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11 beta-Hydroxysteroid dehydrogenases: key enzymes in determining tissue-specific glucocorticoid effects
C R Edwards1, R Benediktsson, R S Lindsay
1Imperial College School of Medicine, Imperial College, London, United Kingdom.
Steroids
|April 1, 1996
Summary
Low placental 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) activity increases fetal exposure to maternal glucocorticoids, leading to low birth weight and adult hypertension. This highlights a link between the in utero environment and adult disease.
Area of Science:
- Endocrinology
- Reproductive Biology
- Developmental Origins of Health and Disease
Background:
- The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) interconverts active and inactive glucocorticoids, influencing mineralocorticoid receptor specificity and local glucocorticoid receptor activation.
- Two isoforms exist: 11 beta-HSD1 (reductase in liver) and 11 beta-HSD2 (dehydrogenase in kidney and placenta).
- Deficiency in 11 beta-HSD2 causes apparent mineralocorticoid excess (SAME), while low placental 11 beta-HSD2 is linked to fetal glucocorticoid exposure and low birth weight.
Purpose of the Study:
- To investigate the role of placental 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) in fetal glucocorticoid exposure and its impact on birth weight and adult health.
- To explore the mechanisms linking in utero environmental changes to common adult diseases.
Main Methods:
- Correlational studies in rats examining the relationship between placental 11 beta-HSD levels, birth weight, and placental weight.
- In vivo experiments administering dexamethasone or carbenoxolone to pregnant rats.
- Studies on rats fed a low protein diet during pregnancy.
- Analysis of placental 11 beta-HSD activity and cortisol inactivation in human placental cotyledons.
Main Results:
- In rats, low birth weight correlated positively with placental 11 beta-HSD levels, while placental weight correlated negatively.
- Administration of dexamethasone or carbenoxolone to pregnant rats resulted in decreased pup birth weight and adult hypertension.
- Low protein diet in pregnant rats led to low birth weight, increased placental weight, decreased placental 11 beta-HSD activity, and adult hypertension.
- Human studies showed a correlation between birth weight and placental 11 beta-HSD activity or cortisol inactivation capacity.
Conclusions:
- Reduced placental 11 beta-HSD2 activity increases fetal exposure to maternal glucocorticoids, contributing to low birth weight.
- This increased fetal glucocorticoid exposure is a potential mechanism linking adverse in utero conditions to adult hypertension.
- The findings underscore the importance of placental glucocorticoid metabolism in programming long-term health outcomes.