Corticotropin-releasing hormone inhibits progesterone production in cultured human placental trophoblasts

Abstract

Placental-derived corticotropin-releasing hormone (CRH) seems to play a major role in the mechanisms controlling human pregnancy and parturition. It has been suggested that CRH directly modulates the endocrine function of placental trophoblasts, including the production of estrogen, ACTH, and prostaglandin. In this study, we sought to investigate the effect of CRH, locally produced by placenta, on progesterone production. Percoll-purified placental trophoblasts were obtained from uncomplicated term pregnancies and cultured for 72 h. Progesterone concentration in culture media was measured by RIA. The mRNA transcripts encoding CYP11A1 and HSD3B1, the enzymes for progesterone synthesis, were determined by quantitative real-time reverse transcription (RT)-PCR. Results showed that CRH (10K6 mol/l) caused a significant decrease in progesterone levels in a dose-dependent manner. The CRH antagonist, a-helical CRH 9-41, at 10K5 mol/l stimulated progesterone secretion. Consistent with this thesis, CRH decreased, whereas a-helical CRH increased, the mRNA levels of CYP11A1 and HSD3B1. Since CRH has been shown to activate the phospholipase C-protein kinase C (PKC) signal pathway in placenta, we examined whether the effect of CRH on progesterone synthesis was dependent on PKC signal pathway. Treatment of cells with PKC inhibitor, Gö 6976, resulted in a significant increase in progesterone production, and exogenous CRH restored progesterone production. In conclusion, placental CRH exhibits a tonic inhibitory effect on progesterone production in a PKC-dependent fashion.

Steroid metabolome in fetal and maternal body fluids in human late pregnancy

“…Placental CRH stimulates the production of estradiol in a time-and dosedependent manner and also the mRNA levels of the key enzymes for estrogen synthesis such as CYP19A1, type 1 17␤-HSD (HSD17B1) [116] as well as enzymes involved in progesterone synthesis like type 1 3␤-HSD (HSD3B1) and CYP11A1 [117].…”

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

“…Thus, we could not exclude the possibility that the change in P 4 is due to a change in estrogen production in cultured placental cells. Nota- bly, our previous studies have shown that CRH stimulates the expression of all the enzymes required for estrogen synthesis but inhibits all the enzymes required for progesterone synthesis (17,18). It is known that functions of CRH and its related peptides are mediated by two subtypes of CRH receptors, CRH-R1 and CRH-R2 (35).…”

“…Human placenta has been shown to express both subtypes of CRH receptors (30,31). Although our previous study had demonstrated CRH regulation of estrogen and progesterone production in placenta (17,18), the effects of other CRH-related peptides and the specific subtype(s) of CRH receptors responsible for the actions of placenta-derived CRH and CRH-related peptides remains unknown. Therefore, in the present study, we conducted a series of experiments to determine the effects of endogenous CRH and UCNI produced locally on the production of estrogen and progesterone in placenta, determine the roles of CRH-R1 and CRH-R2, and define signaling pathway(s) of CRH-R in the regulation of estrogen and progesterone production.…”

“…For instance, CRH modulates prostaglandin production by the fetal membranes and placenta (12), induces vasodilation of the fetoplacental circulation by activating nitric oxide synthase (13,14), and stimulates fetal adrenal DHEAS output directly (15) or indirectly via fetal pituitary ACTH (16). More recently we have demonstrated that placental CRH is able to regulate the expression of enzymes needed for estrogen and progesterone synthesis, thereby modulating estrogen and progesterone production by an autocrine/paracrine fashions (17,18).…”

Modulation of Free Corticotrophin-Releasing Hormone, Adrenal and Placental Steroid Hormone Levels Induced by Mifepristone during Pregnancy

“…These results are consistent with those of Karalis et al [5] who demonstrated in vitro that the administration of mifepristone to primary cultured trophoblastic cells triggered the production of CRH mRNA. Yang et al [10] showed on Percoll-purified placental trophoblasts that CRH has an inhibitory effect on progesterone production via a phospholipase C-protein kinase C signal pathway.…”