs at ages 15-19 and only 7.7% (3,580) started OCs before a first birth.4 20 years after enrolment, although few women had early age Pill use before their first full-time pregnancy, the increased risk of breast cancer was considerable.5 In 1988 Kay and Hannaford reported increases of 2.53 for women aged 25-29; 3.33 for women aged 30-34; 10.17 for more than 10 years of use; and 15.8 at 8-9 years after use. Breast cancer mortality risk increased to 1.5 by 5-9 years after use. There is no doubt now that breast cancer incidence and mortality falls quickly and dramatically when progestogen/oestrogen use is discontinued.6 Today, 40 years after enrolment and an average OC use of 44 months, the authors seem to find reassurance because they included an unknown large number of older HRT Takers with cancer in the Never (Pill) Taker group. I do not understand why these authors are happy with their results. Their deeply flawed and underestimating analysis revealed a large and significant increased risk of CNS or pituitary tumours (5.51, 1.38-22.05) with less than 4 year of use. This is not very jolly! ellengrant@talktalk.net 1.Hannaford P C, Selvaraj S, Elliott AM, Angus V, Iversen L, Lee AJ. Cancer risk among users of oral contraceptives: cohort data from the Royal College of General Practitioner's oral contraception study. BMJ 2007;335: 651 bmj.39289.649410.55v1 2 Million Women Study Collaborators. Patterns of use of hormone replacement therapy in one million women in Britain, 1996-2000. British Journal of Obstetrics and Gynaecology 2002, 109, 1319-1330. 3 Li CI, Malone KE, Porter PL, Lawton TJ, Voigt LF, Cushing-Haugen KL, Lin MG, Yuan X, Daling JR. Relationship between Menopausal Hormone Therapy and Risk of Ductal, Lobular, and Ductal-Lobular Breast Carcinomas. Cancer Epidemiol Biomarkers Prev. 2008 Jan;17(1):43-50. 4 Kay CR, Hannaford PC. Breast cancer and the pill. A further report from The Royal College of General Practitioners Oral Contraception Study. Br J Cancer 1988: 58: 678-80. 5 The Royal College of General Practitioners. Oral Contraception and Health: An Interim Report. London: Pitman Medical 1974 6 Colditz GA. Decline in breast cancer incidence due to removal of promoter: combination estrogen plus progestin. Breast Cancer Res. 2007 Nov 15;9:401. Competing interests: None declared |
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suzanne l adams, cytologist 49006
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I agree with Ellen Grant regarding the ridiculous conclusion that oral contraceptives are good because they appear to prevent ovarian cancer. Even if this were true, ovarian cancer is rare compared to cervical and breast cancer which the pill increases. How could the same hormones taken in younger women be protective, when in older women they dramatically increase the risk of breast cancer in the least, as well as heart disease and strokes? It is lethal to suggest all young women take the pill just to prevent a rare type of reproductive cancer, when in reality it increases the risk of the most common types of reproductive cancers.
Competing interests: None declared |
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