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ENDO 2003
The Endocrine Society
19-22 June 2003

ENDO 2003 - Day 1 - Thursday 19 June 2003

ENDO 2003 - Day 2 - Friday 20 June 2003

Report:
The HRT debate that wasn't
Investigators: Marcia Stefanick and Fred Naftolin


20 May 2003

by Tabitha M. Powledge


Data from the big hormone replacement study that the US government shut down
last year cannot answer the question everyone is asking: can long-term
hormone-replacement therapy started early in menopause decrease the diseases of
aging, and do it safely?

It was supposed to be a debate about the very controversial random clinical
trial of hormone replacement in post-menopausal women that the US government
shut down last year. But at the government's Women's Health Initiative (WHI)
study debate held at ENDO 2003, the debaters agreed: the massive study is
worthless for answering the question that's really plaguing millions of women,
their physicians, and the regulatory agencies. Is it useful and safe to begin
hormone replacement early in the menopause?

According to one of its principal investigators, the study of hormone
replacement therapy (HRT) sponsored by the government's answered a different
question: should women, especially women well beyond menopause, be using
Prempro - the most popular estrogen-progestin combination - for primary
prevention of heart disease?

The answer to that question is clearly no, says Marcia Stefanick, who headed
the WHI study site at Stanford University. Fred Naftolin of Yale, a vociferous
critic of the study, argues that it does not have the statistical power to
address the risk of long-term treatment that begins in the menopausal
transition.

The National Institutes of Health stopped the WHI study in July 2002, two years
early, because the data showed an increased risk of invasive breast cancer for
HRT subjects. There were also increases in coronary heart disease, stroke, and
pulmonary embolism. The increase in risks was small for all these conditions,
and there were some benefits, among them fewer cases of hip fractures and colon
cancer.

But on balance, NIH concluded, the harm was greater than the benefit. Results
continue to dribble out; new ****yses published in May show increases in
dementia and no protection against mild cognitive impairment in the Prempro
group.

It is interpretation of the WHI study, not the study itself, that has caused
confusion and sometimes unnecessary panic among older women, their doctors, and
regulators, especially the Food and Drug Administration, according to Naftolin.
"The New York Times doesn't understand the difference between menopause, the
climacteric, and aging," he grumbled.

Audience members were also irritated by what many said were media and public
policy overresponses to WHI results. They urged efforts to educate the public
about what the WHI studies truly mean. Marjorie Shuer, of the University of
California at San Diego, called for statements and public education efforts
from the Endocrine Society, and so did others.

However, there was little attention to HRT at ENDO 2003. The WHI study debate
was an informal off-site event organized by the Society's Endocrinology of
Aging interest group and the National Institute on Aging.

The WHI study was launched because HRT was being prescribed for millions of
older women, not for the symptoms of menopause, but to prevent the diseases of
aging, Stefanick says. The off-label prescribing was based on observational
studies that had suggested HRT could reduce the risk of cardiovascular heart
disease and other disorders.

The trial tested Prempro instead of other types of hormone replacement because,
she says, the drug - a complex ****tail of conjugated horse estrogens
(Premarin) and the progestin medroxyprogesterone acetate - was far and away the
most widely prescribed HRT.

But the observational studies that generated belief in the healing power of
hormones usually involved conjugated equine estrogens only, not in combination
with progestins, adds Stefanik. A WHI study of estrogen-only HRT is continuing.
It is being conducted in women without uteruses because it is believed that
unopposed estrogen increases the risk of endometrial cancer.

Much of the discussion at the non-debate focused on study group demography.
Naftolin points out that the WHI subjects' average age was 63, and the average
time since menopause was 12 years. Subjects in the observational studies were
usually much younger and healthier. They had also begun HRT earlier, whilst
relatively few of the WHI subjects had been on HRT when they entered the study.

Stefanick notes that 75% of the ill effects in the WHI Prempro groups occurred
in women in their 70s and 80s. About a third of the WHI subjects were in their
50s, although there is no evidence that women in their 50s are affected less
than women in their 70s, she says.

see also:
The effect of various regimens of hormone replacement therapy on mammographic
breast density
[Maturitas]
G Christodoulakos and I Lambrinoudaki
Maturitas, 2003, 45:2:109 - 118
Estrogen alone or combined with medroxyprogesterone but not raloxifene reduce
myocardial infarct size
[European Journal of Pharmacology]
E Sbarouni and E Iliodromitis
European Journal of Pharmacology, 2003, 467:1-3:163-168
Comparison of hormonal activity (estrogen, androgen and progestin) of
standardized plant extracts for large scale use in hormone replacement therapy
[The Journal of Steroid Biochemistry and Molecular Biology]
V Beck and E Unterrieder
The Journal of Steroid Biochemistry and Molecular Biology, 2003, 84:2-3:259-268

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Report:
Does hormone replacement protect the brain?
Investigators: Phyllis Wise and Robert Gibbs


19 May 2003

by Tabitha M. Powledge


Does hormone replacement protect the brain? Never mind the equivocal results of
clinical trial data, animal researchers say yes, definitely.

The conclusions of recent clinical trials may be confusing and controversial,
but Phyllis Wise and her colleagues consistently report that very low levels of
estrogen replacement reduce injury from stroke in animals.

In studies at the University of Kentucky in Lexington and the University of
California at Davis, the researchers have shown that 17ß-estradiol - the
estrogen produced in the human ovary - protects animal brains by changing the
expression of several genes, thereby altering the level of neurogenesis.

There is agreement from Robert Gibbs, a reproductive physiologist at the
University of Pittsburgh, that animal studies clearly demonstrate that hormone
replacement helps prevent age-related cognitive decline. "Definitely yes," he
said.

However, this view contrasts with the most recently published data from the
large Women's Health Initiative, which suggests that not only does combination
hormone replacement therapy have no obvious neuroprotective benefit for women,
but it even seems to increase their risk of stroke.

There are several reasons for the apparent discrepancy, say researchers. Wise
explains the differences between the latest clinical trial and her lab's
results this way: "This was hormone replacement, not estrogen replacement, and
the estrogen is not estradiol 17ß but a combination of multiple estrogens made
in horses," she told BioMedNet News.

"Also, what we're looking at is not the risk of stroke, but injury after you
have a stroke," she added. Gibbs, among others, suggests there may be a window
of opportunity in which hormone replacement must be initiated in order to be
effective, and that the size of the estradiol dose matters.

In a recent unpublished study, researchers in Wise's lab showed that estrogen
increases proliferation of cells in the dorsal sub-ventricular zone of the
brain, and that a significant proportion of the cells created were neural
precursors. However, what subsequently happens to these precursors is still a
mystery, she says. "We don't know whether they go on to become neurons," she
said.

Many of the animal studies in the Wise lab are designed to mimic comparisons of
postmenopausal women on hormone replacement therapy and women not taking
hormones. In one, ovariectomized rats were given both low and high
physiological levels of estradiol for a week before occlusion of their cerebral
arteries. In the rats that got estradiol, the volume of the resulting infarct
was significantly lower than it was in control rats treated with oil, she says.


But different brain regions responded differently to estradiol. Injury size was
reduced overall and in the cortex, but not in the striatum, says Wise.
Protection was not due to alterations in cerebral blood flow that permitted
more nutrients to reach the brain, she says. And estradiol protected even
middle-aged animal brains. "To our surprise, it was very efficacious in the
cortex," said Wise.

Estrogen protects the brain in several different ways, depending on the type of
injury, the brain region affected, and the hormone dose. Wise and her
colleagues believe that low, physiological levels of estradiol protect the
brain from stroke injury by upregulating estrogen receptor mRNA, thus
preventing downregulation of expression of estrogen receptor (ER) genes in the
cerebral cortex. They also found that estradiol does not protect against injury
in tissue explants treated with an ER antagonist.

With the help of two kinds of knockout mice, one lacking ERa and the other
without ERß, the researchers showed that physiological levels of estradiol
reduced the volume of stroke injury both in the ERß- knockouts and wild-type
mice, but not in the ERa-knockouts. Wise concludes that only the ERa receptor
is critical to preventing ischemic injury.

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