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

Hospital for Children and Adolescents (E.K., L.D., S.A.), Laboratory (U.T.), and Departments of Clinical Chemistry (U.-H.S.) and Obstetrics and Gynecology (M.N., S.A.), Helsinki University Central Hospital, 00029 HUS, Helsinki, Finland; Endocrine Unit (P.J.W.), Southampton General Hospital, SO16 6YD Southampton, United Kingdom

Address all correspondence and requests for reprints to: Eero Kajantie, M.D., The Hospital for Children and Adolescents, Helsinki University Central Hospital, PL 280, 00029 HUS, Finland. E-mail: eero.kajantie{at}hus.fi.

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 11ß-hydroxysteroid dehydrogenase-2 (11ß-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 11ß-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 11ß-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 11ß-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 11ß-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 11ß-HSD2 activity rate (r = -0.25; P = 0.009). We conclude that, in small preterm infants, reduced placental 11ß-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.

This work was supported by grants from Finska Läkaresällskapet, Helsinki University Central Hospital Research Fund, The Foundation for Pediatric Research, Paulo Foundation, Sigrid Jusélius Foundation, Sydäntutkimussäätiö, and Wiipurilaisen osakunnan stipendirahastot.

Abbreviations: E, cortisone; F, cortisol; HPA, hypothalamo-pituitary-adrenal; 11ß-HSD, 11ß-hydroxysteroid dehydrogenase; IUGR, intrauterine growth restriction.

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