Transfer and Metabolism of Cortisol by the Isolated Perfused Human Placenta

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 hypothesized placental 11-β-hydroxysteroid dehydrogenase-type 2 (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 modeling, 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 11-β-hydroxysteroid dehydrogenase (11β-HSD) activity was inhibited. At the highest inlet concentration, only 3.0% of the maternal cortisol was transferred to the fetal circulation, whereas 26.5% was metabolized 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, whereas 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.

Association among placental 11β‐HSD2, PPAR‐γ, and NF‐κB p65 in small‐for‐gestational‐age infants: A nested case‐control study

“…It is now widely accepted that 11β‐hydroxysteroid dehydrogenase 2 (11β‐HSD2), a glucocorticoid‐inactivating enzyme, acts as the placental glucocorticoid barrier 4,5 . Several studies have indicated that 11β‐HSD2 catalyzes active glucocorticoids, such as cortisol, into their inactive products, such as cortisone, thus preventing glucocorticoids from passing maternal circulation into the fetus 6‐8 . Ontogeny studies indicate that the expression of 11β‐HSD2 is initiated at a very early stage after conception, increases with gestational age, and declines around term 9 .…”

The impact of maternal obesity in pregnancy on placental glucocorticoid and macronutrient transport and metabolism

“…11β-HSD-2 is located in the syncytiotrophoblast ( Figure 2) and converts biologically active maternal cortisol into inactive cortisone. This enzyme acts as a 'barrier' to prevent excessive fetal exposure to cortisol derived from the activated maternal system [52,53]. It was previously reported that placental 11β-HSD-2 inactivates the majority of maternal cortisol, however a recent study examining placental glucocorticoid transfer reported that even when 11β-HSD-2 activity was inhibited with carbenoxolone, (a potent HSD inhibitor), less than 10% of maternal cortisol crossed the placenta.…”

“…It was previously reported that placental 11β-HSD-2 inactivates the majority of maternal cortisol, however a recent study examining placental glucocorticoid transfer reported that even when 11β-HSD-2 activity was inhibited with carbenoxolone, (a potent HSD inhibitor), less than 10% of maternal cortisol crossed the placenta. This finding suggests other mechanisms are active in protecting the fetus from high maternal cortisol levels [53]. It has been suggested that due to the significantly higher cortisol concentrations in the maternal circulation compared to the fetal circulation, relatively small changes in 11β-HSD-2 activity may result in clinically significant alterations in fetal glucocorticoid exposure [28].…”

The Hypothalamic-Pituitary-Adrenal Axis and the Fetus

“…This enzyme limits fetal exposure to maternal GC because the predominant activity of placental HSD11B2 is oxidation of maternal cortisol to the inactive GC, cortisone. However, this enzyme only prevents approximately 80–90% of maternal cortisol from crossing the placenta [48, 49]. Expression of HSD11B2 increases throughout pregnancy with a rapid decline late in the third trimester.…”