Urocortin 2 stimulates estradiol secretion from cultured human placental cells: An effect mediated by the type 2 Corticotrophin-releasing Hormone (CRH) receptor

Estrogens produced by the placenta are pivotal in human pregnancy and parturition. Several hormones are involved in regulating estrogen production. Recently, the corticotrophin releasing hormone family of peptides has expanded and among the new members, urocortin 2 is expressed from human placenta. The aim of the current study was to determine urocortin 2 effects on estradiol secretion and cytochrome P450 aromatase mRNA levels and protein expression from cultured human trophoblast cells. Trophoblast cell cultures were treated with urocortin 2 and for comparison, corticotrophin releasing hormone, or urocortin 1 in the presence of estrogen precursors dehydroepiandrosterone-sulfate, androstenedione, and testosterone. Estradiol output was measured using enzyme-linked immunosorbent assay. Cytochrome P450 aromatase mRNA levels and protein expression were evaluated using reverse transcriptase-polymerase chain reaction and Western blot. Trophoblast cell cultures treated with increasing amounts of corticotrophin releasing hormone and urocortin 1 showed increased secretion of E2 in the presence of androstenedione. In the presence of urocortin 2, E2 output in cultures treated with dehydroepiandrosterone, androstenedione, and testosterone was consistently raised in a time and dose-dependent manner to maximum values at 24 hours. P450 aromatase mRNA levels and protein expression were upregulated by urocortin 2 in the presence of C19 precursors. The addition of antisauvagine-30, a corticotrophin releasing hormone-receptor-2 antagonist, significantly reversed urocortin 2 effects on E2 secretion and P450 aromatase expression. Our results suggest that urocortin 2 may play a role in the regulation of E2 production throughout pregnancy, thereby contributing to the placental regulation of key reproductive events in pregnancy maintenance and parturition.