Regulation of Estradiol and Progesterone Production by CRH-R1 and -R2 Is through Divergent Signaling Pathways in Cultured Human Placental Trophoblasts

Abstract

CRH and its related peptides urocortins (UCN) have been identified in placenta and implicated to play pivotal roles in the regulation of pregnancy and parturition in humans. The objectives of present study were to investigate the effects of endogenous CRH and its related peptides in the regulation of steroid production in placenta. Placental trophoblasts were isolated from term placenta tissues and cultured for 72 h. Estradiol (E(2)) and progesterone (P(4)) contents in culture media were determined by radioimmunoassay. Treatment of cultured trophoblasts with CRH or UCNI antibody showed decreased E(2), whereas increased P(4) production. Treatment of cells with CRH receptor type 1 antagonist antalarmin or CRH receptor type 2 (CRH-R2) antagonist astressin-2b also decreased E(2) but increased P(4) production. Knockdown of CRH receptor type 1 or CRH-R2 cells showed a decrease in E(2) production and an increase in P(4) production. In CRH-R2 knockdown cells, CRH stimulated GTP-bound Gαs protein and phosphorylated phospholipase C-β3. Adenylyl cyclase and protein kinase A inhibitors blocked CRH-induced increased E(2) production but not decreased P(4) production. PLC inhibitor U73122 and protein kinase C inhibitor chelerythrine blocked the effects of CRH on E(2) and P(4) production in CRH-R2 knockdown cells. UCNIII, the specific CRH-R2 agonist, stimulated GTP-bound Gαi protein and phosphorylated phospholipase C-β3 expression. Both U73122 and chelerythrine blocked UCNIII-induced increased E(2) production and decreased P(4) production. We suggest that CRH and its related peptides might be involved in changes in the progesterone to estrogen ratio during human pregnancy.

The endocrine function of human placenta: an overview

“…In fact, aromatase is enhanced by cAMP (Lobo and Bellino, 1989), cortisol, HCG (Wang et al, 2014c), oestradiol (Kumar et al, 2009), p38 phosphorylation and ERK 1/2 inhibition (Costa et al, 2015). Moreover, oestradiol synthesis is stimulated by calcitriol (Barrera et al, 2007), CRH (Gao et al, 2012) and diminished by insulin (Hochberg et al, 1983) and leptin (Coya et al, 2006).…”

“…On the other hand, p38 and ERK 1/2 phosphorylation increase 3β-HSD transcripts (Costa et al, 2015). Other modulators of progesterone synthesis have been described: oestradiol (Shanker and Rao, 1997), insulin and insulin-like growth factor 1 (IGF-1) (Nestler, 1989), calcitriol (Barrera et al, 2007) stimulate the synthesis of this steroid, whereas leptin (Cameo et al, 2003) and corticotrophin-releasing hormone (CRH) (Gao et al, 2012;Yang et al, 2006) inhibit progesterone production by the syncytiotrophoblast.…”

Effects of corticotrophin releasing hormone (CRH) on cell viability and differentiation in the human BeWo choriocarcinoma cell line: a potential syncytialisation inducer distinct from cyclic adenosine monophosphate (cAMP)

“…Moreover, other results from our laboratory have shown that CRH promoter activity is increased by 8-Br-cAMP in human placental cells [15], while others have shown that CRH can act via CRH-receptors to stimulate GNAS and increase cAMP production [16,17]. Therefore, in this paper we investigated potential roles of CRH on the viability and differentiation of human trophoblast BeWo cells.…”

Prenatal two-hit stress affects maternal and offspring pregnancy outcomes and uterine gene expression in rats: match or mismatch?†

“…CRH and IL-1β, produced by reproductive tissues and inflammatory cells alike, fulfill key roles in those interactions on both levels, and interrelate with prostaglandins and steroid hormones [83,84]. The stimulatory effects of IL-1 and CRH on cytokine and chemokine production [17,19,85] and the effects of CRH during pregnancy on myometrium [17,86,87], placenta [88,89] and fetal membranes [90], are widely recognized. CRH and its analogs as well as their receptors play important roles in the relative quiescence of the uterus during pregnancy as well as myometrial contractility and interact with cytokines for both processes [17,52,86].…”