Background: Oral contraceptives are known to influence the risk of cancers of the female reproductive system. Evidence regarding the relationship between injectable contraceptives and these cancers is limited, especially in black South Africans, among whom injectable contraceptives are used more commonly than oral contraceptives. Methods and Findings: We analysed data from a South African hospital-based case-control study of black females aged 18-79 y, comparing self-reported contraceptive use in patients with breast (n = 1,664), cervical (n = 2,182), ovarian (n = 182), and endometrial (n = 182) cancer, with self-reported contraceptive use in 1,492 control patients diagnosed with cancers with no known relationship to hormonal contraceptive use. We adjusted for potential confounding factors, including age, calendar year of diagnosis, education, smoking, alcohol, parity/age at first birth, and number of sexual partners. Among controls, 26% had used injectable and 20% had used oral contraceptives. For current and more recent users versus never users of oral or injectable contraceptives, the odds ratios (ORs) for breast cancer were significantly increased in users of oral and/or injectable contraceptives (OR 1.66, 95% CI 1.28-2.16, p<0.001) and separately among those exclusively using oral (1.57, 1.03-2.40, p = 0.04) and exclusively using injectable (OR 1.83, 1.31-2.55, p<0.001) contraceptives; corresponding ORs for cervical cancer were 1.38 (1.08-1.77, p = 0.01), 1.01 (0.66-1.56, p = 0.96), and 1.58 (1.16-2.15, p = 0.004). There was no significant increase in breast or cervical cancer risk among women ceasing hormonal contraceptive use ≥10 y previously (p = 0.3 and p = 0.9, respectively). For durations of use ≥5 y versus never use, the ORs of ovarian cancer were 0.60 (0.36-0.99, p = 0.04) for oral and/or injectable contraceptive use and 0.07 (0.01-0.49, p = 0.008) for injectable use exclusively; corresponding ORs for endometrial cancer were 0.44 (0.22-0.86, p = 0.02) and 0.36 (0.11-1.26, p = 0.1). Conclusions: In this study, use of oral and of injectable hormonal contraceptives was associated with a transiently increased risk of breast and cervical cancer and, for long durations of use, with a reduced risk of ovarian and endometrial cancer. The observed effects of injectable and of oral contraceptives on cancer risk in this study did not appear to differ substantially. Please see later in the article for the Editors' Summary. © 2012 Urban et al.
