Ultra-Low-Dose Estrogen Patch Found Safe in Later Menopause

SAN FRANCISCO, July 17 -- Unopposed transdermal estradiol at an ultra-low dose over two years did not affect cognitive function or health-related quality of life in post-menopausal women, researchers here reported.

Their randomized, placebo-controlled, double-blind trial of 417 post-menopausal women, ages 60 to 80, at nine U.S. clinical centers, contrasted with two nationwide randomized trials (the Women's Health Initiative Memory Study and the Heart and Estrogen/Progestin Replacement Study).

The earlier studies showed that opposed and unopposed estrogen at the standard dose of 0.625 mg/d worsened cognitive function and increased the risk of heart attack and stroke.

But the new study showed no such cognitive worsening with a weekly transdermal patch that delivered estradiol at 0.014 mg/d to 209 women compared with 208 placebo controls, Kristine Yaffe, M.D., of the University of California San Francisco and the VA Medical Center here, and colleagues, reported in the July issue of the Archives of Neurology.

Still, the findings did not back up several small trials and observational studies that have suggested that estrogen treatment in postmenopausal women improves cognition, they noted.

The study had two outcomes: improvement in bone mineral density, the primary outcome; changes in cognition and health-related quality of life, the secondary outcome.

At one-year and two-year follow-up for the study's pre-planned secondary outcome, there were no statistically significant differences between the two groups on any of the cognitive tests scores or on the 36-item Short Form General Health Survey (P>0.12 for all), the researchers reported.

Seven cognitive tests administered at baseline included the Modified Mini-Mental State Examination, a brief general cognitive battery with components for orientation, concentration, languages, and immediate and delayed memory; and the Modified Boston Naming Tests, a 15-item test of language function. Participants also completed a depression scale to assess depressed mood at cognitive-function testing.

Health-related quality of life was assessed at baseline with the self-administered Medical Outcome Study 36-Item Short Form General Health Survey, which assessed social functioning, limitation in role functioning due to physical and emotional problems, mental health, bodily pain, vitality, and general health perceptions.

As for the bone mineral density results, the researchers reported inprovement in density over two years at the lumbar spine (2.1% increase compared with placebo; 95% CI, 1.3%-2.8%; P= 0.001), and at the total hip (1.2% increase compared with placebo; CI 0.6%-1.8%; P < 0.001).

"Our results do not support the hypothesis that transdermal estradiol, at least in ultra-low doses, improves cognitive function in postmenopausal women. However, our results should provide reassurance to women and to practitioners that ultra-low-dose estradiol taken for up to two years does not adversely affect cognition, at least in clinically significant amounts," Dr. Yaffe said.

Dr. Yaffe suggested that the differences in health and cognition in this study compared with results from the Women's Health Initiative study could be related to the 44-times-smaller dose of pure estrogen (estradiol) and delivery through a skin patch. Medications taken in pill form are processed through the liver, Dr. Yaffe said, adding that estrogen in pill form might stimulate the liver to produce substances that can lead to clotting or other adverse side effects.

Among the study's limitations, the researchers noted that because most of the study participants were white, it was not possible to generalize these finding to other ethnic groups.

Also, women in the study were at least 60 years old at enrollment, so that it was not possible to determine whether estradiol given in the period during the perimenopausal years might have had a different effect, they said.

On the other hand, they pointed out that a strength of the study was the older age of the women. In trials enrolling newly menopausal women, relief of insomnia and hot flashes with estrogen treatment might have improved their concentration and cognitive performance, the investigators said.

Finally, they noted that although the study had the power to detect clinically significant differences in cognitive function by treatment groups (≥0.29 SD), the study could not detect smaller differences.

Prior analyses have reported that two years of unopposed ultra-low-dose transdermal estradiol improved bone density, as it did in this study, but did not increase the risk of uterine hyperplasia or cancer, urinary incontinence, or breast density.

The results of this study are very reassuring, Dr. Yaffe said. "This information should be helpful in assessing the relative safety of ultra-low-dose transdermal estradiol vs standard-dose hormone therapy regimens, she concluded.

The study was partially funded by Berlex, a maker of the estrogen patch used in the study. Dr. Yaffe reported receiving grant support from Pfizer and Eli Lilly, and has served as a consultant for Wyeth-Ayerst. Other co-authors have also received grant or salary support from these firms as well as from Merck and Bionovo.