Thyroid hormone and atherosclerosis

It is generally accepted that the euthyroid state is preferred for the cardiovascular system because both hyperthyroidism and hypothyroidism cause or accelerate cardiovascular diseases. And hypothyroidism is known to be associated with atherosclerosis and ischemic heart diseases. The accelerated atherosclerosis in hypothyroid state has been traditionally ascribed to atherogenic lipid profile, diastolic hypertension and impaired endothelial function. In addition, recent studies suggest that hypothyroidism is associated with the emerging risk factors for atherosclerosis such as hyperhomocysteinemia and an increase in C-reactive protein level. Thyroid hormone also has direct anti-atherosclerotic effects such as blood vessel dilatation, production of vasodilatory molecules, and inhibition of angiotensin II receptor expression and its signal transduction. These data suggest that thyroid hormone inhibits atherogenesis through direct effects on the vasculature as well as modifying risk factors for atherosclerosis. This review summarizes the basic and clinical studies on the role of thyroid hormone in atherogenesis and a possible application of thyroid hormone mimetics for the therapy of hypercholesterolemia and atherosclerosis.     

Thyroid hormone ligands and metabolic diseases

Thyroid hormones regulate fundamental genes involved in the metabolism, development and homeostasis of vertebrates. The endogenous hormones, L-3, 5, 3'-triiodo-L-thyronine (T(3)) and L-3, 5, 3', 5'-tetraiodo-L-thyronine (T(4)), are of limited use in pharmacological intervention, mainly due to cardiovascular liabilities. There exist two subtypes of thyroid hormone receptors (TR), alpha and beta, unequally distributed in the body. As TRalpha is most abundant in the heart and most effects of thyroid hormones on the heart are mediated through TRalpha, a reasonable strategy is the development of TR agonists that either are tissue selective or that interact selectively with TRbeta. The prospects for the treatment of metabolic diseases with such ligands are considerable and this review describes the massive efforts of the academic and industrial communities during the last decade. It is, however, the author's view that the development of selective ligands only is in its infancy, an opinion highlighted by the limited chemical structural variation of TR ligands as well as the present lack of TR ligands for the treatment of metabolic diseases in clinical phases.     

Thyroid hormone and myocardial mitochondrial biogenesis

Mitochondria have been central in the development of some of the most important ideas in modern biology. Since the discovery that mitochondria have its own DNA and specific mutations and deletions were found in association with neuromuscular and heart diseases, as well as in aging, an extraordinary number of publications have followed, and the term mitochondrial medicine was coined. Recently, it has been found that thyroid hormone (TH) stimulates cardiac mitochondrial biogenesis increasing myocardial mitochondrial mass, mitochondrial respiration, oxidative phosphorylation (OXPHOS), enzyme activities, mitochondrial protein synthesis (by stimulation in a T3-dependent manner), cytochrome, phospholipid and mtDNA content. Also, TH therapy may modulate cardiac mitochondrial protein-import apparatus. To identify the sequence of events, molecules and signaling pathways that is activated by TH affecting mitochondrial structure, biogenesis and function further research is warranted.     

Thyroid hormone in cardiac surgery

Thyroid hormone has a wide range of cardiovascular effects which are mediated at both genomic and non-genomic levels. As a stress response to surgery, the non-thyroidal illness syndrome or euthyroid sick syndrome occurs in the post-operative period following cardiac surgery. There remains debate about the potential benefits of the treatment of the non-thyroidal illness syndrome in this setting with acute thyroid hormone supplementation. This review article sets out to discuss the potential benefits of thyroid hormone supplementation and the results from trials relating to both adult and paediatric cardiac surgical population as well as in the setting of brain stem death to optimise the potential cardiac donor.     

Thyroid hormone concentrations in epileptic patients

Summary Anticonvulsants are associated with decreased serum thyroid hormone concentrations. We have studied thyroid function in 54 epileptic patients on a variety of drugs (19 on carbamazepine, 13 on phenytoin, 10 on sodium valproate, 12 on polypharmacy). For comparison, 14 untreated epileptics and 11 healthy unmedicated volunteers were included as controls.Total thyroxine (T₄) concentrations were reduced in patients taking enzyme-inducing drugs (carbamazepine and/or phenytoin) compared with both controls and patients taking sodium valproate. Similar differences were shown with each individual drug. All nine patients whose circulating T₄ was below the lower limit of the reference range were taking enzyme inducers. Free thyroxine concentrations were also reduced in individuals treated with carbamazepine and phenytoin with five values falling beneath the reference range. Tri-iodothyronine and thyrotropin appeared unaffected by anticonvulsant administration. Thyrotropin releasing hormone stimulation revealed no true hypothyroidism.The lowering effect of anticonvulsant drugs on circulating total and free T₄ was not exhibited by the non-inducing sodium valproate. These data support the influence of enzyme induction as a likely mechanism for reduced thyroxine concentrations in treated epileptic patients.     

Thyroid hormone replacement: current status and challenges

INTRODUCTION: Correction of hypothyroidism with synthetic levothyroxine is simple, effective and safe. In most cases levothyroxine restores well-being and normalizes serum thyrotropin (TSH) concentrations. However, up to 30 - 50% of levothyroxine users do not achieve adequate biochemical euthyroidism. Also, a small proportion of hypothyroid individuals remain dissatisfied with treatment even with normal TSH concentrations. AREAS COVERED: This review addresses strategies for achieving optimal thyroid hormone replacement based on a systematic search of the literature for controlled trials, cohort studies or systematic reviews published on the topic since 1960. EXPERT OPINION: Careful attention to factors that affect levothyroxine availability such as medication adherence, drug interactions and co-morbidities should improve the adequacy of therapy, but these factors are challenging to manage in practice. The case for combined therapy with levothyroxine and triiodothyronine (T3) is compelling but is not supported by current evidence from randomized controlled trials. Recent studies of common genetic variations in deiodinase and thyroid hormone transport proteins offer fresh insights in understanding the variable response to thyroid hormone therapy and future research may clarify whether subsets of patients will benefit from combined therapy. Despite significant challenges, opportunities abound for improving therapeutic outcomes.     

Thyroid hormone replacement: current status and challenges

Introduction: Correction of hypothyroidism with synthetic levothyroxine is simple, effective and safe. In most cases levothyroxine restores well-being and normalizes serum thyrotropin (TSH) concentrations. However, up to 30 – 50% of levothyroxine users do not achieve adequate biochemical euthyroidism. Also, a small proportion of hypothyroid individuals remain dissatisfied with treatment even with normal TSH concentrations.

Areas covered: This review addresses strategies for achieving optimal thyroid hormone replacement based on a systematic search of the literature for controlled trials, cohort studies or systematic reviews published on the topic since 1960.

Expert opinion: Careful attention to factors that affect levothyroxine availability such as medication adherence, drug interactions and co-morbidities should improve the adequacy of therapy, but these factors are challenging to manage in practice. The case for combined therapy with levothyroxine and triiodothyronine (T3) is compelling but is not supported by current evidence from randomized controlled trials. Recent studies of common genetic variations in deiodinase and thyroid hormone transport proteins offer fresh insights in understanding the variable response to thyroid hormone therapy and future research may clarify whether subsets of patients will benefit from combined therapy. Despite significant challenges, opportunities abound for improving therapeutic outcomes.     

Thyroid hormone modulation of rat sulphotransferase mRNA expression

1. Thyroid hormones modulate sulphotransferase (SULT) enzyme expression. Specific substrates are not available for the study of the SULT isoforms, so the regulation of hepatic SULT mRNA expression by thyroid hormones was examined by Northern blot analysis with oligonucleotide probes specific for each SULT mRNA, including maledominant phenol SULT(1A1,1C1,1E2), female-dominant hydroxysteroidSULT(20} 21, 40} 41, 60), and a non-sex-dependent SULT, 1B1. The male and female rat were either untreated, thyroidectomized (TX), or TX and given thyroid hormones (thyroxine [T₄, 20 μg kg^?1 day^?1] and 3,5,3′-triiodothyronine [T₃, 5 μg kg^?1 day ^?1]). 2. With regard to phenol SULTs, expression of SULT1A1 or SULT1B1 mRNA was not altered in either sex by TX. TX increased SULT1E2 mRNA expression 3-fold in the male and 2.5-fold in the female rat. The increase in SULT1E2 mRNA was partially reversed by infusion of T₃/T₄ in the male, and was not reversed in the female. 3. With regard to hydroxysteroid SULTs, TX decreased expression of SULT20/21 mRNA in the male rat by 70 and 60% in the female, and these decreases were reversed by T₃/T₄ infusion. SULT40/41 mRNA expression increased in the male rat 3-fold and decreased in the female TX rat by 25%. SULT60 mRNA expression increased 3-fold by TX in the female rats.The effects of TX on SULT40/41 and SULT60 mRNA expression were reversed by infusion of T₃/T₄. 5. Thus, phenol sulphotransferases were not markedly affected by thyroid hormones except for SULT1E2, but each hydroxysteroid sulphotransferase isoform was affected by thyroidectomy. Therefore, thyroid hormones regulate SULT gene expression in an isoform-specific manner.     

Thyroid hormone modulation of rat sulphotransferase mRNA expression

1. Thyroid hormones modulate sulphotransferase (SULT) enzyme expression. Specific substrates are not available for the study of the SULT isoforms, so the regulation of hepatic SULT mRNA expression by thyroid hormones was examined by Northern blot analysis with oligonucleotide probes specific for each SULT mRNA, including male-dominant phenol SULT (1A1, 1C1, 1E2), female-dominant hydroxysteroid SULT (20/21, 40/41, 60), and a non-sex-dependent SULT, 1B1. The male and female rat were either untreated, thyroidectomized (TX), or TX and given thyroid hormones (thyroxine [T4, 20 microg kg(-1) day(-1)] and 3,5,3'-triiodothyronine [T3, 5 microg kg(-1) day(-1)]). 2. With regard to phenol SULTs, expression of SULT1A1 or SULT1B1 mRNA was not altered in either sex by TX. TX increased SULT1E2 mRNA expression 3-fold in the male and 2.5-fold in the female rat. The increase in SULT1E2 mRNA was partially reversed by infusion of T3/T4 in the male, and was not reversed in the female. 3. With regard to hydroxysteroid SULTs, TX decreased expression of SULT20/21 mRNA in the male rat by 70 and 60% in the female, and these decreases were reversed by T3/T4 infusion. SULT40/41 mRNA expression increased in the male rat 3-fold and decreased in the female TX rat by 25%. SULT60 mRNA expression increased 3-fold by TX in the female rats. The effects of TX on SULT40/41 and SULT60 mRNA expression were reversed by infusion of T2/T4. 5. Thus, phenol sulphotransferases were not markedly affected by thyroid hormones except for SULT1E2, but each hydroxysteroid sulphotransferase isoform was affected by thyroidectomy. Therefore, thyroid hormones regulate SULT gene expression in an isoform-specific manner.     

探讨甲状腺自身抗体和促甲状腺素预测流产的价值

目的 追踪研究妊娠妇女甲状腺自身抗体和促甲状腺素水平变化,探讨其对预测流产的价值.方法 选择2007年1月-2009年12月在该院产科门诊就诊,年龄24-36岁,无其他危险因素的250例单胎妊娠妇女,于妊娠20周内检测甲状腺自身抗体和促甲状腺素.结果 250例单胎妊娠妇女中,50例流产,200例持续妊娠,其中单纯自身抗体阳性32例,流产率56.2%,单纯TSH≥2.5 mIU·L^-14例,流产率为25%,TSH≥2.5 mIU·L^-1伴自身抗体阳性10例,流产率100%,TSH﹤2.5 mIU·L^-1 伴自身抗体阴性194例,流产率为10.8%.结论 甲状腺自身抗体和促甲状腺素是预测流产的重要指标,且甲状腺自身抗体预测流产价值更大.     

Thyroid hormone modulates membrane currents in guinea-pig ventricular myocytes

Summary Thyroid hormones have been previously shown to alter cardiac electrophysiological and mechanical properties in humans and in experimental animals. To investigate electrophysiological mechanisms responsible for some of these alterations, we recorded action potentials and membrane currents from isolated ventricular myocytes obtained from euthyroid, hypothyroid and hyperthyroid guinea-pigs. Hyperthyroidism was induced by injecting 150 g/kg triiodothyronine for 8–11 days, and hypothyroidism was induced by propylthiouracil treatment for 35–45 days. We found that the slow inward current, was increased by hyperthyroidism and decreased by hypothyroidism: in euthyroid, hyperthyroid and hypothyroid myocytes peak slow inward current was (mean ± SEM) : –1.08 ± 0.06 nA, –1.83 ±0.18^a nA and –0.64 ± 0.07^a nA, respectively (a,p < 0.005). In addition, the membrane potential at which peak slow inward current occurred was modified by the thyroid state and in euthyroid, hyperthyroid and hypothyroid myocytes it was (mean ± SEM): 4.8 ± 0.7 mV, –1.8 ± 1.6^a mV and 11.0 ± 1.4^a mV, respectively.The outward rectifying current, was also affected by the thyroid state, and in euthyroid, hyperthyroid and hypothyroid myocytes, the amplitude atV _M = + 60 mV was (mean ± SEM): 0.51 ± 0.09 nA, 1.15 ± 0.08^a nA and 0.49 ± 0.05 nA,respectively. a,p < 0.001 compared to euthyroid myocytes. Intraperitoneal administration of a single dose of triiodothyronine to guinea-pigs, 2 h prior to the electrophysiological experiment, increased the slow inward current amplitude, as was seen with chronic hyperthyroidism, but had no significant effect on the outward current and on the action potential. Finally, action potential and membrane currents were not altered by superfusing euthyroid myocytes with 10^–6 mol/l triiodothyronine for 30 min, or by introducing 10^–7 mol/l triiodothyronine into the cell through the recording pipette.From these findings we conclude that cardiac mechanical performance may be modulated by thyroid hormones through their effect on the slow inward current, while shortening of action potential duration is brought about, at least in part, by increasing the amplitude of the outward rectifying current. Send offprint requests to O. Binah at the above address     

Thyroid hormone treatment of primary unipolar depression: a review

A substantial number of depressed patients will fail to respond to standard antidepressant therapy. Thyroid hormones, particularly T3, may be particularly useful in enhancing response to antidepressants. This review focuses on the use of T3 augmentation in unipolar major depression. The study clearly suggests that approximately half of patients will respond to T3 augmentation of antidepressants. There are several limitations to the literature including the fact that most studies have used T3 in tricyclic rather than SSRI failure and most are of relatively short duration, up to 3 wk. Further studies are required of T3 efficacy with newer classes of antidepressants, optimal dose of T3 to be used and the duration of T3 augmentation, particularly if the acute trial is successful.     

老年人甲状腺激素与胰岛素抵抗和脂联素的相关性分析

目的探讨老年人甲状腺激素是否与胰岛素抵抗和脂联素存在相关性。方法 412名老年体检者测试血清促甲状腺激素(TSH),血清游离三碘甲腺原氨酸(FT3)、血清游离甲状腺素(FT4),真胰岛素(TI),脂联素等并进行分析。结果 (1)血清TSH水平在胰岛素抵抗组明显高于非胰岛素抵抗组,FT3、FT4和脂联素在胰岛素抵抗组低于非胰岛素抵抗组;(2)血清TSH水平与体重指数(BMI)、胰岛素抵抗指数(HOMA-IR)呈正相关,FT3、FT4与HOMA-IR呈负相关,与空腹血糖(FPG)和脂联素呈正相关。(3)回归分析表明,与甲功正常组比较,高水平TSH是胰岛素抵抗和肥胖发生的独立风险因素;低水平FT3、FT4与甲功正常组相比胰岛素抵抗的发病风险比率升高;高水平FT3、FT4与甲功正常组相比高血糖的发病风险比率升高。结论甲状腺激素与胰岛素抵抗明显相关。     

Thyroid hormone induction of the adrenoleukodystrophy-related gene (ABCD2)

X-linked adrenoleukodystrophy (X-ALD) is a demyelinating disorder associated with impaired very-long-chain fatty-acid (VLCFA) beta-oxidation caused by mutations in the ABCD1 (ALD) gene that encodes a peroxisomal membrane ABC transporter. ABCD2 (ALDR) displays partial functional redundancy because when overexpressed, it is able to correct the X-ALD biochemical phenotype. The ABCD2 promoter contains a putative thyroid hormone-response element conserved in rodents and humans. In this report, we demonstrate that the element is capable of binding retinoid X receptor and 3,5,3'-tri-iodothyronine (T3) receptor (TRbeta) as a heterodimer and mediating T3 responsiveness of ABCD2 in its promoter context. After a T3 treatment, an induction of the ABCD2 gene was observed in the liver of normal rats but not that of TRbeta-/- mice. ABCD2 was not induced in the brain of the T3-treated rats. However, we report for the first time that induction of the ABCD2 redundant gene is feasible in myelin-producing cells (differentiated CG4 oligodendrocytes). The induction was specific for this cell type because it did not occur in astrocytes. Furthermore, we observed T3 induction of ABCD2 in human and mouse ABCD1-deficient fibroblasts, which was correlated with normalization of the VLCFA beta-oxidation. Finally, ABCD3 (PMP70), a close homolog of ABCD2, was also induced by T3 in the liver of control rats, but not that of TRbeta-/- mice, and in CG4 oligodendrocytes.