Hübner Stephanie, Sunny Donna E, Pöhlke Christine, Ruhnau Johanna, Vogelgesang Antje, Reich Bettina, Heckmann Matthias
Department of Neonatology and Pediatric Intensive Care, University Medicine Greifswald, 17457 Greifswald, Germany.
Section of Neuroimmunology, Department of Neurology, University Medicine Greifswald, 17457 Greifswald, Germany.
Endocrinology. 2017 May 1;158(5):1419-1435. doi: 10.1210/en.2016-1763.
Impaired neurodevelopment in preterm infants is caused by prematurity itself; however, hypoxia/ischemia, inflammation, and hyperoxia contribute to the extent of impairment. Because preterm birth is accompanied by a dramatic decrease in 17β-estradiol (E2) and progesterone, preliminary clinical studies have been carried out to substitute these steroids in preterm infants; however, they failed to confirm significantly improved neurologic outcomes. We therefore hypothesized that the persistently high postnatal production of fetal zone steroids [mainly dehydroepiandrosterone (DHEA)] until term could interfere with E2-mediated protection. We investigated whether E2 could reduce hyperoxia-mediated apoptosis in three immature glial cell types and detected the involved receptors. Thereafter, we investigated protection by the fetal zone steroids DHEA, 16α-hydroxy-DHEA, and androstenediol. For DHEA, the involved receptors were evaluated. We examined aromatases, which convert fetal zone steroids into more estrogenic compounds. Finally, cotreatment was compared against single hormone treatment to investigate synergism. In all cell types, E2 and fetal zone steroids resulted in significant dose-dependent protection, whereas the mediating receptors differed. The neuroprotection by fetal zone steroids highly depended on the cell type-specific expression of aromatases, the receptor repertoire, and the potency of the fetal zone steroids toward these receptors. No synergism in fetal zone steroid and E2 cotreatment was detected in two of three cell types. Therefore, E2 supplementation may not be beneficial with respect to neuroprotection because fetal zone steroids circulate in persistently high concentrations until term in preterm infants. Hence, a refined experimental model for preterm infants is required to investigate potential treatments.
早产儿神经发育受损是由早产本身引起的；然而，缺氧/缺血、炎症和高氧会加重损伤程度。由于早产伴随着17β-雌二醇（E2）和孕酮的显著下降，已开展初步临床研究在早产儿中补充这些类固醇；然而，这些研究未能证实神经学结局有显著改善。因此，我们推测直到足月时胎儿区类固醇[主要是脱氢表雄酮（DHEA）]持续高水平的产后分泌可能会干扰E2介导的保护作用。我们研究了E2是否能减少三种未成熟神经胶质细胞类型中高氧介导的细胞凋亡，并检测了相关受体。此后，我们研究了胎儿区类固醇DHEA、16α-羟基-DHEA和雄烯二醇的保护作用。对于DHEA，评估了相关受体。我们检测了将胎儿区类固醇转化为更具雌激素活性化合物的芳香化酶。最后，比较联合治疗与单一激素治疗以研究协同作用。在所有细胞类型中，E2和胎儿区类固醇均产生了显著的剂量依赖性保护作用，而介导受体有所不同。胎儿区类固醇的神经保护作用高度依赖于芳香化酶的细胞类型特异性表达、受体库以及胎儿区类固醇对这些受体的亲和力。在三种细胞类型中的两种中未检测到胎儿区类固醇与E2联合治疗的协同作用。因此，补充E2在神经保护方面可能并无益处，因为早产儿中胎儿区类固醇在足月前持续处于高浓度循环状态。因此，需要一种针对早产儿的精细实验模型来研究潜在的治疗方法。
