Hormone replacement therapy fails to improve cognitive function for women with coronary disease

Another menopausal myth is challenged: Women with existing coronary disease do not realize improvement in their cognitive function as a result of taking the most common form of hormone replacement therapy, a UCSF study has found. Investigators followed more than 1000 women from ten US test sites for four years. Half took a placebo; the other half took hormone replacement therapy (HRT). Although other, smaller studies have shown an improvement, in the UCSF study the women who received HRT performed no better on standard tests of cognitive function than those who received placebo.

The study was conducted with the participants in the Heart and Estrogen/Progestin Replacement study (HERS), a randomized, placebo-controlled study involving 2763 women with coronary disease that extensively tested HRT consisting of conjugated estrogen plus medroxyprogesterone, the most common formulation prescribed in the U.S.

“This is clear evidence that HRT should not be prescribed to improve cognitive function in older women,” said Deborah Grady, MD, MPH, UCSF professor of medicine and epidemiology and biostatistics. She said the findings reinforce her opinion that the only appropriate use of HRT is for short-term relief of menopausal symptoms.

Grady is author of the cognition study and HERS co-principle investigator.  She is a physician in General Internal Medicine at the San Francisco VA Medical Center and director of the UCSF Mount Zion Women’s Health Clinical Research Center.

For the cognition study, participants at ten of the 20 HERS centers were contacted and invited to enroll. At the conclusion of HERS, researchers measured cognitive function in 517 women in the hormone group and 546 in the placebo group using six standard tests: the modified Mini-Mental Status Examination, Verbal Fluency, Boston Naming, Word List Memory, Word List Recall, and Trails B.  Researchers adjusted for age, education, years postmenopausal, statin use, depression (as measured by the Geriatric Depression Scale), alcoholic drinks per week, hot flushes and trouble sleeping. Regardless of those other factors, better cognitive function did not result after four years of postmenopausal HRT.

Some (but not all) previous studies of estrogen-only HRT have shown an improvement in cognitive function. The HERS researchers said those studies examined much smaller groups of women and for a shorter duration than HERS. Also, most of the prior studies that have shown some benefit of HRT to cognition have been conducted in younger women around the time of menopause. In these women, who are often suffering from flushes and trouble sleeping, treatment with hormones might improve attention and performance on cognitive tests. The HERS trial provides no evidence regarding the effect of estrogen-only therapy on cognitive function.

Because cognitive function was not measured at the beginning of HERS, information cannot be derived from this study about the rate of cognitive decline among participants. However, the investigators said HERS women appear to be very similar to other populations of elderly women in their cognitive function, and the trial’s randomization of a large number of participants generally assures that the HERS group was balanced at the trial’s beginning.

Therefore, lack of baseline measurement of cognitive function is unlikely to have skewed the comparison of cognitive function.
An estimated four million Americans suffer from Alzheimer’s disease, the most common form of cognitive decline. The disease affects twice as many women as men and its incidence increases in postmenopausal women. Sufferers lose their memory and personality as the illness gradually destroys brain cells. The cause of Alzheimer’s disease is unknown, and no preventive measures have been conclusively identified.

The study, “Effect of Postmenopausal Hormone Therapy on Cognitive Function: The Heart and Estrogen/Progestin Replacement Study,” was published in the November 22 issue of The American Journal of Medicine. Funding for the study was provided by Wyeth-Ayerst Research.

Additional authors on the study are Kristine Yaffe, MD, UCSF assistant professor of psychiatry, neurology and epidemiology and chief of Geriatric Psychiatry at the San Francisco VA Medical Center; Margaret Kristof, MA, UCSF academic coordinator; Feng Lin, MS, UCSF specialist. Yaffe is supported by a grant from the National Institute of Aging and a Paul Beeson Faculty Scholars Award.

## Trainers for the cognitive function testing were:

* Wendy McBee, MA and Steven Rapp, PhD, Wake Forest University School of Medicine; and
* Margaret Kristof, MA and Kristine Yaffe, MD, UCSF.

## The HERS Clinical Centers and researchers are:

* Robert Califf, MD, Jennifer Grinnell, Karen Philbrick, MSN, FNP, Duke University Medical Center;
* Nanette K. Wenger, MD, Janice Parrott, RN, Dana Law-McKenzie, RN, Emory University;
* Judith Hsia, MD, Donna Embersit, Ginny Levin, MPH, George Washington University;
* William Haskell, PhD, Kathy Berra, RN, ANP, Sarah French, RN, CNP, Tami Runyan, Stanford University Center for Disease Prevention;
* Elizabeth Barrett-Connor, MD, Susan A. Hawley, RN, Carol Kerridge, RN, MPH University of California, San Diego; 
* Helmut Schrott, Pamela A. Terrill, ARNP, Mary Cherrico, RNP University of Iowa;
* Jane A. Cauley, PhD, Karen Southwick, CCRC, Rana Ezzedine University of Pittsburgh;
* William Applegate, MD, Beth McCammon, RN, Kathleen Meier, RN University of Tennessee; and
* David Herrington, MD, Marcia Davis, BSN, Karen Blinson, BS, Judy Iannuzzi, BSN, Kay Cheshire, MEd, Mary Boozer, LPN, Vickie Wayne, RN, Wake Forest University School of Medicine.