Oral Contraceptives With Higher Levels Of Progestin Protect Against Ovarian Cancer, Study Suggests

Oral contraceptives have long been associated with a decreased risk of ovarian cancers. Some studies show that three or more years of oral contraceptive use reduces the risk of developing epithelial ovarian cancer by 30-50 percent, and the decrease in risk grows with the duration of use.

While it has been commonly considered that this reduction in risk is based in limiting ovulation, the Duke study, led by Joellen Schildkraut of the Duke Comprehensive Cancer Center, indicates that the progestin levels in the oral contraceptives might be as important as ovulation reduction in the prevention of ovarian cancer.

Schildkraut and her colleagues studied 390 women with epithelial ovarian cancer and 2,865 control subjects. The women were between 20 and 54 years of age and had been identified from a study known as the Cancer and Steroid Hormone (CASH) study conducted from 1980 to 1982. The CASH study collected data on ovarian cancer rates and oral contraceptives use in women to characterize the protective effect of specific oral contraceptive formulations on ovarian cancer risk. In the original study, all formulations of oral contraceptives seemed to reduce ovarian cancer risk.

However, Schildkraut and her colleagues re-analyzed the data to determine whether higher estrogen or progestin levels in pill formulations might have more of a protective effect than formulations with lower levels of those hormones.

"If reduction in ovulation alone was the only protective effect of oral contraceptives, then we would find that all formulations had the same reduction in risk," Schildkraut said. "That's not what we found in this study."

Comparing oral contraceptives by estrogen and progestin potency, the researchers found that oral contraceptives with higher levels of progestin are associated with greater reduction of risk of ovarian cancer than those with lower progestin potency, regardless of estrogen content, duration of use and latency. The study also showed that women who took pills with higher progestin levels showed a significant reduction in risk, even when taken for a short period of time -- three to 18 months. The amount of estrogen in the pill did not seem to affect ovarian cancer risk, the scientists found. Non-users of oral contraceptives appeared to be at a greater risk of ovarian cancer than women who took oral contraceptive, regardless of formulation, they found.

The findings of the study by Schildkraut and her colleagues are supported by a study of the biological effects of progestin conducted at Duke that is also published in the January issue of Journal of the National Cancer Institute. The study in monkeys shows that the progestin component of oral contraceptives seems to be related to increased cell turnover in the ovarian epithelium, indicating that progestin might lower ovarian cancer risk by activating cancer-preventative molecular pathways in the ovary. In the study, 80 monkeys were randomly divided into four groups: one receiving an oral contraceptive with both estrogen and progestin, one receiving progestin alone, one receiving estrogen alone and one (the control group) receiving nothing. The two groups of monkeys given the pills containing progestin showed a striking and significant increase in cell death than the control group or the estrogen group. According to researchers, by increasing the cell death and turnover in the ovarian epithelium, there is more of a chance of eliminating damaged cells that can turn cancerous.

"We believe these two studies show that there are biological effects related to the progestin that are playing a role in the reduction in ovarian cancer risk associated with oral contraceptive use," Schildkraut said. "We hope that by identifying this pathway and its key mechanism, future ovarian cancer research will capitalize on information to achieve maximum protection against ovarian cancer, while minimizing side effects."

Schildkraut does caution that while pills that are higher in progestin are protective against ovarian cancer, they might increase risk of certain types of breast cancer. She said this consideration needs to be studied further, and that other agents, such as vitamin D, may be able to capitalize on this prevention pathway without increasing breast cancer risk.

The Duke study did have its limitations, cautioned Schildkraut. The researchers cited possible misclassifications of some of the pills and a lack of formulations and dosages for all oral contraceptives. Also, the women in the CASH study were young (44.1) compared to the average age (59) of women who develop ovarian cancer in the general population. Researchers said this makes it difficult to know whether these results would apply to menopausal women who develop ovarian cancer.

The Duke study was funded by the National Cancer Institute, the National Institutes of Health, Department of Health and Human Services and the Department of Defense.

According to the American Cancer Society, ovarian cancer is the sixth most common cancer among women, excluding non-melanoma skin cancers. Approximately 23,400 new cases of ovarian cancer were diagnosed in the United States in 2001. Approximately 13,900 women died of ovarian cancer in that same year. Ovarian cancer accounts for 4 percent of all cancers in women.