Effects Of Thyroid Hormone Treatment Research Articles

Exogenous triiodothyronine application increases survivorship in larval lake sturgeon (Acipenser fulvescens): Molecular and endocrine regulation of appetite, growth, and stress axes

Lake sturgeon (Acipenser fulvescens) are critically endangered across their native Canadian range and thus conservation aquaculture is practiced to restock historically decimated wild populations. However, as in many aquaculture settings, episodes of mass mortality occur throughout larval development and are often linked to periods of dietary transition. Thyroid hormones play a critical role in larval development and metamorphosis, including the transition from endogenous to exogenous feeding, and thus have been utilized in aquaculture to promote hatch rate, growth, and survivability in multiple fish species. The objective of the present study was to determine whether exogenous application of the biologically active thyroid hormone, triiodothyronine (T3), could improve lake sturgeon growth and survival during early ontogeny in two distinct rearing environments; tumbling jars representing hatchery conditions or egg mats representing more natural conditions. Waterborne application of 3 ppm T3 during fertilization improved growth and survival of lake sturgeon during the first month of life, with greater effects observed in the egg mat environment. Concomitant increases in mRNA abundance of genes involved in appetite regulation (e.g., neuropeptide Y and orexin) and somatic growth (e.g., insulin-like growth factor 1) support accelerated growth of T3 exposed fish through multiple neuroendocrine axes. Following the transition to an exogenous diet, transcript abundance was significantly reduced in the T3 group when compared to controls, perhaps indicating negative feedback regulation. T3 application also caused transient reductions in whole body cortisol content and reduced transcript abundance of genes related to the stress axis later in development; however, no apparent negative consequences were observed as a result. Finally, oral dosing of 3 ppm T3 during an exogenous dietary transition in juvenile lake sturgeon at ∼1.5 months post fertilization significantly increased sturgeon mass, but not survival, indicating that exogenous T3 can contribute to the success of young-of-the-year sturgeon during dietary transitions at multiple life stages. Therefore, these data demonstrate that elevated survivorship and growth associated with exogenous T3 application during fertilization are associated with upregulation of hypothalamus-pituitary-thyroid/interrenal, gut-brain, and somatotropic axes. Overall, exogenous T3 application represents a cost-effective way to positively influence lake sturgeon growth and survival at key dietary transitions during early development. Further, this study adds to a growing body of literature demonstrating beneficial effects of thyroid hormone treatment in fish aquaculture.

Thyroid Function and Mood Disorders: A Mendelian Randomization Study.

BackgroundObservational studies suggest that even minor variations in thyroid function are associated with the risk of mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD). However, it is unknown whether these associations are causal or not. We used a Mendelian Randomization (MR) approach to investigate causal effects of minor variations in TSH and FT4 levels on MDD and BD risk.MethodsWe performed two-sample MR analyses using data from the largest publicly available genome-wide association studies on normal-range TSH (N=54,288) and FT4 (N=49,269) levels, MDD (170,756 cases, 329,443 controls) and BD (20,352 cases, 31,358 controls). Secondary MR analyses investigated the effects of TSH and FT4 levels on specific MDD and BD subtypes. Reverse MR was also performed to assess the effects of MDD and BD on TSH and FT4 levels.ResultsThere were no associations between genetically predicted TSH and FT4 levels and MDD risk, nor MDD subtypes and minor depressive symptoms. A one standard deviation increase in FT4 levels was nominally associated with an 11% decrease in the overall BD risk (OR=0.89, 95%CI=0.80-0.98, P=0.022) and a 13% decrease in the BD type 1 risk (OR=0.87, 95%CI=0.75-1.00, P=0.047). In the reverse direction, genetic predisposition to MDD and BD was not associated with TSH nor FT4 levels.ConclusionsVariations in normal-range TSH and FT4 levels have no effects on the risk of MDD and its subtypes, and neither on minor depressive symptoms. This indicates that depressive symptoms should not be attributed to minor variations in thyroid function. Borderline associations with BD and BD type 1 risks suggest that further clinical studies should investigate the effect of thyroid hormone treatment in BD.

OR21-03 Determining Novel Therapeutic Targets Using an in Vitro Model of TRb Tumor Suppression in Anaplastic Thyroid Cancer

Anaplastic thyroid cancer (ATC) is one of the most lethal endocrine cancers, with an average survival time of six months after diagnosis. These aggressive tumors are characterized by rapid local extension, distant metastasis, and resistance to radioactive iodine therapy and mainstream chemotherapy. There are very limited treatment options for this aggressive form of thyroid cancer, highlighting a need for a deeper understanding of its mechanisms for development of more effective therapies. Loss of expression of the thyroid hormone receptor beta (TRβ) via epigenetic silencing is common amongst solid tumors, including ATC. Despite its recognized role as a tumor suppressor, the mechanisms underlying TRβ tumor suppressor activity remain uncharacterized. We previously created a stable ATC cell line with constitutive re-expression of TRβ (SW-TRβ). These stable cells exhibit a slower baseline growth rate than both the corresponding parental cell line (SW1736) and the stable empty vector control cell line (SW-EV). Since the effects of thyroid hormone treatment on the growth of cancer cells remain unclear, we investigated changes in growth rates of these cells in response to hormone treatment (triiodothyronine (T3) 10-8M). While T3 had no effect on SW-EV cells, the addition of hormone significantly slowed the growth of the SW-TRβ cells after two days. With longer exposure to T3 (five days), the SW-TRβ cells exhibited an apoptotic phenotype. We confirmed that the observed cell death was due to induction of apoptosis by assessing caspase 3 cleavage by immunoblot. The parental SW1736 cell line harbors a deleterious p53 truncating mutation, which is maintained in our stable cell lines. Therefore, we hypothesize that this T3-induced apoptosis is occurring through an alternate, p53-independent, signaling pathway. This prompted us to examine RNA-seq data obtained from these cell lines under similar conditions to identify potential regulators of this response. Interestingly, pathway analysis revealed decreased CDK4/6-mediated cell cycle progression and activation of JAK1/STAT1 signaling upon T3 treatment. These are novel mechanisms by which activation of T3-TRβ signaling can slow tumor growth and promote apoptosis in p53-deficient cancer cells. Furthermore, these pathways represent novel therapeutic targets specifically for ATC with potential high impact clinical applications.

Effects of Thyroid Hormone Treatment on Diaphragmatic Efficiency in Mechanically Ventilated Subjects With Nonthyroidal Illness Syndrome.

Several respiratory abnormalities can be present in primary hypothyroidism and can be reversed with adequate hormone treatment. However, the role of thyroid hormone replacement therapy on the respiratory system in patients with nonthyroidal illness syndrome is still unclear. This physiologic study evaluated the effect of thyroid hormone treatment on respiratory muscle function in subjects with nonthyroidal illness syndrome and while on mechanical ventilation. The primary end point was neuromechanical efficiency, which provides an estimate of the efficiency of diaphragmatic contraction. Secondary end points were the transdiaphragmatic pressure-time product and the swing of the electrical activity of the diaphragm, which reflect the work of breathing and inspiratory effort, respectively. Fifteen subjects on mechanical ventilation for ≥48 h and with a diagnosis of nonthyroidal illness syndrome who had a failed spontaneous breathing trial, received intravenous triiodothyronine. The hormone was administered as an intravenous bolus of 0.4 μg/kg triiodothyronine, followed by continuous perfusion at 0.6 μg/kg for 24 h. Neuromechanical efficiency was calculated as the ratio between the drop in airway pressure during an expiratory occlusion and the corresponding electrical activity of the diaphragm peak. Recordings were taken at baseline and after 3, 6, and 24 h. After study completion, free triiodothyronine serum concentrations increased in all the subjects (mean ± SD increase, 0.84 ± 0.34 pg/mL). Neuromechanical efficiency showed no significant changes throughout the study (mean ± SD baseline, 1.40 ± 0.87 cm H2O/μV; 3 h, 1.28 ± 0.64 cm H2O/μV; 6 h, 1.33 ± 0.87 cm H2O/μV; 24 h, 1.41 ± 0.96 cm H2O/μV). Similarly, no variations in transdiaphragmatic pressure-time product per min (mean ± SD baseline, 238.1 ± 124 cm H2O × s/min; 3 h, 242.5 ± 140.3 cm H2O × s /min; 6 h, 247.5 ± 161.7 cm H2O × s/min; 24 h, 281.2 ± 201.2 cm H2O × s/min) or swing of electrical activity of the diaphragm (mean ± baseline, 20.9 ± 13.1 μV; 3 h, 17.2 ± 8.3 μV; 6 h, 17.4 ± 11.3 μV; 24 h, 20.3 ± 13.7 μV) were observed during hormone administration. In the subjects on mechanical ventilation who were admitted to the ICU with nonthyroidal illness syndrome, thyroid hormone replacement treatment did not yield any benefit on respiratory muscle function when assessed by neuromechanical efficiency, which indicated that, in these subjects restoring normal levels of serum thyroid hormones is debatable. (ClinicalTrials.gov registration NCT03157466.).

Efficacy and safety of levothyroxine (L-T4) replacement on the exercise capability in chronic systolic heart failure patients with subclinical hypothyroidism: Study protocol for a multi-center, open label, randomized, parallel group trial (ThyroHeart-CHF)

BackgroundSubclinical hypothyroidism is a common condition in patients with heart failure and is defined as elevated serum thyroid hormone (TSH) with normal circulating free thyroxine (FT4). Evidence on the effect of thyroid hormone treatment is lacking. We designed a randomized controlled trial to compare the efficacy and safety of thyroid hormone supplementation in patients with chronic heart failure complicated with subclinical hypothyroidism.Methods/designEligible participants were identified from the cardiology units of five study centers based on the following criteria: 18 years or older, systolic heart failure with NewYork Heart Association (NYHA) class II–III, left ventricular ejection fraction ≤ 40%, and subclinical hypothyroidism (TSH > 4.78μIU/ml, < 10 μIU/ml + FT4 level within reference range). Eligible patients will be randomly assigned in a 1:1 manner to receive thyroxine replacement therapy plus standard chronic heart failure (CHF) treatment or only standard CHF therapy. Levothyroxine will be administered at an initial dose of 12.5 μg once daily and will be titrated until TSH is within the normal range. The primary endpoints include the difference in distance of the six-minute walk test between 24 weeks and baseline. The secondary endpoints include differences in plasma NT-proBNP levels and serum lipid profiles, changes in the NYHA classification, cardiovascular death, re-hospitalization, differences in echocardiographic and cardiac magnetic resonance imaging measures, and Minnesota Living With Heart Failure Questionnaire (MLHFQ) results between 24 weeks and baseline.DiscussionThyroHeart-CHF is designed as a prospective, multi-center, randomized, controlled clinical trial to study the efficacy and safety of thyroid hormone supplementation in patients with chronic heart failure complicated with subclinical hypothyroidism. The study findings will have significant implications for discovering the new therapeutic targets and methods of heart failure.Trail RegistrationClinicalTrials.gov, NCT03096613. Registered on 30 March 2017.

Antidepressant-Resistant Depression in Patients With Comorbid Subclinical Hypothyroidism or High-Normal TSH Levels.

Antidepressant-Resistant Depression in Patients With Comorbid Subclinical Hypothyroidism or High-Normal TSH Levels.

Time‑dependent and independent effects of thyroid hormone administration following myocardial infarction in rats.

Cardiac function is reduced following myocardial infarction (MI) due to myocardial injury and alterations in the viable non-ischemic myocardium, a process known as cardiac remodeling. The current treatments available for patients with acute MI (AMI) reduce infarct size, preserve left ventricular (LV) function and improve survival; however, these treatments do not prevent remodeling, which can lead to heart failure. The aim of the present study was to investigate the effects of thyroid hormone (TH) treatment following MI in an in vivo rat model. A total of 199 rats were separated into 3 groups: Sham operated and 2 different coronary artery ligation (CAL) groups. Rats subjected to CAL were randomly divided into a further 2 groups 24 h following surgery. The first group received standard rat chow (designated the CAL group), while the second group received food containing 0.05% thyroid powder (designated the CALTH group). The mean daily intake of TH per rat was estimated at 3.0 µg T3 and 12 µg T4. Echocardiography was used to monitor the rats. Large-scale analysis confirmed the favorable effects of TH treatment following CAL on various parameters of cardiac function. TH treatment reduced LV dilation, and increased global and regional LV function. The development of cardiac hypertrophy was induced and, thus, wall stress was limited. Furthermore, TH treatment improved cardiac geometry, which manifested as an increased sphericity index. Myocardial function, as well as LV dilatation, following CAL and TH treatment was not closely associated with the extent of injury, indicating a novel therapeutic intervention that may alter the course of LV remodeling that typically leads to post-MI heart failure. Data modelling and regressions may be developed to enable the simulation of the pathophysiological processes that occur following MI, and to predict with accuracy the effects of novel or current treatments that act via the modulation of tissue injury, LV dilation, LV geometry and hypertrophy.

Thyroid hormone treatment activates protective pathways in both in vivo and in vitro models of neuronal injury

Thyroid hormone plays an important role in brain development and adult brain function, and may influence neuronal recovery after Traumatic Brain Injury (TBI). We utilized both animal and cell culture models to determine the effects of thyroid hormone treatment, post TBI or during hypoxia, on genes important for neuronal survival and neurogenesis. We show that TBI in rats is associated with a reduction in serum thyroxine (T4) and triiodothyronine (T3). A single dose of levothyroxine (T4), one hour after injury, increased serum T4 and normalized serum T3 levels. Expression of genes important for thyroid hormone action in the brain, MCT8 and Type 2 deiodinase (Dio2) mRNA, diminished after injury, but were partially restored with T4 treatment. mRNA from the Type 3 deiodinase (Dio3) gene, which inactivates T4 to reverse T3 (rT3), was induced 2.7 fold by TBI, and further stimulated 6.7-fold by T4 treatment. T4 treatment significantly increased the expression of mRNA from Bcl2, VEGFA, Sox2 and neurotrophin, genes important for neuronal survival and recovery. The cortex, compared to the hippocampus and cerebellum, sustained the greatest injury and had the most significant change in gene expression as a result of injury and the greatest response to T4 treatment. We utilized hypoxia to study the effect of neuronal injury in vitro. Neuroblastoma cells were exposed to reduced oxygen tension, 0.2%, and were compared to cells grown at control oxygen levels of 21%. T3 treatment significantly increased hypoxia inducible factor (HIF)-2α protein, but not HIF-1α. In a hypoxia time course exposure, expression of hypoxia-mediated genes (VEGF, Enolase, HIF2α, c-Jun) peaked at least 8 h earlier with T3-treatment, compared to cells grown without T3. The early induction of these genes may promote cellular growth after injury. After hypoxic injury, T3 induced mRNA expression of the genes, KLF9 and hairless, important for T3-mediated brain function. The findings from both in vitro and in vivo studies support a role of thyroid hormone in activating pathways important for neuronal protection and promotion of neuronal recovery after injury.

Study protocol; Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism - a randomised placebo controlled Trial (TRUST)

BackgroundSubclinical hypothyroidism (SCH) is a common condition in elderly people, defined as elevated serum thyroid-stimulating hormone (TSH) with normal circulating free thyroxine (fT4). Evidence is lacking about the effect of thyroid hormone treatment. We describe the protocol of a large randomised controlled trial (RCT) of Levothyroxine treatment for SCH.MethodsParticipants are community-dwelling subjects aged ≥65 years with SCH, diagnosed by elevated TSH levels (≥4.6 and ≤19.9 mU/L) on a minimum of two measures ≥ three months apart, with fT4 levels within laboratory reference range. The study is a randomised double-blind placebo-controlled parallel group trial, starting with levothyroxine 50 micrograms daily (25 micrograms in subjects <50Kg body weight or known coronary heart disease) with titration of dose in the active treatment group according to TSH level, and a mock titration in the placebo group. The primary outcomes are changes in two domains (hypothyroid symptoms and fatigue / vitality) on the thyroid-related quality of life questionnaire (ThyPRO) at one year. The study has 80% power (at p = 0.025, 2-tailed) to detect a change with levothyroxine treatment of 3.0% on the hypothyroid scale and 4.1% on the fatigue / vitality scale with a total target sample size of 750 patients.Secondary outcomes include general health-related quality of life (EuroQol), fatal and non-fatal cardiovascular events, handgrip strength, executive cognitive function (Letter Digit Coding Test), basic and instrumental activities of daily living, haemoglobin, blood pressure, weight, body mass index and waist circumference. Patients are monitored for specific adverse events of interest including incident atrial fibrillation, heart failure and bone fracture.DiscussionThis large multicentre RCT of levothyroxine treatment of subclinical hypothyroidism is powered to detect clinically relevant change in symptoms / quality of life and is likely to be highly influential in guiding treatment of this common condition.Trial registrationClinicaltrials.gov NCT01660126; registered 8th June 2012.

Variable Cold-Induced Brown Adipose Tissue Response to Thyroid Hormone Status.

In addition to its role in adaptive thermogenesis, brown adipose tissue (BAT) may protect from weight gain, insulin resistance/diabetes, and metabolic syndrome. Prior studies have shown contradictory results regarding the influence of thyroid hormone (TH) levels on BAT volume and activity. The aim of this pilot study was to gain further insights regarding the effect of TH treatment on BAT function in adult humans by evaluating the BAT mass and activity prospectively in six patients, first in the hypothyroid and then in the thyrotoxic phase. The study subjects underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) scanning after cold exposure to measure BAT mass and activity while undergoing treatment for differentiated thyroid cancer, first while hypothyroid following TH withdrawal at the time of the radioactive iodine treatment and then three to six months after starting TH suppressive treatment when they were iatrogenically thyrotoxic. Thermogenic and metabolic parameters were measured in both phases. All study subjects had detectable BAT under cold stimulation in both the hypothyroid and thyrotoxic state. The majority but not all (4/6) subjects showed an increase in detectable BAT volume and activity under cold stimulation between the hypothyroid and thyrotoxic phase (total BAT volume: 72.0 ± 21.0 vs. 87.7 ± 16.5 mL, p = 0.25; total BAT activity 158.1 ± 72.8 vs. 189.0 ± 55.5 SUV*g/mL, p = 0.34). Importantly, circulating triiodothyronine was a stronger predictor of energy expenditure changes compared with cold-induced BAT activity. Iatrogenic hypothyroidism lasting two to four weeks does not prevent cold-induced BAT activation, while the use of TH to induce thyrotoxicosis does not consistently increase cold-induced BAT activity. It remains to be determined which physiological factors besides TH play a role in regulating BAT function.

Trialkyltin Rexinoid-X Receptor Agonists Selectively Potentiate Thyroid Hormone Induced Programs of Xenopus laevis Metamorphosis.

The trialkyltins tributyltin (TBT) and triphenyltin (TPT) can function as rexinoid-X receptor (RXR) agonists. We recently showed that RXR agonists can alter thyroid hormone (TH) signaling in a mammalian pituitary TH-responsive reporter cell line, GH3.TRE-Luc. The prevalence of TBT and TPT in the environment prompted us to test whether they could also affect TH signaling. Both trialkyltins induced the integrated luciferase reporter alone and potentiated TH activation at low doses. Trimethyltin, which is not an RXR agonist, did not. We turned to a simple, robust, and specific in vivo model system of TH action: metamorphosis of Xenopus laevis, the African clawed frog. Using a precocious metamorphosis assay, we found that 1nM TBT and TPT, but not trimethyltin, greatly potentiated the effect of TH treatment on resorption phenotypes of the tail, which is lost at metamorphosis, and in the head, which undergoes extensive remodeling including gill loss. Consistent with these responses, TH-induced caspase-3 activation in the tail was enhanced by cotreatment with TBT. Induction of a transgenic reporter gene and endogenous collagenase 3 (mmp13) and fibroblast-activating protein-α (fap) genes were not induced by TBT alone, but TH induction was significantly potentiated by TBT. However, induction of other TH receptor target genes such as TRβ and deiodinase 3 by TH were not affected by TBT cotreatment. These data indicate that trialkyltins that can function as RXR agonists can selectively potentiate gene expression and resultant morphological programs directed by TH signaling in vivo.

Translating thyroid hormone effects into clinical practice: the relevance of thyroid hormone receptor α1 in cardiac repair.

Thyroid hormone (TH) appears to have a critical role in cardiac repair after injury beyond its role in development and metabolism homeostasis. This unique action is due to the fact that TH effect on the heart is shown to be differentiated depending on its administration on injured or healthy myocardium. Thus, TH can limit ischemia-reperfusion injury via a fine balance between pro-apoptotic and pro-survival signaling pathways. This response is thyroid hormone receptor (TRα1) dependent. Furthermore, an interaction between stress-induced growth kinase signaling and TRα1 is shown to occur and determine postischemic remodeling and cardiac recovery depending on the availability of TH. This new evidence is consistent with clinical observations showing the cardioprotective effect of TH treatment in cardiac surgery, transplantation and heart failure. TH and/or thyroid analogs may be novel agents in treating heart diseases.

The Evaluation of Carotid Intima Thickness in Clinical and Subclinical Hypothyroidism and Effects of Thyroid Hormone Treatment

Objectives: In this study, our aim was to investigate the CA-IMT in clinical hypothyroidism(CH) and subclinical hypothyroidism(SCH) and the effects of L-thyroxine replacement. Materials and methods: The study group consisted of 20 patients with clinical hypothyroidism(CH group) and 20 patients with subclinical hypothyroidism(SCH group) and 20 patients with with normal thyroid hormone function tests (control group). Serum TSH, fasting glucose, lipid profile(total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglyceride),HbA1c,insulin,HOMA and carotid intima media thickness(CA-IMT) of all subjects were measured at admission. Thereafter, all hypothyroid patients received L- thyroxine treatment. The previous tests were re-examined after achievement of euthyroidism for 6 months. The results of the tests before and after L- thyroxine treatment were compared. Results: The levels of TSH, total cholesterol, triglyceride, LDL for CH and SCH group were statistically different before and after treatment(p≤ 0.05). The levels of glucose, HDL,VLDL, HbA1c, insulin and HOMA for CH and SCH group were similar before and after treatment(p≥ 0.05). The difference of CA-IMT for both sides before and after treatment was statistically significant(p ≤0.05). Conclusion: This study suggests that subjects with clinical and subclinical hypothyroidism are characterized by an increment in the CA-IMT resulting from an adverse lipid profile, which can be reversed by thyroid hormone replacement. So, thyroid hormone replacement may be helpful to prevent or at least slow down atherosclerosis in hypothyroid subjects.

Regulation of Gene Expression with Thyroid Hormone in Rats with Myocardial Infarction

IntroductionThe expression of hundreds of genes is altered in response to left ventricular (LV) remodeling following large transmural myocardial infarction (MI). Thyroid hormone (TH) improves LV remodeling and cardiac performance after MI. However, the molecular basis is unknown.MethodsMI was produced by ligation of the left anterior descending coronary artery in female SD rats. Rats were divided into the following groups: (1) Sham MI, (2) MI, and (3) MI+T4 treatment (T4 pellet 3.3 mg, 60 days release, implanted subcutaneously immediately following MI). Four weeks after surgery, total RNA was isolated from LV non-infarcted areas for microarray analysis using the Illumina RatRef-12 Expression BeadChip Platform.ResultsSignals were detected in 13,188 genes (out of 22,523), of which the expression of 154 genes were decreased and the expression of 200 genes were increased in MI rats compared with Sham MI rats (false discovery rate (FDR) <0.05). Compared to MI rats, T4 treatment decreased expression of 27 genes and increased expression of 28 genes. In particular, 6 genes down-regulated by MI and 12 genes up-regulated by MI were reversed by T4. Most of the 55 genes altered by T4 treatment are in the category of molecular function under binding (24) and biological processes which includes immune system process (9), multi-organism process (5) and biological regulation (19) nonexclusively.ConclusionsThese results suggest that altered expression of genes for molecular function and biological process may be involved in the beneficial effects of thyroid hormone treatment following MI in rats.

Exposure to thyroid hormone in ovo affects otolith crystallization in rainbow trout Oncorhynchus mykiss

Calcareous otoliths in the inner ears of fishes are necessary for proper hearing and vestibular function. Sagittal otoliths are usually composed of the calcium carbonate polymorph aragonite but may contain the polymorph vaterite, a phenomenon called otolith crystallization. The causes of otolith crystallization are poorly understood. Thyroid hormone (TH) can influence the chemical microenvironment and structure of the inner ear, suggesting that TH may influence otolith crystallization. The present study examined the effect of exogenous TH treatment on sagittal otolith crystallization and growth in larval and juvenile rainbow trout, Oncorhynchus mykiss. In the first experiment, 110–179 day-old fish raised from TH-treated oocytes had significantly fewer sagittal otoliths containing the crystalline calcium carbonate polymorph vaterite as compared to untreated fish. Vaterite-containing otoliths were significantly longer than those containing the typical polymorph aragonite, although there was no effect of TH treatment on otolith length. In the second experiment, juveniles immersed in an exogenous solution of TH for 6 weeks had slightly longer otoliths (relative to fish length) than age-matched controls, but this effect was not significant. This juvenile population had a very high percentage (88.3 %) of vaterite sagittae overall and this percentage did not change significantly with treatment, suggesting the switch from aragonite to vaterite occurred prior to inclusion of the fish in the study. These results suggest that early manipulation of TH levels may affect calcium carbonate deposition on the otolith but that later TH exposure is unable to restore typical otolith composition.

A child with a deletion in the monocarboxylate transporter 8 gene: 7-year follow-up and effects of thyroid hormone treatment

The monocarboxylate transporter 8 (MCT8; SLC16A2) has a pivotal role in neuronal triiodothyronine (T(3)) uptake. Mutations of this transporter determine a distinct X-linked psychomotor retardation syndrome (Allan-Herndon-Dudley syndrome (AHDS)) that is attributed to disturbed thyroid hormone levels, especially elevated T(3) levels. We describe the genetic analysis of the MCT8 gene in a patient suspected for AHDS and the clinical and endocrine effects of L-thyroxine (LT(4)) or liothyronine (LT(3)) treatment intending to overcome the T(3) uptake resistance through alternative transporters. The six exons of the MCT8 gene were amplified individually by PCR. As multiple exons were missing, the length of the X-chromosomal deletion was determined by a dense SNP array, followed by PCR-based fine mapping to define the exact borders of the deleted segment. The clinical and endocrine data of the patient during 6.5 years of LT(4) treatment and two periods (3 months each) of low- and high-dose LT(3) were evaluated. A partial deletion of the MCT8 gene (comprising five of six exons) was detected, confirming the suspected AHDS. MCT8 dysfunction was associated with partial resistance to T(3) at the hypothalamus and pituitary level, with normal responsiveness at the peripheral organs (liver and cardiovascular system). Thyroid hormone administration had no beneficial effect on the neurological status of the patient. We identified a 70 kb deletion encompassing exons 2-6 of the MCT8 gene in our AHDS patient. Both LT(4) and LT(3) administration had no therapeutic effect. Alternatively, treatment of AHDS patients with thyroid hormone analogs should be considered.

Thyroid function during critical illness

The metabolic support of the critically ill patient is a relatively new target of active research and little is as yet known about the effects of critical illness on metabolism. The nonthyroidal illness syndrome, also known as the low T3 syndrome or euthyroid sick syndrome, describes a condition characterized by abnormal thyroid function tests encountered in patients with acute or chronic systemic illnesses. The laboratory parameters of this syndrome include low serum levels of triiodothyronine (T3) and high levels of reverse T3, with normal or low levels of thyroxine (T4) and normal or low levels of thyroid-stimulating hormone (TSH). This condition may affect 60 to 70% of critically ill patients. The changes in serum thyroid hormone levels in the critically ill patient seem to result from alterations in the peripheral metabolism of the thyroid hormones, in TSH regulation, in the binding of thyroid hormone to transport-protein and in receptor binding and intracellular uptake. Medications also have a very important role in these alterations. Hormonal changes can be seen within the first hours of critical illness and, interestingly, these changes correlate with final outcome. Data on the beneficial effect of thyroid hormone treatment on outcome in critically ill patients are so far controversial. Thyroid function generally returns to normal as the acute illness resolves.

Hypothyroidism and dyslipidemia: modern concepts and approaches.

Subclinical and overt hypothyroidism are relatively common disorders in the general population. Thyroid hormone is known to play a role in regulating the synthesis, metabolism, and mobilization of lipids. In patients with overt hypothyroidism there is an increase in serum total cholesterol, low-density lipoprotein (LDL) cholesterol, apolipoprotein B, lipoprotein(a) levels, and possibly triglyceride levels. The effects of subclinical hypothyroidism on serum lipid values are less clear. The preponderance of evidence suggests that total cholesterol, LDL cholesterol, and possibly triglycerides are increased in patients with subclinical hypothyroidism, whereas high-density lipoprotein (HDL) cholesterol and Lp(a) remain unchanged. Most lipid abnormalities in patients with overt hypothyroidism will resolve with thyroid hormone replacement therapy. However, clinical trials to date have not shown a beneficial effect of thyroid hormone treatment on serum lipid levels in patients with subclinical hypothyroidism. The lipid-altering effects of thyroid hormone make it an appealing target for drug development. The development of specifically targeted thyroid hormone analogues that could potentially treat hyperlipidemia without causing systemic thyrotoxicosis is currently ongoing.

Thyroid hormones: beneficial or deleterious for bone?

The mechanism of action as well as the clinical effects of thyroid hormones on bone has been of interest for more than a century. With the appearance of new treatment modalities for thyroid function disorders, the accompanying alterations in bone metabolism appeared to be rare. However, the introduction of new diagnostic tools, such as osteodensitometry and biochemical bone markers, has changed our view since they were able to show smaller but important changes in bone mineral metabolism associated with thyroid function disorders. Now, we know that hyperthyroidism is associated with an increased life-time risk for fractures, even after achieving euthyroidism. This fact may play an important role in the higher mortality rate among previously hyperthyroid patients later in life. Subclinical hyperthyroidism may also affect bone density, however, its effect on fracture rate remains to be established. The lack of thyroid hormones will alter normal growth during childhood. Adult hypothyroid patients tend to exhibit higher than normal bone density. Despite rather increased bone quantity, hypothyroidism is accompanied with increased fracture risk before and after diagnosis. The effect of thyroid hormone treatment on bone tissue is somewhat controversial. Nevertheless, only patients with suppressed thyroid-stimulating hormone (TSH) appear to loose bone and have higher fracture incidence, whereas patients with a TSH level in the normal range seem to have similar bone mineral content and fracture rate as euthyroid subjects. In summary, most of thyroid function disorders may result in reduced bone density and/or increased fracture rate that should be taken into consideration at clinical evaluation.

Thyroxine induces pancreatic beta cell apoptosis in rats.

Thyroid hormones reduce glucose tolerance in animals and humans. This effect is accompanied by a reduction in the beta-cell volume of the pancreas. We studied the underlying mechanism using terminal UTP nick end labelling (TUNEL) and caspase-3 to analyse apoptosis and BrdU labelling of beta-cell proliferation. The reason for the reduction of the beta-cell volume of the pancreas after thyroxine treatment is apparently an increased rate of beta-cell apoptosis by an increase of TUNEL and caspase-3 positive rat beta cells. In parallel, thyroxine treatment increased the rate of apoptosis in rat pancreatic ductal cells which are considered to contribute to the pool of stem cells from which insulin-producing beta cells originate. The effects of thyroid hormone treatment are reversible through an increase of the beta-cell replication rate when thyroxine is withdrawn as documented by an increase of the BrdU labelling index. An increased rate of beta-cell death due to apoptosis causes a decrease of insulin content and glucose-induced insulin secretion from the pancreas in hyperthyroidism. The resulting reduction of beta cells in the pancreas can provide an explanation for the decrease of glucose tolerance in hyperthyroidism.