In search of estrogen alternatives for the brain

Editors' introduction This chapter briefly reviews recent advancements in the search for a non-feminizing estrogen alternative that can mimic estrogen's positive effects on cognitive health without eliciting an undesirable impact on reproductive and cardiovascular systems. The discussion focuses on two avenues of translational development, tissue-selective and subtype-selective estrogen receptor (ER) modulators (SERMs), in particular ERβ-selective phytoSERMs as a natural approach for potentially promoting neurological health and preventing age-associated cognitive impairment and risk of Alzheimer's disease in both genders. Estrogen for the female brain Postmenopausal women are prone to cognitive changes as a result of diminished serum levels of female sex hormones following menopause, which increase the risks for cognitive impairment and dementia such as Alzheimer's disease (AD). A large body of evidence suggests that estrogen therapy (ET) can potentially counteract these changes by sustaining the brain in a proactively defensive status against neurodegeneration (reviewed in Chapter 6). Until recently, this well documented concept has been complicated by the findings of the largest randomized and controlled clinical study, the Women's Health Initiative Memory Study (WHIMS), which was designed to evaluate the relationship between estrogen and cognition. It was found that ET was either to be of no benefit (estrogen-alone) or to afford a negative impact (estrogen plus progestin) on global cognition in postmenopausal women aged 65 years or older [1-4] (see also Chapters 1-5).