A life course approach to the relationship between fetal growth and hypothalamic-pituitary-adrenal axis function

Wrivu N Martin, Carol A Wang, Stephen J Lye, Stephen G Matthews, Rebecca M Reynolds, Carly E McLaughlin, Roger Smith, Craig E Pennell

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)


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: 917 participants aged 18 from Gen 2 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 birth weight and 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) AUCg (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 per cent optimal birth weight. No consistent quadratic relationships were identified. No associations were found between measures of fetal adiposity and HPA-A function at age 18, 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. This differs from the inverse parabolic relationship (inverted U curve) reported in adults of advanced age. Altered adrenal sensitivity may underlie this relationship.

Original languageEnglish
Pages (from-to)2646-2659
Number of pages14
JournalThe Journal of clinical endocrinology and metabolism
Issue number9
Early online date17 May 2021
Publication statusPublished - 1 Sep 2021
Externally publishedYes


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