Fliers Eric, Alkemade Anneke, Wiersinga Wilmar M, Swaab Dick F
Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Prog Brain Res. 2006;153:189-207. doi: 10.1016/S0079-6123(06)53011-0.
The role of the human hypothalamus in the neuroendocrine response to illness has only recently begun to be explored. Extensive changes in the hypothalamus-pituitary-thyroid (HPT) axis occur within the framework of critical illness. The best-documented change in the HPT axis is a decrease in serum concentrations of the biologically active thyroid hormone triiodothyronine (T3). From studies in post-mortem human hypothalamus it appeared that low serum T3 and thyrotropin (TSH) during illness (nonthyroidal illness, NTI) are paralleled by decreased thyrotropin-releasing hormone (TRH)mRNA expression in the hypothalamic paraventricular nucleus (PVN), pointing to a major alteration in HPT axis setpoint regulation. A strong decrease in TRHmRNA expression is also present in the PVN of patients with major depression as well as in glucocorticoid-treated patients. By inference, hypercortisolism in hospitalized patients with severe depression or in critical illness may induce down-regulation of the HPT axis at the level of the hypothalamus. In order to start defining the determinants and mechanisms of these setpoint changes in various clinical conditions, it is important to note that an increasing number of hypothalamic proteins appears to be involved in central thyroid hormone metabolism. In recent studies, we have investigated the distribution and expression of thyroid hormone receptor (TR) isoforms, type 2 and type 3 deiodinase (D2 and D3), and the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) in the human hypothalamus by a combination of immunocytochemistry, mRNA in situ hybridization and enzyme activity assays. Both D2 and D3 enzyme activities are detectable in the mediobasal hypothalamus. D2 immunoreactivity is prominent in glial cells of the infundibular nucleus/median eminence region and in tanycytes lining the third ventricle. Combined D2, D3, MCT8 or TR immunocytochemistry and TRHmRNA in situ hybridization indicates that D3, MCT8 and TRs are all expressed by TRH neurons in the PVN, whereas D2 is not. Taken together, these results suggest that the prohormone thyroxine (T4) is taken up in glial cells that convert T4 into the biologically active T3 via the enzyme D2; T3 is subsequently transported to TRH producing neurons in the PVN where it may bind to TRs and/or may be degraded into inactive iodothyronines by D3. This model for thyroid hormone action in the human hypothalamus awaits confirmation in future experimental studies.
人类下丘脑在对疾病的神经内分泌反应中的作用直到最近才开始被探索。下丘脑 - 垂体 - 甲状腺（HPT）轴在危重病的框架内会发生广泛变化。HPT轴中记录最充分的变化是生物活性甲状腺激素三碘甲状腺原氨酸（T3）的血清浓度降低。从对人类下丘脑的尸检研究来看，疾病期间（非甲状腺疾病，NTI）血清T3和促甲状腺激素（TSH）降低的同时，下丘脑室旁核（PVN）中促甲状腺激素释放激素（TRH）mRNA表达也降低，这表明HPT轴设定点调节发生了重大改变。在重度抑郁症患者以及接受糖皮质激素治疗的患者的PVN中，TRHmRNA表达也大幅降低。由此推断，患有严重抑郁症的住院患者或危重病患者的高皮质醇血症可能会在下丘脑水平诱导HPT轴的下调。为了开始确定各种临床情况下这些设定点变化的决定因素和机制，需要注意的是，越来越多的下丘脑蛋白质似乎参与中枢甲状腺激素代谢。在最近的研究中，我们通过免疫细胞化学、mRNA原位杂交和酶活性测定相结合的方法，研究了甲状腺激素受体（TR）亚型、2型和3型脱碘酶（D2和D3）以及甲状腺激素转运体单羧酸转运体8（MCT8）在人类下丘脑中的分布和表达。在中基底下丘脑可检测到D2和D3酶活性。D2免疫反应性在漏斗核/正中隆起区域的神经胶质细胞以及第三脑室衬里的伸长细胞中很突出。联合D2、D3、MCT8或TR免疫细胞化学和TRHmRNA原位杂交表明，D3、MCT8和TRs均由PVN中的TRH神经元表达，而D2则不然。综上所述，这些结果表明，甲状腺激素原甲状腺素（T4）被神经胶质细胞摄取，这些细胞通过D2酶将T4转化为生物活性T3；随后T3被转运到PVN中产生TRH的神经元，在那里它可能与TRs结合和/或可能被D3降解为无活性的碘甲状腺原氨酸。人类下丘脑中甲状腺激素作用的这个模型有待未来实验研究的证实。
