Hormone therapy’s unanswered
Earlier this year, the Women’s Health Initiative (WHI) trial
of estrogen-only hormone therapy (Premarin) was halted due to an increase
in stroke risk. It was the second time WHI participants were told to
stop taking their pills. In 2002, the combined hormone trial ended
early after Prempro (Premarin plus a progestin) prompted an unacceptable
risk for breast cancer, heart attack, and stroke. Once considered a
panacea for many postmenopausal ills, hormone therapy is now generally
prescribed only for treating hot flashes and vaginal dryness — and
only at the lowest dose, for the shortest period of time.
But several questions have arisen in the wake of the WHI’s landmark
effort to ascertain hormone therapy’s long-term risks and benefits,
and its role in disease prevention. For example, the WHI tested hormone
therapy mostly in women who began taking it long after the start
of menopause. If the women had started taking hormones earlier, would
the results have been different?
Before the WHI, scientists consistently observed that hormone therapy
lowered heart disease risk by 35%–50% in populations of postmenopausal
women. Clinical studies found good effects on cholesterol levels and
improved blood vessel function — so-called surrogate evidence of
heart benefits. Also, laboratory animals undergoing experimentally induced
menopause that were treated with estrogen had less atherosclerosis than
those that got no estrogen. That’s why, until 2002, many physicians
encouraged women 50 and older to take hormone therapy to prevent heart
Interestingly, in most of the animal experiments, the estrogen used
was estradiol, not Premarin (a brew that contains many forms of estrogens
and other compounds). This also raises the question, what if women in
the WHI had taken estradiol, or another estrogen, rather than Premarin-based
After the hazards of long-term combined hormone therapy became known,
attention focused on the estrogen-only trial, which included more than
10,000 postmenopausal women, average age 63, who had all had hysterectomies.
The trial ended because of a nearly 40% increased stroke risk in estrogen
takers, compared to those getting a placebo. Estrogen had no effect on
coronary heart disease risk, slightly decreased breast cancer risk, and
significantly lowered the chances of hip fracture.
Some experts contend that the increased stroke risk reflects possible
underlying disease in the WHI subjects, who, on average, started hormone
therapy later than most women do. Also, it may be harmful to boost estrogen
in women whose bodies have grown accustomed to making do with less of
it. In both WHI trials, the women who began hormone therapy closer to
menopause had fewer cardiovascular events than those who started it later.
Premarin and Prempro at specific doses were the only hormone drugs
studied in the WHI. Might other preparations and doses have different
effects? Is patch estrogen better than oral estrogen? Would starting
sooner, during perimenopause, offer greater benefits and fewer risks?
Although women 60 and older shouldn’t start hormone therapy for
disease prevention, we have no idea if that’s good advice for women
Researchers are gearing up to answer these questions with studies that
address the issues raised by the WHI (see box below).
Hormone study to start in younger
A five-year, multi-center trial
privately funded by the Kronos Longevity Research Institute and
involving several investigators, including Harvard Women’s
Health Watch advisory board member Dr. JoAnn Manson, will
test whether hormone therapy prevents atherosclerosis progression
in women ages 40–55. Subjects will be randomly assigned
to transdermal (patch) or oral estrogen plus vaginal progesterone
given cyclically, or to a placebo.
August 2004 Update
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