203. Partial progesterone withdrawal during late gestation increases placental expression of 11β-HSD1 in the rat

Abstract

Fetal glucocorticoid excess programs adverse outcomes in adult offspring, including hypertension, obesity and insulin resistance. Access of maternal glucocorticoids to the fetus is regulated by the placental glucocorticoid barrier which consists of the 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) enzyme and P-glycoprotein (Abcb1). Both proteins act to reduce fetal and placental exposure to active, circulating glucocorticoids. In addition, placental expression of 11β-HSD1 is thought to limit the effectiveness of the barrier by local reactivation of inert glucocorticoids. The present study measured expression of placental 11β-HSD1 and 11β-HSD2 in normal rat pregnancy and after either partial progesterone withdrawal or treatment with dexamethasone, both of which reduce fetal growth. Placentas were collected and dissected into their morphologically- and functionally-distinct zones (junctional and labyrinth) on days 16 and 22 of normal pregnancy (term = 23 days) and after either dexamethasone treatment (0.75 μg/mL in drinking water from day 13) or ovariectomy (day 16) plus full oestrogen and partial progesterone replacement (to approximately one-third of day 22 levels). Junctional and labyrinth zone expression of 11β-HSD1 and 11β-HSD2 mRNA were determined by qRT–PCR. Labyrinthine expression of 11β-HSD1 increased markedly between days 16 and 22 and there was a concomitant decrease in labyrinthine 11β-HSD2 expression. Dexamethasone administration had no effect on the expression of either 11β-HSD isoform in either placental zone. Partial progesterone withdrawal increased 11β-HSD1 expression in both placental zones (1.9 and 3.1-fold in LZ and JZ respectively, P < 0.05), but had no effect on 11β-HSD2 levels. In conclusion, these data confirm the pattern of placental 11β-HSD isoform expression in late rat pregnancy and suggest that that labyrinth zone 11β-HSD1 is normally suppressed by progesterone. Thus, the normal pre-partum decline in circulating progesterone may provide a key stimulus for the marked rise in labyrinth zone 11β-HSD1 that occurs between days 16 and 22 of pregnancy.