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

Growing preclinical evidence suggests that hormonal programming by androgens in utero may contribute to cardiovascular disease risk in adult offspring. However, the effect of prenatal androgens on cardiometabolic outcomes in the human population, especially their potential differential impact on male vs female offspring, has not been well studied.

Adult offspring (n = 274) of mothers enrolled in the New England birth cohorts of the Collaborative Perinatal Project were assessed at ages 39 to 50. Androgen bioactivity was measured in maternal serum during the third trimester using a receptor-mediated luciferase expression bioassay. Metabolic syndrome (MetS) using Adult Treatment Panel III criteria was assessed in adult offspring. Bioactive androgens were analyzed as quartiles, with the lowest quartile (Q1) 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.

Mean age and body mass index of adult offspring were 44.7 ± 2.6 years and 29.7 ± 6.7 kg/m2, respectively. Participants born to mothers with the highest quartile (Q4) compared with Q1 of bioactive androgens had higher risk for MetS [adjusted odds ratio (aOR): 2.53(1.07 to 6.02)]. Stratified by sex, this association was found to be significant among women [Q4 vs Q1; aOR: 4.06 (1.10 to 14.93)] but not men [Q4 vs Q1; aOR: 1.67 (0.53 to 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 to 20.85)].

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.