Increased Risk of Ovarian Cancer Is Linked to Estrogen Replacement Therapy
Researchers from the National Cancer Institute (NCI) have found that women in a
large study who used estrogen replacement therapy after menopause were at
increased risk for ovarian cancer. The report was published in the July 17,
2002, issue of JAMA.*
The scientists followed 44,241 women for approximately 20 years. Compared to
postmenopausal women not using hormone replacement therapy, users of
estrogen-only therapy had a 60 percent greater risk of developing ovarian
cancer. The risk increased with length of estrogen use. The women, who were
followed from 1979 to 1998, were former participants in the Breast Cancer
Detection Demonstration Project, a mammography screening program conducted
between 1973 and 1980.
"The main finding of our study was that postmenopausal women who used estrogen
replacement therapy for 10 or more years were at significantly higher risk of
developing ovarian cancer than women who never used hormone replacement
therapy," said James V. Lacey, Jr., Ph.D., lead author of the study from NCI's
Division of Cancer Epidemiology and Genetics. The relative risk for 10 to 19
years of use was 1.8, which translates to an 80 percent higher risk than
non-users, and increased to 3.2 (a 220 percent higher risk than non-users) for
women who took estrogen for 20 or more years.
Estrogen is a natural hormone produced primarily by the ovaries. After
menopause, the ovaries produce lower levels of the hormones estrogen and
progesterone. By the time natural menopause is complete - usually between ages
45 and 55 - hormone output decreases significantly. As early as the 1940s,
women began using estrogens in high doses to counteract some of the short-term
discomforts of menopause (hot flashes, vaginal drying and thinning, and urinary
tract incontinence and infections).
However, after it became clear in the 1970s that women who took estrogen alone
had a six to eight times higher risk of developing endometrial cancer (cancer
of the lining of the uterus), doctors began prescribing progestin along with
much lower doses of estrogen. Progestin is a synthetic form of the natural
hormone progesterone. The addition of progestin to estrogen therapy reduces the
increased risk of endometrial cancer associated with using estrogen alone. As a
result, it has become increasingly common to prescribe estrogen-progestin
therapy for women who have not had a hysterectomy.
In addition to studying the effect of estrogen use alone, Lacey and his
colleagues looked at whether women using estrogen-progestin therapy were more
likely to develop ovarian cancer. No increased risk was found.
Lacey commented, "Even though our data showed that women who took estrogen
combined with progestin were not at increased risk for ovarian cancer, only a
few women in our study who developed ovarian cancer had used estrogen-progestin
therapy for more than four years. So, at this point, there simply aren't enough
data to say whether taking the combined therapy has any effect on ovarian
cancer."
Past studies suggested that postmenopausal hormone treatments might be effective
in preventing or reducing some of the negative long-term effects of aging, such
as heart disease and osteoporosis. However, the results from a large
multi-center clinical trial, also published in the July 17 issue of JAMA
(JAMA 2002;288:321-333), showed increases in breast cancer, coronary
heart disease, stroke, and blood clots in the lungs and legs for women on
estrogen-progestin therapy for an average of 5.2 years. The trial, part of the
Women's Health Initiative (WHI), also found fewer cases of hip fractures and
colon cancer among women taking the combined therapy. However, because overall
the harm was greater than the benefit, the trial was stopped last week, three
years ahead of schedule. The WHI randomized trial for estrogen alone in women
who have had their uterus removed is continuing.
Lacey emphasized the complexity of weighing the various risks and benefits of
hormone use. "Because hormone therapy may influence so many conditions that
affect women after menopause - cardiovascular disease, osteoporosis, breast
cancer, uterine cancer, gallbladder disease, blood clots, and now potentially
ovarian cancer - we should no longer think of a woman basing her decision to
use hormones on the potential risk of just one condition. Women should continue
to talk to their health care providers about whether hormones might be right
for them."
Previous studies looking at the effect of postmenopausal hormones on ovarian
cancer risk have been inconsistent. Some reported increased risk with estrogen
use while others reported either no effect or a protective one. Most of these
earlier studies were relatively small and limited by incomplete information
about ovarian cancer risk factors.
Two recent large studies found a link between hormone use and ovarian cancer. A
large prospective study published last year (JAMA 2001;285:1460-1465)
showed that postmenopausal estrogen use for 10 or more years was associated
with increased risk of ovarian cancer mortality, and a recent Swedish study (J.
Natl. Cancer Inst. 2002;94:497-504) reported that estrogen use alone
and estrogen-progestin used sequentially (progestin used on average 10
days/month) may be associated with an increased risk for ovarian cancer. In
contrast, estrogen-progestin used continuously (progestin used on average 28
days/month) seemed to confer no increased ovarian cancer risk.
Lacey said that some of the unknowns concerning hormone use and ovarian cancer
include the following:
- Duration vs. dose of estrogen therapy
It is not clear from this study whether the increased risk with estrogen use is
due to higher doses of estrogen, longer duration of estrogen use, or both dose
and duration. It is also not clear whether long-term use of lower-dose estrogen
is associated with ovarian cancer.
- Duration of estrogen-progestin therapy
Most women in this study were on the combined therapy for less than four years,
so more data will be needed to determine whether estrogen-progestin use
increases risk. The effect of long-term use of estrogen-progestin therapy is
not known.
- The type of estrogen-progestin regimen
The continuous regimen involves taking both hormones simultaneously throughout
the month. The sequential regimen, on the other hand, involves taking estrogen
every day, and progestin for 10 to 14 days each month.
- Use of more than one type of hormone replacement therapy
For instance, after taking estrogen alone, some women changed to a combined
regimen after reports of increased endometrial cancer risk with estrogen alone.
More data are needed to analyze the effect of switching from one regimen to
another.
- The form of estrogen administration
Most studies have analyzed the use of estrogens in pill form, but it can also
be administered by patches, shots, and creams.
Every year, about 23,000 U.S. women are diagnosed with ovarian cancer and 14,000
women die from the disease. A woman's lifetime risk of developing ovarian
cancer is 1.7 percent. This means that in a group of 100 women followed from
birth to age 85, fewer than two would get ovarian cancer. In comparison, about
13 women would get breast cancer (lifetime risk is 13.3 percent), fewer than
three women would develop uterine cancer (lifetime risk is 2.7 percent), and
between 16 and 32 women would develop osteoporosis.
An estimated 40 million U.S. women will experience menopause during the next 20
years, and women today are living approximately one-third of their life after
menopause.
Anywhere from 20 percent to 45 percent of U.S. women take some form of hormone
therapy between the ages of 50 and 75. According to industry estimates, about 8
million U.S. women use estrogen alone and about 6 million U.S. women use
estrogen-progestin therapy. About 20 percent of hormone users continue for more
than five years.
* The study is titled "Menopausal hormone replacement therapy and risk of
ovarian cancer." The authors are James V. Lacey, Jr., Pamela J. Mink, Jay H.
Lubin, Mark E. Sherman, Rebecca Troisi, Patricia Hartge, Arthur Schatzkin, and
Catherine Schairer.JAMA 2002;288:334-341.
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