ESPE Yearbook of Paediatric Endocrinology

Short summary: This study describes sex differences in fetal liver-specific androgen signalling that are altered in response to maternal obesity in baboons. It reveals that livers of male fetuses favour a pro-androgenic environment in response to maternal obesity by suppressing the activity of testosterone-metabolising CYP enzymes (CYP2B6 and CYP3A) and by reducing cytoplasmic and nuclear androgen receptor (AR-45) expression. By comparison and most interestingly, there were minimal changes in hepatic androgen signalling in females in response to maternal obesity.

This study adds to the growing evidence that females and males generate distinct adaptations to similar intrauterine environments. Changes to the molecular regulation of hepatic androgen signalling in response to maternal obesity results in a male-specific pro-androgenic environment that may contribute to early programming of liver dysfunction and disease in later life.

Questions remain how exactly maternal obesity causes this sex-specific regulation of enzymes and AR expression in the fetal liver and how this could lead to a permanently altered program of liver function resulting in adult liver disorders. An unsolved conundrum is also that changes in liver function in the male fetus with maternal obesity relate to increased androgens, while in adult men liver diseases relate to decreased androgens; how to explain this switch? Overall, we seem still far from understanding long-term pathways of possible adverse events occurring during pregnancy on later disease of offspring in adult life. Therefore, the authors’ idea - that targeting androgen signalling in pregnancies of obese mothers could prevent liver disease in later life of males - is hypothetically correct but far from ready for clinical testing.