Maintaining placental endocrine homeostasis is crucial for a successful pregnancy. Pre-eclampsia (PE), a gestational complication, is a leading cause of maternal and perinatal morbidity and mortality. Aberrant elevation of testosterone (T₀) synthesis, reduced estradiol (E₂), and melatonin productions have been identified in preeclamptic placentas. However, the precise contribution of disrupted homeostasis among these hormones to the occurrence of PE remains unknown. In this study, we established a strong correlation between suppressed melatonin production and decreased E₂ as well as elevated T₀ synthesis in PE placentas. Administration of the T₀ analog testosterone propionate (TP; 2 mg/kg/day) to pregnant mice from E7.5 onwards resulted in PE-like symptoms, along with elevated T₀ production and reduced E₂ and melatonin production. Notably, supplementation with melatonin (10 mg/kg/day) in TP-treated mice had detrimental effects on fetal and placental development and compromised hormone synthesis. Importantly, E₂, but not T₀, actively enhanced melatonin synthetase AANAT expression and melatonin production in primary human trophoblast (PHT) cells through GPER1-PKA-CREB signaling pathway. On the other hand, melatonin suppressed the level of estrogen synthetase aromatase while promoting the expressions of androgen synthetic enzymes including 17β-HSD3 and 3β-HSD1 in PHT cells. These findings reveal an orchestrated feedback mechanism that maintains homeostasis of placental sex hormones and melatonin. It is implied that abnormal elevation of T₀ synthesis likely serves as the primary cause of placental endocrine disturbances associated with PE. The suppression of melatonin may represent an adaptive strategy to correct the imbalance in sex hormone levels within preeclamptic placentas. The findings of this study offer novel evidence that identifies potential targets for the development of innovative therapeutic strategies for PE.

中文翻译：

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褪黑激素和性激素之间精心策划的反馈调节涉及胎盘中的 GPER1-PKA-CREB ​​信号传导

维持胎盘内分泌稳态对于成功妊娠至关重要。先兆子痫（PE）是一种妊娠并发症，是孕产妇和围产期发病和死亡的主要原因。在先兆子痫胎盘中已发现睾酮 (T ₀ ) 合成异常升高、雌二醇 (E _{2 ) 和褪黑激素生成减少。}然而，这些激素之间的稳态破坏对 PE 发生的确切影响仍不清楚。在这项研究中，我们建立了PE 胎盘中褪黑激素产生抑制与 E ₂减少以及 T _{0合成增加之间的密切相关性。}从E7.5开始对怀孕小鼠施用T ₀类似物丙酸睾酮（TP；2 mg/kg/天）会导致类似PE的症状，同时T 0 产量增加，E 2 和褪黑_激素产量减少。值得注意的是，TP 治疗小鼠补充褪黑激素（10 毫克/公斤/天）会对胎儿和胎盘发育产生不利影响，并会损害激素合成。重要的是，E ₂（而非 T ₀）通过 GPER1-PKA-CREB ​​信号通路主动增强原代人滋养层（PHT）细胞中褪黑激素合成酶 AANAT 的表达和褪黑激素的产生。另一方面，褪黑素抑制PHT细胞中雌激素合成酶芳香酶的水平，同时促进雄激素合成酶包括17β-HSD3和3β-HSD1的表达。这些发现揭示了一种精心策划的反馈机制，可以维持胎盘性激素和褪黑激素的稳态。这表明 T ₀合成异常升高可能是与 PE 相关的胎盘内分泌紊乱的主要原因。褪黑激素的抑制可能代表了纠正先兆子痫胎盘内性激素水平不平衡的适应性策略。这项研究的结果提供了新的证据，确定了开发肺栓塞创新治疗策略的潜在目标。