The human fetal adrenal produces cortisol but no detectable aldosterone throughout the second trimester

Johnston, Z. C. et al. (2018) The human fetal adrenal produces cortisol but no detectable aldosterone throughout the second trimester. BMC Medicine, 16, 23. (doi:10.1186/s12916-018-1009-7) (PMID:29429410) (PMCID:PMC5808459)

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Abstract

Background: Human fetal adrenal glands are highly active and, with the placenta, regulate circulating progesterone, estrogen and corticosteroids in the fetus. At birth the adrenals are essential for neonate salt retention through secretion of aldosterone, while adequate glucocorticoids are required to prevent adrenal insufficiency. The objective of this study was to carry out the first comprehensive analysis of adrenal steroid levels and steroidogenic enzyme expression in normal second trimester human fetuses. Methods: This was an observational study of steroids, messenger RNA transcripts and proteins in adrenals from up to 109 second trimester fetuses (11 weeks to 21 weeks) at the Universities of Aberdeen and Glasgow. The study design was balanced to show effects of maternal smoking. Results: Concentrations of 19 intra-adrenal steroids were quantified using liquid chromatography and mass spectrometry. Pregnenolone was the most abundant steroid while levels of 17α-hydroxyprogesterone, dehydroepiandrosterone sulphate (DHEAS) and progesterone were also high. Cortisol was present in all adrenals, but aldosterone was undetected and Δ4 androgens were low/undetected. CYP17A1, CYP21A2 and CYP11A1 were all highly expressed and the proteins localized to the adrenal fetal zone. There was low-level expression of HSD3B and CYP11B2, with HSD3B located mainly in the definitive zone. Maternal smoking altered fetal plasma adrenocorticotropic hormone (ACTH) (P = 0.052) and intra-adrenal progesterone, 17α-hydroxyprogesterone and 16α-hydroxyprogesterone, but not plasma or intra-adrenal cortisol, or intra-adrenal DHEAS. Fetal adrenal GATA6 and NR5A1 were increased by maternal smoking. Conclusions: The human fetal adrenal gland produces cortisol but very low levels of Δ4 androgens and no detectable aldosterone throughout the second trimester. The presence of cortisol in fetal adrenals suggests that adrenal regulation of circulating fetal ACTH remains a factor in development of congenital adrenal hyperplasia during the second trimester, while a relative lack of aldosterone explains the salt-wasting disorders frequently seen in extreme pre-term neonates. Finally, maternal smoking may alter fetal adrenal sensitivity to ACTH, which could have knock-on effects on post-natal health.

Item Type:Articles
Keywords:Adrenal, fetus, human, maternal smoking, steroid.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Bellingham, Dr Michelle and Johnston, Zoe and O'Shaughnessy, Professor Peter and Soffientini, Mr Ugo and Hough, Dr Denise
Authors: Johnston, Z. C., Bellingham, M., Filis, P., Soffientini, U., Hough, D., Bhattacharya, S., Simard, M., Hammond, G. L., King, P., O'Shaughnessy, P. J., and Fowler, P. A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:BMC Medicine
Publisher:BioMed Central
ISSN:1741-7015
ISSN (Online):1741-7015
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in BMC Medicine 16: 23
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
609701The human fetal liver: development and response to maternal drug usePeter O'ShaughnessyMedical Research Council (MRC)ME/L010011/1RI BIODIVERSITY ANIMAL HEALTH & COMPMED
632341MRC Doctoral Training Grant 2013/14, 2014/15 and 2015/16George BaillieMedical Research Council (MRC)MR/K501335/1MVLS GRADUATE SCHOOL