甲状腺激素与妊娠

本文复习了妇女妊娠期甲状腺功能的变化，以及胎儿甲状腺功能的发育并介绍了对妊娠并发甲状腺功能亢进症或甲状腺功能减退症的处理原则。     

甲状腺激素与肥胖:孰因孰果?

肥胖是心血管疾病、代谢性疾病及肿瘤等多种疾病的重要风险因素。过去的几十年间,尽管学者在不断探索肥胖的发病机制和管理方案,但其患病率仍在飞速攀升,并逐渐成为一个全球性的公共健康问题。人体脂肪成分作为内分泌组织,不但受多种内分泌激素的调节,亦影响着激素内环境的稳态。研究发现,甲状腺激素作为主要的能量代谢调节激素,即使在正常范围内,仍与肥胖存在显著相关性。但两者之间的因果关系尚不明了,阐明两者关系有助于指导肥胖及其相关并发症的干预和管理。     

促甲状腺激素与肥胖

肥胖患者常出现甲状腺功能异常,这种异常在体重减轻后有所恢复,而甲状腺功能的异常又可引起脂肪堆积或体重增加.研究发现,人类脂肪细胞表达功能性的促甲状腺激素受体（TSHR）,促甲状腺激素（TSH）可能作用于表达TSHR的脂肪细胞,调节脂肪细胞的生长、增殖、分化及脂肪因子的分泌.目前,TSH与体重指数、腰臀比、腰围等的关系尚存争议,但较多研究肯定了TSH与大部分肥胖相关参数存在正相关.     

Thyroid hormones and thyroid hormone receptors: effects of thyromimetics on reverse cholesterol transport

Reverse cholesterol transport (RCT) is a complex process which transfers cholesterol from peripheral cells to the liver for subsequent elimination from the body via feces. Thyroid hormones (THs) affect growth, develop- ment, and metabolism in almost all tissues. THs exert their actions by binding to thyroid hormone receptors (TRs). There are two major subtypes of TRs, TRα and TRβ, and several isoforms (e.g. TRα1, TRα2, TRβ1, and TRβ2). Activation of TRα1 affects heart rate, whereas activation of TRβ1 has po...     

甲状腺激素转运体MCT8的病理生理作用

甲状腺激素(THs)进出细胞需要转运体蛋白的介导.单羧酸转运体(MCT)8是介导T3进入神经元的主要转运体蛋白,是迄今为止唯一具有明确的临床意义、在转运THs入脑中起着重要作用的转运体蛋白,其编码基因(SLC16A2)突变导致了艾伦-赫恩登-达得利综合征(AHDS),以严重的神经运动发育迟滞和高T3、低T4的血清学改变为临床特征.Mct8基因敲除的小鼠模型能够完全复制人MCT8基因突变的血清学改变,但神经症状轻微,部分解释了MCT8缺陷患者的临床表现,为THs转运体病理生理作用的研究提供依据.     

Thyroid hormone analogs for treatment of hypercholesterolemia and heart failure: past, present and future prospects

Thyroid hormone has the unique properties of lowering cholesterol in hypothyroid individuals and improving cardiac performance. Beginning in the 1950s, extensive efforts were made to develop thyroid hormone analogs that could utilize the cholesterol-lowering property in euthyroid individuals without affecting the heart. These efforts culminated in the development of analogs that selectively bind to beta1-type nuclear thyroid hormone receptors (TRs), which are responsible for cholesterol-lowering activity, without activating alpha1-type receptors in the heart. beta1-Selective compounds may be useful in lowering cholesterol in euthyroid individuals who are intolerant to treatment with 'statins'. Screening of compounds for those that might be suitable for improving cardiac performance in heart failure led to the identification of 3,5-diiodothyropropionic acid (DITPA). DITPA binds to both alpha- and beta-type TRs with relatively low affinity. In postinfarction models of heart failure and in a pilot clinical study, DITPA increased cardiac performance without affecting heart rate. This compound also lowers cholesterol and may be a useful adjunct to standard heart failure therapy. Although there is both experimental and clinical evidence indicating that thyroid analogs act differently than thyroid hormones, the details of their mechanism of action have not been completely elucidated. A number of potential mechanisms are reviewed, including serum protein binding, tissue disposition, receptor binding, and gene activation. Clinical trials for thyroid hormone analogs are in prospect.     

甲状腺疾病与妊娠

妊娠期甲状腺激素的产生、循环、代谢、调节以及甲状腺免疫均会随妊娠的不同阶段而改变。相关的改变包括:(1)雌激素刺激的血清甲状腺素结合球蛋白水平升高。(2)由于人绒毛膜促性腺激素与促甲状腺激素(TSH)的同源性导致的甲状腺激素产生增加。(3)碘在胎盘的降解加快和在肾脏的排除增加。母体甲状腺这些生理性的变化为妊娠期甲状腺疾病的诊断和治疗带来困惑,因此,需要建立孕期特异的TSH、总T4和游离T4正常参考范围。遗憾的是,目前尚无这样的标准。如非妊娠状态一样,TSH也可以作为诊断妊娠期甲状腺疾病首选的指标,TSH检测不受方法学的限制,下限介于0.2~0.4 mIU/L之间,2.5 mIU/L可以作为TSH在妊娠早期正常范围保守的上限。TT4结果稳定,可以通过非妊娠状态的正常值乘以系数1.5来推断妊娠期的参考范围。妊娠期甲状腺功能减退的患者应该接受左旋T4(L-T4)替代治疗,并尽快使TSH低于2.5 mIU/L,L-T4的剂量在妊娠期要较妊娠前增加30%~50%。对于妊娠期甲状腺功能亢进的患者,丙硫氧嘧啶是首选的治疗药物。甲状腺功能正常的自身免疫性甲状腺炎的孕妇在妊娠期发生甲状腺功能减退、分娩后发生产后甲状腺炎的危险性提高,应该注意监测甲状腺功能。     

Thyroid hormone and phenotypes of cardioprotection

Abstract. Thyroid hormone has multiple effects on the cardiovascular system with important physiological consequences. Several genes that encode important regulatory and structural proteins in the heart have been shown to be thyroid hormone responsive. More notably, certain effects of thyroid hormone have been exploited therapeutically. Thyroid hormone is currently being evaluated as an inotrope and vasodilator in various clinical settings. Furthermore, new information has been recently accumulated on the role of thyroid hormone in the response of the heart to ischaemic stress. In fact, hyperthyroid and hypothyroid hearts display a phenotype of cardioprotection against ischaemia-reperfusion. Based on this evidence, the various actions of thyroid hormone on the cardiovascular system are highlighted in this review. Thyroid hormone, although limited by its adverse effects, might prove a suitable treatment for cardiovascular illnesses. Various thyroid hormone analogues are currently under development.     

Thyroid hormone activates Akt and prevents serum starvation-induced cell death in neonatal rat cardiomyocytes

Thyroid hormone is known to cause hypertrophy, tachycardia, vasorelaxation, and enhanced contractile function. The exact mechanisms responsible for these effects are unknown but classical regulation of gene expression through binding to nuclear receptors has been widely implicated. Data have also accumulated suggesting that TH can exert effects through non-classical mechanisms involving activation of signal transduction pathways. Whether thyroid hormone can activate signal transduction pathways in the heart is unknown. In this study, we treated neonatal rat cardiomyocytes with T3 and determined the expression and phosphorylation of signaling molecules. T3 caused specific activation of Akt/PKB signaling after 24 h of treatment. Since Akt is known to protect against cell death, cells were serum-starved in the presence or absence of T3 to determine whether T3 could protect against serum starvation-induced cell death. Indeed, myocytes treated with T3 displayed enhanced sarcomeric structure after 4 days of serum starvation. T3 increased cell viability as measured by MTT assays, prevented DNA laddering, and reduced TUNEL positive cells, which was associated with increased phosphorylated Akt and glycogen synthase kinase 3beta (GSK-3beta). The protective effect of T3 on cell viability, DNA laddering and TUNEL positive cells were blocked by LY294002, a phosphoinositide-3 kinase (PI3K) inhibitor that blocks Akt signaling. Overall these data suggest that T3 can activate Akt in cardiomyocytes which protects myocytes against cell death.     

妊娠肝内胆汁淤积症患者胎盘促肾上腺皮质激素释放激素受体CRHR-1的表达

目的 观察妊娠肝内胆汁淤积症(ICP)胎盘CRHR-1的表达情况. 方法 随机选择于37 ～ 40周择期剖宫产终止妊娠的ICP与正常妊娠各10例,采用Western blot及巢式实时荧光定量PCR测定胎盘CRHR-1表达强度.正态分布数据以均数土标准差(-x±s)表示,采用t检验.偏态分布数据采用中位数(M)及四分位距(IQR)表示为M(IQR),采用Wilcoxon秩和检验.检验水准a(双侧)=0.05. 结果 CRHR-1 cDNA目的扩增片段为172 bp.ICP组胎盘CRHR-1表达的免疫杂交蛋白条带荧光强度1.55±0.28弱于正常组1.60±0.37,但两组比较,差异无统计学意义(t=0.349,P=0.732);巢式实时荧光定量PCR扩增CRHR-1 mRNA相对含量0.139 (0.268)高于正常组的0.031 (0.245),两组比较,t=1.504,P=0.136,差异无统计学意义. 结论 ICP胎盘CRHR-1有低表达趋势,可能导致ICP胎盘小叶绒毛血管容积下降和CRH超短阳性反馈回路受损.     

甲状腺激素类似物的研究进展

甲状腺激素类似物是一类新兴药物,通过与甲状腺激素受体选择性结合,在特定组织中发挥拟甲状腺激素作用,尤其在降血脂和能量代谢方面.本文主要介绍了靶向特异的甲状腺激素类似物在临床前动物实验和临床试验的研究进展及应用前景.     

Thyroid hormone and glucocorticoid regulation of receptor and target gene mRNAs in pituitary GH3 cells

We have examined the effects of triiodothyronine (T₃), in dose-response and time-course studies, on T₃ receptor (T₃R) and β and glucocorticoid receptor (GR) mRNAs in rate pituitary GH₃ cells, in parallel with T₃ actions on expression of the growth hormone (GH) target gene. Modulatory influences of dexamethasone (dex) on T₃ action were studied by treatment with dex before and during T₃ treatment. T₃ treatment (1–100 nM) for 24 h reduced T₃R mRNA, while the presence of dex (1 μM) enhanced the T₃ effect on T₃R mRNA and induced T₃ inhibition of T₃R β mRNA. Stimulatory effects of T₃ treatment on GH mRNA and release were seen in the face of inhibition of T₃R mRNAs; these effects on GH were also enhanced by the presence of dex. T₃ treatment for 24 h increased GR mRNA; this effect was inhibited by the presence of dex. We next examined the influence of dex on GR and T₃R and β mRNAs, in parallel with effects of dex on the prolactin (PRL) target gene. Modulatory influences of T₃ on dex action were studied by treatment of cells with T₃ before and during dex treatment. Treatment with dex (0.1–10 μM) for 24 h reduced GR mRNA, an action enhanced by the presence of T₃ (100 nM). Dex treatment resulted in inhibition of PRL mRNA and release despite parallel inhibition of GR mRNA by dex; these effects were enhanced by the presence of T₃. In contrast to actions on GR, dex has no effect on T₃R mRNAs. These effects of T₃ and dex on receptor mRNAs suggest that glucocorticoid modulation of T₃ action is not related to direct actions on T₃R synthesis. In contrast, the mechanism of T₃ modulation of glucocorticoid action may be due in part to alteration of GR mRNA expression. Effects of T₃ and dex on target gene expression were observed in the presence of parallel reduction of their respective receptor mRNAs. This provides new evidence that interactions between these hormones are likely to be mediated by mechanisms other than regulation of receptor gene expression.     

Thyroid hormone stimulates hepatic IGF-I mRNA expression in a bony fish,the tilapia Oreochromis mossambicus,in vitro and in vivo

To gain more knowledge about the physiological regulation of hepatic insulin-like growth factor-I (IGF-I) production in bony fish, we examined the potential influence of thyroid hormone (T3, 3,5,3'-triiodothyronine) on the expression of IGF-I in the liver of the tilapia Oreochromis mossambicus, using in vitro and in vivo methods. The in vitro experiments were performed using a recently established primary hepatocyte cell culture and IGF-I expression was determined by means of semiquantitative RT-PCR. T3 (100 nM) significantly enhanced the synthesis rate of IGF-I mRNA in short (>8h) and long (>42h) time courses. The stimulating effect of T3 was detected already after 1h. After 4h, the IGF-I mRNA expression was more than 150% of the starting amount. In long time courses, after 6h the IGF-I mRNA value was about 170% of that in untreated cells and at the end of the experiment, it was still three times higher than in the control. In addition, the increase in IGF-I mRNA expression evoked by T3 (1 nM to 1 microM) was dose-dependent. In the in vivo approach, 10 individuals of tilapia received 4 daily intraperitoneal injections of T3 (6 microg/g body weight). IGF-I mRNA was assessed using dot blot technique with a tilapia specific IGF-I cRNA probe. The T3 treatment led to an increase of the IGF-I mRNA level up to 45% in the liver compared to the untreated animals. In conclusion, our results show that T3 directly stimulates the hepatic production of IGF-I in the tilapia in vitro and in vivo and indicate that in tilapia liver regulatory mechanisms seem to exist, as they are discussed for mammals.     

恶性肿瘤患者甲状腺激素的变化及意义

采用放射免疫分析法检测１０９例恶性肿瘤患者及３７例正常人血清甲状腺激素（Ｔ３、Ｔ４、ＦＴ３、ＦＴ４、ｒＴ３、ＴＳＨ）的变化。结果显示,恶性肿瘤患者血清Ｔ３、ＦＴ３、ＦＴ４值均明显降低（Ｐ〈０．００１）,ｒＴ３值明显增高（Ｐ〈０．００１）,且病情越重,Ｔ３、ＦＴ３、ＦＴ４值越低,ｒＴ３值越高,预后越差,治疗好转后,上述差异变小。Ｔ４值无明显变化（Ｐ〉０．０５）,少数危重患者Ｔ４值明显降低。ＴＳＨ值明     

Thyroid hormones and the control of cell proliferation or cell differentiation: Paradox or duality?

Amphibian metamorphosis perfectly illustrates a key paradox: thyroid hormones control diverse cellular processes depending on the tissue context. This point is also reinforced by a recent accumulation of evidence. For example, thyroid hormones and their nuclear receptor TRs have been described to function in different systems in synergy and/or in antagonism with other signaling pathways. This interaction helps explain their pleiotropic roles. This review summarizes the most important advances in this field, focusing in particular on the key action of thyroid hormones in controlling the balance between the processes of cell proliferation and cell differentiation in a few organs, with special attention paid to the intestine. We highlight similarities between the cellular and molecular events occurring during postnatal intestinal maturation at metamorphosis in amphibians, and comparable events observed at weaning in mice.     

甲状腺激素受体研究进展

甲状腺激素受体(TRs)属于核受体超家族,由TRα和TRβ基因编码。目前发现共有9种亚型。其分子结构由4个功能区组成,分别是A/B区、DNA结合区域、铰链区和配体结合区域,每个区域都有其各自不同的功能。TRs可以单体、同二聚体、异二聚的形式与甲状腺激素应答元件结合,介导甲状腺激素调节靶基因。TRs在各组织器官中广泛分布但不同亚型在组织中表达是不同的,这与它们在组织器官中的作用有密切关系。