Disruption of fetal hormonal programming (prenatal stress) implicates shared risk for sex differences in depression and cardiovascular disease

Abstract

Comorbidity of major depressive disorder (MDD) and cardiovascular disease (CVD) represents the fourth leading cause of morbidity and mortality worldwide, and women have a two times greater risk than men. Thus understanding the pathophysiology has widespread implications for attenuation and prevention of disease burden. We suggest that sex-dependent MDD-CVD comorbidity may result from alterations in fetal programming consequent to the prenatal maternal environments that produce excess glucocorticoids, which then drive sex-dependent developmental alterations of the fetal hypothalamic-pituitary-adrenal (HPA) axis circuitry impacting mood, stress regulation, autonomic nervous system (ANS), and the vasculature in adulthood. Evidence is consistent with the hypothesis that disruptions of pathways associated with gamma aminobutyric acid (GABA) in neuronal and vascular development and growth factors have critical roles in key developmental periods and adult responses to injury in heart and brain. Understanding the potential fetal origins of these sex differences will contribute to development of novel sex-dependent therapeutics.

Keywords: Cardiovascular disease; Depression; Fetal hormonal programming; Hypothalamus; MDD–CVD comorbidity; Prenatal stress; Sex differences.

Figure 1. Shared Brain Circuitry between Stress Response, Mood and HPA Regulation

Stress response circuitry in the brain is shared with HPA and HPG regulation and a number of these regions are found to be abnormal in MDD, structurally (operationalized as MRI brain volumes) and functionally (operationalized in studies of fMRI or Positron Emission Tomography or PET).

Figure 2. Potential interactions of PVN neuronal and vascular development

Schematic diagram of coronal section illustrates the development of PVN neurons (red dots) along the proliferative zone of the third ventricle (3V) and their migration laterally with age (A). At later ages there is a major expansion of PVN vasculature (Green lines). The neuronal relationship to vascular elements (e.g., proximity) could be altered to create disease susceptibility (B), or the blood brain barrier function could be compromised leading to disease susceptibility (C).

Figure 3. Brain Regions Shared between Mood, Stress, and ANS

Brain regions implicated in CNS regulation of stress, mood and anxiety disorders are also involved in the CNS control of the heart (through ANS). Left image and upper right is parasagittal and lower right is horizontal. Shared sex-dependent development of this neural circuitry provides a rationale for the fetal programming of sex differences in the comorbidity of MDD and CVD. (Image adapted from Lane and Wager, NeuroImage 2009, volume 47, issue 3)

Figure 4. Stress Response Circuitry in the Brain is Highly Sexually Dimorphic

Brain regions implicated in the stress response circuitry are some of the most highly sexually dimorphic brain regions in the brain (e.g., hypothalamic nuclei, central medial amygdala, hippocampus, mPFC, ACC). Figure 3 highlights the brain regions in MR images and shows which regions are larger in volume (cm³) in the female brain (in red), relative to cerebrum size, and which are larger in the male brain, relative to cerebrum size (in blue). (Adapted from Goldstein, et al., 2001, Cerebral Cortex)

Figure 5. Mechanisms Associated with Sex-Dependent Fetal Stress Circuitry Development Implicating Comorbidity of MDD and CVD in Adulthood

Schematic depiction of the interactions among stressors of the mother leading to dysregulation of her HPA axis that then influences maternal-fetal interactions in a sex-dependent developmental manner. In the fetal compartment, glucocorticoids and sex steroid influences (e.g., estrogen and androgen receptors (ER, AR)) impact GABA and growth factors, which alter neuronal and vascular cellular components.