Regulation of 20a-Hydroxysteroid Dehydrogenase Expression in Term Pregnant Human Myometrium Ex Vivo

Metabolic inactivation of progesterone within uterine myocytes by 20a-hydroxysteroid dehydrogenase (20a-HSD) has been pos-tulated as a mechanism contributing to functional progesterone withdrawal at term. In humans, 20a-HSD is encoded by the gene AKR1C1. Myometrial AKR1C1 mRNA abundance has been reported to increase significantly during labor at term. In spontaneous preterm labor, however, we previously found no increase in AKR1C1 mRNA level in the myometrium except for preterm labor asso-ciated with clinical chorioamnionitis. This suggests that increased 20a-HSD activity is a mechanism through which inflammation drives progesterone withdrawal in preterm labor. In this study, we have determined the effects of various treatments of therapeutic relevance on AKR1C1 expression in pregnant human myometrium in an ex vivo culture system. AKR1C1 expression increased spontaneously during 48 h culture (p < 0.0001), consistent with the myometrium transitioning to a labor-like phenotype ex vivo, as reported previously. Serum supplementation, prostaglandin F2a, phorbol myristate acetate, and mechanical stretch had no effect on the culture-induced increase, whereas progesterone (p = 0.0058) and cAMP (p = 0.0202) further upregulated AKR1C1 expression. In contrast, culture-induced upregulation of AKR1C1 expression was dose-dependently repressed by three histone/protein dea-cetylase inhibitors: trichostatin A at 5 (p = 0.0172) and 25 i.tM (p = 0.0115); suberoylanilide hydroxamic acid at 0.5 (p = 0.0070), 1 (p = 0.0045), 2.5 (p = 0.0181), 5 (p = 0.0066) and 25 i.tM (p = 0.0014); and suberoyl bis-hydroxamic acid at 5 (p = 0.0480) and 25 i.tM (p = 0.0238). We propose the inhibition of histone/protein deacetylation helps to maintain the anti-inflammatory, pro-quiescence signaling of progesterone in pregnant human myometrium by blocking its metabolic inactivation. Histone deacetylase inhibitors may represent a class of agents that preserve or restore the progesterone sensitivity of the pregnant uterus.

Automated summary

In this study, the effects of various treatments on AKR1C1 expression in pregnant human myometrium were determined. It was found that culture-induced upregulation of AKR1C1 expression was repressed by histone/protein deacetylase inhibitors, suggesting the importance of histone deacetylase in maintaining progesterone sensitivity in the uterus.