open access publication

Article, 2020

Pharmacological sex hormone manipulation as a risk model for depression

Journal of Neuroscience Research, ISSN 0360-4012, 1097-4547, Volume 98, 7, Pages 1283-1292, 10.1002/jnr.24632

Contributors

Frokjaer, Vibe Gedsoe 0000-0002-9321-2365 (Corresponding author) [1] [2]

Affiliations

  1. [1] Lundbeck Foundation
    2. [NORA names: Lundbeck Foundation; Non-Profit Organisations; Denmark; Europe, EU; Nordic; OECD];
  2. [2] Rigshospitalet
    3. [NORA names: Capital Region of Denmark; Hospital; Denmark; Europe, EU; Nordic; OECD]

Abstract

Sex hormone transition may trigger severe depressive episodes in some women. In order to map mechanisms related to such phenomena we developed a pharmacological preclinical human model using sex hormone manipulation with gonadotropin releasing hormone agonist (GnRHa) in a placebo-controlled design. Here the findings from this model is synthesized and discussed in the context of related literature on hormonal contributions to reproductive mental health disorders. The GnRha model work points to an estradiol-dependent depressive response in healthy women undergoing short-term sex hormone manipulation with GnRHa, which is linked to serotonin transporter changes (a key regulator of synaptic serotonin), a disengagement of hippocampus, and overengagement of brain networks recruited when processing emotional salient information. Further, the GnRHa model suggest that key brain regions in the reward circuit are less engaged in positive stimuli when undergoing sex hormone manipulation, which may underlie anhedonia. Also, the work supports that enhanced sensitivity to estrogen signaling at the level of gene expression may drive increased risk for depressive symptoms when exposed to sex steroid hormone fluctuations. In conclusion, the GnRHa model work highlights the brain signatures of rapid and profound changes in sex steroid hormone milieu, which reflect plausible mechanisms by which risk for mood disorders works. This model points to the role of estrogen dynamics and sensitivity, and offers a rationale for personalized prevention in hormonal transition phases, for example pregnancy to postpartum transition, perimenopause, and hormone treatments, which now can move into clinical translation and ideally pave the way for protecting mental and cognitive health.

Keywords

GnRHa, agonists, anhedonia, brain, brain networks, brain regions, brain signatures, changes, circuit, clinical translation, cognitive health, context, contribution, depressed response, depression, depressive episode, depressive symptoms, design, disengagement, disorders, dynamics, emotionally salient information, episodes, estrogen, estrogen signaling, expression, findings, fluctuations, gene expression, gonadotropin, gonadotropin-releasing hormone agonist, health, health disorders, healthy women, hippocampus, hormonal contributions, hormonal fluctuations, hormonal manipulation, hormonal milieu, hormonal transition, hormonal transition phases, hormone, hormone agonist, hormone treatment, human model, increased risk, information, level of gene expression, levels, literature, manipulation, mapping mechanism, maps, mechanism, mental health disorders, milieu, model, modeling work, mood, mood disorders, network, perimenopause, personalized prevention, phase, phenomenon, placebo-controlled design, positive stimuli, postpartum transition, preclinical human models, pregnancy, pregnancy to postpartum transition, prevention, processing emotionally salient information, rationale, region, releasing hormone agonist, response, reward, reward circuit, risk, risk model, salient information, sensitive to estrogen signaling, sensitivity, serotonin, serotonin transporter changes, severe depressive episode, sex, sex hormone manipulation, sex steroid hormonal milieu, sex steroid hormone fluctuations, signal, signature, steroid hormone milieu, stimuli, symptoms, transition, transition phase, translation, transport changes, treatment, women, work

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