A Life Course Approach to the Relationship Between Fetal Growth and Hypothalamic-Pituitary-Adrenal Axis Function

Abstract

Context: Human and animal studies suggest that hypothalamic-pituitary-adrenal axis (HPA-A) function may be programmed in utero; however, these findings are inconsistent. Given the powerful metabolic actions of cortisol, it is important to clarify the influence of early life on adult HPA-A function.

Objective: To determine the relationship between fetal growth and HPA-A stress response to a psychosocial stressor in young adults.

Design: Multigenerational, prospective cohort study (the Raine Study) conducted between 1989 and 1991.

Setting: King Edward Memorial Hospital, Perth, Western Australia, Australia.

Participants: A total of 917 participants aged 18 years from Gen2 of the Raine Study.

Main outcome measures: Measures of hypothalamic-pituitary-adrenal axis function before and after exposure to the Trier Social Stress Test.

Results: In fully adjusted models, an inverse linear relationship was observed between birthweight and plasma measures of (1) baseline cortisol (β = -0.90%, 95% CI: -1.73 to -0.07; P = 0.03); (2) peak cortisol (β = -0.78%, 95% CI -1.51 to -0.06; P = 0.03); (3) area under the curve with respect to ground (β = -0.89%, 95% CI -1.60 to -0.18; P = 0.01); and (4) adrenal sensitivity (β = -1.02, 95% CI: -1.85 to -0.18; P = 0.02). Similar results were demonstrated for percent optimal birthweight. No consistent quadratic relationships were identified. No associations were found between measures of fetal adiposity and HPA-A function at age 18 years, or fetal growth and HPA-A response pattern. Removal of anticipatory responders from the models substantially attenuated the observed relationships.

Conclusion: We observed an inverse linear relationship between fetal growth and HPA-A function at age 18 years. This differs from the inverse parabolic relationship (inverted U curve) reported in adults of advanced age. Altered adrenal sensitivity may underlie this relationship.

Keywords: DOHaD; HPA; Trier Social Stress Test; developmental origins; fetal growth; hypothalamic-pituitary-adrenal axis.