A framework for testing pathways from prenatal stress-responsive hormones to cardiovascular disease risk

Abstract

Cardiovascular disease (CVD) is a leading cause of death globally, with the prevalence projected to keep rising. Risk factors for adult CVD emerge at least as early as the prenatal period. Alterations in stress-responsive hormones in the prenatal period are hypothesized to contribute to CVD in adulthood, but little is known about relations between prenatal stress-responsive hormones and early precursors of CVD, such as cardiometabolic risk and health behaviors. The current review presents a theoretical model of the relation between prenatal stress-responsive hormones and adult CVD through cardiometabolic risk markers (e.g., rapid catch-up growth, high BMI/adiposity, high blood pressure, and altered blood glucose, lipids, and metabolic hormones) and health behaviors (e.g., substance use, poor sleep, poor diet and eating behaviors, and low physical activity levels). Emerging evidence in human and non-human animal literatures suggest that altered stress-responsive hormones during gestation predict higher cardiometabolic risk and poorer health behaviors in offspring. This review additionally highlights limitations of the current literature (e.g., lack of racial/ethnic diversity, lack of examination of sex differences), and discusses future directions for this promising area of research.

Keywords: cardiometabolic risk; cardiovascular disease (CVD); cortisol; health behaviors; placental CRH.

Figure 1

The regulation of the maternal HPA axis changes dramatically over the course of gestation, largely due to the development of the placenta, which is an organ of fetal origin. In non-pregnant individuals, exposure to a stressor activates the HPA axis, which involves the release of CRH, ACTH and cortisol. This stress system is regulated by a negative feedback loop (illustrated in black). During pregnancy (illustrated in green), CRH is released from the placenta into both the maternal and fetal compartments. In contrast to the inhibitory effect that cortisol has on hypothalamic CRH, maternal cortisol stimulates placental CRH production, producing a positive feedback loop. Placental CRH normatively increases exponentially over the course of gestation. In addition to placental CRH, maternal cortisol passes through the placenta to the fetus. However, transfer of maternal cortisol into the fetal compartment is somewhat blocked due to placental 11β-HSD-2, a placental enzyme which oxidizes cortisol into inactive cortisone. 11β-HSD-2 activity decreases late in pregnancy in order to allow maternal cortisol to reach the fetus to aid in maturation of vital organs such as the lungs. The fetal HPA axis begins to develop early in gestation and becomes increasingly active close to birth. See text for further description.

Figure 2

Theoretical model for potential risk factors for the development of adult CVD. The strength of the literature on each path is illustrated by the solidity of the line (solid lines indicate a larger body of research). While there are likely bidirectional relations between cardiometabolic risk markers and health behaviors, this literature is beyond the scope of the current review. Metabolic hormones include hormones such as leptin, ghrelin, and adiponectin.