Abstract

BACKGROUND

Fear from increased cancer risk is one of the most significant reasons for low acceptance of reliable contraceptive methods and low compliance.

METHODS

In this review, we included all cohort and case–control studies published in English up to December 2008. They were identified through a search of the literature using Pubmed and EMBASE.

RESULTS

Data about breast cancer risk indicate a slightly increased risk among current users of oral contraceptives (OC), an effect which disappears 5–10 years after stopping. Combined OC have a significant protective effect on the risk of ovarian cancer, and the protection increases with duration of use (relative risk decreased by 20% for each 5 years of use). The significant risk reduction has been confirmed for BRCA 1 and 2 mutation carriers. The risk of endometrial cancer is reduced by about 50% in ever users, a benefit which is greater with increasing duration of use. An association has been found between increased risk of cervical cancer and long-term OC use. Current OC use has been associated with an excess risk of benign liver tumours and a modest increased risk of liver cancer. None of large prospective cohort studies with prolonged follow-up has observed an increased overall risk of cancer incidence or mortality among ever users of OC, indeed several have suggested important long-term benefits. Specifically, protective effect of OC can be used as chemoprevention in young women who are BRCA mutation carriers.

CONCLUSIONS

Women wishing to use combined OC can be reassured that their decision is unlikely to place them at higher risk of developing cancer.

Introduction

It is well documented that reproductive factors significantly modulate risk of certain cancers. Data from prospective controlled studies documented that hormonal replacement therapy in post-menopausal women may increase the risk of breast and ovarian cancer, whereas decreasing the risks of endometrial cancer (Anderson et al., 2003). Benefits and risks of oral contraceptives (OC) use on cancer were reviewed in 1998 by Working Groups of the International Agency for Research on Cancer (IARC/WHO), which concluded that combined OC are carcinogenic to humans, based on an increased risk for hepatocellular carcinoma (IARC, 1999), breast and cervical cancer (IARC, 2007). Colorectal cancer was considered possibly inversely related to OC use. The evidence for other cancers in relation to OC use was considered inadequate (IARC, 2007).

The research concerning the relationship between cancer risk and OC use is complicated by a number of other factors: peak incidence of the majority of cancers at an older age with a long interval from last or first OC use, the use of multiple hormonal formulations during the women's life, the existence of many confounding factors, some of which may be directly related to contraceptive use (number of pregnancies, breast-feeding, age of first pregnancy, the number of sexual partners, the use of barrier contraceptives, etc.), different composition of OC formulations. Moreover, it should be emphasized that it will never be possible to conduct a prospective controlled study on the use of OC, with the number of subjects and length of follow-up sufficient to assess the risk of malignancy. Nevertheless, much consideration has been given to the relationship between OC use and the risk of cancer, and good quality data are being regularly published. The aim of our review is to summarize the data available and to provide an update for current clinical practice, especially the counselling of women before and during contraception use.

Methods

Included were all cohort and case–control studies published in English up to December 2008. They were identified through a search of the literature using Pubmed and EMBASE with the keywords (‘oral contraceptives’ or ‘combined oral contraceptives’) AND (‘cancer’ or ‘neoplasm’ or ‘ovarian cancer’ or ‘breast cancer’ or ‘endometrial cancer’ or ‘cervical cancer’ or ‘liver cancer’ or ‘colorectal cancer’) AND (‘case–control study’ or ‘ cohort study’). We retrieved and assessed potentially relevant articles, and checked the reference lists of all papers of interest to identify additional relevant publications. Studies were considered only if they considered information on OC separately from hormone replacement therapy or other hormonal therapies. We did not consider abstracts and case reports.

Breast cancer

Introduction

Breast cancer is the leading cause of cancer in women worldwide. It is a multifactorial disease. Moreover, there are multiple biological profiles of breast cancer. Major risk factors (increasing the relative risk more than 4-fold) are family history, increased breast density, previous diagnosis of atypical hyperplasia and thoracic radiotherapy. Other factors act with a relative lower increase risk (less than a 2-fold increase; Cummings et al., 2009), including endogenous and exogenous hormones.

The age of the first full term pregnancy (FFTP) has dramatically changed in Western world since the end of the 70s and oral contraceptives (OC) are used thus much longer prior FFTP than in past. There is a serious concern that OC could be responsible in part for the burden of breast cancer, which was reinforced by the recent classification of OC as carcinogenetic agents by IARC (2007). However, analysis of the current knowledge challenges this assertion.

Underlying mechanisms

Experimental data strongly suggest that estrogens have a role in the development and growth of breast cancer. Estrogens promote the development of mammary cancer in rodents and exert both direct and indirect proliferative effects on cultured breast cancer cells. The role of progestin is more controversial. They have been reported to be either anti-proliferative or proliferative, very likely depending on the phenotype of the cell, the micro-environment and the species (Medina et al., 2007). Progestins are able to bind different steroid receptors and progesterone is converted to metabolites with different properties (Pasqualini, 2007). These pharmacological properties may also explain their different actions on breast tissues. More recently, some in vitro data suggest that they could exert a proliferative activity on myoepithelial/basal breast cells/progenitor cells (Graham et al., 2009). The FFTP promotes differentiation of breast tissue, which can be protective against potentially carcinogenic substances, especially if it occurs early in life (Russo et al., 2005). OC may exert different effect according to the age when they are used and the state of breast tissue.

Invasive cancer risk

Two meta-analyses and several observational studies have reported on breast cancer risk and mostly failed to show any robust association with the use of OC. The Collaborative Group on Hormonal Factors in Breast Cancer meta-analysis pooled 54 studies from 25 countries (Table I; CGHFBC, 1996). This study reported that current and recent use of OC, rather than a long duration of use, carries a small increase in the relative risk (RR) in current users (Table I) which disappeared within 10 years of stopping. This could suggest a promoter effect of hormone therapy on pre-existing lesions or bias of screening in OC users. The RR increased with a young age (<20 years) at start. Because of the low incidence of breast cancer in this age group, the absolute numbers remain very low: the attributable numbers of breast cancer cases in the USA and in Europe per 10 000 women within 10 years after stopping the OC were 0.5 [95% confidence interval (CI): 0.3–0.7], 1.5 (95% CI: 0.7–2.3) and 4.7 (95% CI: 2.7–6.7) for age groups between 16–19, 20–24 and 25–29 years, respectively. In addition, breast cancers diagnosed in OC users were of better prognosis with a better differentiation (CGHFBC, 1996).

Table I

Effect of OC use on breast cancer risk.

Study Number
 
RR 95% CI
 
 Cases Controls   
Oxford meta-analysis (CGHFBC, 199653 297 100 239 Current/recent users: 1.24 1.15–1.33 
Nurses' (cohort) (Hankinson et al., 19973383 1.11 0.94–1.32 
  >5 years use 0.96 0.65–1.43 
RCGP (cohort) (Hannaford et al., 200746 000 (744 000 women-years) 0.98 0.87–1.10 
Oxford Family Planning (cohort) (Vessey and Painter, 200617 032 1.0 0.8–1.1 
Women's CARE (Marchbanks et al., 20024575 4682 1.0 0.8–1.1 
Women's Lifestyle and Health study (cohort) (Kumle et al., 2002103 027 Former users: 1.2 1.1–1.4 
   Current/recent users: 1.6 1.2–2.0 
Mayo Clinic (meta-analysis) (Kahlenborn et al., 2006Premenopausal breast cancer Ever users: 1.19 1.09–1.29 
Study Number
 
RR 95% CI
 
 Cases Controls   
Oxford meta-analysis (CGHFBC, 199653 297 100 239 Current/recent users: 1.24 1.15–1.33 
Nurses' (cohort) (Hankinson et al., 19973383 1.11 0.94–1.32 
  >5 years use 0.96 0.65–1.43 
RCGP (cohort) (Hannaford et al., 200746 000 (744 000 women-years) 0.98 0.87–1.10 
Oxford Family Planning (cohort) (Vessey and Painter, 200617 032 1.0 0.8–1.1 
Women's CARE (Marchbanks et al., 20024575 4682 1.0 0.8–1.1 
Women's Lifestyle and Health study (cohort) (Kumle et al., 2002103 027 Former users: 1.2 1.1–1.4 
   Current/recent users: 1.6 1.2–2.0 
Mayo Clinic (meta-analysis) (Kahlenborn et al., 2006Premenopausal breast cancer Ever users: 1.19 1.09–1.29 

Since the above publication, some other important studies have been published and confirmed very low or absent increase in the risk. The Nurses' Health study reported on 3383 cases of breast cancer among 1.6 million person-years of follow-up (Hankinson et al., 1997). Women at entry were 30–55 years old and 6% of them reported current OC use, 40% past use and 54% never use of OC. Authors observed no increased risk among the whole population, in women who used OC for over 10 years, in a subgroup of women <45 years old or after >5 years of use (Table I).

The British large cohort of women recruited for the Royal College of General Practitioners' (RCGP) Oral Contraception Study, which included 46 000 women followed up since 1968–1969, did not find an increased risk of breast cancer among ever users (Hannaford et al., 2007; Table I). In this study, 75% of the ever users had used an OC containing 50 µg ethinylestradiol (EE) and 63.6% of the women were below 30 years when they started using OC (Hannaford et al., 2007). Similarly, The Oxford Family Planning Association (FPA) study included 17 032 women 25–39 years between 1968 and 1974 and has not observed any increase in the RR (Vessey and Painter, 2006).

The Women's Contraceptive and Reproductive Experiences (Women's CARE) study did not observed any increase in the RR in the whole cohort (Table I; Marchbanks et al., 2002). Interestingly, more than 2500 women had begun using OC before the age of 20 and no increase in the RR was observed in users. In this study, most of the women used newer OC formulations than in the studies analysed in the Oxford meta-analysis, which could explain the difference in the results. They also found that women 45–64 years old who had ever used OC, had a small but significant reduction in the RR of breast cancer. A complementary study has looked at the effect of a short duration use (≤6 months) and the possible interaction with other risk factors on 1025 cases and 2032 controls. No overall increase in the risk was reported. There was a small increase in women with premenopausal breast cancer (OR = 1.3; 95% CI: 1.0–1.7). An earlier age of menarche, infertility, later age at FFTP and first degree of family history was associated with a higher risk of breast cancer in OC users. Moreover, a mammogram performed in the last 2 years was associated with an increased risk (RR = 1.6; 95% CI: 1.1–2.5). These observations strongly suggest that OC use allowed for more frequent or earlier breast cancer diagnosis in women at higher risk. Alternatively, women in whom breast cancer has been recently diagnosed are more likely to recall previous OC use. Similarly, increase risk in women who have used OC for other indications than contraception (menstrual cycle disturbances, endometriosis) could be explained by the fact that they carry other risk factors for breast cancer (Folger et al., 2007).

The Women's Lifestyle and Health study observed an increase risk in users of OC after >5 years. This study enrolled 103 027 women between 1991 and 1999, followed up on registries in Norway and Sweden (Kumle et al., 2002). There was a small increase for current, recent and former users (Table I). The increase in RR before FFTP and below age of 20 was not influenced by OC use.

In the Norwac cohort study, the increase in the RR was associated with the estrogen cumulative dose (RR = 1.3 for 50–99 mg; RR = 1.5 for ≥100 mg; Dumeaux et al., 2003), but not with the progestin dose, whereas a relation with the progestin dose was observed in another study but with very few cases in the category of high-progestin dose and before 35 years, which precludes any conclusion (Althuis et al., 2003).

Finally, a meta-analysis published in 2006 estimated the premenopausal breast cancer risk from 34 previous studies (Kahlenborn et al., 2006; Table I). Multiparous women who have used OC before the FFTP had an OR = 1.44 (95% CI: 1.28–1.62), higher than those who started after the FFTP (OR = 1.15; 95% CI: 1.06–1.26). Duration of use >4 years before FFTP was associated with an OR = 1.52 (95% CI: 1.26–1.82). Nulliparous women had no increase of the risk irrespective of the duration of use. Results of this study suggest that pregnancy could reveal breast cancer risk promoted by OC. This meta-analysis used only case–control studies and crude odd ratio (not adjusted), which could have increased the RR values.

In most studies, mortality rates from breast cancer diagnosed in OC users were lower or equivalent to non-users (dos Santos Silva and Swerdlow, 1995; Trivers et al., 2007; Wingo et al., 2007; Barnett et al., 2008).

Histological types of breast cancer

Only a few studies have addressed potential impact of OC use on different histological types of breast cancer. No strong difference has been observed between lobular or ductal subtypes (Newcomer et al., 2003; Nyante et al., 2008). Two case–control studies did not find any increase related to OC use for ER+ or ER− breast cancer (Cotterchio et al., 2003; Ma et al., 2006). A recent study showed that OC use significantly increases (2.5-fold) the RR of triple negative cancer diagnosed before the age of 40 (Dolle et al., 2009); however, these data were not confirmed in the CARE study (except for a subset of breast cancers among women of 45–64 years who started OC use before age 18 years; Ma et al., 2010). BRCA status was not known in any of the above studies.

Three studies have addressed the risk of in situ cancer in OC users. A case–control study in the USA recruited 567 cases newly diagnosed with breast carcinoma in situ (BCIS) and 614 controls between 1995 and 1998. OC use was not associated with risk of BCIS (OR = 1.04; 95% CI: 0.76–1.42). Risk did not increase with longer use, use before FFTP, age at first use or time since last use (Gill et al., 2006).

In another large case–control study from the USA on 1878 BCIS and 8041 controls ever use was associated with a non-significant OR = 1.11 (95% CI: 0.99–1.25) for BCIS and for ductal carcinoma in situ (DCIS; OR = 1.15; 95% CI: 1.01–1.31; Nichols et al., 2007). A marginal but already significant increase in risk was observed only in former users, but not in current users and there was no effect with increasing duration of use. These studies also suggest bias of earlier detection in OC users.

Another case–control study compared 446 cases with DCIS to 1808 with invasive cancer. Ten or more years of OC use showed no association with comedo-type DCIS (OR = 1.31; 95% CI: 0.70–2.47), a positive association for invasive cancer (OR = 2.33; 95% CI: 1.06–5.09), but a possible inverse association for non-comedo DCIS (OR = 0.51; 95% CI: 0.25–1.04). This could suggest that OC could promote the more transformed phenotypes of DCIS, however, the evidence is weak (Phillips et al., 2009).

Confounding factors

None of the previous studies has highlighted any predictive factor for an increase risk of breast cancer in OC users, except possibly a long use before FFTP or at young age. However, it is important for a clinician to know if, in women with specific conditions which have been linked to an increase in breast cancer risk, OC can further alter the risk.

Benign breast disease

Fibroadenoma does not increase the RR of breast cancer. Fibrocystic disease especially with proliferative lesions is associated with an increased risk. Hyperplasia with atypia is considered as precancerous lesions with an important increase in the risk of breast cancer. It was reported by several studies that OC use significantly decreases the incidence of benign breast disease (BBD; fibroadenoma and fibrocystic diseases) with increase duration of use, and this was recently confirmed with the new OC formulations (Ory et al., 1976; Vessey and Yeates, 2007). However, some studies shown that the OC protective effect concerned only BBD without atypia and that risk of BBD with atypia were not decreased and possibly even increased by OC (LiVolsi et al., 1979; Rohan and Miller, 1999). This observation is consistent with the fact that progestin may act as mitogenic agent on transformed cells but as anti-proliferative agent in normal or non-transformed cells.

Family history

The effect of OC in women with family history is an important issue, related to the question whether OC should be recommended to women with first or second degree relatives with breast cancer. Analysis of the literature shows that the data remains controversial, likely due to lack of statistical power, different populations or different definitions of family history (Gaffield et al., 2009). To date, in addition to the Oxford pooled analysis, there have been three cohort studies on OC use and breast cancer risk among women with a family history of breast cancer, and without data on the BRCA status.

In 2001, an analysis on the risk of breast cancer was published by the Collaborative Group on Hormonal Factors in Breast Cancer (CGHFBC, 2001). Data were collected from 52 published and two unpublished studies concerning first degree relatives with breast cancer in 58 209 women with breast cancer and 101 986 without cancer. Together 7496 (12.9%) women with breast cancer and 7438 (7.3%) controls reported that one or more first degree relatives had a history of breast cancer. The RR of breast cancer was increased by the family history, but use of OC did not alter the risk. Even in women younger than 50 years with an affected relative, the RR of breast cancer was similar for OC users in the previous 10 years (RR = 3.85; 95% CI: 2.41–6.13) and those who had never used OC (RR = 2.91; 95% CI: 2.15–3.93).

In the Nurses' Health Study (71 incident cases), no association was observed between OC use and a family history of breast cancer (Lipnick et al., 1986). These data were reanalysed in 1996 including 310 incident cases (but only four current OC users) and found statistically non-significant 2.5-fold increased risk (95% CI: 0.88–6.94) among current OC users with a family history of breast cancer (Colditz et al., 1996).

An original study, which included 426 families with a breast cancer diagnosed between 1944 and 1955, analysed 394 sisters and daughters, 3002 grand-children or nieces and 2754 spouses. A RR of 3.3 (95% CI: 1.6–6.7) was observed in women with a first but not a second degree relative and in women who used OC before 1975 (Grabrick et al., 2000).

A Canadian study has analysed data from 27 975 women with any family history of breast cancer and 1707 incident cases and found conflicting results. They showed significant effect in the whole cohort and a protective effect of marginal significance (P = 0.03 for trend) in women with long use (>7 years) and a first degree relative with breast cancer (Silvera et al., 2005). In all these reports, the BRCA status was not known.

BRCA mutation carriers

Several recent studies have reported conflicting data on the RR in OC users who are carriers of BRCA1/2 mutations (Jernstrom et al., 1999; Heimdal et al., 2002; Narod et al., 2002; Milne et al., 2005; Haile et al., 2006; Brohet et al., 2007; Lee et al., 2008; Dolle et al., 2009). These studies are retrospective, information recall is not similar, in some studies cases were matched to controls without mutation (Milne et al., 2005; Haile et al., 2006) and some studies are under-powered due to low number of cases. In addition certain proportion of the mutation carriers have underwent prophylactic mastectomy during the follow-up.

In the majority of published studies, there was a mild or moderate increase in the RR for OC users (Table II), but with a low power. In a large study (Narod et al., 2002), the increased RR was observed only for BRCA1 women and for breast cancer at young age. The multivariate OR for ever use of OC was 1.38 (95% CI: 1.11–1.72) for BRCA1 carriers who were diagnosed with breast cancer before the age of 40 and 0.96 (95% CI: 0.75–1.24) for BRCA1 carriers who were diagnosed at the age of 40 or older. In the second large study (Brohet et al., 2007), there was an increase in the risk if OC was used before FFTP for at least 4 years (Table II). However, the RR was not dramatically different from that in women without any family risk.

Table II

Effect of OC use on breast cancer risk in BRCA mutation carriers.

Study Mutation Number RR CI 95% 
Sweden (Jernstrom et al., 1999BRCA1/2 245 1.65 0.95–2.87 
Use <20 years 2.10 1.02–2.62 
Before FFTP 1.63 1.32–3.33 
Norway (Heimdal et al., 2002Familial 1423 0.90 0.68–1.18 
BRCA1 96 2.00 0.36–10.9 
USA, Canada, Australia (Haile et al., 2006BRCA1 497/195cases 0.77 0.53–1.12 
BRCA2 307/128cases Use >5 years 2.06 1.08–3.94 
  Before FFTP 3.46 2.10–5.70 
USA, Canada, Australia BRCA1 47 cases 0.22 0.10- 
(Milne et al., 2005BRCA2 36 cases 0.93 0.34–3.09 
USA, Canada, Europe (Narod et al., 2002BRCA1 981 pairs 1.18 1.01–1.38 
   Use <5 years NS  
   Use >5 years 1.33 1.11–1.60 
 BRCA2 330 pairs 0.93 0.72–1.21 
Europe (Brohet et al., 2007BRCA1 1181/597 cases 1.4 1.13–1.91 
   Before FFTP + greater than 4 years: 1.49 1.05–2.11 
 BRCA2 412/249 cases 1.49 0.8–2.70 
   Before FFTP + greater than 4 years: 2.58 1.21–5.49 
USA (Lee et al., 2008BRCA1/2 94 cases NS  
USA (Figueiredo et al., 2010BRCA1 109 cases 2.38 0.72–7.83 
BRCA2 72 cases 0.82 0.21–3.13 
Study Mutation Number RR CI 95% 
Sweden (Jernstrom et al., 1999BRCA1/2 245 1.65 0.95–2.87 
Use <20 years 2.10 1.02–2.62 
Before FFTP 1.63 1.32–3.33 
Norway (Heimdal et al., 2002Familial 1423 0.90 0.68–1.18 
BRCA1 96 2.00 0.36–10.9 
USA, Canada, Australia (Haile et al., 2006BRCA1 497/195cases 0.77 0.53–1.12 
BRCA2 307/128cases Use >5 years 2.06 1.08–3.94 
  Before FFTP 3.46 2.10–5.70 
USA, Canada, Australia BRCA1 47 cases 0.22 0.10- 
(Milne et al., 2005BRCA2 36 cases 0.93 0.34–3.09 
USA, Canada, Europe (Narod et al., 2002BRCA1 981 pairs 1.18 1.01–1.38 
   Use <5 years NS  
   Use >5 years 1.33 1.11–1.60 
 BRCA2 330 pairs 0.93 0.72–1.21 
Europe (Brohet et al., 2007BRCA1 1181/597 cases 1.4 1.13–1.91 
   Before FFTP + greater than 4 years: 1.49 1.05–2.11 
 BRCA2 412/249 cases 1.49 0.8–2.70 
   Before FFTP + greater than 4 years: 2.58 1.21–5.49 
USA (Lee et al., 2008BRCA1/2 94 cases NS  
USA (Figueiredo et al., 2010BRCA1 109 cases 2.38 0.72–7.83 
BRCA2 72 cases 0.82 0.21–3.13 

The RR of breast cancer in these selected patients may be weakly increased, but uncertainty remains; in addition the balance of benefit/risk in women with BRCA mutations is positively driven by a significant protective effect of OC on substantially increased risk of ovarian cancer (see later).

Composition of OC formulations

So far, there is no robust indication of variable effect on breast cancer risk in relation to different OC formulations. Most data, due to the need of long-term follow-up to see any effect on breast cancer risk, have predominantly concerned formulations containing ≥50 µg of EE. There is no evidence for a different risk of breast cancer in users of newer formulations but strong evidence is lacking. A Norwegian cohort study reported a positive correlation between the estrogen content and breast cancer risk but remains the only study with such finding (Dumeaux et al., 2003).

Conclusions

In a majority of studies there is no increase in the risk of breast cancer reported in OC users. When the RR was shown to be increased, this effect disappeared progressively after stopping OC use. Long duration of OC use at a young age before the FFTP seems to be the most important risk factor, as hormones act on a less differentiated tissue. The number of events attributable to OC use remains below 1% of the total breast cancers and 7% for premenopausal breast cancer if the RR of the Oxford meta-analysis is applied to calculate the attributable fraction of breast cancer in France (CGHFBC, 1996).

The level of the increase in the RR is so low that it is not fully convincing and may have concerned the first generation of OC formulations. Although the modest and inconsistent associations may be attributable to variation in study design, it is also possible that they result from disease heterogeneity. Furthermore, significant involvement of screening or recall bias cannot be excluded (Marchbanks et al., 2002; Rosenberg et al., 2009; Shapiro, 2009). None of these studies has shown a role for the composition of OC on breast cancer risk. The possible, whereas currently unconfirmed, small increase in the risk of breast cancer in OC users with BRCA1/2 mutations is strongly counterbalanced by the benefits in terms of ovarian cancer protection.

Ovarian cancer

Introduction

Each year the Journal of Clinical Oncology publishes an analysis of major achievements in oncology. In 2008, the whole field of onco-gynaecology was represented by a single issue, the confirmation of a significant risk reduction of ovarian cancer in OC users (Winer et al., 2009). Although this positive and important effect of OC has been discussed since 1970s, a good quality meta-analysis was published in 2008, not only summarizing most relevant articles, but also using source data from all 45 studies (Beral et al., 2008). We refer to the results of the meta-analysis here, but focus more extensively on areas which so far have received little or marginal attention.

Underlying mechanisms

Several possible mechanisms have been suggested for ovarian cancerogenesis and each are potentially influenced by hormonal contraceptives.

The incessant ovulation hypothesis (Fathalla, 1971) assumes that the development of ovarian cancer is a consequence of repeated microtrauma to the ovarian surface epithelium (OSE) during ovulation. It is hypothesized that repeated DNA damage during ovulation and dysfunction of its recognition and repair are crucial for ovarian cancerogenesis. The inhibition of ovulation could thus explain the protective influence of hormonal contraception, pregnancy and breast-feeding. This does not, however, fully explain other epidemiological findings. The protective effect of even short-term OC use, as well as that of pregnancy go beyond what a simple reduction in the number of ovulations would suggest (Gwinn et al., 1990; Siskind et al., 2000; Greer et al., 2005). Moreover, some diseases causing chronic anovulation, in particular polycystic ovary syndrome, do not have the protective effect (Schildkraut et al., 1996).

The gonadotrophin hypothesis states that malignant transformation can be caused by the exposure of OSE to excessive gonadotrophin levels (Cramer and Welch, 1983). This theory would explain both the protective effect of OC that significantly inhibit gonadotrophin levels (Spona et al., 1996), as well as the sharp increase of ovarian cancer incidence after the menopause. On the other hand, it runs counter to the protective role of breast-feeding, as lactating women have raised FSH levels, and it fails to explain why hormonal treatment in post-menopause, which also reduces gonadotrophin levels, increases the risk of ovarian cancer (Anderson et al., 2003; Beral et al., 2007).

The hormonal hypothesis presumes a decisive role for ovarian hormones, progesterone in particular. In experimental studies progesterone up-regulated p53 tumour suppressor gene expression and inhibited proliferation of cultured sheep ovarian epithelial cells (Murdoch and Van Kirk, 2002), or induced apoptosis in normal and malignant human ovarian epithelial cell lines (Bu et al., 1997; Syed and Ho, 2003). Progesterone had an inhibitory effect on proliferation in ovarian epithelium cell cultures obtained from premenopausal and post-menopausal women (Ivarsson et al., 2001). Moreover, in a 3-year randomized controlled trial in monkeys it was demonstrated that synthetic progestin levonorgestrel can induce apoptosis in OSE (Rodriguez et al., 1998). These experimental data allow us to speculate that exposure to high progesterone levels in pregnancy or progestins contained in OC may lead to a ‘clearing’ of cells in OSE containing sub-lethal DNA damage by the induction of apoptosis.

A new theory is emerging from recent data concerning the possibility of developing epithelial cancers from one precursor cell derived from the Müllerian duct (Shih Ie and Kurman, 2004). The Müllerian duct forms the fallopian tube, uterus, cervix and upper vagina, and HOX genes play a significant role in such differentiation (Cheng et al., 2005). OC might interfere with the mechanisms of cancerogenesis through several mechanisms: the inhibition of ovulation prevents the invagination of cells from the Müllerian duct, sex steroids may directly regulate the expression of HOX genes, one can also speculate on the possible interference with endometrium and tubal epithelium transformation, decreasing risk of shedding cells derived from the Müllerian duct.

None of these theories explain the epidemiology data in full. Moreover, there is an overlap in mechanisms involved in individual hypotheses. It is therefore very likely that several mechanisms contribute to the protective effect of OC.

Risk in OC users

A possible positive influence of OC on the risk of ovarian cancer has been discussed since 1970s (Casagrande et al., 1979). A number of epidemiological retrospective analyses assessing the risk and protective factors of ovarian cancer, and large-scale prospective trials have been conducted. The broadest meta-analysis to date was published in 2008 (Beral et al., 2008) endorsing the findings of previous meta-analyses (Hankinson et al., 1992; Whittemore, 1992; Bosetti et al., 2002). It included all studies published up to January 2006 which recruited at least 100 women with ovarian cancer. They analysed data from 23 257 cases and 87 303 controls. An important strength of the study was the fact that source data from all the 45 studies were available. The meta-analysis confirmed a significantly reduced RR of ovarian cancer for ever OC users, which was comparably reduced regardless of the study design in 13 major prospective (RR = 0.74; SE: 0.03), 19 population-based case–control (RR = 0.69; SE: 0.03) and 13 hospital-based case control studies (RR = 0.81; SE:0.05; Beral et al., 2008). Another important supporting argument is a confirmed trend between the RR of ovarian cancer and the duration of OC use. After adjustment for various potential confounding factors, the RR decreased by 20% for each 5 years of use.

Since the meta-analysis was published, its results have been endorsed by several other studies. The Oxford FPA prospective cohort study recruited more than 17 000 women between 1968 and 1974 and followed them until 2004. It found a significantly reduced RR of ovarian cancer in ever OC users (RR = 0.5; 95% CI: 0.3–0.7), although it was incapable of confirming the trend regarding the duration of use (Vessey and Painter, 2006). A significantly reduced risk was observed as early as after 1 year of use (OR = 0.47;95% CI: 0.33–0.67), and an average odds ratio reduction of 5% per each year of OC use was observed in population-based case–control study carried out in USA, which included 813 cases of ovarian cancer and 992 controls (Lurie et al., 2008). Significant risk reductions of ovarian cancer, together with decreasing trend with duration of OC use, were also confirmed in large RCGP Oral Contraception Study (Hannaford et al., 2007). RR of 0.54 (95% CI: 0.40–0.71) was shown in the whole cohort and 0.38 (95% CI: 0.16–0.88) for users of OC ≥ 97 months. On the contrary, a large prospective Chinese trial with median follow-up of 7.5 years, which followed a cohort of more than 66 000 women, failed to confirm a reduced risk in OC users although a positive trend was seen with ≥2 years of OC use (Dorjgochoo et al., 2009). However, only 19% of women had ever used OC in the Chinese study and only 94 cases of ovarian cancer were diagnosed during the follow-up.

Confounding factors

Evidence from a number of epidemiological studies indicates that there are numerous other reproductive factors significantly affecting the risk of ovarian cancer, in particular parity and breast-feeding (Gwinn et al., 1990; Jordan et al., 2008). It is therefore important to ascertain whether these factors influence the protective effect of OC. In a meta-analysis of 12 case–control studies conducted between 1956 and 1986, protection was more pronounced in women who breastfed for a long period, but this finding was only seen in population studies (Whittemore, 1992). The majority of other studies found no difference in the protective effect of OC depending on other reproductive factors. In one meta-analysis, a number of parameters were assessed including ethnicity, BMI or tobacco use, but none of the15 parameters assessed, with the exception of age at diagnosis and menopausal status, significantly changed the declining trend in RR (Beral et al., 2008). Similar protection was also confirmed among women with and without endometriosis (Modugno et al., 2004). Thus, the protective effect of OC is probably not significantly influenced by other parameters, including those which constitute significant risk or protective factors for the development of ovarian cancer.

Time dependency of risk modulation

The incidence of ovarian cancer increases with age, peaking at about 70 years of age, whereas the use of OC is limited to the fertile period of life. Consequently the duration of protection after the cessation of OC is significant for reduction of absolute risk. The protective effect of OC diminishes slowly 10 years after cessation, although a protective effect has been confirmed after >20 years (Moorman et al., 2008) or >30 years (Beral et al., 2008; Lurie et al., 2008). The Beral meta-analysis showed a reduction of the RR for ovarian cancer by 48, 38 and 31%, respectively, in women who used OC for 5–9 years and ceased <10 years, 10–19 years or 20–29 years previously. The most important factor determining the duration of protection was the duration of OC use, whereas the age of first or last use seems to be less important (Tworoger et al., 2007; Beral et al., 2008; Lurie et al., 2008; Moorman et al., 2008).

Considering the absolute lifetime risk of ovarian cancer, regardless of the duration of protection, it is crucial whether the same level of protection is maintained in post-menopausal women. Menopause was one of the few factors that diminished the decline in RR of ovarian cancer in the meta-analysis by Beral et al. (2008). Reduction of RR per 5 years of OC use reached 27% (SE 3.2) versus 16.6% (SE 2.5) in pre- versus post-menopausal women. It should be stressed, however, that the average age of women included in the meta-analysis was 56 years and fewer than one-third of ovarian cancer cases were diagnosed in patients over 65 years old. Furthermore, a number of other studies have shown smaller or even non-existent protection in post-menopausal women (Lurie et al., 2008; Moorman et al., 2008). This might significantly affect the estimated reduction of absolute ovarian cancer risk post-menopause.

Histological types of ovarian cancer

A number of studies found different risk factors for mucinous ovarian cancers compared with two other frequent histological types, serous and endometrioid cancers. In accordance with this different epidemiological nature, a lower degree of risk reduction by OC use was observed for mucinous invasive cancers (Risch et al., 1996; Tung et al., 2003; Soegaard et al., 2007). These findings are confirmed by the results of the meta-analysis by Beral which showed a risk reduction of ≥20% per 5 years of use for endometrioid and serous cancers, although the risk was reduced by just 12% for mucinous cancers.

Of much greater importance is whether the protective effect of OC is maintained for borderline ovarian tumours (BTO) occurring at a much younger age than invasive cancers. Epidemiological studies confirmed similar reproductive risk factors in BTO as in invasive ovarian cancers (Risch et al., 1996; Riman et al., 2001; Huusom et al., 2006). The data concerning the protective effect of OC on BTO risk are more heterogeneous. A number of studies did not find significantly decreased RR (Riman et al., 2001; Kumle et al., 2004; Huusom et al., 2006); however, others present a positive trend and the absence of significance is probably related to the smaller number of cases (Kumle et al., 2004; Huusom et al., 2006). Moreover, a comparable level of protection by OC for serous BTO and serous invasive ovarian cancer was confirmed in the Beral meta-analysis, although not significant due to wide CIs.

Composition of OC formulations

The majority of published prospective and retrospective trials investigating ovarian cancer risk and OC use included women between 50 and 70 years old (Beral et al., 2008). In the meta-analysis of 2008 only 20% of ovarian cancer patients used OC within the preceding 10 years. Thus, the majority of women included in those studies used older OC formulations with higher hormonal doses.

The differences in the estrogen component have been easier to study. The majority of studies compare the effect of older formulations containing >50 µg EE (or equivalent dose of mestranol) to a lower dose (Rosenblatt et al., 1992; Rosenberg et al., 1994; Ness et al., 2000; Sanderson et al., 2000). Rosenblatt did not find significant differences in protection, even though the OR was lower for doses >50 µg, another study reported a comparable modest risk reduction for both doses (Rosenberg et al., 1994), and the Sanderson study observed an even lower OR in users of ≤50 µg EE (OR 0.6; 95% CI: 0.3–1.1 versus OR 0.8; 95% CI: 0.5–1.2). In a population-based case–control study, identical protection was reported for formulations containing ≥50 µg EE in combination with high-potency progestin (OR = 0.5; 95% CI: 0.3–0.6) and <50 µg EE in combination with low-potency progestin (OR = 0.5; 95% CI: 0.3, 0.7; Ness et al., 2000). All these studies are limited by small number of cases. The Beral meta-analysis utilized an interesting methodology to compare the protective effect of OC by decade of use from 1960s till 1980s, and found a comparable RR of ovarian cancer of 0.52–0.55 (Beral et al., 2008). The dramatic reduction of estrogen dose over the 30 years did not weaken the protective effect. These data, however, do not reflect the formulations containing ≤35 µg of EE, which only gained dominance in the market in 1980s.

Only four studies enabled differentiation of users of formulations with <35 µg EE, and there was no significant difference found in risk reduction in any of those studies compared with formulations with >35 µg EE (Royar et al., 2001; Pike et al., 2004; Lurie et al., 2007).

An evaluation of the role of the progestin component is complicated by a large variety of different compounds used, and the absence of unified classification or methodology for assessing progestin potency. Older literature quoted risk for individual formulations (CASH, 1987; Rosenberg et al., 1994), but lately efforts have been made at clustering according to progestin potency measured by the delay of menstruation test, or induction of secretory transformation in endometrium (Dickey and Stone, 1976). The available findings are divergent, claiming both comparable risk reduction (Ness et al., 2000), as well as stronger protection in formulations with higher progestin potency (Schildkraut et al., 2002; Pike et al., 2004). A major recent publication using photographs of OC packages to improve women's recall, made a separate assessment of women who reported exclusive use of the same formulation during all OC use episodes, and found a lower OR for users of low-potency progestin in combination with low-dose of estrogen (OR = 0.19; 95% CI: 0.05–0.75) as opposed to high-potency progestin and high estrogen dose (OR = 0.62; 95% CI: 0.43–0.92; Lurie et al., 2007). It must be emphasized, however, that those studies are limited by a low number of subjects.

In conclusion, the data available, albeit limited due to the small numbers of subjects, suggest that the protective effect of OC is maintained in formulations with <50 µg EE, just as in low-dose formulations with <35 µg.

BRCA mutation carriers

Women with higher risk of ovarian cancer, particularly carriers of BRCA 1/2 mutation, constitute an important target group for any protective effect from the use of OC.

Since 1998, six studies have investigated OC use in BRCA carriers, of which only one failed to confirm a protective effect (Modan et al., 2001). A population-based case–control study in Jewish women confirmed the protective effect of OC use in general population (≥5 years of use OR 0.53; 95% CI: 0.34–0.84), but did not find this protection in mutation carriers (0.2% risk reduction for each year of use). The specific ethnic background, as well as the small number of OC users, may provide an explanation for this discrepancy, but the study provides no further details. All five other case–control studies showed conclusively decreased ovarian cancer risk in OC users who were carriers of BRCA mutations (Narod et al., 2002; McGuire et al., 2004; Whittemore et al., 2004; McLaughlin et al., 2007; Antoniou et al., 2009). The largest study included both BRCA mutation carriers (670 with BRCA 1 and 128 with BRCA 2) and population controls (2043 with BRCA 1 and 380 with BRCA 2; McLaughlin et al., 2007). The use of OC was associated with highly significant risk reduction of ovarian cancer for mutation carriers (OR = 0.53; 95% CI: 0.43–0.66). Numbers of subjects were sufficient for separate analysis and confirmed similar protective effect for both BRCA 1 and BRCA 2.

For young women with a hereditary increased risk of ovarian cancer who plan further pregnancy, or do not accept prophylactic salpingo-oophorectomy, the recent data confirms a protective effect in BRCA 1 mutation carriers.

Conclusion

The use of OC has a significant protective effect on the risk of ovarian cancer and the risk reduction is dependent on the duration of use. The exact mechanism of action has not been elucidated, ovulation inhibition seems to be the most important factor, but suppression of gonadotrophin levels and direct effect of progestin compounds may also play a role. The reduction in RR is maintained for several decades, but diminishes in post-menopausal women. The risk reduction applies to all main histotypes, including BTO, with the exception of mucinous tumours. The data available provide evidence of maintained protective effect even in modern formulations containing ≤35 µg EE. Recent studies confirm a significant risk reduction in BRCA 1 and 2 mutation carriers.

Endometrial cancer

Underlying mechanisms

A total of 41 000 new cases of endometrial cancer were diagnosed in the USA in 2006 (ACS, 2006). Two different clinicopathological subtypes are recognized: the estrogen-related type 1 (endometroid), comprising 70–80% of newly diagnosed cancer and the non-estrogen-related type 2 (non-endometroid such as papillary serous and clear cell).

Regarding histology, the biological basis is that estrogen stimulates endometrial cell division, whereas progestins block that effect. During progestin action, cell proliferation ceases despite continuous exposure to estrogen levels (like in the luteal phase). Progestins protect from estrogen-induced hyperplasia and changes in proliferative status. They induce glandular epithelial secretory activity and decidual transformation of stromal fibroblasts; these terminally differentiated cells can no longer proliferate and are shed in withdrawal bleedings (if implantation not occur), with strong differences dependent on the pharmacology of progestins used (type, dosage, pharmacokinetics etc.; Pike and Spicer, 2000). Interestingly comparing OC containing EE/norethindrone in different dosages with hormone replacement therapy containing conjugated equine estrogen/MPA, the subjects using OC had significantly less endometrial proliferation and in consequence also less progestin-induced pro-secretory effects (Portman et al., 2003).

However, changes in histological features during OC include different proliferatory, secretory and atrophic (like) patterns, changes in gland-to-stroma ratio, stromal factors (e.g. very potent growth factors), architectural structures (e.g. cribiform and/or papillary patterns), glandular cellularity, cytoplasmic changes, mitotic activity, (tumour-)angiogenesis and increases or decreases in cytologic atypia. The latter of these are powerful markers and predictors for progestin potency (Portman et al., 2003; Amant et al., 2005; Wheeler et al., 2007). All these effects may explain, why and how OC use can reduce the risk of endometrial cancer.

Risk in OC users

The first relevant systematic review using the criteria of the U.S. Preventive Services Task Force and evaluating the association between OC and endometrial cancer was published in 1995 (Grimes and Economy, 1995), assessing 13 case–control studies (Fig. 1).

Figure 1

Effect of OC use on risk of endometrial cancer (adapted from Grimes and Economy, 1995).

Figure 1

Effect of OC use on risk of endometrial cancer (adapted from Grimes and Economy, 1995).

Only one cohort study found a modest, non-significant increase in risk (Trapido, 1983), but included high-dose sequential preparations (100 µg EE) combined with low-dose, short sequential progestin, a formulation which has been unavailable for >20 years. Two of the three cohort studies reported a significant protective effect. This includes the Walnut Creek Contraceptive Drug Study from California (Ramcharan et al., 1981) and the RCGP Oral Contraception Study (Beral et al., 1988). The UK study is the most important cohort study, which in a report published in 1988 found an 80% reduction in risk among ever users of OC compared with non-users (RR 0.2; 95% CI: 0.0–0.7).

According to this first systematic review (Fig. 1) the protective effect in preventing endometrial cancer using OC seems to be very clear, despite placebo-controlled studies being impossible. Few further relevant studies have been published since, especially investigating follow-up of earlier large studies or investigating risk factors which could modulate the effect of OC use. Table III summarizes the most important studies of OC use and risk of endometrial cancer.

Table III

Effect of OC use on risk of endometrial cancer (relevant studies listed in chronological sequence).

First author Country Cases Controls Age (years) Risk influenced by
 
RR (ever users) 
     Invest. factors OC-duration  
Horwitz and Feinstein (1979USA 104 87 50  n.a. 0.94 
Weiss and Sayvetz (1980) USA 110 249 35–54 b,d n.a. 0.5 
Kaufman et al. (1980USA 152 516 >60 c,d yes 0.5 
Ramcharan et al. (1981USA 58 16 638 (cohort) >65  n.a 0.6 
Kelsey et al. (1982USA 37 342 45–74  yes 0.6 
Hulka et al. (1982USA 79 203 n.ans. yes 0.3–0.6 
Henderson et al. (1983USA 110 110 <45 b,c,d,f yes 0.75 
Ory (CASH), (1983USA 187 1320 20–54 b,c,d yes 0.5 
Trapido (1983) USA 98 97 300 (cohort) <58  n.a. 1.4 
La Vecchia et al. (1986Italy 170 1282 <60  n.a. 0.56 
Pettersson et al. (1986Sweden 362 367 <60 n.a. 0.4 
CASH (1987) USA 433 3191 25–54 a,b,c,d,f,g yes 0.6 
Beral et al. (1988UK  47 000 (cohort) n.ans.  n.a. 0.2 
Koumantaki et al. (1989Greece 83 164 40–79  yes 0.65 
Levi et al. (1991Switzerland 122 309 ≤75 a,c,e,f yes 0.5 
WHO (1991USA 220 1537 >65 b,c n.a. 1.101; 0.152; 0.593 
Stanford et al. (1993USA 405 297 n.ans. a,d,e,f yes 0.4 
Weiderpass et al. (1999Sweden 709 3368 50–74 a–g yes 0.5 
Heinemann et al. (2003Germany 485 1570 32–65 a–g yes 0.36 
Maxwell (CASH) (2006USA 434 2557 25–54 b,e,f yes 0.214; 0.395 
Vessey and Painter (2006) UK 77 17 032 (cohort) 25–39 (recrution) a,b,c yes 0.1 
Hannaford et al. (2007UK 156 47 173 (cohort)   yes 0.58 
First author Country Cases Controls Age (years) Risk influenced by
 
RR (ever users) 
     Invest. factors OC-duration  
Horwitz and Feinstein (1979USA 104 87 50  n.a. 0.94 
Weiss and Sayvetz (1980) USA 110 249 35–54 b,d n.a. 0.5 
Kaufman et al. (1980USA 152 516 >60 c,d yes 0.5 
Ramcharan et al. (1981USA 58 16 638 (cohort) >65  n.a 0.6 
Kelsey et al. (1982USA 37 342 45–74  yes 0.6 
Hulka et al. (1982USA 79 203 n.ans. yes 0.3–0.6 
Henderson et al. (1983USA 110 110 <45 b,c,d,f yes 0.75 
Ory (CASH), (1983USA 187 1320 20–54 b,c,d yes 0.5 
Trapido (1983) USA 98 97 300 (cohort) <58  n.a. 1.4 
La Vecchia et al. (1986Italy 170 1282 <60  n.a. 0.56 
Pettersson et al. (1986Sweden 362 367 <60 n.a. 0.4 
CASH (1987) USA 433 3191 25–54 a,b,c,d,f,g yes 0.6 
Beral et al. (1988UK  47 000 (cohort) n.ans.  n.a. 0.2 
Koumantaki et al. (1989Greece 83 164 40–79  yes 0.65 
Levi et al. (1991Switzerland 122 309 ≤75 a,c,e,f yes 0.5 
WHO (1991USA 220 1537 >65 b,c n.a. 1.101; 0.152; 0.593 
Stanford et al. (1993USA 405 297 n.ans. a,d,e,f yes 0.4 
Weiderpass et al. (1999Sweden 709 3368 50–74 a–g yes 0.5 
Heinemann et al. (2003Germany 485 1570 32–65 a–g yes 0.36 
Maxwell (CASH) (2006USA 434 2557 25–54 b,e,f yes 0.214; 0.395 
Vessey and Painter (2006) UK 77 17 032 (cohort) 25–39 (recrution) a,b,c yes 0.1 
Hannaford et al. (2007UK 156 47 173 (cohort)   yes 0.58 

n.ans., no answer; a, duration; b, composition; c, persistence of protection; d, hormone therapy after OC; e, parity; f, weight; g, histology; n.s., not significant; n.a., not applicable; CASH, Cancer and Steroid Hormone Study. 1high-dose estrogen/low-dose progestin; 2high-dose estrogen/high-dose progestin; 3low-dose estrogen/low-dose progestin; 4high potency progestin; 5low-potency progestin.

The most important study using incident cohort data in large patient samples is the RCGP Oral Contraception Study (Beral et al., 1988), and the recently published new data for the 46 000 women in the cohort, followed for up to 38 years (Hannaford et al., 2007). The data came from six monthly reports from the women's general practitioners until 1996, and from linkage of the 35 050 women still in the study in the mid-1970s to National Health Service central registries. The main dataset contained ∼339 000 woman years of observation for never users and 744 000 woman years for ever users. Most of the users received a combined formulation, whereas 3% used the progesterone-only pill.

Compared with never users, ever users had statistically significant lower rates of cancers of the uterine body, calculated in the main data set with RR 0.58 (95% CI: 0.42–0.79), standardized rate per 100 000 woman years, 11.30 for ever and 19.53 for never users (adjusted for age, parity, smoking and social status). The risk was also assessed by duration of OC use, and although based on smaller numbers the trend for longer use was statistically significant. Regarding recent use, <5 years after stopping reached significance. Since only 566 women exclusively used a formulation with >50 µg EE, this study does not elucidate whether the risk reduction is dependent on the hormonal potencies of the OC used.

The WHO Collaborative Study (WHO, 1991) classified OC use according to the dosage of EE and potency/dosage of progestin. Neither high-dose EE/low-progestin nor low-EE/low-progestin (OR 0.59; 95% CI: 0.26–1.30) altered the risk. When high- and low-progestin combinations were assessed independently of EE dosage, significant risk reduction was shown (OR 0.21; 95% CI: 0.05–0.84).

The Cancer and Steroid Hormone Study (CASH; Maxwell et al., 2006) also focused on hormonal potencies, and evaluated 434 endometrial cancer cases and 2557 controls. Compared with non-users, both high-progestin and low-progestin OC users had a significantly reduced risk (OR 0.21; 95% CI: 0.10–0.43 and OR 0.39; 0.25–0.60), but among women with BMI > 22 only high-progestin OC were protective (OR 0.31; 95% CI: 0.11–0.92).

Likewise, in a large population-based Swedish case–control study (n = 709/3368; Weiderpass et al., 1999) high-, medium- and low-progestin OC use reduced the risk, although significantly so only with high and medium dosages (adjusted OR 0.7; 95% CI: 0.5–0.9). This protective effect was similar for all degrees of tumour differentiation and invasiveness. Since only post-menopausal women aged 50–74 years have been investigated, subsequent use of hormone replacement therapy was assessed, and did not modify the protective effect of the OC used in younger age. The reduction of risk was measurable after 3 years of use (OR 0.5; 95% CI: 0.3–0.7), and increased with duration of intake, reaching 80% lower risk after 10 years of use (OR 0.2; 0.1–0.4), and as in the CASH study, the protective effect persisted for at least 15–20 years after cessation of OC use.

Similar results have been found in a German population-based case–control study (n = 485/1570; Heinemann et al., 2003). The reduction of risk was comparable for all OC formulation used (adjusted OR 0.36; 95% CI: 0.28–0.45, ever versus never), including low-dose OC (OR 0.30; 95% CI: 0.12–0.74). The protective effect started within 5 years usage (OR 0.63; 0.47–0.86), increased with duration of use, reaching 75% reduced risk after 10 years (OR 0.25; 0.18–0.34) and persisted for >10 years after cessation of OC.

Similar trends also were observed in large recent Chinese case–control study (Tao et al., 2006; n = 1204/1212). The risk for ever users of OC was decreased (OR = 0.75; 95% CI: 0.60–0.93), the protective effect increased with duration of use (5 years or more: OR = 0.50; 95% CI: 0.30–0.85) and persisted for 25 years after cessation of use (OR = 0.57; 95% CI: 0.42–0.78).

The 2006 update of the Oxford FPA cohort study, evaluating 17 032 women and 77 cases, showed a >50% risk reduction in ever users (RR = 0.1 for 97+ months; 95% CI: 0.0–0.4) and a protective effect lasting >20 years after OC cessation (Vessey and Painter, 2006). In this analysis the data for the cancers of the cervix, uterine body and ovary were combined, resulting in age-adjusted RR of 0.7 (95% CI: 0.5–0.8).

Time dependency of risk modulation

The increasing protective effect with duration of OC use has been found in most studies investigating this issue. A systematic meta-analysis (Schlesselman, 1997) including 10 case–control studies and the RCGP cohort study (Beral et al., 1988), calculated a significant reduction of risk with RR of 0.44, 0.33, 0.28 after 4, 8 and 12 years of OC use, respectively, on the basis of 33 time-dependent estimates of RR, adjusted for age, adiposity, parity and use of estrogen replacement therapy. The trend of decreasing risk with increasing duration of OC use was highly significant (P < 0.0001, one-sided).

In this meta-analysis, the adjusted RR was also calculated by recency of use, based on 19 RR estimates. After OC cessation, the risk decrease persisted for 20 years after discontinuation, and the trend for decrease of risk reduction was significant (P = 0.011, one-sided), but still remained about 50% (RR 0.33, 0.41, 0.51 after 5, 10, 20 years after discontinuation). Of interest is the fact that the residual protective effect from prior OC use continues through menopause, a time when the risk of endometrial cancer is greatest.

Confounding factors

As previously described, the hormonal dosage has only a minor impact on the protective effect of OC, although use of higher progestin potency components in women of higher risk, especially in obese women has been suggested (Tao et al., 2006). Although a number of studies have adjusted for factors such as age, family history, BMI, parity and smoking, these studies are limited by small subgroup numbers (Stanford et al., 1993). On the basis of the available data, it appears that these factors have only minor influence, if at all, on the protective effect of OC.

Age, a strong risk factor for endometrial cancer, did not influence the protective effect in the Swedish case–control study, and long-term exposure to endogenous estrogen had no modulating effect, comparing women with different intervals of OC use and menopause (Weiderpass et al., 1999). Positive or negative family history was also without effect, as demonstrated in the German study (Heinemann et al., 2003; OR 0.44; 95% CI: 0.27–0.71 and OR 0.31; 95% CI: 0.23–0.41), whereas genetics may have only minor impact on endometrial cancer risk, even with first degree family history of any specific site (e.g. endometrium, colon, breast; Olson et al., 1999; Terry et al., 1999).

Obesity is a well-known strong risk factor for endometrial cancer; 2–20-fold increase of risk was observed in more than 20 reports (Grimes and Economy, 1995). For women on OC, the protective effect against endometrial cancer was found to be decreased in obese compared with non-obese women (Henderson et al., 1983; Maxwell et al., 2006), however, no modulating effect of obesity has also been reported (WHO, 1988; Weiderpass et al., 1999). Nulliparity, strong risk factor for endometrial cancer (Parazzini et al., 1998; Salvesen et al., 1998; Terry et al., 1999), did not influence the protective effect of OC (Weiderpass et al., 1999; Maxwell et al., 2006). Likewise smoking did not have any effect on the cancer protection caused by the use of OC (Weiderpass et al., 1999) although the risk of endometrial cancer in smokers is reduced up to 50% due to increased hepatic estrogen metabolism (Mueck and Seeger, 2003).

Conclusions

More than 15 case–control studies and at least four large cohort studies demonstrated a decrease of the risk of endometrial cancer of about 50% with ever use of OC. In most of these studies this protective effect persisted for up to 20 years after stopping of OC use. Longer duration of use is associated with an increased protective effect. The beneficial effect is independent of the OC formulation and not dependent on modulating or known risk factors of endometrial cancer, although in high-risk patients OC formulations with higher progestin potency seem to be more beneficial. OC use effectively reduces endometrial hyperplasia, but should only be used in exceptional cases in patients with or after endometrial cancer.

Cervical cancer

Introduction

The causal role of human papillomavirus (HPV) infections in cervical cancer has been documented beyond reasonable doubt (Cogliano et al., 2005a, b; Leppaluoto, 2006). Co-factors that modify the risk among HPV DNA-positive women include contraceptive method, smoking, high parity and previous exposure to other sexually transmitted diseases such as chlamydia trachomatis and herpes simplex virus type 2. The identification of such co-factors, however, requires an adequate control for the strong effect of HPV and a large study population.

Risk in OC users

IARC conducted a study between 1985 and 1993 in 10 countries which covers the demands for adequate control and study population to detect of the reproductive co-factors. This study included nearly 2000 women with cervical cancer and a similar number of healthy control women recruited from high-risk areas for cervical cancer in Colombia, Brazil, Peru, Paraguay and Morocco, from intermediate-risk areas in Thailand and the Philippines, and from Spain, a low-risk country. To take into account the strong causative effect of HPV, the main analyses were restricted to women who were infected by the virus. Two reports from the IARC study have been published. One analyses the effects of parity (Munoz et al., 2002) whereas the other concerns combined OC (Moreno et al., 2002). The data demonstrated that women who had five children or more had a 3-fold increase in risk compared with women with no children. Women who had an HPV infection and who have used OC for over 5 years have a 3-fold increase in the risk of cervical cancer compared with never users. The impact of parity has been verified in a later meta-analysis (ICESCC, 2006) and may partly explain the differences in cervical cancer between developed and developing countries.

A systematic review (Smith et al., 2003) confirmed the association between long-term OC use and increased risk of cervical cancer and in 2005, a Working Group for the IARC classified OC as carcinogenic to the human uterine cervix (Cogliano et al., 2005a, b). The IARC statement was based upon the results of clinical, in vitro and animal studies, suggesting in concordance that estrogens and progestins may enhance expression of certain HPV genes and stimulate cell proliferation in the human cervix through hormone-response elements in the viral genome and through receptor-mediated mechanisms. However, there is reason for caution. Although cervical cancer is caused by HPV infection, exposure to genital HPV is not independent of OC use (Hogewoning et al., 2003). Women using OC are more likely to be exposed to HPV than are those using barrier contraceptive methods or not having sexual intercourse. OC formulations used in the late 1960s and 1970s contained higher dosages of EE and different types and doses of progestins than the currently used formulations. Thus, long-term OC users would have started with higher dose OCs, with a progressive switch to the lower dose formulations used today. The incidence of cervical cancer increases with age and so the contribution of OC to the lifetime incidence of cervical cancer will depend largely on the effects at ages, when most women are past users. The public health concern and the key question is to what extent any adverse effect of OC use persists after women stop taking them. In the 2006 update on the Oxford FPA study significantly increased RR are apparent in the 49–144 months group (RR = 3.9; 95% CI: 1.4–12.3) and the 145–240 months group (RR = 4.6; 95% CI: 1.5–15.6) suggesting that some adverse effect of OC on cervical cancer may persist for many years after cessation of use (Vessey and Painter, 2006). Less convincing is the update on the cohort data from the RCGP Oral Contraceptive Study. It demonstrates no increased risk of invasive cervical cancer, although a significant increasing trend in RR was found in the subgroup of women after OC use for more than 8 years (2.73; 1.61–4.61; Hannaford et al., 2007). The recent meta-analysis from the International Collaboration of Epidemiological Studies of Cervical Cancer has provided the most important information on the effect of duration on OC use. Information from 24 studies worldwide including individual data for 16 573 women with cervical cancer and 35 509 without cervical cancer were reanalysed centrally. RR of cervical cancer was estimated by conditional logistic regression, stratifying by study, age, number of sexual partners, age at first intercourse, parity, smoking and screening. Among current users of OC the RR of invasive cervical cancer increased with increasing duration of use (5 or more years use RR = 1.90; 95% CI: 1.69–2.13). The risk declined after use ceased, and by 10 or more years had returned to that of never users. A similar pattern of risk was seen both for invasive and in situ cancer, and in women who tested positive for high-risk HPV. The interpretation from the authors is that the RR of cervical cancer is increased in current users of OC and declines after use ceases. Ten years' use of OC from around age 20–30 years is estimated to increase the cumulative incidence of invasive cervical cancer by age 50 from 7.3 to 8.3 per 1000 in less developed countries and from 3.8 to 4.5 per 1000 in more developed countries.

Conclusion

Cervical cancer is caused by HPV infection. It is of obvious importance to elucidate what factors affect the development of cervical cancer in women exposed to HPV. Exposure to genital HPV is significantly related to contraceptive method with condom use preventing infection and ameliorating cure and IUD/LNG-IUS without significant impact on subsequent cancer development. Despite the risk of residual confounding from non-hormonal co-variables, early and more recent studies demonstrate an association, whether causal or promoting, with long-term (>5 years) use of OC. The association is diminished after cessation of OC use and is very weak 10 years after last use. Consequently long-term users of OC deserve specific targeting for cervical cancer screening programmes. Improved screening programmes and initiation of vaccination against HPV infection in the adolescence period establish a new paradigm in cervical cancer control and fear of the disease should not be a reason to avoid OC use.

Other cancers

Benign and malignant liver tumours

Benign liver tumours, including hepatocellular adenoma (HA), focal nodular hyperplasia (FNH) and hepatic haemangiomas (HH) are more common in women than in men and have been associated with female hormones and hormone-related factors, including pregnancy and OC use (La Vecchia and Tavani, 2006). However, these diseases are exceedingly rare in young women (Hannaford et al., 1997).

With reference to HA, in a case–control study from the USA, 82% of 34 cases had ever used OC versus 56% of 34 controls. The RR were 1.3 for 1–3 years of OC use, 5.0 for 5–7 years, 7.5 for 8–11 years and 25 for >11 years (Edmondson et al., 1976). In another USA study, 91% of 74 cases of HA and 45% of 220 controls had used OC for >12 months. The RR was 9 for 13–36 months, 116 for 37–60 months, 123 for 61–84 months and 503 for ≥85 months (Rooks et al., 1979). In a more recent multicentric case–control study of 51 HA cases and 240 population controls from Germany, the RR for ever OC use was 1.25 (95% CI: 0.37–4.22; Heinemann et al., 1998). There was no relation between duration and age at first or last OC use and the prevalence of HA. The data mainly reflected recent low-dose OC. There is therefore evidence that HA is strongly related to current and recent (first generation, high-dose) OC use. Low-dose OC appears less strongly associated with HA, if at all. Moreover, HA remains exceedingly rare in young women, even among long-term OC users.

A role for female hormones has also been suggested in FNH, given the female predominance of the disease. Of women diagnosed with FNH, 51–75% of cases are OC users, particularly those with symptoms and large nodules. In a study of 216 women, OC use did not influence the size of FNH, and pregnancy was unrelated to FNH changes or complications (Mathieu et al., 1998). However, in a multicentric case–control study of 143 cases of FNH and 240 population controls, the RR for ever OC use was 1.96 (95% CI: 0.85–4.57). The RR increased with longer duration and more recent usage (Heinemann et al., 1998). In another case–control study of 25 FNH cases and 94 controls, the multivariate RR was 2.8 (95% CI: 0.8–9.4) for ever OC use and increased to 4.5 (95% CI: 1.2–16.9) for OC use lasting ≥3 years. The trend in risk with duration was significant (Scalori et al., 2002).

Liver cancer (hepatocellular carcinoma) is also exceedingly rare in young women. The evidence of OC and liver cancer is based on at least 12 case–control studies, including 739 cases and 5223 controls, which were reviewed in a meta-analysis (Maheshwari et al., 2007). The overall RR was 1.57 (95% CI: 0.96–2.54), with some evidence of duration-risk association in six studies. Exclusion of a recent multinational European study increased the pooled RR to 1.70 (95% to 1.12–2.59) and decreased heterogeneity. The association is less strong in studies from developing countries, where hepatitis B and C infections are more common (IARC, 2007). It is also possible that the RR is smaller for recent, low hormone OC formulations.

There was no evidence of persistent liver cancer excess risk after stopping OC use. Thus, there was no excess liver cancer incidence in the long-term follow-up of the RCGP Oral Contraceptive Study, based on 27 cases of liver and gallbladder cancer (Hannaford et al., 2007). Consequently, the long-term public health implications of any modest excess liver cancer risk among current OC users are also minimal.

Colorectal cancer

In a meta-analysis of epidemiological studies on colorectal cancer published up to June 2000, and including quantitative information on OC use, the pooled RR of colorectal cancer for ever OC use was 0.81 from eight case–control studies, 0.84 from four cohort studies and 0.82 from all studies combined (Fernandez et al., 2001). However, no relation with duration of use was observed. The pattern of risk was similar for colon and rectal cancer. Among studies published after that meta-analysis, the RR was 0.8 (95% CI: 0.4–1.7) for ever OC use in a Swiss case–control study on 131 women with colorectal cancer (Levi et al., 2003). The Oxford FPA cohort study, including 46 cases of colorectal cancer, reported no association with OC use (Vessey et al., 2003). In a cohort study of female textile workers in China, including 655 women with colorectal cancer, the RR was 1.56 (95% CI: 1.01–2.40) for women who had used OC for over 3 years, in the absence, however, of any trend in risk with duration of OC use (Rosenblatt et al., 2004). In a nested case–control study within the RCGP Oral Contraception Study, there were 146 cases of colorectal cancer (Hannaford and Elliott, 2005). The RR was 0.84 for ever users, with greater reduction in risk for current (RR = 0.38) than for former (RR = 0.89) users. In a later paper (of up to 38 years of follow-up) there were 323 cases of colorectal cancer and a RR of 0.72 for ever OC users (Hannaford et al., 2007). In a case–control study from USA, including 1722 cases of colon cancer, 366 of rectal cancer and 4297 population controls, the overall RR for ever OC use was 0.89 (95% CI: 0.75–1.06) with no difference between colon (RR = 0.88) and rectal (RR = 0.87) cancer. For rectal, but not for colon cancer, there was some indication of a stronger inverse relation for recent use (Nichols et al., 2005). In the 11 years follow-up of the Women's Health Study, including 267 cases of colorectal cancer, the RR for ever OC use was 0.67 (95% CI: 0.50–0.89), with little evidence, however, of duration-risk relation (Lin et al., 2007). In a cohort study of Canadian women within a breast cancers screening program, followed for an average of 16.4 years, there were 1142 incident colorectal cancers. The overall RR for ever OC use was 0.83 (95% CI: 0.73–0.94). There was no relation with duration of OC use (Kabat et al., 2008).

Table IV gives the main results from 11 case–control studies giving information on OC and colorectal cancer risk, and Table V corresponding data from nine cohort studies. The overall RR was 0.82 for both case–control and cohort studies, and the summary RR, including both case–control and cohort studies, was also 0.82 (95% CI: 0.72–0.93). Corresponding values were 0.85 (95% CI: 0.79–0.83) for colon and 0.80 (95% CI: 0.70–0.92) for rectal cancer (Bosetti et al., 2009).

Table IV

Case–control studies on effect of OC use and colorectal cancer risk.

Reference Country, study acronym Site No. of cases No. of controls Relative riska (95% CI) 
Weiss et al. (1981Washington State, USA Colorectum 143 707 1.58 (0.80–3.10) 
Potter and McMichael (1983Adelaide, Australia Colorectum 155 311 0.61 (0.52–0.72) 
Colon 199 0.50 (0.25–1.00) 
Rectum 56 0.70 (0.29–1.71) 
Furner et al. (1989Chicago, USA Colorectum 90 208 0.62 (0.28–1.36) 
Kune et al. (1990Melbourne, Australia Colorectum 190 200 1.36 (0.21–1.53) 
Colon 108 1.17 (0.59–2.31) 
Rectum 82 2.04 (1.00–4.15) 
Peters et al. (1990Los Angeles, USA Colon 327 327 1.03 (0.64–1.66) 
Wu-Williams et al. (1991North America Colorectum 189 494 0.84 (0.75–0.94) 
Colon 114 1.20 (0.52–2.78) 
Rectum 75 0.40 (0.17–0.96) 
Wu-Williams et al. (1991China Colorectum 206 618 0.70 (0.61–0.82) 
Colon 78 0.55 (0.19–1.59) 
Rectum 128 0.70 (0.34–1.46) 
Kampman et al. (1997) USA, KPMC Colon 894 1120 0.86 (0.67–1.10) 
Fernandez et al. (1996Italy Colorectum 1232 2793 0.64 (0.49–0.85) 
Talamini et al. (1998Colon 803 0.63 (0.45–0.88) 
Fernandez et al. (1998)b Rectum 429 0.66 (0.43–1.01) 
Levi et al. (2003Switzerland Colorectum 131 373 0.83 (0.40–1.71) 
Nichols et al. (2005WI, USA Colorectum 1488 4297 0.89 (0.75–1.06) 
Colon 1112 0.87 (0.72–1.06) 
Rectum 366 0.87 (0.65–1.17) 
Reference Country, study acronym Site No. of cases No. of controls Relative riska (95% CI) 
Weiss et al. (1981Washington State, USA Colorectum 143 707 1.58 (0.80–3.10) 
Potter and McMichael (1983Adelaide, Australia Colorectum 155 311 0.61 (0.52–0.72) 
Colon 199 0.50 (0.25–1.00) 
Rectum 56 0.70 (0.29–1.71) 
Furner et al. (1989Chicago, USA Colorectum 90 208 0.62 (0.28–1.36) 
Kune et al. (1990Melbourne, Australia Colorectum 190 200 1.36 (0.21–1.53) 
Colon 108 1.17 (0.59–2.31) 
Rectum 82 2.04 (1.00–4.15) 
Peters et al. (1990Los Angeles, USA Colon 327 327 1.03 (0.64–1.66) 
Wu-Williams et al. (1991North America Colorectum 189 494 0.84 (0.75–0.94) 
Colon 114 1.20 (0.52–2.78) 
Rectum 75 0.40 (0.17–0.96) 
Wu-Williams et al. (1991China Colorectum 206 618 0.70 (0.61–0.82) 
Colon 78 0.55 (0.19–1.59) 
Rectum 128 0.70 (0.34–1.46) 
Kampman et al. (1997) USA, KPMC Colon 894 1120 0.86 (0.67–1.10) 
Fernandez et al. (1996Italy Colorectum 1232 2793 0.64 (0.49–0.85) 
Talamini et al. (1998Colon 803 0.63 (0.45–0.88) 
Fernandez et al. (1998)b Rectum 429 0.66 (0.43–1.01) 
Levi et al. (2003Switzerland Colorectum 131 373 0.83 (0.40–1.71) 
Nichols et al. (2005WI, USA Colorectum 1488 4297 0.89 (0.75–1.06) 
Colon 1112 0.87 (0.72–1.06) 
Rectum 366 0.87 (0.65–1.17) 

KPMC, Kaiser Permanente Medical Care.

aEver versus never use.

bPooled analysis of data from Fernandez et al. (1996) and Talamini et al. (1998).

Table V

Cohort studies on effect of OC use and colorectal cancer risk.

Reference Country, study acronym Site No. of cases Cohort size Follow-up Relative riska (95% CI) 
Martinez et al. (1997USA, NHS Colorectum 501 89 448 12 years 0.84 (0.69–1.02) 
Colon 396 89 448 0.64 (0.40–1.02) 
Rectum 105 89 448 0.76 (0.49–1.18) 
Bostick et al. (1994IA, USA, WHS Colon 212 35 215 4 years 0.96 (0.67–1.38) 
Troisi et al. (1997USA, BCDDP Colorectum 330 57 529 10 years 1.00 (0.73–1.37) 
Van Wayenburg et al. (2000Netherlands Colorectum 95b 10 671 18 years 0.68 (0.21–2.21) 
Vessey et al. (2003UK, OPFA Colorectum 46b 17 032 30 years 0.92 (0.57–1.51) 
Rosenblatt et al. (2004China Colon 655 267 400 10 years 1.09 (0.86–1.38) 
Hannaford et al. (2007) UK, RCGP OC Colorectum 323 46 000 35 years 0.72 (0.58–0.90) 
Lin et al. (2007USA, WHI Colorectum 267 39 680 11 years 0.67 (0.50–0.89) 
Colon 205 0.73 (0.52–1.02) 
Rectum 55 0.52 (0.28–0.96) 
Kabat et al. (2008Canada, CNBSS Colorectum 1142 89 835 16 years 0.83 (0.73–0.94) 
Colon 790 0.81 (0.70–0.94) 
Rectum 366 0.85 (0.66–1.05) 
Reference Country, study acronym Site No. of cases Cohort size Follow-up Relative riska (95% CI) 
Martinez et al. (1997USA, NHS Colorectum 501 89 448 12 years 0.84 (0.69–1.02) 
Colon 396 89 448 0.64 (0.40–1.02) 
Rectum 105 89 448 0.76 (0.49–1.18) 
Bostick et al. (1994IA, USA, WHS Colon 212 35 215 4 years 0.96 (0.67–1.38) 
Troisi et al. (1997USA, BCDDP Colorectum 330 57 529 10 years 1.00 (0.73–1.37) 
Van Wayenburg et al. (2000Netherlands Colorectum 95b 10 671 18 years 0.68 (0.21–2.21) 
Vessey et al. (2003UK, OPFA Colorectum 46b 17 032 30 years 0.92 (0.57–1.51) 
Rosenblatt et al. (2004China Colon 655 267 400 10 years 1.09 (0.86–1.38) 
Hannaford et al. (2007) UK, RCGP OC Colorectum 323 46 000 35 years 0.72 (0.58–0.90) 
Lin et al. (2007USA, WHI Colorectum 267 39 680 11 years 0.67 (0.50–0.89) 
Colon 205 0.73 (0.52–1.02) 
Rectum 55 0.52 (0.28–0.96) 
Kabat et al. (2008Canada, CNBSS Colorectum 1142 89 835 16 years 0.83 (0.73–0.94) 
Colon 790 0.81 (0.70–0.94) 
Rectum 366 0.85 (0.66–1.05) 

BCDDP, Breast Cancer Detection Demostration Project; CNBSS, Canadian National Breast Screening Study; NHS, Nurses' Health Study; OFPA, Oxford Family Planning Association; OC, oral contraceptives; RCGP, Royal College of General Practitioners; WHI, Women's Health Initiative; WHS, Women Health Study.

aEver versus never use.

bDeaths.

Only a few studies (Fernandez et al., 1998; Beral et al., 1999; Levi et al., 2003; Nichols et al., 2005; Hannaford et al., 2007) included information on recency of use, and gave some indication that the apparent protection was stronger for women who had used OC more recently. Scant information was available on type of OC, however, no consistent pattern of trends was observed across calendar year of use (which in most countries is a good proxy of type of OC formulation).

Lung cancer

A population-based case–control study of 811 women with lung cancer and 922 controls from Germany (Kreuzer et al., 2003) showed a reduced lung cancer risk (RR 0.69, 95% CI: 0.51–0.92) among ever OC users, in the absence, however, of any trend in risk with duration of use, age at first use, or calendar year at first use. The RR was non-significantly above unity in the 30-year follow-up of the Oxford FPA cohort study (Vessey et al., 2003), and 1.05 (95% CI: 0.82–1.35) in the 35-year follow-up of the RCGP cohort study, based on 297 cases (Hannaford et al., 2007). There is therefore inadequate evidence on the relation between OC use and lung cancer risk, but it is unlikely that any major association is present.

Other cancers

Information on OC use and cutaneous malignant melanoma was available from at least 4 cohorts at 18 case–control studies (IARC, 2007). There was no consistent association and a pooled analysis of case–control studies gave an overall RR of 1.0 (95% CI: 0.9–1.0).

The results of 13 case–control studies of thyroid cancer were also reviewed in a collaborative re-analysis of original data (La Vecchia et al., 1999). The overall RR for current OC users was 1.5 (95% CI: 1.0–2.1), which declined to 1.1 10 years after cessation of OC use. Six subsequent studies were revised (IARC, 2007), of which, one gave a RR below unity, one above unity, and the remaining four close to unity.

OC use was considered in a small number of studies for various additional neoplasms, including oesophageal, gastric, pancreatic, gallbladder, renal cell, neuroblastoma and Hodgkin's and non-Hodgkin's lymphomas (IARC, 2007). For none of them, there was adequate evidence of association. Only gestational trophoblastic disease was directly associated with OC use in two studies with RR of 1.8 (Palmer et al., 1999) and 1.5 (Parazzini et al., 2002), both of borderline significance.

Conclusion

Current, but not past OC use, is associated with excess risk of benign liver tumours, and a modest excess risk of liver cancer. There was no evidence of association between OC use and lung, other digestive tract neoplasms, cutaneous malignant melanoma, thyroid cancer and any of the other neoplasms investigated (IARC, 2007). The data for colorectal cancer are suggestive of a favourable effect of OC, in the absence, however, of any consistent duration or recency risk relation. A better understanding of any potential relation between OC use and colorectal cancer may therefore help informed choice of contraception (La Vecchia et al., 2001; IARC, 2007).

Net cancer effect

Several researchers have constructed statistical models to estimate the net effect of oral contraception on combined risk of all reproductive cancers (Petitti and Porterfield, 1992), or breast, uterine cervix, endometrial, ovarian and liver cancer (Schlesselman, 1995). Such modelling makes several important assumptions, which cohort studies do not need to make since they measure directly the risks and benefits associated with an exposure, although any combining of events implies equivalence of importance.

Twelve-year mortality data from the Nurses Health Study of 167 000 women recruited in North America in 1976, revealed no difference in the risk of death from any cancer among ever and never users of OC (adjusted RR (ARR) 0.92, 95% CI 0.81–1.03; Colditz, 1994). Similarly, there was no difference in the rate of any cancer death in the same groups among 46 000 British women recruited to the RCGP Oral Contraception Study in the late 1960s and followed up for 25 years (ARR 1.0, 95% CI: 0.8–1.1; Beral et al., 1999).

Several cohort studies have examined the risk of various combinations of incident cancer among OC users. In 1988, the RCGP study reported on all invasive genital cancer, using data available at the end of the late 1980s (Beral et al., 1988). The balance of events among ever users of OC was neutral, when compared with never users (ARR 1.0, 95% CI: 0.5–1.7). A Norwegian study of 96 000 women recruited between 1991 and 1997, and followed up to 1999, found no significant association between OC use and the combined risk of breast, endometrial and ovarian cancer (Kumle et al., 2003). Follow-up to December 2004 of 17 000 women recruited in Britain between 1968 and 1974 for the Oxford Family FPA Oral Contraceptive Study, to December 2004, revealed a significantly reduced risk of any gynaecological cancer among OC ever users compared with never users (ARR 0.7, 95% CI: 0.5–0.8; Vessey and Painter, 2006). An almost identical reduction in risk of all main gynaecological cancers was also found by the RCGP study in 2007 when it examined incident cancers accumulated during 36 years of follow-up (ARR 0.71, 95% CI: 0.60–0.85; Hannaford et al., 2007). The changing risk estimate from the RCGP study over time, suggests that as OC users age persisting protection against ovarian and endometrial cancer has a progressively greater impact on the balance of cancers experienced.

The latest RCGP analysis also examined the overall risk of any type of incident cancer among ever and never users of OC (Hannaford et al., 2007). Ever users had a statistically significant 12% relative reduction in cancer risk (ARR 0.88, 95% CI: 0.83–0.94), which translated into an absolute risk reduction of about 45 fewer cases of cancer for every 100 000 woman years of OC use. The effect, however, was not uniform among all OC users. Subgroup analyses indicated that, compared with never users, women who used OC for short to medium-term lengths of time had a reduced risk of any cancer (up to 4 years: ARR 0.93, 95% CI: 0.82–1.06, 4–8 years use: ARR 0.85, 95% CI: 0.74–0.98), whereas long-term users had a significantly increased risk (more than 8 years: ARR 1.22, 95% CI: 1.07–1.39). The increased risk in long-term users was mostly because of a higher risk of invasive uterine cervical cancer. Importantly, most OC users in the study used the method for relatively short periods (median duration 44 months), so were not exposed to the higher risks of long-term use.

The experience of women living in Britain may not reflect that of women residing elsewhere, where levels of OC usage, duration of use, age at stopping and incidence of cancer may be different. A study of 259 000 Chinese textile workers recruited between 1989 and 1991, and followed up to 2000, found no association between OC use and overall risk of 12 site-specific (breast, colon, gallbladder, liver, lung, ovary, pancreas, rectum, stomach, thyroid, uterine cervix and uterine corpus) cancers (ARR 0.94, 95% CI: 0.88–1.01; Rosenblatt et al., 2009). This result is reassuring, although an important limitation of the study was the low prevalence of OC use, for relatively short durations.

There have been few studies examining the balance of cancer risks and benefits among users of other contraceptives. The Chinese cohort study of textile workers also examined the site-specific and combined risk of 12 cancers associated with use of monthly combined injectable contraceptives (Rosenblatt et al., 2007). There was no evidence of an altered risk of all cancers combined among users of the monthly injection (ARR 0.91, 95% CI: 0.81–1.03), although the prevalence and duration of use was low, thereby limiting the statistical power of the study. A smaller population-based Chinese cohort of 67 000 urban dwellers in Shanghai, recruited between 1997 and 2000 and follow-up for a median of 7.5 years, observed no increased overall risk of 11 major cancers (all of those reported in the textile worker study except uterine cervical cancer) among ever users of any contraceptive method, including OC, contraceptive injections, intrauterine devices and tubal sterilization (adjusted hazards ratio 1.02, 95% CI: 0.92–1.12; Dorjgochoo et al., 2009). Combined results for particular contraception methods were not reported separately, although site-specific findings were. An analysis of data from the RCGP study found that women who had a tubal sterilization had a similar risk of any cancer as that of those who did not have this operation (adjusted hazards ratio 0.92, 95% CI: 0.78–1.08; Iversen et al., 2007).

In conclusion, although the number of studies is small, several large cohort investigations have assessed, with prolonged follow-up, the risk of different combinations of cancer among contraceptive users. It is reassuring, therefore, that none of the studies have indicated an overall increased cancer risk among ever users of different contraceptives. Indeed, several have suggested, from a population perspective, important long-term benefits among ever users of OC.

Authors' roles

D.C.: author of chapter ‘Ovarian cancer’ and editor of the whole article. A.G.: author of chapter ‘Breast cancer’. A.O.M.: author of chapter ‘Endometrial cancer’. P.C.H.: author of chapter ‘Net effect’. C.L.V.: author of chapter ‘Other cancers’. S.O.S.: author of chapter ‘Cervical cancer’. M.Z.: co-editor of the article. L.D.: statistician.

Acknowledgement

Authors thank Prof. Piergiorgio Crosignani for his significant contribution.

References

ACS
Cancer Facts and Figures.
 , 
2006
Atlanta
American Cancer Society
Althuis
MD
Brogan
DR
Coates
RJ
Daling
JR
Gammon
MD
Malone
KE
Schoenberg
JB
Brinton
LA
Hormonal content and potency of oral contraceptives and breast cancer risk among young women
Br J Cancer
 , 
2003
, vol. 
88
 (pg. 
50
-
57
)
Amant
F
Moerman
P
Neven
P
Timmerman
D
Van Limbergen
E
Vergote
I
Endometrial cancer
Lancet
 , 
2005
, vol. 
366
 (pg. 
491
-
505
)
Anderson
GL
Judd
HL
Kaunitz
AM
Barad
DH
Beresford
SA
Pettinger
M
Liu
J
McNeeley
SG
Lopez
AM
Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial
J Am Med Assoc
 , 
2003
, vol. 
290
 (pg. 
1739
-
1748
)
Antoniou
AC
Rookus
M
Andrieu
N
Brohet
R
Chang-Claude
J
Peock
S
Cook
M
Evans
DG
Eeles
R
Nogues
C
, et al.  . 
Reproductive and hormonal factors, and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: results from the International BRCA1/2 Carrier Cohort Study
Cancer Epidemiol Biomarkers Prev
 , 
2009
, vol. 
18
 (pg. 
601
-
610
)
Barnett
GC
Shah
M
Redman
K
Easton
DF
Ponder
BA
Pharoah
PD
Risk factors for the incidence of breast cancer: do they affect survival from the disease?
J Clin Oncol
 , 
2008
, vol. 
26
 (pg. 
3310
-
3316
)
Beral
V
Hannaford
P
Kay
C
Oral contraceptive use and malignancies of the genital tract. Results from the Royal College of General Practitioners' Oral Contraception Study
Lancet
 , 
1988
, vol. 
2
 (pg. 
1331
-
1335
)
Beral
V
Hermon
C
Kay
C
Hannaford
P
Darby
S
Reeves
G
Mortality associated with oral contraceptive use: 25 year follow up of cohort of 46 000 women from Royal College of General Practitioners' oral contraception study
Br Med J
 , 
1999
, vol. 
318
 (pg. 
96
-
100
)
Beral
V
Bull
D
Green
J
Reeves
G
Ovarian cancer and hormone replacement therapy in the Million Women Study
Lancet
 , 
2007
, vol. 
369
 (pg. 
1703
-
1710
)
Beral
V
Doll
R
Hermon
C
Peto
R
Reeves
G
Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls
Lancet
 , 
2008
, vol. 
371
 (pg. 
303
-
314
)
Bosetti
C
Negri
E
Trichopoulos
D
Franceschi
S
Beral
V
Tzonou
A
Parazzini
F
Greggi
S
La Vecchia
C
Long-term effects of oral contraceptives on ovarian cancer risk
Int J Cancer
 , 
2002
, vol. 
102
 (pg. 
262
-
265
)
Bosetti
C
Bravi
F
Negri
E
La Vecchia
C
Oral contraceptives and colorectal cancer risk: a systematic review and meta-analysis
Hum Reprod Update
 , 
2009
, vol. 
15
 (pg. 
489
-
498
)
Bostick
RM
Potter
JD
Kushi
LH
Sellers
TA
Steinmetz
KA
McKenzie
DR
Gapstur
SM
Folsom
AR
Sugar, meat, and fat intake, and non-dietary risk factors for colon cancer incidence in Iowa women (United States)
Cancer Causes Control
 , 
1994
, vol. 
5
 (pg. 
38
-
52
)
Brinton
LA
Hoover
RN
Estrogen replacement therapy and endometrial cancer risk: unresolved issues. The Endometrial Cancer Collaborative Group
Obstet Gynecol
 , 
1993
, vol. 
81
 (pg. 
265
-
271
)
Brohet
RM
Goldgar
DE
Easton
DF
Antoniou
AC
Andrieu
N
Chang-Claude
J
Peock
S
Eeles
RA
Cook
M
Chu
C
, et al.  . 
Oral contraceptives and breast cancer risk in the international BRCA1/2 carrier cohort study: a report from EMBRACE, GENEPSO, GEO-HEBON, and the IBCCS Collaborating Group
J Clin Oncol
 , 
2007
, vol. 
25
 (pg. 
3831
-
3836
)
Bu
SZ
Yin
DL
Ren
XH
Jiang
LZ
Wu
ZJ
Gao
QR
Pei
G
Progesterone induces apoptosis and up-regulation of p53 expression in human ovarian carcinoma cell lines
Cancer
 , 
1997
, vol. 
79
 (pg. 
1944
-
1950
)
Casagrande
JT
Louie
EW
Pike
MC
Roy
S
Ross
RK
Henderson
BE
Incessant ovulation’ and ovarian cancer
Lancet
 , 
1979
, vol. 
2
 (pg. 
170
-
173
)
CASH
The reduction in risk of ovarian cancer associated with oral-contraceptive use. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development
N Engl J Med
 , 
1987
, vol. 
316
 (pg. 
650
-
655
)
CGHFBC
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. Collaborative Group on Hormonal Factors in Breast Cancer
Lancet
 , 
1996
, vol. 
347
 (pg. 
1713
-
1727
)
CGHFBC
Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease
Lancet
 , 
2001
, vol. 
358
 (pg. 
1389
-
1399
)
Cheng
W
Liu
J
Yoshida
H
Rosen
D
Naora
H
Lineage infidelity of epithelial ovarian cancers is controlled by HOX genes that specify regional identity in the reproductive tract
Nat Med
 , 
2005
, vol. 
11
 (pg. 
531
-
537
)
Cogliano
V
Baan
R
Straif
K
Grosse
Y
Secretan
B
El Ghissassi
F
Carcinogenicity of human papillomaviruses
Lancet Oncol
 , 
2005
, vol. 
6
 pg. 
204
 
Cogliano
V
Grosse
Y
Baan
R
Straif
K
Secretan
B
El Ghissassi
F
Carcinogenicity of combined oestrogen-progestagen contraceptives and menopausal treatment
Lancet Oncol
 , 
2005
, vol. 
6
 (pg. 
552
-
553
)
Colditz
GA
Oral contraceptive use and mortality during 12 years of follow-up: the Nurses' Health Study
Ann Intern Med
 , 
1994
, vol. 
120
 (pg. 
821
-
826
)
Colditz
GA
Rosner
BA
Speizer
FE
Risk factors for breast cancer according to family history of breast cancer. For the Nurses' Health Study Research Group
J Natl Cancer Inst
 , 
1996
, vol. 
88
 (pg. 
365
-
371
)
Cotterchio
M
Kreiger
N
Theis
B
Sloan
M
Bahl
S
Hormonal factors and the risk of breast cancer according to estrogen- and progesterone-receptor subgroup
Cancer Epidemiol Biomarkers Prev
 , 
2003
, vol. 
12
 (pg. 
1053
-
1060
)
Cramer
DW
Welch
WR
Determinants of ovarian cancer risk. II. Inferences regarding pathogenesis
J Natl Cancer Inst
 , 
1983
, vol. 
71
 (pg. 
717
-
721
)
Cummings
SR
Tice
JA
Bauer
S
Browner
WS
Cuzick
J
Ziv
E
Vogel
V
Shepherd
J
Vachon
C
Smith-Bindman
R
, et al.  . 
Prevention of breast cancer in postmenopausal women: approaches to estimating and reducing risk
J Natl Cancer Inst
 , 
2009
, vol. 
101
 (pg. 
384
-
398
)
Dickey
RP
Stone
SC
Progestational potency of oral contraceptives
Obstet Gynecol
 , 
1976
, vol. 
47
 (pg. 
106
-
112
)
Dolle
JM
Daling
JR
White
E
Brinton
LA
Doody
DR
Porter
PL
Malone
KE
Risk factors for triple-negative breast cancer in women under the age of 45 years
Cancer Epidemiol Biomarkers Prev
 , 
2009
, vol. 
18
 (pg. 
1157
-
1166
)
Dorjgochoo
T
Shu
XO
Li
HL
Qian
HZ
Yang
G
Cai
H
Gao
YT
Zheng
W
Use of oral contraceptives, intrauterine devices and tubal sterilization and cancer risk in a large prospective study, from 1996 to 2006
Int J Cancer
 , 
2009
, vol. 
124
 (pg. 
2442
-
2449
)
dos Santos Silva
I
Swerdlow
AJ
Recent trends in incidence of and mortality from breast, ovarian and endometrial cancers in England and Wales and their relation to changing fertility and oral contraceptive use
Br J Cancer
 , 
1995
, vol. 
72
 (pg. 
485
-
492
)
Dumeaux
V
Alsaker
E
Lund
E
Breast cancer and specific types of oral contraceptives: a large Norwegian cohort study
Int J Cancer
 , 
2003
, vol. 
105
 (pg. 
844
-
850
)
Edmondson
HA
Henderson
B
Benton
B
Liver-cell adenomas associated with use of oral contraceptives
N Engl J Med
 , 
1976
, vol. 
294
 (pg. 
470
-
472
)
Fathalla
MF
Incessant ovulation–a factor in ovarian neoplasia?
Lancet
 , 
1971
, vol. 
2
 pg. 
163
 
Fernandez
E
La Vecchia
C
D'Avanzo
B
Franceschi
S
Negri
E
Parazzini
F
Oral contraceptives hormone replacement therapy the risk of colorectal cancer
Br J Cancer
 , 
1996
, vol. 
73
 (pg. 
1431
-
1435
)
Fernandez
E
La Vecchia
C
Franceschi
S
Braga
C
Talamini
R
Negri
E
Parazzini
F
Oral contraceptive use and risk of colorectal cancer
Epidemiology
 , 
1998
, vol. 
9
 (pg. 
295
-
300
)
Fernandez
E
La Vecchia
C
Balducci
A
Chatenoud
L
Franceschi
S
Negri
E
Oral contraceptives and colorectal cancer risk: a meta-analysis
Br J Cancer
 , 
2001
, vol. 
84
 (pg. 
722
-
727
)
Figueiredo
JC
Haile
RW
Bernstein
L
Malone
KE
Largent
J
Langholz
B
Lynch
CF
Bertelsen
L
Capanu
M
Concannon
P
, et al.  . 
Oral contraceptives and postmenopausal hormones and risk of contralateral breast cancer among BRCA1 and BRCA2 mutation carriers and noncarriers: the WECARE Study
Breast Cancer Res Treat
 , 
2010
, vol. 
120
 (pg. 
175
-
183
)
Folger
SG
Marchbanks
PA
McDonald
JA
Bernstein
L
Ursin
G
Berlin
JA
Daling
JR
Norman
SA
Strom
BL
Weiss
LK
, et al.  . 
Risk of breast cancer associated with short-term use of oral contraceptives
Cancer Causes Control
 , 
2007
, vol. 
18
 (pg. 
189
-
198
)
Furner
SE
Davis
FG
Nelson
RL
Haenszel
W
A case–control study of large bowel cancer and hormone exposure in women
Cancer Res
 , 
1989
, vol. 
49
 (pg. 
4936
-
4940
)
Gaffield
ME
Culwell
KR
Ravi
A
Oral contraceptives and family history of breast cancer
Contraception
 , 
2009
, vol. 
80
 (pg. 
372
-
380
)
Gill
JK
Press
MF
Patel
AV
Bernstein
L
Oral contraceptive use and risk of breast carcinoma in situ (United States)
Cancer Causes Control
 , 
2006
, vol. 
17
 (pg. 
1155
-
1162
)
Grabrick
DM
Hartmann
LC
Cerhan
JR
Vierkant
RA
Therneau
TM
Vachon
CM
Olson
JE
Couch
FJ
Anderson
KE
Pankratz
VS
, et al.  . 
Risk of breast cancer with oral contraceptive use in women with a family history of breast cancer
J Am Med Assoc
 , 
2000
, vol. 
284
 (pg. 
1791
-
1798
)
Graham
JD
Mote
PA
Salagame
U
van Dijk
JH
Balleine
RL
Huschtscha
LI
Reddel
RR
Clarke
CL
DNA replication licensing and progenitor numbers are increased by progesterone in normal human breast
Endocrinology
 , 
2009
, vol. 
150
 (pg. 
3318
-
3326
)
Greer
JB
Modugno
F
Allen
GO
Ness
RB
Short-term oral contraceptive use and the risk of epithelial ovarian cancer
Am J Epidemiol
 , 
2005
, vol. 
162
 (pg. 
66
-
72
)
Grimes
DA
Economy
KE
Primary prevention of gynecologic cancers
Am J Obstet Gynecol
 , 
1995
, vol. 
172
 (pg. 
227
-
235
)
Gwinn
ML
Lee
NC
Rhodes
PH
Layde
PM
Rubin
GL
Pregnancy, breast feeding, and oral contraceptives and the risk of epithelial ovarian cancer
J Clin Epidemiol
 , 
1990
, vol. 
43
 (pg. 
559
-
568
)
Haile
RW
Thomas
DC
McGuire
V
Felberg
A
John
EM
Milne
RL
Hopper
JL
Jenkins
MA
Levine
AJ
Daly
MM
, et al.  . 
BRCA1 and BRCA2 mutation carriers, oral contraceptive use, and breast cancer before age 50
Cancer Epidemiol Biomarkers Prev
 , 
2006
, vol. 
15
 (pg. 
1863
-
1870
)
Hankinson
SE
Colditz
GA
Hunter
DJ
Spencer
TL
Rosner
B
Stampfer
MJ
A quantitative assessment of oral contraceptive use and risk of ovarian cancer
Obstet Gynecol
 , 
1992
, vol. 
80
 (pg. 
708
-
714
)
Hankinson
SE
Colditz
GA
Manson
JE
Willett
WC
Hunter
DJ
Stampfer
MJ
Speizer
FE
A prospective study of oral contraceptive use and risk of breast cancer (Nurses' Health Study, United States)
Cancer Causes Control
 , 
1997
, vol. 
8
 (pg. 
65
-
72
)
Hannaford
P
Elliott
A
Use of exogenous hormones by women and colorectal cancer: evidence from the Royal College of General Practitioners' Oral Contraception Study
Contraception
 , 
2005
, vol. 
71
 (pg. 
95
-
98
)
Hannaford
PC
Kay
CR
Vessey
MP
Painter
R
Mant
J
Combined oral contraceptives and liver disease
Contraception
 , 
1997
, vol. 
55
 (pg. 
145
-
151
)
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
Br Med J
 , 
2007
, vol. 
335
 pg. 
651
 
Heimdal
K
Skovlund
E
Moller
P
Oral contraceptives and risk of familial breast cancer
Cancer Detect Prev
 , 
2002
, vol. 
26
 (pg. 
23
-
27
)
Heinemann
LA
Weimann
A
Gerken
G
Thiel
C
Schlaud
M
DoMinh
T
Modern oral contraceptive use and benign liver tumors: the German Benign Liver Tumor Case–control Study
Eur J Contracept Reprod Health Care
 , 
1998
, vol. 
3
 (pg. 
194
-
200
)
Heinemann
K
Thiel
C
Mohner
S
Lewis
MA
Raff
T
Kuhl-Habich
D
Heinemann
LA
Benign gynecological tumors: estimated incidence. Results of the German Cohort Study on Women's Health
Eur J Obstet Gynecol Reprod Biol
 , 
2003
, vol. 
107
 (pg. 
78
-
80
)
Henderson
BE
Casagrande
JT
Pike
MC
Mack
T
Rosario
I
Duke
A
The epidemiology of endometrial cancer in young women
Br J Cancer
 , 
1983
, vol. 
47
 (pg. 
749
-
756
)
Hogewoning
CJ
Bleeker
MC
van den Brule
AJ
Voorhorst
FJ
Snijders
PJ
Berkhof
J
Westenend
PJ
Meijer
CJ
Condom use promotes regression of cervical intraepithelial neoplasia and clearance of human papillomavirus: a randomized clinical trial
Int J Cancer
 , 
2003
, vol. 
107
 (pg. 
811
-
816
)
Horwitz
RI
Feinstein
AR
Case–control study of oral contraceptive pills and endometrial cancer
Ann Intern Med
 , 
1979
, vol. 
91
 (pg. 
226
-
227
)
Hulka
BS
Chambless
LE
Kaufman
DG
Fowler
WC
Jr
Greenberg
BG
Protection against endometrial carcinoma by combination-product oral contraceptives
J Am Med Assoc
 , 
1982
, vol. 
247
 (pg. 
475
-
477
)
Huusom
LD
Frederiksen
K
Hogdall
EV
Glud
E
Christensen
L
Hogdall
CK
Blaakaer
J
Kjaer
SK
Association of reproductive factors, oral contraceptive use and selected lifestyle factors with the risk of ovarian borderline tumors: a Danish case–control study
Cancer Causes Control
 , 
2006
, vol. 
17
 (pg. 
821
-
829
)
IARC
Hormonal Contraception and Post-menopausal Hormonal Therapy.
 , 
1999
Lyon
IARC
IARC
Combined estrogen-progestogen contraceptives and combined estrogen-progestogen menopausal therapy
IARC Monogr Eval Carcinog Risks Hum
 , 
2007
, vol. 
91
 (pg. 
1
-
528
)
ICESCC
Cervical carcinoma and reproductive factors: collaborative reanalysis of individual data on 16,563 women with cervical carcinoma and 33,542 women without cervical carcinoma from 25 epidemiological studies
Int J Cancer
 , 
2006
, vol. 
119
 (pg. 
1108
-
1124
)
Ivarsson
K
Sundfeldt
K
Brannstrom
M
Hellberg
P
Janson
PO
Diverse effects of FSH and LH on proliferation of human ovarian surface epithelial cells
Hum Reprod
 , 
2001
, vol. 
16
 (pg. 
18
-
23
)
Iversen
L
Hannaford
PC
Elliott
AM
Tubal sterilization, all-cause death, and cancer among women in the United Kingdom: evidence from the Royal College of General Practitioners' Oral Contraception Study
Am J Obstet Gynecol
 , 
2007
, vol. 
196
 (pg. 
447 e1
-
448
)
Jernstrom
H
Lerman
C
Ghadirian
P
Lynch
HT
Weber
B
Garber
J
Daly
M
Olopade
OI
Foulkes
WD
Warner
E
, et al.  . 
Pregnancy and risk of early breast cancer in carriers of BRCA1 and BRCA2
Lancet
 , 
1999
, vol. 
354
 (pg. 
1846
-
1850
)
Jick
SS
Walker
AM
Jick
H
Oral contraceptives and endometrial cancer
Obstet Gynecol
 , 
1993
, vol. 
82
 (pg. 
931
-
935
)
Jordan
SJ
Green
AC
Whiteman
DC
Moore
SP
Bain
CJ
Gertig
DM
Webb
PM
Serous ovarian, fallopian tube and primary peritoneal cancers: a comparative epidemiological analysis
Int J Cancer
 , 
2008
, vol. 
122
 (pg. 
1598
-
1603
)
Kabat
GC
Miller
AB
Rohan
TE
Oral contraceptive use, hormone replacement therapy, reproductive history and risk of colorectal cancer in women
Int J Cancer
 , 
2008
, vol. 
122
 (pg. 
643
-
646
)
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
, vol. 
81
 (pg. 
1290
-
1302
)
Kampman
E
Potter
JD
Slattery
ML
Caan
BJ
Edwards
S
Hormone replacement therapy, reproductive history, and colon cancer: a multicenter, case-control study in the United States
Cancer Causes Control
 , 
1997
, vol. 
8
 (pg. 
146
-
58
)
Kaufman
DW
Shapiro
S
Slone
D
Rosenberg
L
Miettinen
OS
Stolley
PD
Knapp
RC
Leavitt
T
Jr
Watring
WG
Rosenshein
NB
, et al.  . 
Decreased risk of endometrial cancer among oral-contraceptive users
N Engl J Med
 , 
1980
, vol. 
303
 (pg. 
1045
-
1047
)
Kelsey
JL
LiVolsi
VA
Holford
TR
Fischer
DB
Mostow
ED
Schwartz
PE
O'Connor
T
White
C
A case–control study of cancer of the endometrium
Am J Epidemiol
 , 
1982
, vol. 
116
 (pg. 
333
-
342
)
Koumantaki
Y
Tzonou
A
Koumantakis
E
Kaklamani
E
Aravantinos
D
Trichopoulos
D
A case–control study of cancer of endometrium in Athens
Int J Cancer
 , 
1989
, vol. 
43
 (pg. 
795
-
799
)
Kreuzer
M
Gerken
M
Heinrich
J
Kreienbrock
L
Wichmann
HE
Hormonal factors and risk of lung cancer among women?
Int J Epidemiol
 , 
2003
, vol. 
32
 (pg. 
263
-
271
)
Kumle
M
Weiderpass
E
Braaten
T
Persson
I
Adami
HO
Lund
E
Use of oral contraceptives and breast cancer risk: the Norwegian-Swedish Women's Lifestyle and Health Cohort Study
Cancer Epidemiol Biomarkers Prev
 , 
2002
, vol. 
11
 (pg. 
1375
-
1381
)
Kumle
M
Alsaker
E
Lund
E
[Use of oral contraceptives and risk of cancer, a cohort study]
Tidsskr Nor Laegeforen
 , 
2003
, vol. 
123
 (pg. 
1653
-
1656
)
Kumle
M
Weiderpass
E
Braaten
T
Adami
HO
Lund
E
Risk for invasive and borderline epithelial ovarian neoplasias following use of hormonal contraceptives: the Norwegian-Swedish Women's Lifestyle and Health Cohort Study
Br J Cancer
 , 
2004
, vol. 
90
 (pg. 
1386
-
1391
)
Kune
GA
Kune
S
Watson
LF
Oral contraceptive use does not protect against large bowel cancer
Contraception
 , 
1990
, vol. 
41
 (pg. 
19
-
25
)
La Vecchia
C
Tavani
A
Female hormones and benign liver tumours
Dig Liver Dis
 , 
2006
, vol. 
38
 (pg. 
535
-
536
)
La Vecchia
C
Decarli
A
Fasoli
M
Franceschi
S
Gentile
A
Negri
E
Parazzini
F
Tognoni
G
Oral contraceptives and cancers of the breast and of the female genital tract. Interim results from a case–control study
Br J Cancer
 , 
1986
, vol. 
54
 (pg. 
311
-
317
)
La Vecchia
C
Ron
E
Franceschi
S
Dal Maso
L
Mark
SD
Chatenoud
L
Braga
C
Preston-Martin
S
McTiernan
A
Kolonel
L
, et al.  . 
A pooled analysis of case–control studies of thyroid cancer. III. Oral contraceptives, menopausal replacement therapy and other female hormones
Cancer Causes Control
 , 
1999
, vol. 
10
 (pg. 
157
-
166
)
La Vecchia
C
Altieri
A
Franceschi
S
Tavani
A
Oral contraceptives and cancer: an update
Drug Saf
 , 
2001
, vol. 
24
 (pg. 
741
-
754
)
Lee
E
Ma
H
McKean-Cowdin
R
Van Den Berg
D
Bernstein
L
Henderson
BE
Ursin
G
Effect of reproductive factors and oral contraceptives on breast cancer risk in BRCA1/2 mutation carriers and noncarriers: results from a population-based study
Cancer Epidemiol Biomarkers Prev
 , 
2008
, vol. 
17
 (pg. 
3170
-
3178
)
Leppaluoto
PA
The pillOC and cervical cancer: the causal association
Acta Cytol
 , 
2006
, vol. 
50
 (pg. 
704
-
706
)
Levi
F
La Vecchia
C
Gulie
C
Negri
E
Monnier
V
Franceschi
S
Delaloye
JF
De Grandi
P
Oral contraceptives and the risk of endometrial cancer
Cancer Causes Control
 , 
1991
, vol. 
2
 (pg. 
99
-
103
)
Levi
F
Pasche
C
Lucchini
F
La Vecchia
C
Oral contraceptives and colorectal cancer
Dig Liver Dis
 , 
2003
, vol. 
35
 (pg. 
85
-
87
)
Lin
J
Zhang
SM
Cook
NR
Manson
JE
Buring
JE
Lee
IM
Oral contraceptives, reproductive factors, and risk of colorectal cancer among women in a prospective cohort study
Am J Epidemiol
 , 
2007
, vol. 
165
 (pg. 
794
-
801
)
Lipnick
RJ
Buring
JE
Hennekens
CH
Rosner
B
Willett
W
Bain
C
Stampfer
MJ
Colditz
GA
Peto
R
Speizer
FE
Oral contraceptives and breast cancer. A prospective cohort study
J Am Med Assoc
 , 
1986
, vol. 
255
 (pg. 
58
-
61
)
LiVolsi
VA
Stadel
BV
Kelsey
JL
Holford
TR
Fibroadenoma in oral contraceptive users: a histopathologic evaluation of epithelial atypia
Cancer
 , 
1979
, vol. 
44
 (pg. 
1778
-
1781
)
Lurie
G
Thompson
P
McDuffie
KE
Carney
ME
Terada
KY
Goodman
MT
Association of estrogen and progestin potency of oral contraceptives with ovarian carcinoma risk
Obstet Gynecol
 , 
2007
, vol. 
109
 (pg. 
597
-
607
)
Lurie
G
Wilkens
LR
Thompson
PJ
McDuffie
KE
Carney
ME
Terada
KY
Goodman
MT
Combined oral contraceptive use and epithelial ovarian cancer risk: time-related effects
Epidemiology
 , 
2008
, vol. 
19
 (pg. 
237
-
243
)
Ma
H
Bernstein
L
Ross
RK
Ursin
G
Hormone-related risk factors for breast cancer in women under age 50 years by estrogen and progesterone receptor status: results from a case–control and a case-case comparison
Breast Cancer Res
 , 
2006
, vol. 
8
 pg. 
R39
 
Ma
H
Wang
Y
Sullivan-Halley
J
Weiss
L
Marchbanks
PA
Spirtas
R
Ursin
G
Burkman
RT
Simon
MS
Malone
KE
, et al.  . 
Use of four biomarkers to evaluate the risk of breast cancer subtypes in the women's contraceptive and reproductive experiences study
Cancer Res
 , 
2010
, vol. 
70
 (pg. 
575
-
587
)
Maheshwari
S
Sarraj
A
Kramer
J
El-Serag
HB
Oral contraception and the risk of hepatocellular carcinoma
J Hepatol
 , 
2007
, vol. 
47
 (pg. 
506
-
513
)
Marchbanks
PA
McDonald
JA
Wilson
HG
Folger
SG
Mandel
MG
Daling
JR
Bernstein
L
Malone
KE
Ursin
G
Strom
BL
, et al.  . 
Oral contraceptives and the risk of breast cancer
N Engl J Med
 , 
2002
, vol. 
346
 (pg. 
2025
-
2032
)
Martinez
ME
Grodstein
F
Giovannucci
E
Colditz
GA
Speizer
FE
Hennekens
C
Rosner
B
Willett
WC
Stampfer
MJ
A prospective study of reproductive factors, oral contraceptive use, and risk of colorectal cancer
Cancer Epidemiol Biomarkers Prev
 , 
1997
, vol. 
6
 (pg. 
1
-
5
)
Mathieu
D
Kobeiter
H
Cherqui
D
Rahmouni
A
Dhumeaux
D
Oral contraceptive intake in women with focal nodular hyperplasia of the liver
Lancet
 , 
1998
, vol. 
352
 (pg. 
1679
-
1680
)
Maxwell
GL
Schildkraut
JM
Calingaert
B
Risinger
JI
Dainty
L
Marchbanks
PA
Berchuck
A
Barrett
JC
Rodriguez
GC
Progestin and estrogen potency of combination oral contraceptives and endometrial cancer risk
Gynecol Oncol
 , 
2006
, vol. 
103
 (pg. 
535
-
540
)
McGuire
V
Felberg
A
Mills
M
Ostrow
KL
DiCioccio
R
John
EM
West
DW
Whittemore
AS
Relation of contraceptive and reproductive history to ovarian cancer risk in carriers and noncarriers of BRCA1 gene mutations
Am J Epidemiol
 , 
2004
, vol. 
160
 (pg. 
613
-
618
)
McLaughlin
JR
Risch
HA
Lubinski
J
Moller
P
Ghadirian
P
Lynch
H
Karlan
B
Fishman
D
Rosen
B
Neuhausen
SL
, et al.  . 
Reproductive risk factors for ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case–control study
Lancet Oncol
 , 
2007
, vol. 
8
 (pg. 
26
-
34
)
Medina
D
Kittrell
FS
Tsimelzon
A
Fuqua
SA
Inhibition of mammary tumorigenesis by estrogen and progesterone in genetically engineered mice
Ernst Schering Found Symp Proc
 , 
2007
, vol. 
1
 (pg. 
1109
-
1126
)
Milne
RL
Knight
JA
John
EM
Dite
GS
Balbuena
R
Ziogas
A
Andrulis
IL
West
DW
Li
FP
Southey
MC
, et al.  . 
Oral contraceptive use and risk of early-onset breast cancer in carriers and noncarriers of BRCA1 and BRCA2 mutations
Cancer Epidemiol Biomarkers Prev
 , 
2005
, vol. 
14
 (pg. 
350
-
356
)
Modan
B
Hartge
P
Hirsh-Yechezkel
G
Chetrit
A
Lubin
F
Beller
U
Ben-Baruch
G
Fishman
A
Menczer
J
Ebbers
SM
, et al.  . 
Parity, oral contraceptives, and the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2 mutation
N Engl J Med
 , 
2001
, vol. 
345
 (pg. 
235
-
240
)
Modugno
F
Ness
RB
Allen
GO
Schildkraut
JM
Davis
FG
Goodman
MT
Oral contraceptive use, reproductive history, and risk of epithelial ovarian cancer in women with and without endometriosis
Am J Obstet Gynecol
 , 
2004
, vol. 
191
 (pg. 
733
-
740
)
Moorman
PG
Calingaert
B
Palmieri
RT
Iversen
ES
Bentley
RC
Halabi
S
Berchuck
A
Schildkraut
JM
Hormonal risk factors for ovarian cancer in premenopausal and postmenopausal women
Am J Epidemiol
 , 
2008
, vol. 
167
 (pg. 
1059
-
1069
)
Moreno
V
Bosch
FX
Munoz
N
Meijer
CJ
Shah
KV
Walboomers
JM
Herrero
R
Franceschi
S
Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case–control study
Lancet
 , 
2002
, vol. 
359
 (pg. 
1085
-
1092
)
Mueck
AO
Seeger
H
Smoking, estradiol metabolism and hormone replacement therapy
Arzneimittelforschung
 , 
2003
, vol. 
53
 (pg. 
1
-
11
)
[PubMed]
Munoz
N
Franceschi
S
Bosetti
C
Moreno
V
Herrero
R
Smith
JS
Shah
KV
Meijer
CJ
Bosch
FX
Role of parity and human papillomavirus in cervical cancer: the IARC multicentric case–control study
Lancet
 , 
2002
, vol. 
359
 (pg. 
1093
-
1101
)
Murdoch
WJ
Van Kirk
EA
Steroid hormonal regulation of proliferative, p53 tumor suppressor, and apoptotic responses of sheep ovarian surface epithelial cells
Mol Cell Endocrinol
 , 
2002
, vol. 
186
 (pg. 
61
-
67
)
Narod
SA
Dube
MP
Klijn
J
Lubinski
J
Lynch
HT
Ghadirian
P
Provencher
D
Heimdal
K
Moller
P
Robson
M
, et al.  . 
Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers
J Natl Cancer Inst
 , 
2002
, vol. 
94
 (pg. 
1773
-
1779
)
[PubMed]
Ness
RB
Grisso
JA
Klapper
J
Schlesselman
JJ
Silberzweig
S
Vergona
R
Morgan
M
Wheeler
JE
Risk of ovarian cancer in relation to estrogen and progestin dose and use characteristics of oral contraceptives. SHARE Study Group. Steroid Hormones and Reproductions
Am J Epidemiol
 , 
2000
, vol. 
152
 (pg. 
233
-
241
)
Newcomer
LM
Newcomb
PA
Trentham-Dietz
A
Longnecker
MP
Greenberg
ER
Oral contraceptive use and risk of breast cancer by histologic type
Int J Cancer
 , 
2003
, vol. 
106
 (pg. 
961
-
964
)
Nichols
HB
Trentham-Dietz
A
Hampton
JM
Newcomb
PA
Oral contraceptive use, reproductive factors, and colorectal cancer risk: findings from Wisconsin
Cancer Epidemiol Biomarkers Prev
 , 
2005
, vol. 
14
 (pg. 
1212
-
1218
)
Nichols
HB
Trentham-Dietz
A
Egan
KM
Titus-Ernstoff
L
Hampton
JM
Newcomb
PA
Oral contraceptive use and risk of breast carcinoma in situ
Cancer Epidemiol Biomarkers Prev
 , 
2007
, vol. 
16
 (pg. 
2262
-
2268
)
Nyante
SJ
Gammon
MD
Malone
KE
Daling
JR
Brinton
LA
The association between oral contraceptive use and lobular and ductal breast cancer in young women
Int J Cancer
 , 
2008
, vol. 
122
 (pg. 
936
-
941
)
Olson
JE
Sellers
TA
Anderson
KE
Folsom
AR
Does a family history of cancer increase the risk for postmenopausal endometrial carcinoma? A prospective cohort study and a nested case–control family study of older women
Cancer
 , 
1999
, vol. 
85
 (pg. 
2444
-
2449
)
Ory
HW
Mortality associated with fertility and fertility control: 1983
Fam Plann Perspect
 , 
1983
, vol. 
15
 (pg. 
57
-
63
)
Ory
H
Cole
P
MacMahon
B
Hoover
R
Oral contraceptives and reduced risk of benign breast diseases
N Engl J Med
 , 
1976
, vol. 
294
 (pg. 
419
-
422
)
[PubMed]
Palmer
JR
Driscoll
SG
Rosenberg
L
Berkowitz
RS
Lurain
JR
Soper
J
Twiggs
LB
Gershenson
DM
Kohorn
EI
Berman
M
, et al.  . 
Oral contraceptive use and risk of gestational trophoblastic tumors
J Natl Cancer Inst
 , 
1999
, vol. 
91
 (pg. 
635
-
640
)
Parazzini
F
Negri
E
La Vecchia
C
Benzi
G
Chiaffarino
F
Polatti
A
Francheschi
S
Role of reproductive factors on the risk of endometrial cancer
Int J Cancer
 , 
1998
, vol. 
76
 (pg. 
784
-
786
)
Parazzini
F
Cipriani
S
Mangili
G
Garavaglia
E
Guarnerio
P
Ricci
E
Benzi
G
Salerio
B
Polverino
G
La Vecchia
C
Oral contraceptives and risk of gestational trophoblastic disease
Contraception
 , 
2002
, vol. 
65
 (pg. 
425
-
427
)
Pasqualini
JR
Progestins and breast cancer
Gynecol Endocrinol
 , 
2007
, vol. 
23
 
Suppl. 1
(pg. 
32
-
41
)
[PubMed]
Peters
RK
Pike
MC
Chang
WW
Mack
TM
Reproductive factors and colon cancers
Br J Cancer
 , 
1990
, vol. 
61
 (pg. 
741
-
748
)
[PubMed]
Petitti
DB
Porterfield
D
Worldwide variations in the lifetime probability of reproductive cancer in women: implications of best-case, worst-case, and likely-case assumptions about the effect of oral contraceptive use
Contraception
 , 
1992
, vol. 
45
 (pg. 
93
-
104
)
Pettersson
B
Adami
HO
Bergstrom
R
Johansson
ED
Menstruation span–a time-limited risk factor for endometrial carcinoma
Acta Obstet Gynecol Scand
 , 
1986
, vol. 
65
 (pg. 
247
-
255
)
Phillips
LS
Millikan
RC
Schroeder
JC
Barnholtz-Sloan
JS
Levine
BJ
Reproductive and hormonal risk factors for ductal carcinoma in situ of the breast
Cancer Epidemiol Biomarkers Prev
 , 
2009
, vol. 
18
 (pg. 
1507
-
1514
)
Pike
MC
Spicer
DV
Hormonal contraception and chemoprevention of female cancers
Endocr Relat Cancer
 , 
2000
, vol. 
7
 (pg. 
73
-
83
)
Pike
MC
Pearce
CL
Peters
R
Cozen
W
Wan
P
Wu
AH
Hormonal factors and the risk of invasive ovarian cancer: a population-based case–control study
Fertil Steril
 , 
2004
, vol. 
82
 (pg. 
186
-
195
)
Portman
DJ
Symons
JP
Wilborn
W
Kempfert
NJ
A randomized, double-blind, placebo-controlled, multicenter study that assessed the endometrial effects of norethindrone acetate plus ethinyl estradiol versus ethinyl estradiol alone
Am J Obstet Gynecol
 , 
2003
, vol. 
188
 (pg. 
334
-
342
)
Potter
JD
McMichael
AJ
Large bowel cancer in women in relation to reproductive and hormonal factors: a case–control study
J Natl Cancer Inst
 , 
1983
, vol. 
71
 (pg. 
703
-
709
)
[PubMed]
Ramcharan
S
Pellegrin
FA
Ray
R
Hsu
JP
The Walnut Creek Contraceptive Drug Study: A Prospective Study of the Side Effects of Oral Contraceptives
 , 
1981
Bethesda
National Institutes of Child Health and Human Development
Riman
T
Dickman
PW
Nilsson
S
Correia
N
Nordlinder
H
Magnusson
CM
Persson
IR
Risk factors for epithelial borderline ovarian tumors: results of a Swedish case–control study
Gynecol Oncol
 , 
2001
, vol. 
83
 (pg. 
575
-
585
)
Risch
HA
Marrett
LD
Jain
M
Howe
GR
Differences in risk factors for epithelial ovarian cancer by histologic type. Results of a case–control study
Am J Epidemiol
 , 
1996
, vol. 
144
 (pg. 
363
-
372
)
[PubMed]
Rodriguez
GC
Walmer
DK
Cline
M
Krigman
H
Lessey
BA
Whitaker
RS
Dodge
R
Hughes
CL
Effect of progestin on the ovarian epithelium of macaques: cancer prevention through apoptosis?
J Soc Gynecol Investig
 , 
1998
, vol. 
5
 (pg. 
271
-
276
)
Rohan
TE
Miller
AB
A cohort study of oral contraceptive use and risk of benign breast disease
Int J Cancer
 , 
1999
, vol. 
82
 (pg. 
191
-
196
)
Rooks
JB
Ory
HW
Ishak
KG
Strauss
LT
Greenspan
JR
Hill
AP
Tyler
CW
Jr
Epidemiology of hepatocellular adenoma. The role of oral contraceptive use
J Am Med Assoc
 , 
1979
, vol. 
242
 (pg. 
644
-
648
)
Rosenberg
L
Palmer
JR
Zauber
AG
Warshauer
ME
Lewis
JL
Jr
Strom
BL
Harlap
S
Shapiro
S
A case–control study of oral contraceptive use and invasive epithelial ovarian cancer
Am J Epidemiol
 , 
1994
, vol. 
139
 (pg. 
654
-
661
)
[PubMed]
Rosenberg
L
Zhang
Y
Coogan
PF
Strom
BL
Palmer
JR
A case–control study of oral contraceptive use and incident breast cancer
Am J Epidemiol
 , 
2009
, vol. 
169
 (pg. 
473
-
479
)
Rosenblatt
KA
Thomas
DB
Noonan
EA
High-dose and low-dose combined oral contraceptives: protection against epithelial ovarian cancer and the length of the protective effect. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives
Eur J Cancer
 , 
1992
, vol. 
28A
 (pg. 
1872
-
1876
)
[PubMed]
Rosenblatt
KA
Gao
DL
Ray
RM
Nelson
ZC
Thomas
DB
Contraceptive methods and induced abortions and their association with the risk of colon cancer in Shanghai, China
Eur J Cancer
 , 
2004
, vol. 
40
 (pg. 
590
-
593
)
Rosenblatt
KA
Gao
DL
Ray
RM
Nelson
ZC
Wernli
KJ
Li
W
Thomas
DB
Monthly injectable contraceptives and the risk of all cancers combined and site-specific cancers in Shanghai
Contraception
 , 
2007
, vol. 
76
 (pg. 
40
-
44
)
Rosenblatt
KA
Gao
DL
Ray
RM
Nelson
ZC
Wernli
KJ
Li
W
Thomas
DB
Oral contraceptives and the risk of all cancers combined and site-specific cancers in Shanghai
Cancer Causes Control
 , 
2009
, vol. 
20
 (pg. 
27
-
34
)
Royar
J
Becher
H
Chang-Claude
J
Low-dose oral contraceptives: protective effect on ovarian cancer risk
Int J Cancer
 , 
2001
, vol. 
95
 (pg. 
370
-
374
)
Russo
J
Moral
R
Balogh
GA
Mailo
D
Russo
IH
The protective role of pregnancy in breast cancer
Breast Cancer Res
 , 
2005
, vol. 
7
 (pg. 
131
-
142
)
Salvesen
HB
Akslen
LA
Albrektsen
G
Iversen
OE
Poorer survival of nulliparous women with endometrial carcinoma
Cancer
 , 
1998
, vol. 
82
 (pg. 
1328
-
1333
)
Sanderson
M
Williams
MA
Weiss
NS
Hendrix
NW
Chauhan
SP
Oral contraceptives and epithelial ovarian cancer. Does dose matter?
J Reprod Med
 , 
2000
, vol. 
45
 (pg. 
720
-
726
)
[PubMed]
Scalori
A
Tavani
A
Gallus
S
La Vecchia
C
Colombo
M
Oral contraceptives and the risk of focal nodular hyperplasia of the liver: a case–control study
Am J Obstet Gynecol
 , 
2002
, vol. 
186
 (pg. 
195
-
197
)
Schildkraut
JM
Schwingl
PJ
Bastos
E
Evanoff
A
Hughes
C
Epithelial ovarian cancer risk among women with polycystic ovary syndrome
Obstet Gynecol
 , 
1996
, vol. 
88
 (pg. 
554
-
559
)
Schildkraut
JM
Calingaert
B
Marchbanks
PA
Moorman
PG
Rodriguez
GC
Impact of progestin and estrogen potency in oral contraceptives on ovarian cancer risk
J Natl Cancer Inst
 , 
2002
, vol. 
94
 (pg. 
32
-
38
)
[PubMed]
Schlesselman
JJ
Net effect of oral contraceptive use on the risk of cancer in women in the United States
Obstet Gynecol
 , 
1995
, vol. 
85
 (pg. 
793
-
801
)
Schlesselman
JJ
Risk of endometrial cancer in relation to use of combined oral contraceptives. A practitioner's guide to meta-analysis
Hum Reprod
 , 
1997
, vol. 
12
 (pg. 
1851
-
1863
)
Shapiro
S
Re: ‘a case–control study of oral contraceptive use and incident breast cancer
Am J Epidemiol
 , 
2009
, vol. 
170
 (pg. 
802
-
803
author reply 803–4
Shih Ie
M
Kurman
RJ
Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis
Am J Pathol
 , 
2004
, vol. 
164
 (pg. 
1511
-
1518
)
[PubMed]
Silvera
SA
Miller
AB
Rohan
TE
Oral contraceptive use and risk of breast cancer among women with a family history of breast cancer: a prospective cohort study
Cancer Causes Control
 , 
2005
, vol. 
16
 (pg. 
1059
-
1063
)
Siskind
V
Green
A
Bain
C
Purdie
D
Beyond ovulation: oral contraceptives and epithelial ovarian cancer
Epidemiology
 , 
2000
, vol. 
11
 (pg. 
106
-
110
)
Smith
JS
Green
J
Berrington de Gonzalez
A
Appleby
P
Peto
J
Plummer
M
Franceschi
S
Beral
V
Cervical cancer and use of hormonal contraceptives: a systematic review
Lancet
 , 
2003
, vol. 
361
 (pg. 
1159
-
1167
)
Soegaard
M
Jensen
A
Hogdall
E
Christensen
L
Hogdall
C
Blaakaer
J
Kjaer
SK
Different risk factor profiles for mucinous and nonmucinous ovarian cancer: results from the Danish MALOVA study
Cancer Epidemiol Biomarkers Prev
 , 
2007
, vol. 
16
 (pg. 
1160
-
1166
)
Spona
J
Elstein
M
Feichtinger
W
Sullivan
H
Ludicke
F
Muller
U
Dusterberg
B
Shorter pill-free interval in combined oral contraceptives decreases follicular development
Contraception
 , 
1996
, vol. 
54
 (pg. 
71
-
77
)
Stanford
JL
Brinton
LA
Berman
ML
Mortel
R
Twiggs
LB
Barrett
RJ
Wilbanks
GD
Hoover
RN
Oral contraceptives and endometrial cancer: do other risk factors modify the association?
Int J Cancer
 , 
1993
, vol. 
54
 (pg. 
243
-
248
)
Syed
V
Ho
SM
Progesterone-induced apoptosis in immortalized normal and malignant human ovarian surface epithelial cells involves enhanced expression of FasL
Oncogene
 , 
2003
, vol. 
22
 (pg. 
6883
-
6890
)
Talamini
R
Franceschi
S
Dal Maso
L
Negri
E
Conti
E
Filiberti
R
Montella
M
Nanni
O
La Vecchia
C
The influence of reproductive and hormonal factors on the risk of colon and rectal cancer in women
Eur J Cancer
 , 
1998
, vol. 
34
 (pg. 
1070
-
1076
)
Tao
MH
Xu
WH
Zheng
W
Zhang
ZF
Gao
YT
Ruan
ZX
Cheng
JR
Gao
J
Xiang
YB
Shu
XO
Oral contraceptive and IUD use and endometrial cancer: a population-based case–control study in Shanghai, China
Int J Cancer
 , 
2006
, vol. 
119
 (pg. 
2142
-
2147
)
Terry
P
Baron
JA
Weiderpass
E
Yuen
J
Lichtenstein
P
Nyren
O
Lifestyle and endometrial cancer risk: a cohort study from the Swedish Twin Registry
Int J Cancer
 , 
1999
, vol. 
82
 (pg. 
38
-
42
)
Trapido
EJ
A prospective cohort study of oral contraceptives and cancer of the endometrium
Int J Epidemiol
 , 
1983
, vol. 
12
 (pg. 
297
-
300
)
Trivers
KF
Gammon
MD
Abrahamson
PE
Lund
MJ
Flagg
EW
Moorman
PG
Kaufman
JS
Cai
J
Porter
PL
Brinton
LA
, et al.  . 
Oral contraceptives and survival in breast cancer patients aged 20 to 54 years
Cancer Epidemiol Biomarkers Prev
 , 
2007
, vol. 
16
 (pg. 
1822
-
1827
)
Troisi
R
Schairer
C
Chow
WH
Schatzkin
A
Brinton
LA
Fraumeni
JF
Jr
Reproductive factors, oral contraceptive use, and risk of colorectal cancer
Epidemiology
 , 
1997
, vol. 
8
 (pg. 
75
-
79
)
[PubMed]
Tung
KH
Goodman
MT
Wu
AH
McDuffie
K
Wilkens
LR
Kolonel
LN
Nomura
AM
Terada
KY
Carney
ME
Sobin
LH
Reproductive factors and epithelial ovarian cancer risk by histologic type: a multiethnic case–control study
Am J Epidemiol
 , 
2003
, vol. 
158
 (pg. 
629
-
638
)
Tworoger
SS
Fairfield
KM
Colditz
GA
Rosner
BA
Hankinson
SE
Association of oral contraceptive use, other contraceptive methods, and infertility with ovarian cancer risk
Am J Epidemiol
 , 
2007
, vol. 
166
 (pg. 
894
-
901
)
van Wayenburg
CA
van der Schouw
YT
van Noord
PA
Peeters
PH
Age at menopause, body mass index, and the risk of colorectal cancer mortality in the Dutch Diagnostisch Onderzoek Mammacarcinoom (DOM) cohort
Epidemiology
 , 
2000
, vol. 
11
 (pg. 
304
-
308
)
Vessey
M
Painter
R
Oral contraceptive use and cancer. Findings in a large cohort study, 1968–2004
Br J Cancer
 , 
2006
, vol. 
95
 (pg. 
385
-
389
)
Vessey
M
Yeates
D
Oral contraceptives and benign breast disease: an update of findings in a large cohort study
Contraception
 , 
2007
, vol. 
76
 (pg. 
418
-
424
)
Vessey
M
Painter
R
Yeates
D
Mortality in relation to oral contraceptive use and cigarette smoking
Lancet
 , 
2003
, vol. 
362
 (pg. 
185
-
191
)
Weiderpass
E
Adami
HO
Baron
JA
Magnusson
C
Lindgren
A
Persson
I
Use of oral contraceptives and endometrial cancer risk (Sweden)
Cancer Causes Control
 , 
1999
, vol. 
10
 (pg. 
277
-
284
)
Weiss
NS
Sayvetz
TA
Incidence of endometrial cancer in relation to the use of oral contraceptives
N Engl J Med
 , 
1980
, vol. 
302
 (pg. 
551
-
554
)
[PubMed]
Weiss
NS
Daling
JR
Chow
WH
Incidence of cancer of the large bowel in women in relation to reproductive and hormonal factors
J Natl Cancer Inst
 , 
1981
, vol. 
67
 (pg. 
57
-
60
)
[PubMed]
Wheeler
DT
Bristow
RE
Kurman
RJ
Histologic alterations in endometrial hyperplasia and well-differentiated carcinoma treated with progestins
Am J Surg Pathol
 , 
2007
, vol. 
31
 (pg. 
988
-
998
)
Whittemore
AD
Autogenous saphenous vein versus PTFE bypass for above-knee femoropopliteal reconstruction
J Vasc Surg
 , 
1992
, vol. 
15
 (pg. 
895
-
897
)
[PubMed]
Whittemore
AS
Balise
RR
Pharoah
PD
Dicioccio
RA
Oakley-Girvan
I
Ramus
SJ
Daly
M
Usinowicz
MB
Garlinghouse-Jones
K
Ponder
BA
, et al.  . 
Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 or BRCA2 mutations
Br J Cancer
 , 
2004
, vol. 
91
 (pg. 
1911
-
1915
)
WHO
Endometrial cancer and combined oral contraceptives. The Who Collaborative Study of Neoplasia and Steroid Contraceptives
Int J Epidemiol
 , 
1988
, vol. 
17
 (pg. 
263
-
269
)
WHO
Depot-medroxyprogesterone acetate (DMPA) and risk of endometrial cancer. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives
Int J Cancer
 , 
1991
, vol. 
49
 (pg. 
186
-
190
)
[PubMed]
Winer
E
Gralow
J
Diller
L
Karlan
B
Loehrer
P
Pierce
L
Demetri
G
Ganz
P
Kramer
B
Kris
M
, et al.  . 
Clinical cancer advances 2008: major research advances in cancer treatment, prevention, and screening–a report from the American Society of Clinical Oncology
J Clin Oncol
 , 
2009
, vol. 
27
 (pg. 
812
-
826
)
Wingo
PA
Austin
H
Marchbanks
PA
Whiteman
MK
Hsia
J
Mandel
MG
Peterson
HB
Ory
HW
Oral contraceptives and the risk of death from breast cancer
Obstet Gynecol
 , 
2007
, vol. 
110
 (pg. 
793
-
800
)
[PubMed]
Wu-Williams
AH
Lee
M
Whittemore
AS
Gallagher
RP
Jiao
DA
Zheng
S
Zhou
L
Wang
XH
Chen
K
Jung
D
, et al.  . 
Reproductive factors and colorectal cancer risk among Chinese females
Cancer Res
 , 
1991
, vol. 
51
 (pg. 
2307
-
2311
)
[PubMed]