Androgens and Estrogens in the Human Nervous System

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In the past 30 years, animal studies have shown that reproductive hormones have a wide range of effects in the central nervous system (CNS). For example, the hormone estradiol (major estrogen produced during a female's reproductive years) is a potent neuromodulator in several neurochemical systems, and its CNS effects manifest themselves as changes in behaviour, perception, and cognition. While animal data are plentiful, knowledge of hormonal effects in the human CNS is surprisingly sparse. This is an important and noteworthy theoretical gap, especially given the obvious relevance of such effects to understanding the CNS correlates of normal variations in hormone levels that occur over the lifespan (e.g. with aging) or in clinical conditions (e.g. androgen deprivation therapy for the treatment of prostate cancer). A rarity among Canadian researchers, my lab studies effects of androgens and estrogens in the normal human brain. Our past work suggests that reproductive steroids normally regulate a variety of cognitive, behavioural, appetitive, and affective functions, and may be dysregulated with aging or in certain mental health conditions. Bringing some of the evidence together, we recently hypothesized (Hampson, 2019) that the prefrontal cortex (PFC) is a key site of action in healthy adult brains--sex steroids may modulate certain cognitive or evaluative processes via effects on 2 partially distinct but interfacing regulatory control systems vested in the dorsal and ventral PFC that exert behavioural control by reference to external contextual cues or internal body-related or motivational cues respectively, and that are differentially sensitive to estrogens vs androgens. Over the next 5 years, we plan to test our theory by using specialized tests that recruit target regions of the PFC, combined with immunoassays to quantify hormone concentrations, genotyping, and potentially, functional brain imaging. We will begin to identify the neurochemical mechanisms and specific cognitive processes that are affected. We expect to find qualitative differences between the effects of testosterone vs estradiol in the PFC, and we predict that high circulating estradiol levels will facilitate working memory and other functions heavily dependent on the dorsolateral cortex, perhaps via a dopaminergic mechanism. We also aim to continue our earlier work using virtual environments to study androgen-driven effects at medial temporal lobe sites. All studies involve people tested under natural physiological conditions. This work will advance our understanding of the sites and functional processes that are influenced by androgens and estrogens in the human CNS. If the predicted effects are found, it will identify novel cognitive processes influenced by steroids and implicate the PFC as a site of action. It will expand theories currently at the forefront of neuroendocrine science, and allow us to develop a fuller understanding of male and female sex-based biology.