title: 17β-estradiol differentially regulates stress circuitry activity in healthy and depressed women.
abstract: Many regions within stress neurocircuitry, 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 (E₂) 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 population-based birth cohort, the New England Family Study. Capitalizing on the endogenous fluctuation in 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 across 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.
authors.affiliation: 1] Division of Women's Health, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA [2] Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, USA [3] Harvard Medical School, Boston, MA, USA.
authors.forename: Emily G
authors.initials: EG
authors.lastname: Jacobs
authors.affiliation: 1] Division of Women's Health, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA [2] Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, USA [3] Harvard Medical School, Boston, MA, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Holsen
authors.affiliation: Department of Psychology, University of Virginia, Charlottesville, VA, USA.
authors.forename: Katie
authors.initials: K
authors.lastname: Lancaster
authors.affiliation: 1] Harvard Medical School, Boston, MA, USA [2] Athinoula A. Martinos Center, Massachusetts General Hospital and Massachusetts Institute of Technology, Charlestown, MA, USA.
authors.forename: Nikos
authors.initials: N
authors.lastname: Makris
authors.affiliation: 1] Athinoula A. Martinos Center, Massachusetts General Hospital and Massachusetts Institute of Technology, Charlestown, MA, USA [2] Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Sue
authors.initials: S
authors.lastname: Whitfield-Gabrieli
authors.affiliation: 1] Division of Women's Health, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA [2] Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Remington
authors.affiliation: Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Blair
authors.initials: B
authors.lastname: Weiss
authors.affiliation: Department of Community Health, Brown University, Providence, RI, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Buka
authors.affiliation: Neuroendocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Klibanski
authors.affiliation: 1] Division of Women's Health, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA [2] Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, USA [3] Harvard Medical School, Boston, MA, USA [4] Athinoula A. Martinos Center, Massachusetts General Hospital and Massachusetts Institute of Technology, Charlestown, MA, USA.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Goldstein
mesh_terms: D000328:Adult; D000339:Affect / Q000502:physiology; D001007:Anxiety / Q000503:physiopathology; D001921:Brain / Q000503:physiopathology*; D016022:Case-Control Studies; D003865:Major Depressive Disorder / Q000097:blood / Q000503:physiopathology* / Q000523:psychology; D004958:Estradiol / Q000097:blood / Q000502:physiology*; D005260:Female; D059907:Functional Neuroimaging; D006801:Humans; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D010775:Photic Stimulation; D011374:Progesterone / Q000097:blood; D013739:Testosterone / Q000097:blood
chemical_list: D013739:Testosterone; D011374:Progesterone; D004958:Estradiol
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