A meta-analysis 1 included 45 epidemiological studies in 21 countries involving 23 257 women with ovarian cancer (cases) and 87 303 controls. Overall 7 308 (31%) cases and 32 717 (37%) controls had ever used oral contraceptives, for average durations among users of 4.4 and 5.0 years, respectively. For ever vs. never users the overall relative risk was 0.73 (95% CI 0.70 to 0.76). The longer the use of oral contraceptives, the greater the reduction in ovarian cancer risk (p<0.0001). The overall relative risk decreased by 20 % (95% CI 18 to 23%) for each year of use. This reduction attenuated somewhat over time: the proportional risk reductions per 5 years of use were 29% (95% CI 23-34%) for use that had ceased less than 10 years previously, 19% (14-24%) for use that had ceased 10-19 years previously, and 15% (9-21%) for use that had ceased 20-29 years previously. Use during the 1960s, 1970s, and 1980s was associated with similar proportional risk reductions, although typical oestrogen doses in the 1960s were more than double those in the 1980s. The proportional risk reduction did not vary much between different histological types (except of mucinous tumours which seemed little affected by oral contraceptives). In high-income countries, 10 years use of oral contraceptives was estimated to reduce ovarian cancer incidence before age 75 from 1.2 to 0.8 per 100 users and mortality from 0.7 to 0.5 per 100; for every 5 000 woman-years of use, about two ovarian cancers and one death from the disease before age 75 are prevented.
A prospective, nationwide cohort study 3 included 1 879 227 women. During 21.4 million person years, 1249 incident ovarian cancers occurred. Among ever users of hormonal contraception, 478 ovarian cancers were recorded over 13 344 531 person years. Never users had 771 ovarian cancers during 8 150 250 person years. Compared with never users, reduced risks of ovarian cancer occurred with current or recent use and former use of any hormonal contraception (RR 0.58, 95% CI 0.49 to 0.68 and RR 0.77, 95% CI 0.66 to 0.91, respectively). Relative risks among current or recent users decreased with increasing duration (from 0.82, 95% CI 0.59 to 1.12 with ≤1 year use to 0.26, 95% CI 0.16 to 0.43 with >10 years' use; P<0.001 for trend). Use of progestogen-only products were not associated with ovarian cancer risk.
In a UK cohort study 2 the main dataset contained about 339 000 woman years of observation for never users and 744 000 woman years for ever users of oral contraception. Compared with never users ever users had statistically significant lower rates of cancers of ovaries (RR 0.54, 95% CI 0.40 to 0.71), large bowel or rectum, uterine body, main gynaecological cancers combined, and any cancer. Statistically significant trends of increasing risk of cervical and central nervous system or pituitary cancer, and decreasing risk of uterine body and ovarian malignancies were seen with increasing duration of oral contraceptive use.
The 46 022 women in the UK Royal College of General Practitioners' Oral Contraception Study 4 were observed for up to 44 years to assess very long-term cancer risks or benefits associated with the use of combined oral contraceptives. There were 4661 ever users with at least 1 cancer during 884 895 woman-years of observation and 2341 never users with at least 1 cancer during 388 505 woman-years of observation. Ever use of oral contraceptives was associated with reduced colorectal (incidence rate ratio, 0.81, 99% CI 0.66 to 0.99), endometrial (incidence rate ratio, 0.66, 99% CI 0.48 to 0.89), and ovarian cancer (incidence rate ratio, 0.67, 99% CI 0.50 to 0.89).
An observational study 5 involving a total of 256 661 women from UK Biobank, born between 1939 and 1970 evaluated the long-term oral contraceptive use and cancer risk. The odds were lower among ever users, compared with never users, for ovarian cancer (OR 0.72, 95% CI 0.65 to 0.81) and endometrial cancer (OR 0.68, 95% CI 0.62 to 0.75), an association that was stronger with longer use (P < 0.001). Increased odds were seen for breast cancer in women when limiting the follow-up to 55 years of age (OR = 1.10, 95% CI 1.03 to 1.17), but not for the full timespan; a higher HR for breast cancer in former users was found immediately (≤2 years) after discontinued oral contraceptive use (HR = 1.55, 95% CI 1.06 to 2.28), whereas the protective association for ovarian and endometrial cancer remained significant up to 35 years after last use of oral contraceptives.
Comment: The quality of evidence is upgraded by time-response gradient.
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