Debus Nathalie, Breen Kellie M, Barrell Graham K, Billings Heather J, Brown Martha, Young Elizabeth A, Karsch Fred J
Reproductive Sciences Program, University of Michigan, Ann Arbor 48109-0404, USA.
Endocrinology. 2002 Oct;143(10):3748-58. doi: 10.1210/en.2002-220291.
Bacterial endotoxin (lipopolysaccharide), a commonly used model of immune/inflammatory stress, inhibits reproductive neuroendocrine activity and concurrently induces a profound stimulation of the hypothalamo-pituitary-adrenal axis. We employed two approaches to test the hypothesis that enhanced secretion of cortisol mediates endotoxin-induced suppression of pulsatile GnRH and LH secretion in the ovariectomized ewe. First, we mimicked the endotoxin-induced increase in circulating cortisol by delivering the glucocorticoid in the absence of the endotoxin challenge. Within 1-2 h, experimentally produced increments in circulating cortisol suppressed pulsatile LH secretion in a dose-dependent fashion. Second, we blocked the endotoxin-induced stimulation of cortisol secretion using the drug metyrapone, which inhibits the 11-beta hydroxylase enzyme necessary for cortisol biosynthesis. In the absence of a marked stimulation of cortisol secretion, endotoxin still profoundly inhibited pulsatile GnRH and LH secretion. We conclude that, although enhanced cortisol secretion may contribute to endotoxin-induced suppression of reproductive neuroendocrine activity, the marked stimulation of the glucocorticoid is not necessary for this response. Our findings are consistent with the hypothesis that immune/inflammatory stress inhibits reproductive neuroendocrine activity via more than one inhibitory pathway, one involving enhanced secretion of cortisol and the other(s) being independent of this glucocorticoid.
细菌内毒素（脂多糖）是一种常用的免疫/炎症应激模型，它会抑制生殖神经内分泌活动，同时引发下丘脑-垂体-肾上腺轴的强烈刺激。我们采用了两种方法来检验以下假设：在去卵巢母羊中，皮质醇分泌增加介导了内毒素诱导的促性腺激素释放激素（GnRH）和促黄体生成素（LH）脉冲式分泌的抑制。首先，在没有内毒素刺激的情况下给予糖皮质激素，模拟内毒素诱导的循环皮质醇增加。在1-2小时内，实验性产生的循环皮质醇增加以剂量依赖的方式抑制了LH脉冲式分泌。其次，我们使用甲吡酮药物阻断内毒素诱导的皮质醇分泌刺激，该药物抑制皮质醇生物合成所需的11-β羟化酶。在没有明显的皮质醇分泌刺激的情况下，内毒素仍然深刻抑制了GnRH和LH的脉冲式分泌。我们得出结论，虽然皮质醇分泌增加可能有助于内毒素诱导的生殖神经内分泌活动抑制，但这种糖皮质激素的显著刺激对于这种反应并非必要。我们的发现与以下假设一致：免疫/炎症应激通过多种抑制途径抑制生殖神经内分泌活动，一种途径涉及皮质醇分泌增加，另一种途径则独立于这种糖皮质激素。
