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Default Estrogen Therapy May Adversely Affect Global Cognitive Function (diabetes dementia stroke heart coronary)

Medscape Medical News

Estrogen Therapy May Adversely Affect Global Cognitive Function CME

News Author: Laurie Barclay, MD CME Author: Désirée Lie, MD, MSEd
Authors and Disclosures To earn CME credit, read the news brief, the
paragraphs that follow, and answer the questions below.

Release Date: June 22, 2004; Valid for credit through June 22, 2005

Credits Available Physicians - up to 0.25 AMA PRA category 1 credit(s)

June 22, 2004 — Conjugated equine estrogen (CEE) does not reduce
the incidence of dementia or mild cognitive impairment (MCI) and has
an adverse effect on global cognitive functioning, according to two
reports from the Women's Health Initiative Memory Study (WHIMS)
published in the June 23/30 issue of JAMA.

"The use of estrogen by women 65 years and older to prevent dementia
or cognitive decline is not recommended," lead author Sally A.
Shumaker, PhD, from Wake Forest University Baptist Medical Center in
Winston-Salem, North Carolina, says in a news release. "Clearly,
hormone therapy does not prevent dementia — as was thought when
we began this important research."

Results released from WHIMS last spring showed that estrogen plus
progestin doubled the risk of dementia in older women and did not
improve global cognition. The new report extends these findings to
women receiving only estrogen.

"We found a similar, but slightly weaker, trend toward increased risk
of dementia among the women taking estrogen alone," Dr. Shumaker
says. "Translated to a population of 10,000 older women taking
estrogen alone, there would be an additional 12 cases of dementia per
year. For 10,000 women taking the combined hormone therapy, there
would be an additional 23 cases of dementia per year."

The WHIMS is part of the larger Women's Health Initiative (WHI), a
group of randomized clinical trials of hormone therapy in
approximately 27,000 women from multiple geographic regions. In July
2002, the estrogen plus progestin group of the WHI was terminated
prematurely because of significantly more noncognitive adverse events
associated with CEE plus medroxyprogesterone acetate (MPA) compared
with placebo.

On February 29, 2004, the WHI estrogen-alone trial was terminated when
the National Institutes of Health determined that the excess risk of
stroke in the hormone therapy group was unacceptable in healthy women
in the absence of benefit for coronary heart disease, which was the
primary outcome.

The WHIMS consisted of randomized, double-blind, placebo-controlled
clinical trials of CEE or CEE plus MPA in community-dwelling women
aged 65 to 79 years. The estrogen plus progestin trial was conducted
from June
1995 to July 8, 2002, and enrolled 4,532 women, and the estrogen-alone
trial was conducted from June 1995 to February 29, 2004, and enrolled
2,947 women from 39 of the 40 WHI clinical centers.

In the estrogen-alone trials, women were randomized to receive either
0.625 mg/day of CEE or matching placebo. In the estrogen plus
progestin trials, they were randomized to receive either CEE (0.625
mg/day) plus MPA (2.5 mg/day) or matching placebo.

In the estrogen-alone trial, 47 women were diagnosed with probable
dementia, including 28 women in the CEE group and 19 in the placebo
group (hazard ratio [HR], 1.49; 95% confidence interval [CI], 0.83 to
2.66). During follow-up, the incidence of probable dementia was 49%
higher in the CEE group than in the placebo group, but this
difference did not reach statistical significance.

Incidence of probable dementia in the estrogen-alone trial was
statistically similar to that in the estrogen plus progestin trial.
When data from both trials were pooled, the overall risk for probable
dementia was increased by
76% (HR, 1.76; 95% CI, 1.19 to 2,60; P = .005).

After excluding women with baseline Modified Mini-Mental State
Examination (3MSE) scores at or below the screening cut point, HR for
probable dementia was 1.77 in the estrogen-alone trial (95% CI, 0.74
to 4.23; P =
..20) and 2.19 in the pooled trials (95% CI, 1.25 to 3.84; P = .006).

In the CEE group, the risk of MCI was 34% higher than in the placebo
group, but this difference was not statistically significant. When
data from both trials were pooled, the HR was 1.25 (95% CI, 0.97 to
1.60). Either MCI or probable dementia occurred in 93 women receiving
CEE and in 69 taking placebo (HR, 1.38; 95% CI,
1.01 to 1.89; P = .04).

"The results in the estrogen-alone trial, but not the pooled data,
suggest a possible effect of hypertension, diabetes, and
‘vascular disease' in the brain," the authors write.

A second report from WHIMS suggests that cognitive decline in women
aged 65 years and older was greater in those receiving hormone
therapy than in those receiving placebo.

"This adverse effect was relatively small overall, but was more
pronounced for women who started with relatively lower cognitive
function," says lead author Mark Espeland, PhD, also from Wake Forest.

Of the 2,947 women enrolled in WHIMS, 2,808 women had a baseline and
at least one follow-up measure of global cognitive function based on
a 3MSE score measuring temporal and spatial orientation, immediate and
delayed recall, naming, verbal fluency, abstract reasoning, praxis,
writing, and visuoconstructional abilities. Mean follow-up was 5.4

Women who received CEE had a slightly lower 3MSE score than did women
who received placebo (difference,
0.26 ± 0.13 units; P = .04). These differences were first apparent one
to two years after therapy began and persisted throughout the trial.
Women with lower cognitive function at baseline were at greater risk
for further lowering of 3MSE with hormone therapy (P < .01). Compared
with placebo, the relative risk with CEE of having a 10-unit decrease
in 3MSE scores was 1.47 (95% CI, 1.04 to 2.07).

"Our results suggest that neither CEE nor CEE plus MPA should be
initiated in older women for the purpose of protecting cognitive
function," the authors write. "Furthermore, at least one subgroup of
women was at particularly high risk for the adverse effects of
hormone therapy on cognition — women with relatively low
baseline cognitive function."

Based on the WHI and WHIMS findings, the U.S. Food and Drug
Administration recommends that women who choose to use hormone
therapy should take the lowest dose for the shortest time required to
provide relief of hot flashes or ******l dryness.

Wyeth Pharmaceuticals and Wake Forest Baptist funded WHIMS. Wyeth has
various financial arrangements with some of the investigators. Dr.
Shumaker has served as a consultant for Wyeth and Pfizer, and another
author has received grants from Eli Lilly, Pfizer and Novartis.

In an accompanying editorial, Lon S. Schneider, MD, from the
University of Southern California, Los Angeles, reviews remain
questions regarding estrogen therapy. These include whether short-term
use of estrogen for several years in early postmenopause might be
effective in reducing dementia two or three decades later.

"The WHIMS results do not prove that estrogen therapy has no effect on
AD [Alzheimer's Disease] or dementia, but they do clearly indicate
that women older than 65 years should not be treated with CEE with or
without MPA to attempt to prevent dementia or enhance cognition," Dr.
Schneider writes. "Whether with different populations, lower doses of
CEE, other forms of estrogen or receptor modulators, or delivered in
lower more physiological doses, estrogen therapy could eventually be
proven beneficial remains to be seen. However, the harmful to neutral
effects of estrogen in the WHI and WHIMS trials will make further
development of and research with estrogen therapy a daunting task."

Dr. Schneider reports various financial arrangements with Wyeth,
Novartis, Janssen, and Pfizer.

JAMA. 2004;291:2947-2958, 2959-2968, 3005-3007
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