17b-Estradiol Differentially Regulates Stress Circuitry Activity in Healthy and Depressed Women

Neuropsychopharmacology (Impact Factor: 7.05). 08/2014; in press(in press). DOI: 10.1038/npp.2014.203.


Many regions within stress circuitry, including the anterior hypothalamus, amygdala, hippocampus and medial prefrontal cortex, are densely populated with sex steroid
receptors. Substantial evidence from animal studies indicates that the gonadal hormone 17β- estradiol impacts the structure and function of these regions, but human studies are limited. Characterizing estradiol’s role in stress circuitry in vivo in humans may have important clinical implications given the comorbidity between major depressive disorder (MDD), stress circuitry dysfunction and endocrine dysregulation. In this study, we determined estradiol’s role in modulating activity within cortical and subcortical stress circuitry regions in healthy and MDD women. Subjects were part of a neuroimaging follow-up study of a population-based birth cohort, the New England Family Study. Capitalizing on the endogenous fluctuation in 17β-estradiol (E2) during the menstrual cycle, we conducted a within-person repeated-measures functional neuroimaging study in which 15 women with recurrent MDD, in remission, and 15 healthy
control women underwent hormonal evaluations, behavioral testing and fMRI scanning on two occasions, under low and high E2 conditions. Subjects completed an fMRI scan while undergoing a mild visual stress challenge that reliably activated stress neural circuitry. Results demonstrate that E2 modulates activity aross key stress circuitry regions, including bilateral amygdala, hippocampus and hypothalamus. In healthy women, robust task-evoked BOLD signal changes observed under low E2 conditions were attenuated under high E2 conditions. This hormonal capacity to regulate activity in stress circuitry was not observed in MDD women, despite their remitted status, suggesting that dysregulation of gonadal hormone function may be a characteristic trait of the disease. These findings serve to deepen our understanding of estradiol’s actions in the healthy brain and the neurobiological mechanisms that may underlie the pronounced sex difference in MDD risk.

Download full-text


Available from: Emily G Jacobs, Aug 13, 2014
    • "No significant sex by case interaction effects. cohort (Jacobs et al., 2015). In that experimental within-woman design, 17β estradiol was significantly related to attenuation of BOLD activity in key subcortical stress response regions in healthy women, but no modulation by 17β estradiol in depressed women. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Response to stress is dysregulated in psychosis (PSY). fMRI studies showed hyperactivity in hypothalamus (HYPO), hippocampus (HIPP), amygdala (AMYG), anterior cingulate (ACC), orbital and medial prefrontal (OFC; mPFC) cortices, with some studies reporting sex differences. We predicted abnormal steroid hormone levels in PSY would be associated with sex differences in hyperactivity in HYPO, AMYG, and HIPP, and hypoactivity in PFC and ACC, with more severe deficits in men. We studied 32 PSY cases (50.0% women) and 39 controls (43.6% women) using a novel visual stress challenge while collecting blood. PSY males showed BOLD hyperactivity across all hypothesized regions, including HYPO and ACC by FWE-correction. Females showed hyperactivity in HIPP and AMYG and hypoactivity in OFC and mPFC, the latter FWE-corrected. Interaction of group by sex was significant in mPFC (F=7.00, p=0.01), with PSY females exhibiting the lowest activity. Male hyperactivity in HYPO and ACC was significantly associated with hypercortisolemia post-stress challenge, and mPFC with low androgens. Steroid hormones and neural activity were dissociated in PSY women. Findings suggest disruptions in neural circuitry-hormone associations in response to stress are sex-dependent in psychosis, particularly in prefrontal cortex. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Psychiatry Research: Neuroimaging 03/2015; 232(3). DOI:10.1016/j.pscychresns.2015.03.006 · 2.42 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This article is part of a Special Issue "SBN 2014". Women are more vulnerable to stress- and fear-based disorders, such as anxiety and post-traumatic stress disorder. Despite the growing literature on this topic, the neural basis of these sex differences remains unclear, and the findings appear inconsistent. The neurobiological mechanisms of fear and stress in learning and memory processes have been extensively studied, and the crosstalk between these systems is beginning to explain the disproportionate incidence and differences in symptomatology and remission within these psychopathologies. In this review, we discuss the intersect between stress and fear mechanisms and their modulation by gonadal hormones and discuss the relevance of this information to sex differences in anxiety and fear-based disorders. Understanding these converging influences is imperative to the development of more effective, individualized treatments that take sex and hormones into account. Copyright © 2015. Published by Elsevier Inc.
    Hormones and Behavior 04/2015; DOI:10.1016/j.yhbeh.2015.04.002 · 4.63 Impact Factor