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

Metabolic inactivation of progesterone within uterine myocytes by 20α-hydroxysteroid dehydrogenase (20α-HSD) has been postulated as a mechanism contributing to functional progesterone withdrawal at term. In humans, 20α-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 associated with clinical chorioamnionitis. This suggests that increased 20α-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 F2α, 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 deacetylase inhibitors: trichostatin A at 5 (p = 0.0172) and 25 µM (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 µM (p = 0.0014); and suberoyl bis-hydroxamic acid at 5 (p = 0.0480) and 25 µM (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.

20α-Hydroxysteroid Dehydrogenase Expression in the Human Myometrium at Term and Preterm Birth: Relationships to Fetal Sex and Maternal Body Mass Index.

The mechanism by which human labor is initiated in the presence of elevated circulating progesterone levels remains unknown. Recent evidence indicates that the progesterone-metabolizing enzyme, 20α-hydroxysteroid dehydrogenase (20α-HSD), encoded by the gene AKR1C1, may contribute to functional progesterone withdrawal. We found that AKR1C1 expression significantly increased with labor onset in term myometrium, but not in preterm myometrium. Among preterm laboring deliveries, clinically diagnosed chorioamnionitis was associated with significantly elevated AKR1C1 expression. AKR1C1 expression positively correlated with BMI before labor and negatively correlated with BMI during labor. Analysis by fetal sex showed that AKR1C1 expression was significantly higher in women who delivered male babies compared to women who delivered female babies at term, but not preterm. Further, in pregnancies where the fetus was female, AKR1C1 expression positively correlated with the mother's age and BMI at the time of delivery. In conclusion, the increase in myometrial AKR1C1 expression with term labor is consistent with 20α-HSD playing a role in local progesterone metabolism to promote birth. Interestingly, this role appears to be specific to term pregnancies where the fetus is male. Upregulated AKR1C1 expression in the myometrium at preterm in-labor with clinical chorioamnionitis suggests that increased 20α-HSD activity is a mechanism through which inflammation drives progesterone withdrawal in preterm labor. The link between AKR1C1 expression and maternal BMI may provide insight into why maternal obesity is often associated with dysfunctional labor. Higher myometrial AKR1C1 expression in male pregnancies may indicate fetal sex-related differences in the mechanisms that precipitate labor onset at term.

Histone Deacetylase Inhibitors: Providing New Insights and Therapeutic Avenues for Unlocking Human Birth.

The pregnant uterus remains relaxed throughout fetal gestation before transforming to a contractile phenotype at term to facilitate birth. Despite ongoing progress, the precise mechanisms that regulate this phenotypic transformation are not yet understood. This knowledge gap limits our understanding of how dysregulation of uterine smooth muscle biology contributes to life-threatening obstetric complications, including preterm birth, and hampers our ability to develop effective therapeutic intervention strategies. Protein acetylation plays a vital role in regulating protein structure, function, and subcellular localization, as well as gene transcription availability through regulating chromatin condensation. Histone deacetylase inhibitors (HDACis) are a class of compounds that block the removal of acetyl functional groups from proteins and, as such, have profound effects on important cellular events, including phenotypic transformation. A large body of data now demonstrates that HDACis have profound effects on pregnant human myometrium. Studies to date show that HDACis operate through both genomic and non-genomic mechanisms to affect myometrial function and phenotype. Interestingly, the effects of HDACis on pregnant myometrium are largely "pro-relaxation," including the direct inhibition of contractile machinery as well as repression of pro-labor genes. The "dual action" effects of HDACis make them a powerful tool for unlocking the regulatory processes that underpin myometrial phenotypic transformation and raises prospects of their therapeutic applications. Here, we review the new insights into human myometrial biology that have garnered through the application of HDACis and explore their potential therapeutic application toward the development of novel preterm birth prevention strategies.