Estrogen-Progestin Associated With Increased Risk of Stroke and Dementia

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http://www.medscape.com/viewarticle/456276

 

 

Estrogen-Progestin Associated With Increased Risk of Stroke and Dementia

 

Laurie Barclay, MD

 

 

To read this article for CME,

 

May 27, 2003 — Combination therapy with estrogen and progestin is associated

with increased risk of stroke and dementia and no improvement in cognitive

function, according to three reports in the May 28 issue of The Journal of the

American Medical Association.

 

Based on these findings from the Women's Health Initiative (WHI) and the Women's

Health Initiative Memory Study (WHIMS), the investigators suggest that this

combination should be reserved for menopausal symptoms only. The editorialist

summarizes the status of our current understanding and points out where evidence

is still lacking.

 

" The combination of estrogen and progestins in older women appears to increase

the risk of stroke and all-cause dementia, " Victor Henderson, MD, a professor of

geriatrics and neurology at the University of Arkansas for Medical Sciences in

Little Rock, told Medscape. " These results are in the context of a large,

randomized controlled trial, so they have to be taken seriously even if they are

different from the results prophesied years ago. "

 

Dr. Henderson is a coauthor of a study of the effect of estrogen and progestin

on cognitive function in the WHIMS trial, which began enrolling subjects from

the WHI in May 1996. WHIMS is an ancillary study to the two larger WHI trials.

The WHI study of estrogen plus progestin was discontinued in July 2002 because

of increased health risks in women receiving this hormone combination, including

higher risk of invasive breast cancer, myocardial infarction, and venous

thrombosis.

 

" From a methodological viewpoint, all three of these studies meet the gold

standard of being large, double-blind, placebo-controlled, randomized clinical

trials, " says Phyllis M. Wise, PhD, a professor of neurobiology, physiology, and

behavior at the University of California, Davis. " As a basic scientist, I would

have to say that these results with this hormone combination are not terribly

surprising. "

 

Dr. Wise was not involved in any of these studies, but she commented on them for

Medscape. " In most tissues, progestins downregulate any protective effects of

estrogen, the one exception being breast tissue, where progestin amplifies the

effect of estrogen, " she explains. " So this probably explains why this

combination increases risk of breast cancer while negating any potential

beneficial effect of estrogen on cardiovascular risk. "

 

All women in WHIMS were aged 65 years and older, and they were randomized to

receive daily doses of 0.625 mg of conjugated equine estrogen with 2.5 mg of

medroxyprogesterone acetate or placebo. In a study of dementia risk in the WHIMS

trial, 4,532 postmenopausal women, aged 65 years or older without probable

dementia, were enrolled between May 1996 and December 1999.

 

Baseline and annual evaluation included a structured clinical assessment and

Modified Mini-Mental State Examination (3MSE) testing temporal and spatial

orientation, immediate and delayed recall, executive function, verbal fluency,

abstract reasoning, praxis, and visuoconstructional abilities.

 

Women with follow-up scores suggesting possible cognitive impairment underwent

neuropsychological testing for verbal fluency and memory recall and evaluations

by physicians experienced in diagnosing dementia. Women thought to have possible

dementia also had computed tomography of the brain and blood tests to rule out

possible reversible causes of cognitive decline and dementia.

 

The risk of probable dementia in the estrogen plus progestin group was twice

that in the placebo group (hazard ratio

---

, 2.05; 95% confidence interval

[CI], 1.21 - 3.48; P = .01). Of 61 women diagnosed with probable dementia, 40

(66%) were in the estrogen plus progestin group and 21 (34%) were in the placebo

group.

 

Evidence of increased risk in the estrogen plus progestin group appeared as

early as one year after randomization and persisted over five years of

follow-up. However, the absolute risk of developing dementia was relatively

small: an additional 23 cases of dementia per 10,000 women treated with estrogen

plus progestin for one year.

 

These findings were described as " unexpected and in striking contrast to most of

the earlier research on the effects of hormone therapy on Alzheimer's disease

(AD) and dementia, " according to Sally A. Shumaker, PhD, from Wake Forest

University Health Sciences in Winston-Salem, North Carolina, and colleagues.

 

" The reasons for the differences from results of observational studies may be

simply that the observational studies got it wrong because of unrecognized bias,

or that there are meaningful differences in hormonal preparations used, age of

use, and in duration and timing of use, " Dr. Henderson said. " The primary

outcome was all-cause dementia rather than AD per se, so it's possible that what

we're observing reflects an effect on vascular dementia rather than on AD,

although that's somewhat speculative. "

 

The study of cognitive function in WHIMS, coauthored by Dr. Henderson, evaluated

4,381 women who provided at least one valid follow-up score on the 3MSE between

June 1995 and July 8, 2002. Mean 3MSE total scores in both groups increased

slightly over a mean follow-up of 4.2 years, which the investigators attributed

to a learning effect.

 

Women in the estrogen-progestin group had smaller mean increases in total scores

than did women in the placebo group (P = .03), but these differences were not

clinically significant. A substantial and clinically important decline of at

least two standard deviations in 3MSE occurred in 6.7% of the hormone therapy

group and in 4.8% of the placebo group (P = .008).

 

Excluding women who developed overt dementia, mild cognitive impairment or

stroke, or those who did not adhere to the study protocol, did not affect the

results, nor did adjustment for prior use of hormone therapy or duration of

prior use.

 

An offshoot of the WHI studied the effect of estrogen plus progestin on ischemic

and hemorrhagic stroke. The WHI was a multicenter, double-blind,

placebo-controlled, randomized clinical trial enrolling 16,608 women aged 50 to

79 years. Subjects received 0.625 mg of conjugated equine estrogen per day plus

2.5 mg of medroxyprogesterone acetate per day, and average follow-up was 5.6

years.

 

Strokes occurred in 151 patients (1.8%) in the estrogen plus progestin group and

in 107 patients (1.3%) in the placebo group, yielding an overall increased risk

of 31% for total stroke (HR, 1.31; 95% CI, 1.02 - 1.68; or HR, 1.50 adjusted for

adherence; 95% CI, 1.09 - 1.90). Ischemic strokes accounted for 79.8% of the

total, with increased risk of 44% for hormone therapy compared with placebo (HR,

1.44; 95% CI, 1.09 - 1.90). The risk for hemorrhagic stroke was not

significantly different between groups.

 

" The stroke study doesn't really contradict prevailing beliefs in the medical

community, " Dr. Henderson said. " There was really no strong evidence that

hormone therapy would have a beneficial effect in stroke, so most did not expect

a dramatic benefit for stroke, even though they did for AD. Hormone therapy may

have both positive and negative effects on vascular factors involving

inflammation, clotting, and thrombolysis, so the net effect on vascular risk may

be more difficult to predict. "

 

Increased stroke risk related to estrogen plus progestin was independent of

other risk factors, including age, history of cardiovascular disease, or

hypertension. There was no interaction between estrogen plus progestin exposure

and other risk factors that could identify a subgroup of women at highest risk

of stroke with estrogen plus progestin.

 

" Not only was this a huge study population, but it also showed increased stroke

risk across the board, " Dr. Wise said. " One might have predicted that women in

their seventies, some of whom never had hormone therapy before entering this

trial and who therefore were unexposed to estrogen and progestin for two

decades, might have reacted differently than women who recently entered

menopause. But the increased risk was observed at all ages. "

 

So what is the take-home message for clinicians concerning prescription of

hormone therapy? In an accompanying editorial, Kristine Yaffe, MD, an assistant

professor in psychiatry and neurology at the University of California, San

Francisco, points out that the effect of unopposed estrogen on dementia risk

will be evaluated with the ongoing estrogen arm of WHIMS.

 

She notes that progestins, especially medroxyprogesterone, have been reported to

modify the beneficial effects of estrogen and possibly increase the risk of

thromboembolic events. Timing of use and mode of delivery of estrogen may turn

out to be critical factors influencing dementia risk.

 

" Not much is known about the relative roles of progestins and estrogens in

contributing to the negative central nervous system effects of the combination, "

she told Medscape, adding that discrepancies between the WHI findings and those

of earlier studies may be explained by the observational rather than controlled

design of previous studies.

 

Based on these findings and on her own experience, she recommended that hormone

therapy be given " only for menopausal symptoms at this point, but more research

is needed. "

 

" In terms of management, these studies don't really change things much, " Dr.

Henderson agreed. " The WHI study from July of 2002 showed no net benefit from

use of estrogen plus progestin when certain diseases were considered in terms of

outcome. So this study reinforces our earlier conclusions that this combination

should be given only for climacteric symptoms. "

 

In animal models, Dr. Wise is testing the effects of unopposed, low-dose

estradiol-17-beta, which most closely resembles endogenously secreted estrogen.

Although many commercial preparations used in hormone therapy involve a mixture

of estrogens, usually in combination with progestin, she recommends clinical

trials of low-dose, unopposed estradiol.

 

" Both as a middle-aged woman and as a scientist, I am very hopeful that results

with low-dose estrogen alone might be better, " she said. " Especially in older

women for whom contraception is not an issue, we should be testing whether

low-dose estradiol given alone affords protection against heart disease and

stroke.

 

" Some investigators may be debating whether they should change the estrogen arm

in ongoing trials to low-dose unopposed estradiol, but it's difficult to

introduce this type of confounding when you're in the middle of a study. These

studies amplify those from the WHI last year, and their findings present a

significant contraindication to using this particular preparation of estrogen

plus progestin, " Dr. Wise concluded.

 

Dr. Henderson is a consultant for and has received honoraria from Wyeth, and

over the past five years he has received grant funding from Wyeth and consulting

fees from Lilly. Dr. Wise has received grants from Wyeth in the past but is not

presently.

 

These studies were funded in part by the National Heart, Lung, and Blood

Institute, National Institutes of Health, Department of Health and Human

Services. Wyeth Pharmaceuticals helped fund the WHIMS and provided the study

drug and placebo to the WHI trial.

 

Authors of these three studies have various financial arrangements with Wyeth,

Pfizer, Duramed, Eli Lilly, GlaxoSmithKline, Merck, Proctor & Gamble,

Ortho-McNeil, Bristol Myers Squibb, 3M, Organon, TAP, Abbott, Astra-Zeneca, MSD,

Boehringer Ingelheim, Novartis, and/or MGI Pharma.

 

JAMA. 2003;289:2651-2662,2663-2672,2673-2684,2717-2718

 

Reviewed by Gary D. Vogin, MD