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Estrogen treatment impairs cognitive performance after psychosocial stress and monoamine depletion in postmenopausal women

Newhouse, Paul A. MD1; Dumas, Julie PhD1; Wilkins, Heather BA1; Coderre, Emily BA1; Sites, Cynthia K. MD2; Naylor, Magdalena MD, PhD1; Benkelfat, Chawki MD3; Young, Simon N. PhD3

doi: 10.1097/gme.0b013e3181e15df4
Special Section: Menopause, Cognition and Mental Health

Objective: Recent studies have shown that women experience an acceleration of cognitive problems after menopause and that estrogen treatment can improve or at least maintain current levels of cognitive functioning in postmenopausal women. However, we have previously shown that the negative emotional effects of psychosocial stress are magnified in normal postmenopausal women after estrogen treatment. This study examined whether estradiol (E2) administration can modify cognitive performance after exposure to psychological stress and monoamine depletion.

Methods: Participants consisted of 22 postmenopausal women placed on either oral placebo or 17β-E2 (1 mg/d for 1 mo, then 2 mg/d for 2 mo). At the end of the 3-month treatment phase, participants underwent three depletion challenges in which they ingested one of three amino acid mixtures: deficient in tryptophan, deficient in phenylalanine/tyrosine, or balanced. Five hours later, participants performed the Trier Social Stress Test (TSST), followed by mood and anxiety ratings and cognitive testing. Cognitive measures included tests of attention, psychomotor function, and verbal episodic memory.

Results: E2-treated compared with placebo-treated participants exhibited significant worsening of cognitive performance on tasks measuring attentional performance and psychomotor speed. Similar trends for impairment were seen in measures of long-term episodic memory compared with placebo-treated postmenopausal women. E2-treated participants also showed a significant increase in negative mood and anxiety compared with placebo-treated women after, but not before, the TSST, although the worsening of both cognitive and behavioral functioning was not correlated. These effects were independent of tryptophan or tyrosine/phenylalanine depletion and were not manifested before the TSST or at baseline.

Conclusions: These data suggest that the relationship between estrogen administration and cognitive/behavioral performance in postmenopausal women may be more complex than initially appreciated and that the effects of psychosocial stress may influence whether hormone effects are beneficial.

The effects of estrogen on cognition after menopause are complex, but the interactive effects of psychological stress have not been previously studied. In this study, estrogen treatment seems to impair cognitive functioning in postmenopausal women after experimental psychological stress and monoamine depletion.

From the 1Clinical Neuroscience Research Unit, Department of Psychiatry, University of Vermont College of Medicine, Burlington, VT; 2Division of Reproductive Medicine, Baystate Medical Center, Tufts University School of Medicine, Boston, MA; and 3Department of Psychiatry, McGill University School of Medicine, Montreal, Quebec, Canada.

Received February 8, 2010; revised and accepted March 29, 2010.

A partial version of this work was previously presented as a poster at the Society for Neuroscience Annual Meeting, Washington, DC, November 19, 2008.

Funding/support: This work was supported by an Independent Investigator award from National Alliance for Research in Schizophrenia and Depression (NARSAD) and National Institute of Aging (NIA) R01 AG021476 to P.N., Canadian Institutes of Health Research (CIHR) grant MOP-150051 to S.N.Y, and General Clinical Research Center M01-00109.

Financial disclosure/conflicts of interest: None reported.

Address correspondence to: Paul A. Newhouse, MD, Clinical Neuroscience Research Unit, Department of Psychiatry, University of Vermont College of Medicine, 1 South Prospect St., Burlington, VT 05401. E-mail:

©2010The North American Menopause Society