The Androgen Metabolome of Preterm Infants Reflects Fetal Adrenal Gland Involution

Abstract

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. Design Prospective, longitudinal, two centre study collecting spot urines of preterm and term infants during the first 12-18 months of life. Methods Steroid metabolites were measured from spot urines by gas chromatography-mass spectrometry. Data relating were modelled 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 till term compared to full-term babies. Dihydrotestosterone levels and the activity of the classic androgen biosynthesis pathway are lower in premature infants as is 5α-reductase activity. No difference was found in the activity of the alternate backdoor pathway for androgen synthesis. Conclusions 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.

Development and function of the fetal adrenal

“…Ultrasonography in premature neonates suggested that FZ involution occurs soon after parturition independent of the gestational age [46]. Instead, comparison of longitudinal hormonal profiles from term and pre-term babies indicates that fetal typical androgen production, as a proxy for zF activity, declines in accordance with postmenstrual age independent of the timepoint of birth [47]. The failure of the FZ to undergo apoptosis could be linked to the occurrence of early-onset pediatric adrenocortical carcinomas, although this possibility needs to be formally tested [48,49].…”

Mechanisms of Immune Tolerance and Inflammation via Gonadal Steroid Hormones in Preterm Birth

“…Furthermore, testosterone levels in premature infants are reported to be higher at birth and to decline more slowly before term compared with neonates born at term. However, the levels of dihydrotestosterone (DHT) and the activity of the classical androgen biosynthetic pathway were much lower in preterm infants compared with neonates born at term 90 . Another recent study found that in premature offspring, exon-1 of the androgen receptor (AR) has more duplications in the coding sequence of the ligand activation domain 91 .…”

“…However, the levels of dihydrotestosterone (DHT) and the activity of the classical androgen biosynthetic pathway were much lower in preterm infants compared with neonates born at term. 90 Another recent study found that in premature offspring, exon-1 of the androgen receptor (AR) has more duplications in the coding sequence of the ligand activation domain. 91 Currently, few studies have investigated the role of androgens in PTB, although previous studies have speculated that prematurity may be associated with elevated androgen levels.…”

Steroid Metabolomic Signature in Term and Preterm Infants

“…The fetal zone involutes rapidly after birth in term infants [3]. In contrast, the fetal adrenal involution occurs not before term-equivalent age after preterm birth [4][5][6]. Particularly, in early preterm infants born with less than 30 weeks gestational age, the excretion rates of fetal zone steroids (FZS) comprise more than 90% of the total urinary steroid excretion rates [5].…”