Less than three weeks after one major study found a greater
increase in the risk of breast cancer among postmenopausal women
taking both estrogen and progestin than among those taking estrogen
alone, another major study, being published Wednesday, has come to
similar, troubling conclusions.
Taken together, the new studies could dramatically change the
way women take hormone supplements to combat hot flashes and lower
the risks of heart disease and osteoporosis in later life.
For years, doctors have known that taking estrogen without
progestin, a second hormone, can raise the risk of endometrial
cancer, or cancer of the uterus, eight-fold. That's why both
hormones are usually prescribed together.
But the new study, being published in the Journal of the
National Cancer Institute, along with the one published in January
in the Journal of the American Medical Association, show that
``evidence is mounting that combined estrogen and progestin may be
more deleterious in terms of breast cancer than estrogen alone,''
said Dr. JoAnn Manson, chief of preventive medicine at Brigham and
Women's Hospital in Boston.
And what about uterine cancer risk? Some experts say that
progestin may be able to be given in limited doses, perhaps a few
times a year, to lower the risk of endometrial cancer, but this has
not been proven.
This week's study, led by Dr. Ronald K. Ross and Malcolm Pike
and others at the University of Southern California, looked at
1,897 postmenopausal women with breast cancer and 1,637 similar
women who did not have the disease and compared their use of
postmenopausal hormones.
They found that for every five years a woman takes estrogen
alone, the risk of breast cancer increases about six percent. But
for every five years a woman takes both estrogen and progestin --
known as combined therapy -- the risk of breast cancer rises 24
percent.
There are different ways to take the combined therapy -- a woman
can take both hormones every day, or sequentially, that is,
estrogen every day and progestin only part of the month. The
researchers found that the risk of breast cancer was higher in
women who used the sequential therapy than among those who took
both hormones every day: it rose 38 percent for every five years of
sequential hormone use versus 9 percent for every five years of
``combined continuous'' use. These differences suggest that
combined, continuous use may be safer than sequential use, but the
differences did not reach statistical significance.
The data from the new study suggest that ``the overall
risk-benefit equation will be considerably less favorable (for
combined therapy) than for ERT (estrogen replacement therapy)
alone,'' the authors write. ``If the main purpose for prescribing
(combined therapy) is to protect the endometrium from the
carcinogenic effects of estrogen, then this study would argue that
the adverse effect on the breast may outweigh the beneficial effect
on the endometrium . . .''
This study is the largest so far to look at estrogen and
progestin risks for breast cancer and contains more data than ``the
combined world literature on this subject,'' the authors noted in a
prepared statement.
Malcolm Pike, a co-author and renowned researcher into the
hormonal mechanisms underlying breast cancer, said Monday that he
predicted a dozen years ago that adding progestin to estrogen
therapy would be dangerous in terms of breast cancer. ``This is not
out of the blue,'' he said. While progestin stops cell
proliferation -- the underlying mechanism of cancer -- in the uterus,
it can drive it in the breast.
The emerging data suggest it is now time, he said, to abandon
combined hormone replacement therapy, at least as it's now done.
But since the uterus still needs protection from ``unopposed
estrogen'' (estrogen taken alone), he suggests giving women
progestin three to four times a year to trigger bleeding, which
could help the uterus shed precancerous cells.
It might also be possible to give progestin as vaginal
suppositories to achieve the same effect, he said, or to make
special progestin-containing IUDs (intra-uterine devices) for
postmenopausal women.
These measures, however, have not been proven beneficial, notes
Manson of Brigham and Women's Hospital.
But the data do mean ``we should rethink our use'' of hormone
replacement therapy, she said. ``I have noticed in my own practice
that I have less enthusiasm for hormone replacement therapy, though
some women still are good candidates.''
Overall, Manson noted there is conclusive evidence that estrogen
does help prevent osteoporosis, and that adding progestin neither
provides additional protection nor takes away from estrogen's
benefits.
In terms of cholesterol, it is also clear that estrogen alone is
better than estrogen plus progestin, she says. Estrogen alone
lowers LDL or ``bad'' cholesterol and also increases HDL or
``good'' cholesterol. Combined hormone therapy is just as good at
lowering bad cholesterol but does not increase the good form.
For heart disease, she adds, ``the jury is still out.'' For
women who have never had a heart attack, combined hormone therapy
seem to be just as good as estrogen alone at protecting against
heart disease; but for women who have already had one heart attack,
combined hormone therapy does not reduce the risk of subsequent
heart disease.
For Alzheimer's disease, there are strong theoretical reasons to
think that either estrogen alone or in combination with progestin
may reduce the risk. But so far, there is no conclusive evidence on
this from clinical trials.
So, should women currently taking both estrogen and progestin
stop taking the latter?
``No, no, no,'' says Dr. Nananda Col, director of the Women's
Wellness Center at the New England Medical Center. ``If you take
estrogen without progestin, the risk of endometrial cancer
increases eight-fold. That is a whopping difference.. . .
Endometrial cancer is not a cancer to be ignored.''
Furthermore, she says, the new study, like the one in January,
has a number of flaws that make it far from definitive. Among other
things, she says, the apparent increase in breast cancer risk among
women on combination therapy may have occurred because they were
taking higher doses of estrogen, not simply because of the
progestin. ``We haven't disentangled that.''
Dr. Maureen Connelly, an epidemiologist and codirector of the
menopause consultation service at Harvard Vanguard Medical
Associates, takes a similar view.
``People should rethink'' their hormone decisions, ``but they
should be cautioned against automatically throwing their progestin
in the trash and continuing with estrogen alone. We know absolutely
that that will increase the risk of endometrial cancer.''
And Manson adds a final word of advice. Even with all the
emerging data, she says, it still appears that short-term use of
hormones at menopause does not appear to raise breast cancer risk.
``Many women just take hormones for three years. So the good
news is we can be reassuring for those women. . .the key is to
minimize duration of use and total dose of these hormones.''
