Hormonal regulation of human trophoblast differentiation: a possible role for 17β-estradiol and GnRH

Abstract

We have examined the role of 17β-estradiol and gonadotropin releasing hormone (GnRH) in the regulation of functional differentiation in human trophoblasts. In contrast to its recognized functions as a proliferation-promoting hormone in a variety of cell types, we found that 17β-estradiol induced terminal differentiation in human trophoblastic cells, and that this event was estrogen-receptor-mediated. This process involved a loss in expression of Cyclins A2 and E, and a coincident increase in p27^Kip1. The anti-proliferative effects of 17β-estradiol were annulled by specific transforming growth factor-beta 1 (TGFβ1)-neutralizing antibody, suggesting that 17β-estradiol may mediate its growth-inhibitory actions, through TGFβ1 activity. Following exposure to Buserelin, cultured human trophoblastic cells stopped proliferating and formed functionally mature syncytiotrophoblasts. This differentiation event, that involved a drastic loss in expression of proliferating-cell-nuclear-antigen, could be blocked by Cetrorelix, suggesting the involvement of functional GnRH receptors. Preliminary studies on the characterization of the human placental GnRH receptor, indicate the presence of multiple receptor isoforms across human gestation.