Placental 11β-Hydroxysteroid Dehydrogenase-2 and Fetal Cortisol/Cortisone Shuttle in Small Preterm Infants

Abstract

Glucocorticoids rate among the most controversial topics in today's perinatology and neonatology. Many sick preterm infants exhibit signs of adrenal insufficiency, the etiology, diagnostic criteria, and optimal treatment of which are under debate. Moreover, most of these infants are exposed to pharmacological glucocorticoid doses both in utero and after birth. In face of this, surprisingly little is known about the physiological glucocorticoid exposure before early preterm birth. This exposure is highly variable and mainly regulated by the placental enzyme 11 beta-hydroxysteroid dehydrogenase-2 (11 beta-HSD2), which converts excess cortisol (F) to inactive cortisone (E). Impaired activity of this enzyme is common in intrauterine growth restriction and preeclampsia, conditions frequently associated with early preterm birth. To identify clinical determinants associated with decreased placental 11 beta-HSD2 function, we studied 107 small preterm infants [mean birth weight, 1067 g (range, 395-2453 g); gestational age, 28.2 wk (range, 22.4-32.0 wk)] by determining their placental 11 beta-HSD2 activity rate (per milligram protein) and total activity (per placenta) as well as cord vein F and E concentrations. An E/(E+ F) ratio expresses the overall balance of the F/E shuttle. There were positive correlations between relative birth weight and placental 11 beta-HSD2 activity rate (r = 0.30; P = 0.002) and total activity (r = 0.56; P < 0.0001) as well as E/(E+ F) ratio (r = 0.27; P = 0.01) and E concentration (r = 0.32; P = 0.003). Infants with increased umbilical artery resistance had lower total placental 11 beta-HSD2 activity (P = 0.02), E/(E+ F) ratio (P = 0.04), and E concentration (P = 0.0002). Gestational age was inversely associated with placental 11 beta-HSD2 activity rate (r = -0.25; P = 0.009). We conclude that, in small preterm infants, reduced placental 11 beta-HSD2 function is associated with low relative birth weight and severe fetal distress. Whether these conditions are associated with early postnatal adrenal insufficiency or long-term cardiovascular risk remains an important issue for further study.

Impaired Protein Stability of 11β-Hydroxysteroid Dehydrogenase Type 2

“…Inhibition of 11␤-HSD2 by endogenous and exogenous compounds can cause sodium retention and hypertension, resembling the features that are observed in AME (7)(8)(9). In addition, 11␤-HSD2 modulates anti-inflammatory and antiproliferative actions of cortisol (10,11), and placental 11␤-HSD2 protects the fetus from high maternal cortisol concentrations, whereby its decreased activity has been associated with reduced birth weight and an elevated risk for cardiovascular diseases in later life (12,13).…”

The impact of psychological distress during pregnancy on the developing fetus: biological mechanisms and the potential benefits of mindfulness interventions

“…11-Beta-hydroxysteroid dehydrogenase type 2 (HSD11β2) is a barrier between maternal glucocorticoids and the fetal circulation that converts excess cortisol into cortisone [38] and serves as a protective role for the fetus [39]. Prenatal stress has been associated with the decreased expression of HSD11β2 [39,40] in the infant.…”

Early neonatal hypotension in premature infants born to preeclamptic mothers

“…One study has shown that the umbilical cord blood cortisol level in premature infants born to mothers with preeclampsia did not differ from the level in infants born to mothers without preeclampsia. 33 It is also possible that fetal exposure to antenatal steroid therapy may reduce the cord blood cortisol level and result in a lower neonatal mean arterial pressure. However, our analysis did not identify a role for antenatal steroids as a modulator of neonatal arterial pressure.…”