Considerations on the Use of Aromatase Inhibitors in Postmenopausal Women With Breast Cancer

About 1 of every 8 women will develop breast cancer during her lifetime, and approximately 250,000 new cancer cases are expected annually as of 2017. Of those breast cancers, approximately 60% to 75% will express estrogen receptors, suggesting that estrogens are likely to promote growth of those tumors. Because the use of inhibitors of the synthesis of estrogens is the adjuvant treatment of choice for many women, it is essential that we understand the potential adverse effects on quality of life of those treatments. This review addresses the role of estrogens locally synthesized in the brain in laboratory animals and women, the effects of estrogens on cognitive function, the effects of synthesis blockers on cognitive function, and the limitations in performing experiments that will give us strong confidence in the results and conclusions.

Oral Contraceptive Effects on Cognition

Oral contraception (OC) has been a common method of birth control for decades, yet the effects of this hormone manipulation on cognition are largely unknown. Although some studies have addressed this subject, efforts to make definitive conclusions are hampered by methodological issues including variations in OC type and hormone constituents, inconsistencies in cognitive tasks used, and insufficient power to detect effects. This chapter will review existing data on the effects of OCs on verbal memory, spatial memory, and emotional memory. It ends by considering ways in which to improve the methodological approaches used in studies of OCs to enable a better understanding of the ways in which these exogenous hormone treatments may influence cognitive function.

Estrogenic Regulation of Synaptic Health and Cognition in Aging Rhesus Monkeys

A compelling case can be made for estrogen’s role in maintaining synaptic health in the context of cognitive aging. This chapter first reviews clinical literature pertinent to estrogenic actions on cognition in menopausal women. Next, the authors provide a comprehensive summary of recent investigations in aging rhesus monkeys, which have emerged as a particularly powerful model for the study of synaptic and cognitive effects of both natural and surgical menopause. In particular, we focus on hippocampal and dorsolateral prefrontal cortex neurons and circuits that degenerate in normal aging and Alzheimer’s disease. The responsiveness of these brain regions to estrogen and implications for their related memory systems are discussed. Finally, the chapter highlights work that needs to be done to more fully understand the molecular basis for the complex interplay between menopause, aging, and vulnerability to Alzheimer’s disease in higher cognitive function and synaptic health.

Estrogenic Regulation of Hippocampal Neurogenesis Throughout the Lifespan

Neurogenesis in the hippocampus exists across a number of species, including humans. Steroid hormones, such as estrogens, modulate neurogenesis dependent on age, reproductive experience and sex. Findings are discussed in the chapter with reference to how neurogenesis in the hippocampus is related to learning and memory. Natural fluctuations in ovarian hormones or removal of ovaries modulate neurogenesis in the short term but not in the long term. Maternal experience has long-lasting effects on neurogenesis in the hippocampus. Acute estrogens increase proliferation in adult female rodents, but influence survival of new neurons dependent on a number of factors including sex, cognitive training, type of estrogen, and whether or not cells were produced under estrogens. This chapter outlines findings indicating that estrogens can be strong modulators of adult hippocampal neurogenesis, which may have implications for disorders involving hippocampal dysfunction that target women.

Hippocampal Synaptic Stability and Plasticity

Estradiol synthesis depends on the activity of aromatase, the enzyme that specifically and irreversibly converts testosterone to estradiol in steroidogenesis. Aromatase is expressed and is active in the hippocampus, a brain region related to learning and memory. Dynamics of spines and spine synapses, including expression of presynaptic and postsynaptic proteins, are controlled by hippocampus-derived estradiol in female rodents, but not in male rodents. This also holds true for long-term potentiation. Inhibition of aromatase, either pharmacologically or by genetic approaches, results in a decrease in synapse density and synaptic potentiation in female animals and in neonatal hippocampal cultures that originate from females. The consistency of the findings in rodents and in perinatal primary hippocampal cultures points to sex-specific differentiation processes during embryonic development, which underlie sex-dependent differences in neurosteroid action in the hippocampus.

Estrogenic Regulation of Synaptic Actin Proteins and Plasticity

Estrogens are rapid and potent facilitators of synaptic plasticity in the adult brain; however, the steps that link estrogens to factors that regulate synaptic strength remain unclear. The present chapter will first review the acute effects of 17β‎-estradiol on synaptic transmission and long-term potentiation (LTP). It will then describe a synaptic model used to study the substrates of LTP and provide evidence for the ability of estradiol to rapidly engage a selective actin signaling cascade associated with the consolidation of LTP. Finally, it will be shown that chronic reductions in estradiol levels disrupt LTP and actin dynamics but can be reversed by acute infusions of the hormone. It is concluded here that estradiol can promote learning-related plasticity by modifying the synaptic cytoskeleton.

Estrogenic Regulation of Glia and Neuroinflammation

This chapter on estrogenic regulation of glia and neuroinflammation reviews the role of glial cells in the modulation of synaptic function under physiological conditions and in the regulation of the neuroinflammatory response under pathological conditions. The anti-inflammatory actions of estradiol on astrocytes, oligodendrocytes, and microglia and the implication of these actions for the neuroprotective and tissue repair effects of the hormone are also discussed. Finally, the therapeutic potential of synthetic and natural estrogenic compounds for the control of neuroinflammation is examined. Because reducing neuroinflammation prevents the progressive loss of neural structure and function that leads to functional and mental impairments, regulation of glial cell activation via estradiol is a promising therapeutic approach.

Estrogen Neuroprotection and Anti-Inflammation Actions in the Hippocampus

The steroid hormone 17β‎-estradiol (E2) is neuroprotective in several neurodegenerative conditions, including cerebral ischemia, traumatic brain injury, and Alzheimer’s disease (AD). This chapter focuses on the evidence supporting a neuroprotective role of E2 in the hippocampus in cerebral ischemia and AD and reviews various mechanisms thought to underlie E2-induced neuroprotection. Specifically, the chapter discusses the mechanistic role of (a) the various estrogen receptor subtypes, (b) genomic versus nongenomic signaling, (c) regulation of the prosurvival Wnt/β‎−catenin pathway, and (d) anti-inflammatory effects of E2 in the hippocampus. Finally, we also discuss the role of a novel estrogen receptor co-activator protein, proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) in mediating E2 genomic and non-genomic signaling, as well as the neuroprotective and cognitive-enhancing effects of E2 in the hippocampus.

Ovarian Hormones, Cognition, and Reproductive Aging

Increasing evidence has demonstrated that sex steroid hormones, such as estrogens and progestogens, impact nonreproductive behaviors such as cognitive function in women and nonhuman animals. In addition to cognitive alterations associated with the reproductive cycle in young females, endocrine changes in middle-aged and aged females can impact cognition in ways that may increase risk of dementia and neurodegenerative disease. As such, understanding how aging and reproductive senescence influence cognitive functions like memory, and whether hormone therapy can mitigate these effects, is extremely important to maintaining women’s mental health. This chapter reviews the endocrine changes that occur at reproductive senescence in women and rodents, describes rodent models of menopause and memory assessment and discusses the effects of various hormone therapies on learning and memory in aging females. Various factors influencing the effects of hormone therapy on cognition are discussed, as are considerations for future research.

Rapid Effects of Estradiol on Dendritic Spines and Synaptic Plasticity in the Male and Female Hippocampus

Although the potent estrogen, 17β‎-estradiol (E2), has long been known to regulate the hippocampal dendritic spine density and synaptic plasticity, the molecular mechanisms through which it does so are less well understood. This chapter discusses the rapid modulation of hippocampal dendritic spine density and synaptic plasticity in male and female rats, with particular attention to studies in hippocampal slices from male rats. Among the mechanisms described are the roles of specific cell-signaling kinases and estrogen receptors in mediating the effects of E2 and progesterone on hippocampal neurons. In addition, dynamic changes of spine structures over time and sex differences in spine regulation are also considered. Finally, the chapter ends by discussing the importance of local hippocampal synthesis of E2 and androgens to hippocampal spine morphology and plasticity.