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.

中文翻译：

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药理学性激素操作作为抑郁症的风险模型。

性激素转换可能会引发一些女性的严重抑郁发作。为了绘制与此类现象相关的机制，我们在安慰剂对照设计中使用性激素操作和促性腺激素释放激素激动剂 (GnRHa) 开发了一种药理学临床前人体模型。在这里，该模型的研究结果在有关激素对生殖心理健康障碍的贡献的相关文献中进行了综合和讨论。GnRha 模型工作指出，接受 GnRHa 短期性激素操作的健康女性会出现雌二醇依赖性抑郁反应，这与血清素转运蛋白的变化（突触血清素的关键调节剂）、海马体脱离和大脑过度接触有关在处理情感显着信息时招募的网络。更远，GnRHa 模型表明，在进行性激素操纵时，奖赏回路中的关键大脑区域较少参与积极刺激，这可能是快感缺乏的基础。此外，这项工作支持在基因表达水平上增强对雌激素信号的敏感性，当暴露于性类固醇激素波动时，可能会增加出现抑郁症状的风险。总之，GnRHa 模型工作突出了性类固醇激素环境快速而深刻变化的大脑特征，这反映了情绪障碍风险起作用的合理机制。该模型指出了雌激素动力学和敏感性的作用，并提供了在激素过渡阶段个性化预防的基本原理，例如怀孕到产后过渡、围绝经期和激素治疗，