Transfer and metabolism of cortisol by the isolated perfused human placenta
Transfer and metabolism of cortisol by the isolated perfused human placenta
Context: fetal overexposure to glucocorticoids in utero is associated with fetal growth restriction and is postulated to be a key mechanism linking suboptimal fetal growth with cardiovascular disease in later life.
Objective: to develop a model to predict maternal-fetal glucocorticoid transfer. We hypothesised placental 11β-HSD2 would be the major rate-limiting step in maternal cortisol transfer to the fetus.
Design: we used a deuterated cortisol tracer in the ex vivo placental perfusion model, in combination with computational modelling, to investigate the role of interconversion of cortisol and its inactive metabolite cortisone on transfer of cortisol from mother to fetus.
Participants: term placentas were collected from five women with uncomplicated pregnancies, at elective caesarean delivery.
Intervention: maternal artery of the isolated perfused placenta was perfused with D4-cortisol.
Main outcome measures: D4-cortisol, D3-cortisone and D3-cortisol were measured in maternal and fetal venous outflows.
Results: D4-cortisol, D3-cortisone and D3-cortisol were detected and increased in maternal and fetal veins as the concentration of D4-cortisol perfusion increased. D3-cortisone synthesis was inhibited when 11β-HSD activity was inhibited. At the highest inlet concentration only 3.0% of the maternal cortisol was transferred to the fetal circulation, while 26.5% was metabolised and 70.5% exited via the maternal vein. Inhibiting 11β-HSD activity increased the transfer to the fetus to 7.3% of the maternal input, while 92.7% exited via the maternal vein.
Conclusions: our findings challenge the concept that maternal cortisol diffuses freely across the placenta and confirm that 11β-HSD2 acts as a major 'barrier' to cortisol transfer to the fetus.
Journal Article
640-648
Stirrat, Laura I.
f69e0be4-7310-4637-8ba9-3fa7f243d8f0
Sengers, Bram G.
d6b771b1-4ede-48c5-9644-fa86503941aa
Norman, Jane E.
015288c6-14ab-46bf-98eb-ca5325667922
Homer, Natalie Z.M.
bfe271fd-80ca-410b-a50b-5a0305f2705c
Andrew, Ruth
a127d25d-819a-46bb-88e1-68d7ade4fb0f
Lewis, Rohan M.
caaeb97d-ea69-4f7b-8adb-5fa25e2d3502
Reynolds, Rebecca M.
0e42554c-fafd-447c-99ec-19b024c47302
February 2018
Stirrat, Laura I.
f69e0be4-7310-4637-8ba9-3fa7f243d8f0
Sengers, Bram G.
d6b771b1-4ede-48c5-9644-fa86503941aa
Norman, Jane E.
015288c6-14ab-46bf-98eb-ca5325667922
Homer, Natalie Z.M.
bfe271fd-80ca-410b-a50b-5a0305f2705c
Andrew, Ruth
a127d25d-819a-46bb-88e1-68d7ade4fb0f
Lewis, Rohan M.
caaeb97d-ea69-4f7b-8adb-5fa25e2d3502
Reynolds, Rebecca M.
0e42554c-fafd-447c-99ec-19b024c47302
Stirrat, Laura I., Sengers, Bram G., Norman, Jane E., Homer, Natalie Z.M., Andrew, Ruth, Lewis, Rohan M. and Reynolds, Rebecca M.
(2018)
Transfer and metabolism of cortisol by the isolated perfused human placenta.
Journal of Clinical Endocrinology & Metabolism, 103 (2), .
(doi:10.1210/jc.2017-02140).
Abstract
Context: fetal overexposure to glucocorticoids in utero is associated with fetal growth restriction and is postulated to be a key mechanism linking suboptimal fetal growth with cardiovascular disease in later life.
Objective: to develop a model to predict maternal-fetal glucocorticoid transfer. We hypothesised placental 11β-HSD2 would be the major rate-limiting step in maternal cortisol transfer to the fetus.
Design: we used a deuterated cortisol tracer in the ex vivo placental perfusion model, in combination with computational modelling, to investigate the role of interconversion of cortisol and its inactive metabolite cortisone on transfer of cortisol from mother to fetus.
Participants: term placentas were collected from five women with uncomplicated pregnancies, at elective caesarean delivery.
Intervention: maternal artery of the isolated perfused placenta was perfused with D4-cortisol.
Main outcome measures: D4-cortisol, D3-cortisone and D3-cortisol were measured in maternal and fetal venous outflows.
Results: D4-cortisol, D3-cortisone and D3-cortisol were detected and increased in maternal and fetal veins as the concentration of D4-cortisol perfusion increased. D3-cortisone synthesis was inhibited when 11β-HSD activity was inhibited. At the highest inlet concentration only 3.0% of the maternal cortisol was transferred to the fetal circulation, while 26.5% was metabolised and 70.5% exited via the maternal vein. Inhibiting 11β-HSD activity increased the transfer to the fetus to 7.3% of the maternal input, while 92.7% exited via the maternal vein.
Conclusions: our findings challenge the concept that maternal cortisol diffuses freely across the placenta and confirm that 11β-HSD2 acts as a major 'barrier' to cortisol transfer to the fetus.
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Stirrat_Reynolds_PlacentalCortisolMetab_COMBINED_AUTHORS_SUBMITTED
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Accepted/In Press date: 13 November 2017
e-pub ahead of print date: 16 November 2017
Published date: February 2018
Keywords:
Journal Article
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Local EPrints ID: 416077
URI: http://eprints.soton.ac.uk/id/eprint/416077
ISSN: 0021-972X
PURE UUID: 734a1187-ae71-48c0-9aa7-01be6ddf684d
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Date deposited: 01 Dec 2017 17:30
Last modified: 16 Mar 2024 03:51
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Contributors
Author:
Laura I. Stirrat
Author:
Jane E. Norman
Author:
Natalie Z.M. Homer
Author:
Ruth Andrew
Author:
Rebecca M. Reynolds
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