Characterization of Human Adrenal Steroidogenesis During Fetal Development.

Cecilie Melau,Anne Jørgensen,Anna-Maria Andersson,Anders Juul,Kristine Juul Hare,Hanne Frederiksen,Rod T Mitchell,Karen Kilcoyne,Lene Lundvall,Lea Langhoff Thuesen,Signe Perlman,John Erik Nielsen

doi:10.1210/jc.2018-01759

Abstract

ContextThe endocrine function of human fetal adrenals (HFAs) is activated already during first trimester, but adrenal steroidogenesis during fetal life is not well characterized.ObjectiveThis study aimed to investigate HFA steroidogenesis by analyzing adrenal glands from first and second trimesters.Design and SettingMale and female HFA from gestational weeks (GWs) 8 to 19 were examined, including a total of 101 samples from 83 fetuses.Main Outcome Measure(s)Expression level of steroidogenic genes and protein expression/localization were determined by quantitative PCR and immunohistochemistry, respectively, and intra-adrenal steroid levels were quantified by LC-MS/MS.ResultsTranscriptional levels of StAR, CYP11A1, CYP17A1, CYP21A2, CYP11B1/2, and SULT2A1 were significantly higher in second trimester compared to first trimester (P < 0.05), whereas expression levels of 3β-HSD2 and ARK1C3 were unaltered between GWs 8 and 19. All investigated steroidogenic proteins were expressed in a distinct pattern throughout the investigated period, with most enzymes expressed primarily in the fetal zone, except 3β-HSD1/2, which was expressed mainly in the definitive zone. Abundant steroidogenic enzyme expression was reflected in overall high intra-adrenal tissue concentrations of mineralocorticoids, glucocorticoids, and androgens; cortisol was the most abundant (1071 to 2723 ng/g tissue), and testosterone levels were the lowest (2 to 14 ng/g tissue).ConclusionsThe expression profiles of HFA steroidogenic enzymes are distinct from first to second trimester, with no major differences between male and female samples. Intra-adrenal steroid hormone concentrations confirm that cortisol is produced throughout first and second trimesters, suggesting continued regulation of the hypothalamus-pituitary-adrenal axis during this entire period.

Highlights

The morphology of the human fetal adrenal (HFA) gland differs from the adult organ
The selected steroidogenic enzymes were expressed in all investigated human fetal adrenals (HFA) glands at the transcriptional level
Gene expression patterns were investigated separately in male and female samples, which were divided into four age groups: gestational week (GW) 8-9, GW 10-12, GW 14-16, and GW 17-19

Summary

Introduction

The morphology of the human fetal adrenal (HFA) gland differs from the adult organ. The morphology of the HFA gland is established around gestational week (GW) 7 where the adrenal cortex has differentiated from adreno-genital primordial cells into a distinct morphology consisting of two separate zones; a thin outer definitive zone (DZ) and an inner fetal zone (FZ) that accounts for 80-90% of the adrenal tissue [1]. During 2nd trimester an additional transitional zone (TZ) develops at the interface between the DZ and FZ after which the morphology of the HFA gland is unchanged until birth [1]. Activation of the hypothalamus-pituitary-adrenal (HPA) hormone axis is essential for adrenal steroidogenic enzyme expression [2]. Activation of the adrenal melanocortin receptor 2 (MC2R) through binding of pituitary-secreted adrenocorticotropic hormone (ACTH) is necessary for the endocrine capacity of the HFA gland [1,3,4]. The FZ (and later TZ) is described as the most steroidogenic active zone expressing

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