Major depressive disorder topped ischemic heart disease as the number one cause of disability worldwide in 2012, and women have twice the risk of men. Further, the comorbidity of depression and cardiometabolic disorders will be one of the primary causes of disability worldwide by 2020, with women at twice the risk. Thus, understanding the sex-dependent comorbidities has public health consequences worldwide. We propose here that sex differences in MDD-cardiometabolic comorbidity originate, in part, from pathogenic processes initiated in fetal development that involve sex differences in shared pathophysiology between the brain, the vascular system, the CNS control of the heart and associated hormonal, immune, and metabolic physiology. Pathways implicate neurotrophic and angiogenic growth factors, gonadal hormone receptors, and neurotransmitters such as gamma amino butyric acid (GABA) on neuronal and vascular development of HPA axis regions, such as the paraventricular nucleus (PVN), in addition to blood pressure, in part through the renin-angiotensin system, and insulin and glucose metabolism. We show that the same prenatal exposures have consequences for sex differences across multiple organ systems that, in part, share common pathophysiology. Thus, we believe that applying a sex differences lens to understanding shared biologic substrates underlying these comorbidities will provide novel insights into the development of sex-dependent therapeutics. Further, taking a lifespan perspective beginning in fetal development provides the opportunity to target abnormalities early in the natural history of these disorders in a sex-dependent way.

中文翻译：

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重度抑郁症和心脏代谢疾病合并症的性别差异：产前应激和免疫暴露的影响。


2012 年，重度抑郁症超过缺血性心脏病，成为全球第一大致残原因，女性患重度抑郁症的风险是男性的两倍。此外，到 2020 年，抑郁症和心脏代谢疾病的合并症将成为全球残疾的主要原因之一，其中女性的风险是其两倍。因此，了解性别依赖性合并症对全世界的公共卫生产生影响。我们在此提出，MDD-心脏代谢合并症的性别差异部分源于胎儿发育中启动的致病过程，涉及大脑、血管系统、心脏的中枢神经系统控制以及相关的激素、免疫、和代谢生理学。除了血压之外，这些通路还部分涉及神经营养和血管生长因子、性腺激素受体和神经递质（例如γ氨基丁酸（GABA））对HPA轴区域（例如室旁核（PVN））的神经元和血管发育的影响通过肾素-血管紧张素系统以及胰岛素和葡萄糖代谢。我们表明，相同的产前暴露会对多个器官系统的性别差异产生影响，这些器官系统在一定程度上具有共同的病理生理学特征。因此，我们相信，应用性别差异的视角来理解这些合并症背后的共同生物学基础将为性别依赖性疗法的发展提供新的见解。此外，从胎儿发育开始就采取生命周期的观点提供了机会，以性别依赖性方式在这些疾病的自然史早期针对异常。