Neuroprotective effects of female sex steroids in humans: current controversies and future directions

Cell Mol Life Sci. 2005 Feb;62(3):299-312. doi: 10.1007/s00018-004-4385-z.


Recent findings from the Women's Health Initiative (WHI) have raised considerable concern over prolonged use of opposed and unopposed oral conjugated equine estrogen (CEE), given the increased risk of serious adverse effects, including stroke and venous thromboembolic complications. Furthermore, results from the WHI Memory Study (WHIMS) indicated that over 5 years of therapy with Prempro impaired performance on global cognitive tests and nearly doubled the risk of dementia. These surprising findings were contradictory to cumulative evidence from basic science, epidemiological and some intervention studies suggesting hormone therapy was cardioprotective and could potentially reduce the risk of dementia. This review paper focuses on the neurobiology of estrogen, summarizing the clinical evidence for neuroprotective and cognition-enhancing efficacy of estrogen. Further, the paper briefly discusses variables that may account for the unexpected findings of WHIMS, and offers suggestions for future research.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Clinical Trials as Topic / statistics & numerical data
  • Estrogens / pharmacology
  • Female
  • Gonadal Steroid Hormones / pharmacology*
  • Gonadal Steroid Hormones / physiology
  • Humans
  • Neuroprotective Agents / pharmacology*


  • Estrogens
  • Gonadal Steroid Hormones
  • Neuroprotective Agents