Progesterone contraceptives *may* double risk of glioma brain cancer

We are inundated with reports on how this chemical or that behavior can significantly increase the risk for some cancer. Many of these studies are difficult to interpret because of the complexity of the subject matter i.e. cancer pathophysiology. For example, the cancer-causing effect may be small or statistically insignificant, the mechanism of action may be unknown, or the study may not sufficiently control for other factors.

Some of these issues arise in a new study described in The Daily Mail and The Telegraph. Researchers found that women who used progesterone-based contraceptive methods had an approximately two-fold higher incidence of the brain cancer glioma than women who did not. Progesterone is a female sex hormone that is sometimes referred to as Progestin (synthetic derivative) or Progestogen (broader class of Progesterone-like compounds).

Progesterone is found in contraceptive pills, patches, or IUDs. Along with estrogen (another sex hormone), it can inhibit ovulation (the release of an egg) and also prevent sperm entry into the fallopian tubes by making the vaginal mucous thicker.

There is a relationship between sex hormones and the progression of certain cancers. Most notably, about 75% of breast cancers contain high levels of estrogen receptor (ER-positive), and as a result are stimulated by estrogen. Roughly 65% of the ER-positive cancers also contain progesterone receptor which respond to progesterone. It is possible to treat ER-positive breast cancers with hormone therapies like Tamoxifen which inhibits estrogen receptor. Whether or not Progesterone promotes brain cancer growth is not known.

Glioma is a type of brain cancer that arises from glial cells. It represents approximately 30% of all brain tumors and 80% of malignant brain tumors. Glioblastoma multiforme (GBM) is the most common glioma and is very deadly.

Returning to the study in question, researchers identified all women aged 15 to 49 in Denmark with glioma during the years 2000 to 2009. There were 317 cases. The researchers also gathered information (i.e. about contraceptive use) from 2126 risk-matched controls who did not have glioma in the same age range. They then compared the two groups for various attributes.

They found that any type of hormonal contraceptive use (estrogen or progesterone) was associated with a 50% increase in glioma risk (odds ratio OR = 1.5). If the use of the contraceptive was long-term (>5 years), then the risk increased to 90% (OR = 1.9). Perhaps more strikingly, the glioma risk was highest for progesterone-only contraceptives (OR = 2.4) i.e. more than twice the risk compared to those who did not use hormone contraceptives.

One interesting aspect of the study was that there was increased risk with the greater length of time of hormonal contraceptive use, and an increased risk for progesterone-only methods versus those that contained both progesterone and estrogen. Thus there is an apparent duration and dose effect.

One weakness of the report is that it depends heavily on how well-matched the control group is. In other words an important question is does the control accurately reflect the number of women aged 15-49 in Denmark who use hormonal contraceptives? If the control sample underestimates this number, then the true odds ratio is smaller. A second remark is that the number of women with glioma in some of the categories (e.g. Progesterone only for more than 5 years) was a small number and subject to statistical fluctuation. A second larger study would address these concerns.

So should women on progesterone-based contraceptives be worried? It is important to place this two-fold risk increase in proper context. According to Sir David Spiegelhalter, Winton Professor of the Public Understanding of Risk at Cambridge University, they should not be too worried (Daily Mail):

"Glioma is fortunately very rare. Even if oral contraceptives did increase the risk to the extent suggested by this study, it would only mean one extra glioma each year for every 50,000 women taking the pill.

Suppose, however, all these women changed to a less effective form of contraception and 10,000 of them got pregnant: we would then expect one extra mother and 40 extra babies to die."

In other words, doubling a very small risk results in a risk that is still very small. A comparison can be made to breast cancer. The lifetime risk for a woman developing breast cancer is 12% (link). The lifetime risk of developing glioma in a woman is approximately 0.17%, or about 100-fold less. Thus doubling this risk would still make your chance of developing glioma about 50-fold less than getting breast cancer.

The flip-side is that glioma, and in particular Glioblastoma multiforme (GBM), is much more deadly than breast cancer. The five-year survival rate for breast cancer is 80-90% depending on your age (it can be significantly lower for advanced stage breast cancer). The five-year survival for GBM is less than 10%. It is a very deadly cancer with no known effective treatments other than surgery which can be difficult. Thus, for women the lifetime risk of dying of breast cancer is 2.7%, whereas the risk of dying of glioma is 0.25%, about 10-fold lower.

Finally, it should also be mentioned that the risk of GBM increases approximately 10-fold as you age from 35 to 65. Thus a two-fold increase in risk caused by a progesterone contraceptive when you are young is small in comparison to the 10-fold increase in risk caused by aging.

There are several points to be made in closing. First and foremost, this study needs to be repeated on a larger scale to obtain better statistics. Reproducing these important initial findings would give greater confidence to the conclusion that hormonal contraceptives may increase the risk of glioma. Second, we need to understand better how progesterone may promote gliomas from a mechanistic standpoint. Finally, and this is the long-term focus, researchers need to continue to search for better treatments for brain cancer in general, and glioma (i.e. GBM) more specifically.

Figure 1. Long-term use of progesterone-containing contraceptives may significantly increase the relative risk of a woman developing glioma, but the absolute risk is still small.