Institute for Biological Research "Sinisa Stankovic"- National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia.
Section on Cellular Signaling, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
Brain Behav Immun. 2020 Oct;89:233-244. doi: 10.1016/j.bbi.2020.06.025. Epub 2020 Jun 24.
Multiple sclerosis develops during reproductive years in a sex-specific manner. Various neuroendocrine changes have been described in this inflammatory, demyelinating, and debilitating disease. We here aimed to determine the extent and sex specificity of alterations in the hypothalamic-pituitary-gonadal axis in the rat model of multiple sclerosis named experimental autoimmune encephalomyelitis. During the disease course, the hypothalamic tissue showed transient upregulation of inflammatory marker genes Gfap, Cd68, Ccl2, and Il1b in both sexes, but accompanied by sex-specific downregulation of Kiss1 (in females only) and Gnrh1 (in males only) expression. In females, the expression of gonadotrope-specific genes Lhb, Cga, and Gnrhr was also inhibited, accompanied by decreased basal but not stimulated serum luteinizing hormone levels and a transient arrest of the estrous cycle. In contrast, Fshb expression and serum progesterone levels were transiently elevated, findings consistent with the maintenance of the corpora lutea, and elevated immunohistochemical labeling of ovarian StAR, a rate limiting protein in steroidogenic pathway. In males, downregulation of Gnrhr expression and basal and stimulated serum luteinizing hormone and testosterone levels were accompanied by inhibited testicular StAR protein expression. We propose that inflammation of hypothalamic tissue downregulates Kiss1 and Gnrh1 expression in females and males, respectively, leading to sex-specific changes downstream the axis.
多发性硬化症在生殖期以性别特异性的方式发展。在这种炎症性、脱髓鞘性和使人虚弱的疾病中，已经描述了各种神经内分泌变化。我们旨在确定多发性硬化症的大鼠模型——实验性自身免疫性脑脊髓炎中，下丘脑-垂体-性腺轴改变的程度和性别特异性。在疾病过程中，下丘脑组织在两性中均表现出短暂的炎症标志物基因 Gfap、Cd68、Ccl2 和 Il1b 的上调，但伴随着 Kiss1（仅在雌性中）和 Gnrh1（仅在雄性中）表达的性别特异性下调。在雌性中，促性腺激素细胞特异性基因 Lhb、Cga 和 Gnrhr 的表达也受到抑制，伴随着基础但非刺激的血清黄体生成素水平降低和发情周期的短暂停滞。相比之下，Fshb 表达和血清孕激素水平短暂升高，这与黄体的维持一致，以及卵巢 StAR 的免疫组织化学标记物升高，StAR 是类固醇生成途径中的限速蛋白。在雄性中，Gnrhr 表达和基础及刺激的血清黄体生成素和睾酮水平下调伴随着睾丸 StAR 蛋白表达抑制。我们提出，下丘脑组织的炎症分别下调雌性和雄性中的 Kiss1 和 Gnrh1 表达，导致轴下游的性别特异性变化。
