Cognition, mood, and physiological concentrations of sex hormones in the early and late postmenopause

Victor W. Henderson; Jan A. St. John; Howard N. Hodis; Carol A. McCleary; Frank Z. Stanczyk; Roksana Karim; Donna Shoupe; Naoko Kono; Laurie Dustin; Hooman Allayee; Wendy J. Mack

doi:10.1073/pnas.1312353110

Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved October 23, 2013 (received for review June 30, 2013)

Significance

Hormone variations after menopause may influence brain processes concerned with cognition and mood. Effects may differ for exposures near menopause compared with much later. We addressed this prediction using serum concentrations of endogenous estradiol, estrone, progesterone, and testosterone in 643 healthy women not using hormone therapy (early group, <6 y after menopause; late group, 10+ y). In combined analyses, hormone levels were unrelated to verbal memory, executive functions, global cognition, or mood. For serum estradiol (our primary focus), the relation did not differ between postmenopause groups. In early group women, progesterone levels were associated with better memory and global cognition; this finding merits additional study. Results help clarify cognitive effects of physiological concentrations of sex steroids after menopause.

Abstract

Variations in the hormonal milieu after menopause may influence neural processes concerned with cognition, cognitive aging, and mood, but findings are inconsistent. In particular, cognitive effects of estradiol may vary with time since menopause, but this prediction has not been assessed directly using serum hormone concentrations. We studied 643 healthy postmenopausal women not using hormone therapy who were recruited into early (<6 y after menopause) and late (10+ y after menopause) groups. Women were administered a comprehensive neuropsychological battery and assessed with the Center for Epidemiologic Studies Depression Scale. They provided serum for free estradiol, estrone, progesterone, free testosterone, and sex hormone binding globulin measurements. Cognitive outcomes were standardized composite measures of verbal episodic memory, executive functions, and global cognition. Covariate-adjusted linear regression analyses were conducted for each hormone separately and after adjustment for other hormone levels. Endogenous sex steroid levels were unassociated with cognitive composites, but sex hormone binding globulin was positively associated with verbal memory. Results for early and late groups did not differ significantly, although progesterone concentrations were significantly positively associated with verbal memory and global cognition in early group women. Hormone concentrations were not significantly related to mood. Results fail to support the hypothesis that temporal proximity to menopause modifies the relation between endogenous serum levels of estradiol and verbal memory, executive functions, or global cognition. Physiological variations in endogenous postmenopausal levels of sex steroid hormones are not substantially related to these aspects of cognition or mood; positive associations for progesterone and sex hormone binding globulin merit additional study.

Footnotes

↵¹To whom correspondence should be addressed. E-mail: vhenderson{at}stanford.edu.

Author contributions: V.W.H., H.N.H., and W.J.M. designed research; J.A.S.J., C.A.M., F.Z.S., R.K., D.S., and H.A. performed research; V.W.H., J.A.S.J., N.K., L.D., and W.J.M. analyzed data; and V.W.H., J.A.S.J., H.N.H., F.Z.S., and W.J.M. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1312353110/-/DCSupplemental.