Oral contraceptives can substantially reduce the risk of developing endometrial cancer, especially when used for at least 5 years, according to a new meta-analysis.
In high-income countries from 1965 to 2014, oral contraceptives have prevented about 400,000 cases of endometrial cancer, including about 200,000 in the last decade, according to estimates from the Collaborative Group on Epidemiological Studies on Endometrial Cancer. Their report was published online August 5 in the Lancet Oncology.
The longer women use oral contraceptives, the greater the reduction in the risk for endometrial cancer, the researchers report.
On average, every 5 years of oral contraceptive use was associated with a relative risk of 0.76 (P < .0001). On extrapolation, that means 10 to 15 years of use would half the risk for endometrial cancer.
In addition, the protective effect persists for at least 30 years after contraceptive use ceases.
This effect does not depend on the dose of estrogen in the contraceptive formulation. Even though oral contraceptives in the 1960s typically contained about twice the amount of estrogen as products that became available in the 1980s, the reduction in endometrial cancer risk remained about the same.
In fact, despite the higher estrogen doses in pills used in the early years, there was no apparent decrease in relative risk over time.
And the characteristics of the individual woman — such as parity, body weight, menopausal status, use of menopausal hormone therapy, smoking status, age at menarche, ethnic origin, and alcohol use — did not seem to affect the association either.
"Previous research has shown that the Pill also protects against ovarian cancer," said researcher Valerie Beral, DBE, AC, FRS, director of the cancer epidemiology unit at the University of Oxford in the United Kingdom, in a statement. "People used to worry that the Pill might cause cancer, but in the long term, the Pill reduces the risk of getting cancer."
Risk vs Benefit
Although this finding is impressive and instructive, the "important clinical and public health question now is whether or not the available data allow women to optimally balance the benefits and harms of oral contraceptives, and to assess whether an overall health benefit of oral contraceptive use exists that warrants specific recommendations for chemoprevention," write Nicolas Wentzensen, MD, PhD, and Amy Berrington de González, DPhil, from the National Cancer Institute, in an accompanying editorial.
In addition to their main indication for birth control, oral contraceptives have now shown long-term benefits; they reduce the risk for endometrial, ovarian, and colorectal cancers, the pair points out.
But there are potentially serious adverse events associated with their use, including cardiovascular effects, such as venous thrombosis and stroke, and an increase in the risk for breast and cervical cancers, they note. "Assessment of the balance of the risks and benefits of oral contraceptive use is complex."
Oral contraceptive formulations and doses have changed substantially since 1960, when they were approved for birth control by the US Food and Drug Administration. Many formulations are now available, and although all are highly effective for birth control, the risk for other effects differ, the editorialists point out.
"The biological mechanisms of oral contraceptives are not well understood for some of the benefits and harms," they write. "The benefit-to-harm tradeoff seems to be more favorable for existing low-dose estrogen formulations, but the risk of venous thrombosis is still raised in people who use oral contraceptives compared with those who do not."
"It is not trivial to fully assess the benefits and harms of oral contraceptives, considering their wide range of actions," Dr Wentzensen told Medscape Medical News.
"But as we referenced in our editorial, a health technology assessment report attempted to estimate the net benefit of oral contraceptive use," he said. "The conclusion of that report was that there is a net benefit of oral contraceptive use."
However, Dr Wentzensen and Dr Berrington de González emphasize that "women need to be more aware of the unintended benefits and the risks of oral contraceptives, so that they can make informed decisions."
It is important to provide a woman with "information about all the risks and benefits and about other contraceptive methods so that she can make an informed choice," Sarah Hardman, MD, deputy director of the clinical effectiveness unit in the Faculty of Sexual and Reproductive Healthcare of the Royal College of Obstetricians and Gynaecologists, United Kingdom, reiterated in a statement.
"This study does not clarify the effect on endometrial cancer risk of progestogen-only contraceptives, including the most effective long-acting reversible contraceptives or nonoral combined methods," she added. "Future research should aim to address this."
Longer Use, Lower Risk
Since the introduction of oral contraceptives, about 400 million women in high-income countries have used the drugs, and often for prolonged periods of time.
To investigate the association between oral contraceptive use and the subsequent risk for endometrial cancer, Dr Beral and her colleagues used datasets from 36 international epidemiologic studies that involved 27,276 women with and 115,743 women without endometrial cancer.
Their logistic regression model was stratified by study, age, parity, body mass index, smoking, and the use of menopausal hormone therapy.
Median age in the cancer group was 63 years (interquartile range [IQR], 57 - 68), and median year of cancer diagnosis was 2001 (IQR, 1994 to 2005).
Any use of oral contraceptives was reported by 9459 (35%) women with endometrial cancer and by 45,625 (39%) control subjects. Median duration of use was 3.0 years in the cancer group and 4.4 years in the control group.
Overall, the risk for endometrial cancer was significantly lower in women who had used oral contraceptives than in those who had never used them (relative risk [RR], 0.69; 95% confidence interval [CI], 0.67 - 0.72).
The longer the duration of use, the lower the risk for cancer. For those who used them for 10 to 15 years (median, 11.8 years), the relative risk for endometrial cancer was 0.52 (95% CI, 0.48 - 0.50).
In high-income countries, the researchers estimated that 10 years oral contraceptive reduced the absolute risk for endometrial cancer occurring in women younger than 75 years from 2.3 to 1.3 per 100 women.
There was some evidence that the relative risk for the disease was associated with the histologic subtype of endometrial cancer. It was stronger for the 26,877 carcinomas (RR, 0.69, 95% CI, 0.66 - 0.71) than for the 399 sarcomas (RR, 0.83, 95% CI, 0.67 - 1·04; P = .02 for case–case comparison). However, because there were relatively few cases of sarcoma in the study cohort, the association between oral contraceptives and the risk for uterine sarcoma was not significant.
"We have known for some time that oral contraceptives reduce the incidence of womb cancer; however, this study provides robust evidence of how long this protective effect lasts after a woman stops taking the Pill, and takes into account other possible risk factors, such as smoking and obesity," said Clare McKenzie, MD, vice president for education at the Royal College of Obstetricians and Gynaecologists, in a release.
"The results should reassure women of the protective effect the combined pill has against womb cancer, but it's important to remember a third of cases are linked to a women being overweight or obese, so keeping a healthy bodyweight is the most important factor in reducing risk," she added.
This study was funded by the Medical Research Council and Cancer Research UK. Dr Beral, Dr Wentzensen, and Dr Berrington de González have disclosed no relevant financial relationships.
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