Trajectories and phenotypes with estrogen exposures across the lifespan: What does Goldilocks have to do with it?

Abstract

Estrogens impact the organization and activation of the mammalian brain in both sexes, with sex-specific critical windows. Throughout the female lifespan estrogens activate brain substrates previously organized by estrogens, and estrogens can induce non-transient brain and behavior changes into adulthood. Therefore, from early life through the transition to reproductive senescence and beyond, estrogens are potent modulators of the brain and behavior. Organizational, reorganizational, and activational hormone events likely impact the trajectory of brain profiles during aging. A “brain profile,” or quantitative brain measurement for research purposes, is typically a snapshot in time, but in life a brain profile is anything but static – it is in flux, variable, and dynamic. Akin to this, the only thing continuous and consistent about hormone exposures across a female's lifespan is that they are noncontinuous and inconsistent, building and rebuilding on past exposures to create a present brain and behavioral landscape. Thus, hormone variation is especially rich in females, and is likely the destiny for maximal responsiveness in the female brain. The magnitude and direction of estrogenic effects on the brain and its functions depend on a myriad of factors; a “Goldilocks” phenomenon exists for estrogens, whereby if the timing, dose, and regimen for an individual are just right, markedly efficacious effects present. Data indicate that exogenously-administered estrogens can bestow beneficial cognitive effects in some circumstances, especially when initiated in a window of opportunity such as the menopause transition. Could it be that the age-related reduction in efficacy of estrogens reflects the closure of a late-in-life critical window occurring around the menopause transition? Information from classic and contemporary works studying organizational/activational estrogen actions, in combination with acknowledging the tendency for maximal responsiveness to cyclicity, will elucidate ways to extend sensitivity and efficacy into post-menopause.

Cognitive changes across the menopause transition: A longitudinal evaluation of the impact of age and ovarian status on spatial memory

“…To add complexity to this puzzle, what is optimal for one woman may not have the same effect in another woman (for review, see Koebele & Bimonte-Nelson, 2015). Our findings provide further insight into the window of opportunity for hormone therapy by revealing that the age at the onset of the menopause transition matters for memory outcomes.…”

Benefits of Hormone Therapy Estrogens Depend on Estrogen Type: 17β-Estradiol and Conjugated Equine Estrogens Have Differential Effects on Cognitive, Anxiety-Like, and Depressive-Like Behaviors and Increase Tryptophan Hydroxylase-2 mRNA Levels in Dorsal Raphe Nucleus Subregions

“…Over the years, there have been numerous review articles underscoring the importance of these factors (Gibbs and Gabor, 2003; Brinton, 2004; Bimonte-Nelson et al, 2010; Rocca et al, 2011; Maki, 2012; Sherwin, 2012; Acosta et al, 2013; Chisholm and Juraska, 2013; Fischer et al, 2014; Luine, 2014; Koebele and Bimonte-Nelson, 2015; McCarrey and Resnick, 2015). The present study adds to the growing consensus that clarity gained from understanding the impact of these parameters is critical for providing information to offer unique and tailored treatment options for women.…”

Modeling menopause: The utility of rodents in translational behavioral endocrinology research

“…Estrogens have been shown to have beneficial effects on a myriad of body systems, including cardiovascular, bone, and brain health. However, estrogens’ actions are complex, and often exert beneficial effects only when given at a fitting dose, through the ideal route of administration, and with appropriate timing and duration of the treatment [30–32]. In the early 2000’s, findings from the Women’s Health Initiative Memory Study (WHIMS) challenged the tenet that estrogen-containing HT has protective effects against global cognitive decline, mild cognitive impairment, and probable dementia risks when the large, double-blind, placebo-controlled clinical trials indicated that some forms of HT increase the risk of probable dementia development when administered post-menopause [33–36].…”