Corticotropin-Releasing Hormone (CRH) Inhibits Steroid Biosynthesis by Cultured Human Granulosa-Lutein Cells in a CRH and Interleukin-1 Receptor-Mediated Fashion*

The presence of immunoreactive CRH was recently demonstrated in human ovaries. CRH immunoreactivity was localized by immunohistochemistry in the cytoplasm of thecal cells surrounding the ovarian follicles, in luteinized cells of the stroma, and in large granulosa-derived luteinized cells of developing corpora lutea. Also, CRH and its receptors were identified in Leydig cells of the testis where CRH was shown to inhibit testosterone biosynthesis. To examine the role of CRH in the ovary, we studied its effect on estradiol (E2) and progesterone (P4) release by human granulosa cells obtained from women undergoing in vitro fertilization for male factor infertility or uni- or bilateral tubal impatency. In all subjects, superovulation was induced by treatment with gonadotropins. The effects of graded doses of ovine CRH (10−11–10−6 mol/liter) were evaluated in the conditioned medium obtained after 24 h incubation of the cells. All CRH concentrations employed except for the lowest one (10−11 mol/liter) caused a significant decrease of media E2 and P4 levels. Maximal inhibition for both E2 and P4 production was obtained by 10−6 mol/liter CRH concentration, which decreased hormone production by 39% and 34%, respectively. The α-helical CRH9–41 antagonist at 10−6 and 10−7 mol/liter blocked the suppressive effect of 10−9 mol/liter CRH on both E2 and P4 secretion, while it had no effect when added to the culture media without CRH. Since interleukin (IL-1)-1 mediates certain actions of CRH on leukocytes, we examined whether the CRH effect on ovarian steroidogenesis was IL-1-mediated. Interleukin-1 receptor antagonist at 10−7 and 10−6 mol/liter blocked the inhibitory effects of CRH on E2 and P4 secretion, while it had no effect in the absence of CRH. In conclusion, CRH exerts a CRH- and IL-1 receptor-mediated inhibitory effect on ovarian steroidogenesis and might be actively involved in the still enigmatic processes of follicular atresia and luteolysis.