Progesterone Inhibits 20α-Hydroxysteroid Dehydrogenase Expression in the Rat Corpus Luteum through the Glucocorticoid Receptor

Abstract

In this study, we investigated whether progesterone exerts an intraluteal action despite the lack of progesterone receptors (PR) in the rat corpus luteum and whether progesterone acts through the glucocorticoid receptor (GR) to enhance its own levels by down-regulating the expression of 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD). We first established that the corpus luteum constitutively expresses the GR throughout pregnancy and after parturition. We also generated a temperature sensitive SV-40 transformed luteal cell line (GG-CL) that expresses the GR and 20alpha-HSD but lacks the PR. Treatment with different doses of either progesterone or dexamethasone caused a dose-related decrease in 20alpha-HSD mRNA in both cultured corpora lutea and in the luteal cell line. RU486, a PR/GR antagonist, completely blocked both the progesterone and the dexamethasone mediated inhibition of 20alpha-HSD expression in GG-CL cells. In summary, this report provides the first evidence that despite the absence of the PR in the rat corpus luteum, progesterone can act through the GR to down-regulate the expression of 20alpha-HSD, an enzyme that catabolizes progesterone and reduces progesterone secretion by the corpus luteum.

Differential Modulation of TLR3- and TLR4-Mediated Dendritic Cell Maturation and Function by Progesterone

“…Whereas progesterone mediated a reduction in TLR4-and TLR3-induced IL-6 production exclusively through the GR, inhibition of IL-12 production was mediated through the GR and PR. Although it has been shown that glucocorticoids and progesterone can induce upregulation of the anti-inflammatory cytokine IL-10 in human DCs (46), our studies (results not shown) as well as one using rat-derived DCs treated with progesterone did not show an upregulation of IL-10 (47). The timing of LPS treatment relative to the seeding of DC cultures in preparation of stimulation experiments is critical in defining secretion patterns of IL-12 and IL-10 that likely explain the differences between such studies (48).…”

“…Progesterone functions by binding to both the GR and PR (44)(45)(46). Using the receptor-specific agonists dexamethasone and norgestrel, we demonstrate in this study the ability of progesterone to differentially use these receptors to cause downregulation of IL-6 and IL-12 production.…”

Regulation and role of the insulin-like growth factor I system in rat luteal cells

“…Ghahary, 1990;Adesanya et ah, 1996;Clarke et ah, 1997), but downregulates expression of both mRNAs in the rat corpus luteum (Parmer et ah, 1991). A luteal cell line (GG-CL) derived from the large luteal cells of the pregnant rat corpus luteum (Sugino et ah, 1998) (Sugino et al, 1997 and thus the possibility that oestradiol action is mediated by progesterone is eliminated. Another advantage of these cells is that they are responsive to progesterone (Sugino et ah, 1997 (Clayton et al, 1997).…”

Progesterone metabolites in breast cancer

“…The level of expression of 5a-reductase is upregulated by estradiol and P in the uterus (Minjarez et al 2001) and by 5a-dihydrotestosterone (DHT) in the prostate (Andersson et al 1989, Ji et al 2003. And the expression of 20a-HSO may be altered by P in corpora lutea (Sugino et al 1997) and in endometrial cells (Nakajima et al 2003). These examples suggest that the changes in P-metabolizing enzyme activity/ expression that lead to higher ratios of 5a-pregnane:4-pregnene may be induced by an altered milieu within the breast.…”