An association between hormonal contraceptives and an increased risk for glioma in younger women has been found in a Danish nationwide case–control study.
That risk increases with the duration of use, David Gaist, MD, from Odense University Hospital and the University of South Denmark, and colleagues report in their study, published today in the print edition of the British Journal of Clinical Pharmacology.
“A nearly two-fold increased risk of glioma was observed among long-term users of hormonal contraceptives,” they write.
However, “it is important to keep this apparent increase in risk in context,” Dr Gaist said in a statement.
“While we found a statistically significant association between hormonal contraceptive use and glioma risk, a risk/benefit evaluation would still favor the use of hormonal contraceptives in eligible users,” he explained.
He added that although the findings of this study must be interpreted with care, “we feel it is an important contribution and we hope that our findings will spark further research on the relationship between female hormonal agents and glioma risk.”
Search for Glioma in Health Registries
Oral contraceptives are known to influence the risk for certain cancers, but few studies have examined any link to central nervous system tumors, write Dr Gaist and colleagues.
The researchers used Danish administrative and health registries to identify all women in Denmark 15 to 49 years of age with a first-time diagnosis of glioma from 2000 to 2009. The registries provided information on hormonal contraceptive prescriptions filled from 1995 to 2009.
The researchers defined “nonuse” as one or no hormonal contraceptive prescriptions, and “ever use” as at least two prescriptions.
In the ever-use category, “current/recent use” was defined as at least one prescription in the 2 to 5 years before the initial diagnosis of glioma, and “past use” was defined as no recorded prescription in the 2 to 5 years before initial diagnosis.
The 317 patients in the case group and the 2126 in the control group were similar in age, parity, and years of schooling.
Overall, 58.7% of case subjects and 50.1% of control subjects were ever users (P = .004). Among ever users, the odds ratio (OR) for glioma was 1.5 (95% confidence interval [CI], 1.2 – 2.0).
The risk for glioma was higher for current/recent use (OR, 1.7; 95% CI, 1.3 – 2.4) than for past use (OR, 1.2; 95% CI, 0.8 – 2.0).
The risk was elevated for oral contraceptives consisting of a combination of estrogen and progestogen (OR, 1.4; 95% CI, 1.0 – 1.8), but was highest for progestogen-only contraceptives (OR, 2.8; 95% CI, 1.6 – 5.1). The use of both types of contraceptives was also associated with increased risk (OR, 1.5; 95% CI, 0.8 – 3.0).
The risk for glioma increased as the use of oral contraceptives of any type increased. With use for less than 1 year, the OR was 1.4 (95% CI, 0.8 – 2.3); for 5 years or more of use, the OR was 1.9 (95% CI, 1.2 – 2.9).
Previous Studies Inconsistent
Dr Gaist and colleagues note that previous case–control and cohort studies have failed to find any association or only a weak inverse association between ever use of hormonal contraceptives and glioma risk, and none have found any duration–risk pattern.
Other previous studies have been inconsistent, they note, with 2 studies indicating a slightly increased risk for glioma associated with current use and one reporting a substantially reduced risk.
However, most of the women in previous studies were older than 50 years, which could explain the lack of association, the researchers report.
Only one study found an association between ever use of hormonal contraceptives and a higher risk for glioma in women younger than 50 years, they add.
Progesterone Exposure Associated With Highest Risk
The researchers highlight the fact that progestogen exposure was associated with the highest increased risk for glioma in their study.
“Progesterone increases proliferation of high-grade astrocytoma cell lines, as well as growth factor levels, which is in line with increased progesterone receptor protein mRNA with glioma grade,” they write.
The study has limitations, they acknowledge. For one, the results could be biased if contraceptive users were more likely to undergo brain imaging because of socioeconomic factors. However, because the Danish National Health Service provides equal access to healthcare for all Danish citizens, socioeconomic status is not likely to be a factor.
Another limiting factor is the lack of information on anthropometric measures, such as body mass index; some studies have found an association between obesity and glioma risk.
Research on Risks and Benefits a Challenge
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Dr. Brittany Charlton
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For many years, numerous studies have weighed the various health risks and benefits of hormonal contraception, but questions remain, said Brittany M. Charlton, ScD, a postdoctoral research fellow at Boston Children’s Hospital and Harvard Medical School, who has worked with the same Danish registry data on unrelated contraceptive research.
“This area of research poses unique challenges that make these questions difficult to answer,” Dr Charltontold Medscape Medical News. “For example, detailed data collection with lengthy follow-up is necessary because the hormonal contraceptives have changed over time,” she explained. Doses of estrogen have changed, progestins have been added, patterns of use have changed with the elimination of placebo pills, and hormonal IUDs have been introduced.
“Determining how to model hormonal contraceptive use is challenging,” Dr Charlton added. “Ever use may be of the most interest, but age at first use, duration, and even time since last use are important factors.”
In their study, Dr Gaist’s team demonstrates that countrywide registries can be a rich source of information, “especially for rare health outcomes like malignant brain tumors,” she noted.
“Their findings provide evidence that hormonal contraception may increase the risk of glioma, that the risk increases with hormonal contraception duration, and is most elevated with progesterone-only methods and among younger women. The Danish registries offer detailed prospective data on many potential confounders, but a few were not available that could have shed further light on this association, including body mass index, socioeconomic factors, and healthcare access,” she said.
“However, these factors are unlikely to strongly bias the results, given that healthcare is provided to all Danish citizens,” Dr Charlton said.
She pointed out that another limitation of the study is that the prescription registry began in 1995, which means women who used hormonal contraception before then, but not after, would have been misclassified as nonusers. “Nevertheless, as the authors note, this bias would actually have attenuated or underestimated the results.”
Finally, Dr Charlton said the findings are interesting for a number of reasons, but need to be replicated. “Overall, there are countless benefits of hormonal contraception, but continued research on potential health risks, especially in light of these findings, is essential.”
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Dr Kathleen Egan
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Kathleen M. Egan, ScD, from the cancer epidemiology program at the H. Lee Moffitt Cancer Center in Tampa, Florida, agrees.
“Glioma is rare in young women. Nonetheless, as oral contraceptive use is common in this age group, it will be important that additional studies are done to validate the findings,” said Dr Egan, who was not involved in the study.
She told Medscape Medical News that the study has several strengths, including the population-wide coverage and the fact that information on oral contraceptive use came from pharmacy records rather than self-report, and was therefore not dependent on the women’s ability to recall past use.
“Because of the high-quality cancer registry in Denmark, they would have captured all of the gliomas diagnosed during the years of the study, so selection bias was unlikely,” she said.
“But there were also some weaknesses that should be considered. Relatively few women with glioma were included, and many of the results were based on small numbers of exposed women and were imprecise,” Dr Egan pointed out. “Further, the authors could not control for some confounders, such as obesity and older age at menarche, which have been linked to an increased glioma risk in some studies.”
Most important, Dr Egan continued, “the results indicate that current use but not past use of oral contraceptives increased risk, and because women currently using oral contraceptives would be under the regular care of a doctor, it is possible that surveillance bias could account for the increased risk for glioma.
“Interestingly, the association was greatly diminished when the authors excluded exposure during a 5-year period prior to the index date, or the date of glioma diagnosis in the glioma cases, which I think supports this interpretation. The authors reported a dose-response relationship — such that longer-term use was associated with greater risk — as supporting the results, but long-term users were also more likely to be current users. For all of these reasons, the results should be considered only preliminary, pending confirmation,” Dr Egan explained.
Benefits Still Outweigh Risks
A recent overview of the harms and risks of oral contraceptives (Ther Adv in Drug Safe. 2014;5:201-213), which was reproduced recently on Medscape, concluded that, overall, the benefits might still outweigh the risks.
Review author Jan Brynhildsen, MD, PhD, from Linköping University in Sweden, listed the most well-known risks as venous thromboembolism, arterial thrombosis, and some cancers, including breast cancer and cervical cancer. (He was contacted about this glioma study but had not responded by the time this article went to press.)
“COC [combined oral contraceptive] use is associated with a substantial decrease in the risk of ovarian cancer, endometrial cancer, and colorectal cancer. Moreover, COCs are a major option of treatment for women suffering from heavy menstrual bleeding and dysmenorrhea, as well as hirsutism and acne vulgaris,” Dr Brynhildsen writes, adding that the net effect of these added health benefits could be a slight increase in life expectancy.
The study was supported by grants from the Danish Cancer Society, Odense University Hospital, and the University of Southern Denmark. Dr Gaist, Dr Charlton, and Dr Egan have disclosed no relevant financial relationships.
Br J Clin Pharmacol. 2014. Abstract