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

Zoe C. Johnston; Michelle Bellingham; Panagiotis Filis; Ugo Soffientini; Denise Hough; Siladitya Bhattacharya; Marc Simard; Geoffrey L. Hammond; Peter King; Peter J. O'Shaughnessy; Paul A. Fowler

doi:10.1186/s12916-018-1009-7

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

Zoe C. Johnston, Michelle Bellingham, Panagiotis Filis, Ugo Soffientini, Denise Hough, Siladitya Bhattacharya, Marc Simard, Geoffrey L. Hammond, Peter King, Peter J. O'Shaughnessy, Paul A. Fowler ^* (Corresponding Author)

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	23
Number of pages	16
Journal	BMC medicine
Volume	16
DOIs	https://doi.org/10.1186/s12916-018-1009-7
Publication status	Published - 12 Feb 2018

Bibliographical note

Funding
This study was supported by: grants from the Medical Research Council (MR/L010011/1) (to PAF & PJOS) and (MR/K501335/1 to MB, PAF and PJOS), the Canadian Institutes of Health Research (MOP- 111102 to GLH), a Canada Research Chair in Reproductive Health (to GLH), and a postdoctoral fellowship from the Fonds de Recherche du Québec en Santé and the Michael Smith Foundation for Health Research (to MS).

Keywords

human
adrenal
fetus
steroid
maternal smoking

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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The human fetal adrenal produces cortisol but no detectable aldosterone throughout the second trimester
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Final published version, 1.52 MBLicence: CC BY

Paul Alfred François Fowler
- School of Medicine, Medical Sciences & Nutrition, Molecular and Cellular Function
- School of Medicine, Medical Sciences & Nutrition, Applied Medicine - Chair in Translational Medical Sciences
- School of Medicine, Medical Sciences & Nutrition, Institute of Medical Sciences
Person: Academic

Iain Fraser Cytometry Centre
Andrea Holme (Manager), Linda Duncan (Senior Application Scientist), Ailsa Laird (Technician) & Kate Burgoyne (Technician)
Institute of Medical Sciences
Research Facilities: Facility

Cite this

@article{90c3c48aa15549d5ae7ea5ebce601afa,

title = "The human fetal adrenal produces cortisol but no detectable aldosterone throughout the second trimester",

abstract = "BackgroundHuman 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.MethodsThis 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.ResultsConcentrations 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.ConclusionsThe 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.",

keywords = "human, adrenal, fetus, steroid, maternal smoking",

author = "Johnston, {Zoe C.} and Michelle Bellingham and Panagiotis Filis and Ugo Soffientini and Denise Hough and Siladitya Bhattacharya and Marc Simard and Hammond, {Geoffrey L.} and Peter King and O'Shaughnessy, {Peter J.} and Fowler, {Paul A.}",

note = "Funding This study was supported by: grants from the Medical Research Council (MR/L010011/1) (to PAF & PJOS) and (MR/K501335/1 to MB, PAF and PJOS), the Canadian Institutes of Health Research (MOP- 111102 to GLH), a Canada Research Chair in Reproductive Health (to GLH), and a postdoctoral fellowship from the Fonds de Recherche du Qu{\'e}bec en Sant{\'e} and the Michael Smith Foundation for Health Research (to MS).",

year = "2018",

month = feb,

day = "12",

doi = "10.1186/s12916-018-1009-7",

language = "English",

volume = "16",

journal = "BMC medicine ",

issn = "1741-7015",

publisher = "BioMed Central",

}

TY - JOUR

T1 - The human fetal adrenal produces cortisol but no detectable aldosterone throughout the second trimester

AU - Johnston, Zoe C.

AU - Bellingham, Michelle

AU - Filis, Panagiotis

AU - Soffientini, Ugo

AU - Hough, Denise

AU - Bhattacharya, Siladitya

AU - Simard, Marc

AU - Hammond, Geoffrey L.

AU - King, Peter

AU - O'Shaughnessy, Peter J.

AU - Fowler , Paul A.

N1 - Funding This study was supported by: grants from the Medical Research Council (MR/L010011/1) (to PAF & PJOS) and (MR/K501335/1 to MB, PAF and PJOS), the Canadian Institutes of Health Research (MOP- 111102 to GLH), a Canada Research Chair in Reproductive Health (to GLH), and a postdoctoral fellowship from the Fonds de Recherche du Québec en Santé and the Michael Smith Foundation for Health Research (to MS).

PY - 2018/2/12

Y1 - 2018/2/12

N2 - BackgroundHuman 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.MethodsThis 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.ResultsConcentrations 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.ConclusionsThe 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.

AB - BackgroundHuman 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.MethodsThis 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.ResultsConcentrations 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.ConclusionsThe 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.

KW - human

KW - adrenal

KW - fetus

KW - steroid

KW - maternal smoking

U2 - 10.1186/s12916-018-1009-7

DO - 10.1186/s12916-018-1009-7

M3 - Article

SN - 1741-7015

VL - 16

JO - BMC medicine

JF - BMC medicine

M1 - 23

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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Paul Alfred François Fowler

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Iain Fraser Cytometry Centre

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