The Androgen Metabolome of Preterm Infants Reflects Fetal Adrenal Gland Involution

Context: The human adrenal cortex changes with fetal-neonatal transition from the fetal to the adult organ, accompanied by changes in the steroid metabolome. Objective: As it is unclear how the observed developmental changes differ between preterm and full-term neonates, we investigated whether the involution of the fetal adrenals is following a fixed time course related to postmenstrual age or whether it is triggered by birth. Furthermore, the fetal and postnatal androgen metabolome of preterm infants was characterized in comparison to term babies. Methods: This was a prospective, longitudinal, 2-center study collecting spot urines of preterm and term infants during the first 12 to 18 months of life. Steroid metabolites were measured from spot urines by gas chromatography-mass spectrometry. Data relating were modeled according to established pre- and postnatal pathways. Results: Fetal adrenal involution occurs around term-equivalent age in preterm infants and is not triggered by premature birth. Testosterone levels are higher in preterm infants at birth and decline slower until term compared to full-term babies. Dihydrotestosterone levels and the activity of the classic androgen biosynthesis pathway are lower in premature infants as is 5[alpha]-reductase activity. No difference was found in the activity of the alternate backdoor pathway for androgen synthesis. Conclusion: Human adrenal involution follows a strict timing that is not affected by premature birth. By contrast, prematurity is associated with an altered androgen metabolome after birth. Whether this reflects altered androgen biosynthesis in utero remains to be investigated. Key Words: fetal adrenal, steroid metabolome, premature neonates, fetal-neonatal transition Abbreviations: 17HP, 17-OH-pregnanolone; DHEA, dehydroepiandrosterone; DHEA-S, dehydroepiandrosterone sulfate; DHT, dihydrotestosterone; DZ, definitive zone; TZ, transitional zone; FZ, fetal zone.