DURHAM, N.C. -- Researchers at Duke University Medical Center report animal studies that may explain for the first time why oral contraceptives offer protection against ovarian cancer. Their findings suggest that the hormone progestin in birth control pills induces ovarian cells that are damaged to die before they turn malignant.
The discovery offers hope that periodically administering progestin to wipe out precancerous ovarian cells could be a highly effective preventive treatment for ovarian cancer, which kills 17,000 women in the United States annually. The researchers plan to begin human trials of the therapy this fall.
"Progestin could be one of the most significant cancer preventive agents ever developed, and it's one that millions of women are already exposed to through oral contraceptives and hormone replacement therapy," said Dr. Gus Rodriguez, lead author of the study published in the Sept. 9 issue of the Journal of the Society for Gynecologic Investigation. "Theoretically, we could wipe out precancerous cells in the ovarian epithelium by delivering bursts of progestin throughout the life span," he said.
Rodriguez and his colleagues studied how hormones affect the ovaries of macaque monkeys, whose reproductive biology closely mimics that of humans. They found that progestin activated the critical process of apoptosis in the ovarian lining. Apoptosis is a genetic suicide program in all cells that is triggered when cells have sustained irreparable genetic damage. Such mutated cells in the ovarian lining, if allowed to survive, could proliferate and turn malignant.
The researchers said theirs is the first study to directly implicate this action of progestin as the mechanism behind the widely observed phenomenon in which birth control pills protect against ovarian cancer. Well-documented epidemiologic studies spanning three decades have shown that just three years of taking birth control pills can reduce a woman's lifetime risk of ovarian cancer by 40 percent.
Rodriguez said progestin treatment would target precancerous cells in the ovarian lining that should have been slated for apoptosis but somehow escaped the process. Once such cells have been destroyed, it takes years or decades for the ovarian lining to accumulate the kind of damage that would lead to ovarian cancer, at which point progestin could be delivered again. Pregnancy may also confer protection against ovarian cancer because progesterone (the natural form of progestin) peaks during gestation.
Until now, scientists had presumed that oral contraceptives reduced the risk of ovarian cancer by suppressing monthly ovulation, in which constant cell division can spontaneously damage DNA in ovarian cells. By halting ovulation for a period of time, a woman would theoretically have less chance of sustaining enough genetic damage to cause ovarian cancer.
But the Duke researchers questioned how only three years of oral contraceptive use -- or a mere 10 percent fewer lifetime ovulations -- could reduce the lifetime risk of ovarian cancer by 40 percent. So they decided to study the cellular and molecular effects of various contraceptive hormones on the ovaries.
For 35 months, they gave three groups of monkeys one of four different combinations of hormones -- either an oral contraceptive progestin, an oral contraceptive estrogen or a combination of both. A fourth control group received no hormones.
The results showed that the monkeys receiving progestin alone had six times more apoptosis (24 percent) in their ovarian epithelium than did the control group or the group receiving estrogen alone. The combination group also showed a high level of apoptosis, but less than that of the monkeys receiving progestin alone. Monkeys receiving estrogen alone and those in the control group had the lowest rate of apoptosis, about 3.9 percent.
While cells routinely self-destruct when they sustain irreparable DNA damage, the suicide process does not always work as it should. That's especially the case in women who sustain serious damage to critical regulatory genes that normally activate the suicide genetic switch. When such genes are damaged, the apoptosis switch is never activated.
Any compound that can help cells overcome the cells' resistance to apoptosis can prevent them from becoming malignant, Rodgriguez said. "Progestin may lower the threshold of resistance by tipping the scales toward apoptosis," he said.
Although the researchers don't known precisely how progestin activates apoptosis, they said that knowing how progestin works is not critical to its success. As long as it works and is safe in humans, which the researchers plan to test this fall, then the hormone could be used to protect millions of women against ovarian cancer, Rodriguez said.
"If you want to make an impact on ovarian cancer from a public health standpoint, theoretically you should give progestin to the entire population of women," he said. "Most ovarian cancer occurs sporadically, not in response to an inherited genetic defect, so there is no standard for judging definitively who is at risk and who isn't."
The benefits of progestin are many, he says:
- Thirty years of evidence show its safety among women taking oral contraceptives and hormone replacement therapy;
- Progestin selectively targets those cells that have progestin receptors, such as cells in the breast, uterus and ovary, so there is little risk of inadvertently causing harm to other cells in the body;
- Hormone therapy with progestin can be implemented in all age groups;
- Women are already exposed to progestins through oral contraceptives and hormone replacement therapy, and post-menopausal women who aren't taking it can be encouraged to do so;
- A French study has suggested that the type of progestin used in oral contraceptives may decrease the risk of subsequent breast cancer.
Upcoming studies will focus on progestin's effects in women. Specifically, the researchers will develop a risk-assessment profile for women by analyzing their genetic susceptibility and pertinent aspects of their history, relative to risk of ovarian cancer. Researchers will use the profile to determine who is at greatest risk for developing ovarian cancer, with the goal of delivering preventive agents more aggressively to this population.
The researchers also plan to study the molecular pathways through which progestins work, with the hope of developing additional agents that stimulate apoptosis in the ovarian epithelium.
Journal
Journal of the Society for Gynecologic Investigation