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 progestin in birth control pills induces
damaged ovarian cells 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 its one that millions of
are already exposed to through oral contraceptives and hormone
replacement therapy," said Dr. Gus Rodriguez, lead author of the
study published in the September 9th 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 lifespan," he said.
Studies in Macaque Monkeys
Rodriguez and 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 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 by which birth control
pills protect against ovarian cancer--a phenomenon that has been
observed widely. Well-documented epidemiologic studies spanning 3
decades have shown that taking birth control pills for just 3 years
can reduce a womans lifetime risk of ovarian cancer by 40%.
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 3 years of oral
contraceptive use--or a mere 10% fewer lifetime ovulations--could
reduce the lifetime risk of ovarian cancer by 40%. 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 monkeys receiving progestin alone had a six times greater level
of apoptosis (24%) 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,
While cells routinely self-destruct when they sustain irreparable DNA
damage, the suicide process does not always work as it should.
Thats 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
Progestin May Tip the Scales Toward Apoptosis
Any compound that can help cells overcome the cells resistance
to apoptosis can prevent them from becoming malignant, Rodriguez
said. "Progestin may lower the threshold of resistance by
tipping the scales toward apoptosis," he said.
Although the researchers dont know precisely how progestin
activates apoptosis, 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, 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 isnt."
Multiple Benefits of Progestin Cited
The benefits of progestin are many, he says:
Thirty years of evidence show the safety of progestins 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
arent 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 progestins 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.