Endocrine Abstracts

Synthetic glucocorticoids are administered to pregnant women at risk of pre-term delivery to mature organs and improve neonatal survival. We have shown that glucocorticoid action is essential to mature the fetal heart. Here, we tested the hypotheses that antenatal glucocorticoid exposure, prior to the normal increase in glucocorticoid levels, will advance fetal heart maturation and this will depend on cardiovascular glucocorticoid receptor (GR).

Male SMGRKO mice, with Sm22α-Cre mediated deletion of GR in cardiomyocytes and vascular smooth muscle, were crossed with female control (Cre-) mice to generate SMGRKO and control fetuses within the same pregnancy. Dexamethasone (Dex, 100 μg/kg/d) or Vehicle (Veh) was administered in the drinking water of pregnant dams (n=6/group) from E12.5.

Liquid chromatography mass spectrometry showed that dexamethasone was measurable in livers of treated fetuses at E15.5, though levels were variable. Moreover, dexamethasone reduced fetal hepatic 11-dehydrocorticosterone levels (P=0.0006) with no corresponding increase in corticosterone, suggesting HPA axis suppression, though whether in fetus or dam is unclear.

In utero high frequency ultrasound performed at E15.5 showed that dexamethasone had no effect on most parameters related to cardiac function. However, 2-way ANOVA showed genotype and treatment differences in the mitral deceleration index (MDI), a marker of diastolic function. SMGRKO mice showed a lower MDI compared with control littermates (P=0.027). Dexamethasone also significantly lowered MDI (P=0.029), suggesting an improvement in fetal diastolic function in both control and SMGRKO mice.

Minimal differences in cardiac function were apparent at E15.5 in SMGRKO fetuses with cardiovascular GR deficiency. This differs from E17.5, when cardiac function is impaired in SMGRKO fetuses. Precocious glucocorticoid treatment modestly improved fetal diastolic cardiac function in E15.5 control and SMGRKO fetuses. The effects of precocious glucocorticoid administration upon cardiac function at a later time-point in development with the addition of a higher dosage will be examined in a future study.