Pill Positive
Examination of Oral Contraceptive use Reveals Little Evidence that the Pill Increases Breast Cancer Risk.
A hormone is a hormone is a hormone.
Well, maybe not.
Millions of women taking oral contraceptives began to wonder about their own
health after the National Institutes of Health last year halted a portion
of its trial of hormone replacement therapy for postmenopausal women due to
increased breast cancer and other risks.
Hormone replacement therapy, after all, uses a combination of estrogen and
progestin, the same families of hormones in “the Pill.”
But researchers
assure women that hormone replacement therapy and oral contraceptives are
not the same. Further, a team of investigators from the USC/Norris Comprehensive
Cancer Center and other prominent institutions recently found that taking
modern oral contraceptives does not appear to increase breast cancer risk—a
study published in the New England Journal of Medicine.
“The role of oral contraceptives in breast cancer risk appears to have
changed as the composition of oral contraceptives has changed,” says
Leslie Bernstein, Ph.D., the AFLAC Chair in Cancer Research, professor of
preventive medicine at the Keck School of Medicine of USC and one of the study’s
authors. “We found that neither women currently taking oral contraceptives
nor those who took them for long periods of time had an increased risk of
the disease.”
Researchers interviewed more than 4,500 black women and white women between
ages 35 and 64 who had been diagnosed with invasive breast cancer in the mid-1990s,
and matched them to more than 4,500 women without breast cancer. Bernstein
was principal investigator for the Los Angeles arm of the multi-center, case-control
study, called the National Institute of Child Health and Human Development
Women’s Contraceptive and Reproductive Experiences (Women’s CARE)
Study.
Nearly eight of 10 women in both groups had used a type of oral contraceptive,
and the risk of breast cancer among women who had used such contraceptives
was actually slightly lower than that among women who had never used them.
Most used combination contraceptives, those with estrogen and progestin, rather
than progestin-only pills.
Examining aspects of oral contraceptive use—how long a woman used it,
her age when she started, how long since she last used it, and estrogen dose—revealed
little evidence that oral contraceptives increase breast cancer risk. This
held true regardless of age, race and family history of breast cancer.
Although risks and benefits from different hormone replacement therapies are
still under investigation, how can hormone replacement and oral contraceptives
wield disparate risks? The answer lies within the women themselves.
Hormone highs and lows
Giske Ursin, M.D., Ph.D., associate professor at the Keck School and one of
the CARE study authors, says understanding the differences between a woman’s
own hormones before and after menopause—and how they interact with hormonal
medications—is key.
Before menopause, levels of progesterone (the natural version of progestin)
and estrogen in a woman’s body routinely rise and fall over the course
of her monthly cycle. Estrogen thickens the endometrium, the lining of the
uterus, before the ovaries release an egg. After ovulation, progesterone surges
to prepare the uterus for pregnancy. If pregnancy does not happen, progesterone
levels drop and menstruation begins.
But these hormones do not just affect the uterus; they travel through the
blood to breast and other tissues. Estrogen and progesterone stimulate breast
cells to divide and multiply. And the more breast cells multiply, the greater
the chance that genetically faulty cells will arise.
Cancer results when these faulty cells survive and thrive, multiplying out
of control.
The more breast cells proliferate over months and years, the more breast cancer
risk adds up. That is important to understand when considering possible risks
from hormones.
Ursin points to a spike on a chart showing fluctuating estrogen and progesterone
levels during a normal pre-menopausal woman’s cycle. “The greatest
amount of division and proliferation of breast cells happens when estrogen
and progesterone come together here, at the end of the cycle,” she says.
“But something interesting happens with women taking oral contraceptives,”
she notes, pointing to a different chart. “In these women, the levels
of breast cell proliferation remain almost level throughout the month.”
Instead of having the highs and lows of estrogen and progesterone experienced
by premenopausal women, women on oral contraceptives have only subtly fluctuating
hormone levels. Here’s why: The pills serve to “trick” the
body into not ovulating. With no need to release an egg every month, the body
maintains fairly steady levels of estrogen and progestin provided by the Pill.
As it turns out, the average monthly levels of hormones flowing through a
woman on the Pill and those in a woman not on the Pill are about the same—oral
contraceptives just even out spikes and dips in normal hormone levels.
Says Bernstein: “Depending on the composition of the pill used, oral
contraceptives either match the levels of ovarian hormones women would have
produced in an ovulatory menstrual cycle or they provide less hormone.”
More importantly, by the end of a cycle, breast cells in a woman on oral contraceptives
have multiplied and divided about as much—or maybe even slightly less—than
a woman not taking the Pill. That means their breast cancer risk should be
comparable, assuming no additional risks from diet, family history or other
sources.
Menopause means change
But menopause changes the hormonal landscape.
As a woman enters menopause, the ovaries produce less and less estrogen. Menstruation
finally ceases.
The low levels of estrogen remaining in postmenopausal women come mostly from
adrenal hormones that are converted in fat tissue to estrogens. Progesterone
is absent.
These changes may cause numerous uncomfortable menopausal symptoms, from hot
flashes to irritability. Hormone replacement therapy, which can ease symptoms,
provides estrogen and progestin, but in far lower doses than those of typical
combination oral contraceptives.
That can be hard to jibe with possible increased breast cancer risk, Bernstein
notes, until one understands the effects caused by added estrogen and progestin
in postmenopausal women.
Instead of helping to regulate a cycle with fairly normal levels of hormones,
as in premenopausal women on oral contraceptives, hormone replacement therapy
in postmenopausal women actually introduces hormones not normally present
in these women or present in extremely small amounts.
And additional estrogen and progestin means additional breast cell multiplication.
After a few keystrokes on her computer, Ursin brings up two mammography images
from a postmenopausal woman on hormone replacement therapy. They show dense
areas where cells proliferated in the woman’s breast. “Even though
the HRT dose is not that high,” she says, “you still see more mammographic
density—suggesting proliferation of breast cells—than you would
normally see in a postmenopausal woman.”
Hormone history
USC researchers have long been significant players in the sometimes controversial
hormone-and-breast-cancer arena. In a 1983 study, USC preventive medicine
researchers Malcolm Pike, Ph.D., and Brian Henderson, M.D., first linked birth
control pills with a high estrogen and progestin content to increased breast
cancer risk among young Los Angeles women.
Among other studies, in 2000, Ronald K. Ross, M.D., professor and Flora L.
Thornton Chair in Preventive Medicine at the Keck School, and his colleagues
linked use of hormone replacement therapy after menopause with increased breast
cancer risk.
Ursin, Bernstein and their colleagues are already examining the role of oral
contraceptives in breast cancers among women who have an inherited risk for
the cancer. Studies by other USC/Norris researchers will explore breast cancer
among premenopausal women, as well as any increased risk that might be caused
by oral contraceptive use among women undergoing menopause.
“We’d also like to find out if there are subgroups of women at particularly
high risk if they use hormone replacement therapy,” Ursin says. “It
could be that only one out of four or five women is at high risk for breast
cancer when taking hormone replacement.”
Over time, researchers may hone new types of synthetic hormones, new delivery
systems for them and methods to determine which women can safely use them.
Says Ursin: “If we could just have a way of picking out the subset of
women who are at risk for breast cancer from using hormone replacement therapy,
and offer the rest the benefits, that would be the best of all worlds.”
For more information about the Colorectal Cancer Family Registry, or to learn
more about The Doctors of USC, call 1-800-USC-CARE (1-800-872-2273).
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