Sex Differences in the Prenatal Programming of Adult Metabolic Syndrome by Maternal Androgens

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Abstract
Background Growing preclinical evidence suggests that hormonal programming by androgens in utero may contribute to cardiovascular disease risk in adult offspring. However, data linking prenatal androgens to cardiometabolic outcomes in the human population, especially their potential differential impact on male versus female offspring, has not been well-studied. Methods Adult offspring (n=274) of mothers enrolled in the New England birth cohorts of the Collaborative Perinatal Project were assessed at ages 39-50. Androgen bioactivity was measured in maternal serum during third-trimester using a receptor-mediated luciferase expression bioassay. Metabolic syndrome(MetS) using ATPIII criteria was assessed in adult offspring. Bioactive androgens were analyzed as quartiles with the lowest quartile defined as the reference. Generalized estimating equations were used to evaluate the relationship of maternal bioactive androgens on offspring MetS risk overall and by sex, controlling for potential confounders and intrafamilial correlation. Results Mean age and BMI of adult offspring was 44.7±2.6 years and 29.7±6.7kg/m2, respectively. Participants born to mothers with the highest quartile[Q4] compared to the lowest quartile[Q1] of bioactive androgens had higher risk for MetS [aOR:2.53(1.07-6.02)]. Stratified by sex, this association was found to be significant among women [Q4 vs Q1; aOR:4.06 (1.10-14.93)] but not men [Q4 vs Q1; aOR:1.67 (0.53-5.26)]. Women born to mothers with the highest levels of maternal bioactive androgens also demonstrated a 4.84-fold increased odds for having hypertension [Q4 vs Q1; aOR:4.84 (1.12-20.85)]. Conclusion Higher levels of maternal androgens were associated with increased risk for incident MetS in adult offspring, an effect that was significant in women but not men.
Funding Information
  • National Heart, Lung, and Blood Institute (K08 HL132122)
  • Arizona Biomedical Research Commission (ADHS14-00003606)
  • National Institute of Mental Health (R01 MH074679)
  • National Institute on Aging (RC2AG036666, R01 AG023397)

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