Thyroid Hormone Administration Research Articles

Thyroid Remnant Estimation by Tc-99m-Sestamibi Scanning Predicts the Effectiveness of rhTSH-Stimulated I-131 Ablation in Patients With Differentiated Thyroid Carcinoma

To evaluate the relationship between postsurgical cervical Tc-99m-sestamibi scan uptake and the rate of successful remnant ablation after recombinant human-thyrotropin (rhTSH)-aided-I-131 ablation in patients with differentiated thyroid carcinoma (DTC). In all, 154 DTC patients who underwent total thyroidectomy and rhTSH-aided remnant ablation with I-131 (3.7 GBq) were enrolled. Tc-99m-sestamibi scans were performed during continuing thyroid hormone administration in all cases. Thyroid ablation was assessed after 6 to 12 months by rhTSH-stimulated I-131-whole-body scan and thyroglobulin measurement. The rate of successful ablation, occurrence of radioiodine-induced thyroiditis, and length of hospitalization were correlated with the Tc-99m-sestamibi scintigraphy results. Tc-99m-sestamibi uptake was significantly lower in ablated versus nonablated patients (P<0.0001). A visually positive scan and a Tc-99m-sestamibi uptake greater than 0.9% predicted a high-risk of unsuccessful ablation, prolonged hospitalization, and the occurrence of radioiodine-induced thyroiditis. Tc-99m-sestamibi scintigraphy is a simple and feasible tool to evaluate thyroid remnants and to predict radioiodine ablation results in patients with DTC.

Variable clinical presentation and outcome in pediatric patients with resistance to thyroid hormone (RTH)

Resistance to thyroid hormone (RTH) is characterized by elevated levels of thyroid hormones, normal or slightly increased TSH levels respondent to TRH, resistance to thyroid hormone administration, and variable clinical expression. To describe the diverse clinical and biochemical findings of six children from five unrelated families with molecular diagnosis of RTH (0.5-12.7 years) and their follow-up (3-20 years). All RTH patients and 4 affected parents' harbored mutations in exons 9 or 10 of the thyroid receptor β gene: p.M313T (de novo), pN331D, p.L341P, p.L346F, and p.P453L. At consultation 5/6 had goiter, 4/6 tachycardia, and 3/5 learning disabilities. Median hormone levels were: T(4) 257.4 nmol/l (NR: 77.2-180.2); FreeT(4) 39.9 pmol/(NR:10.3-28.3); T(3) 4.28 nmol/l (NR:1.23-3.39) TSH 2.8 mUI/l (NR: 0.5-5) always responsive to TRH. TSH levels remained detectable after supraphysiologic T(3) administration while SHBG levels showed a paradoxical decrease in 4/6. Thyroid antibodies, initially present in two subjects, became positive in other two during follow-up. All patients grew normally and presented variable symptoms that were treated according to need. Two patients developed psychiatric disorders. Only one of the four affected parents exhibited clinical signs of RTH (tachycardia and depression). Parent's thyroid profile showed similar TSH and T(3) levels but lower T(4) and FT(4) than their children. RTH has a distinctive biochemical profile with highly variable clinical manifestations and outcomes. Its recognition and molecular characterization avoid misleading diagnosis. Treatment has to be instituted according to each subject's own clinical requirements.

Triiodothyronine Administration Ameliorates the Demyelination/Remyelination Ratio in a Non-Human Primate Model of Multiple Sclerosis by Correcting Tissue Hypothyroidism

Remyelination failure is a key landmark in chronic progression of multiple sclerosis (MS), the most diffuse demyelinating disease in human, but the reasons for this are still unknown. It has been shown that thyroid hormone administration in the rodent models of acute and chronic demyelinating diseases improved their clinical course, pathology and remyelination. In the present study, we translated this therapeutic attempt to experimental allergic encephalomyelitis (EAE) in the non-human primate Callithrix Jacchus (marmoset). We report that short protocols of triiodothyronine treatment shifts the demyelination/remyelination balance toward remyelination, as assessed by morphology, immunohistochemistry and molecular biology, and improves the clinical course of the disease. We also found that severely ill animals display hypothyroidism and severe alteration of deiodinase and thyroid hormone receptor mRNAs expression in the spinal cord, which was completely corrected by thyroid hormone treatment. We therefore suggest that thyroid hormone treatment improves myelin sheath morphology in marmoset EAE, by correcting the dysfunction of thyroid hormone cellular effectors.

Individualized thyrotropin suppression in patients with differentiated thyroid cancers

The epidemic characteristics of differentiated thyroid cancer(DTC)are changing, thyrotropin(TSH)suppressive therapy is also improving in recent years. The risks of recurrence and the death of patients, as well as the adverse effects of levothyroxine sodium treatment should be fully considered during thyroid hormone administration for patients of DTC. Hence, the degree of TSH suppression should be individualized in patients with DTC. Key words: Differentiated thyroid cancers; Thyrotropin suppressive therapy; Thyrotropin; Individualization

Effect of experimentally induced hypothyroidism during pregnancy and lactation on the retina of juvenile and adult albino rats and the possible role of thyroid hormone supplementation

Objectives Nervous system growth and differentiation are closely correlated with the presence of thyroid hormones in initial development stages. Hypothyroidism during the fetal and postnatal life results in an irreversible mental retardation syndrome. At the cellular level, T3 is known to act on neuronal, neuroretinogenesis, and glial lineages. In this study, we aimed to study the influence of hypothyroidism on retinal development in juvenile and adult rats and the effects of thyroid hormone supplementation on both periods of development. Materials and methods This study was conducted using 56 male albino rats. They were divided into three groups: group 1 (control group) included 24 animals, group 2 (juvenile group) included 16 animals whose mother received carbimazole (NeoMercazol) antithyroid drug at a dose of 0.02 mg/day/pregnant female during gestation and lactation, this group was further subdivided into subgroup 2a (hypothyroid juvenile animals) and subgroup 2b (thyroid hormone-supplemented juvenile animals), and group 3 (adult group) included 16 animals, this group was also further subdivided into subgroup 3a (hypothyroid adult animals) and subgroup 3b (thyroid hormone-supplemented adult animals). At the end of the experiment, the animals were killed. Retinal specimens from all groups were processed for light and electron microscopic studies. Biochemical analysis was carried out to measure the serum levels of triiodothyronine, T4, growth hormone, and insulin growth factor-1. In addition, estimations of lipid peroxidation, catalase activity, and antioxidant enzymes were made. Statistical analysis was carried out to measure the retinal thickness. Results Light and electron microscopic studies showed that thyroid hormone deprivation altered the organization of the retina in juvenile and adult rats. These changes were apparent in the form of significant reduction in the retinal layer thickness. In addition, degenerative changes in some layers were observed. The group with thyroid hormone supplementation showed recovery of both structural changes and retinal thickness, this recovery was apparent in the juvenile group. Adult animals showed minimal recovery. Biochemical analysis of the serum of hypothyroid animals showed a significant increase in lipid peroxidation products and decease in the serum levels of antioxidants, growth hormone, and insulin growth factor-1, comparable with the controls. Administration of thyroid hormone significantly restored their levels especially in the juvenile group. Conclusion Gestational and lactational hypothyroidism induced marked changes in the developing retina in juvenile and adult rats. These changes were mostly normalized by thyroid hormone administration especially in the juvenile group.

Effect of Triiodothyronine on Antidepressant Screening Tests in Mice and on Presynaptic 5-HT1A Receptors: Mediation by Thyroid Hormone α Receptors

Although triiodothyronine (T3) is widely used clinically, preclinical support for its antidepressant-like effects is limited, and the mechanisms are unknown. We evaluated 1) the antidepressant-like effects of T3 in the novelty suppressed feeding test (NSFT), tail suspension test (TST), and forced swim test (FST), 2) the role of presynaptic 5-HT(1A) receptors in the antidepressant-like mechanism of T3 by the hypothermic response to the 5-HT(1A) receptor agonist, 8-hydroxy-N,N-dipropyl-2-aminotetralin (8-OH-DPAT), 3) the thyroid hormone receptor type mediating the antidepressant-like effects by concurrent administration of the specific thyroid hormone α receptor (TRα) antagonist, dronedarone, and 4) the presence of these effects in both genders. Male and female BALB/c mice were administered 1) T3 (20, 50, 200, or 500 μg/kg per day) or vehicle or 2) T3 (50 μg/kg per day), dronedarone (100 μM/day), or the combination intraperitoneally for 21 days and then underwent a behavioral test battery. The NSFT showed a shortened latency to feed in males at the two lower T3 doses. The TST and FST showed decreased immobility in male mice at T3 doses >20 μg/kg per day and in females at all T3 doses. Concurrent dronedarone prevented T3 effects in males on the NSFT and in the TST and FST in both genders. Attenuation of 8-OH-DPAT-induced hypothermia was observed in males only and may be reduced by concurrent dronedarone. These findings support an antidepressant-like effect of T3. Attenuation of 8-OH-DPAT-induced hypothermia in males only suggests the need to evaluate a possible gender disparity in the role of presynaptic 5-HT(1A) receptors in T3 antidepressant mechanisms. Blockade by dronedarone of the antidepressant-like effects of T3 suggests that these effects are TRα receptor-mediated.

Molecular characterization of thyroid hormone-inhibited atrial L-type calcium channel expression: implication for atrial fibrillation in hyperthyroidism

Atrial fibrillation (AF) is a common complication in hyperthyroidism. Earlier studies demonstrate that thyroid hormone decreases L-type calcium channel (LCC) current expression with resultant shortening of action potential duration (APD), providing a substrate for AF. The aim of this study was to investigate the potential mechanism underlying the regulatory effect of thyroid hormone on LCC. In a hyperthyroid rat model, thyroid hormone (triiodothyronine [T3]) administration down-regulated atrial LCC expression. In vitro, treatment of murine atrial myocytes (HL-1) with T3 decreased the expression of LCC and its current, resulting in abbreviation of APD. Furthermore, T3 inhibited the activation of cyclic AMP response element (CRE)-binding protein (CREB), including phosphorylation at Ser133 and its nuclear translocation. Transient transfection studies in HL-1 cells indicated that T3 reduced LCC promoter activity. Deletion and mutation analysis of the LCC promoter region along with chromatin immunoprecipitation using anti-CREB antibody showed that CRE was essential for T3-mediated LCC gene expression. Transfection of dominant-negative CREB (mutated Ser133) and mutant thyroid hormone receptor (TR, mutated Cys51) abolished the T3-dependent effects, suggesting an association between both transcriptional factors. Co-immunoprecipitation documented an increased binding of TR with CREB after T3 treatment. The transcriptional cross-talk 3 between TR and CREB bound to CRE mediates T3-inhibited CREB activity and LCC expression. Thyroid hormone-induced TR binding of CREB inhibits CREB activity and LCC current expression, which may contribute to AF. These findings provide an important mechanistic insight into hyperthyroidism-induced AF.

Le diabète de type 1 diminue la réponse compensatrice après un infarctus du myocarde. Rôle de l’hypothyroïdie tissulaire et effets de l’administration d’hormones thyroïdiennes

Type 1 diabetes (TOD) increases the risk of coronary artery disease and myocardial infarction and is characterized by baseline cardiac dysfunction. We investigated the influence of TOD in post-infarct remodeling (REM) and the role of thyroid hormone (TH) signaling in this response. Acute myocardial infarction (AMI) was induced in rats with type I diabetes (TOD) and in non diabetic rats (NTOD-AMI), sham-operated rats serving as controls (SHAM). AMI resulted in tissue hypothyroidism due to significant downregulation of the TH receptors TRa1 and TRbeta1 in the TOD myocardium, while no change in plasma T3 or T4 was observed This response was associated with increased expression of beta-MHC and distinct changes in cardiac function and geometry: EF % was decreased in TOD-AMI as compared to NTOD-AMI. Systolic and diastolic chamber dimensions were increased, with no concomitant increase in wall thickness. Thus, WTI (the ratio of LVIDd/2 x posterior wall thickness), an index of wall stress, was significantly increased in TOD-AMI. The absence of wall thickening in TOD-AMI hearts was associated with changes in stretch-induced kinase hypertrophic signaling: phosporylated (p) ERK and p-p38 MAPK levels were not changed in TOD-AMI in comparison with non infarcted hearts (TOD-SHAM) and NTOD-A MI hearts. TH administration after AMI prevented tissue hypothyroidism and resulted in decreased beta-MHC expression, increased wall thickening and normalized wallstress, while stretch-induced p38 MAPK activation was increased. We conclude that diabetes exacerbates post-ischemic cardiac remodeling and that tissue hypothyroidism may be involved in this response.

Cytoprotective and suicidal signaling in oxidative stress.

Oxidative stress is an imbalance between pro-oxidants and antioxidants in favor of the pro-oxidants, leading to different responses depending on the level of pro-oxidants achieved and the duration of exposure. In this article, we discuss the cytoprotective or suicidal signaling mechanisms associated with oxidative stress by addressing: (i) the development of an acute and mild pro-oxidant state by thyroid hormone administration eliciting the redox upregulation of the expression of proteins affording cell protection as a preconditioning strategy against ischemia-reperfusion liver injury; and (ii) the role of prolonged and severe oxidative stress and insulin resistance as determinant factors in the pathogenesis of non-alcoholic fatty liver disease associated with obesity.

Thyroid hormone inhibits ERK phosphorylation in pressure overload-induced hypertrophied mouse hearts through a receptor-mediated mechanism

Pressure overload-induced cardiac hypertrophy results in a pathological type of hypertrophy with activation of signaling cascades like the extracellular signal-regulated kinase (ERK) pathway, which promotes negative cardiac remodeling and decreased contractile function. In contrast, thyroid hormone mediates a physiological type of hypertrophy resulting in enhanced contractile function. In addition, thyroid hormone action is diminished in pressure overload-induced cardiac hypertrophy. We hypothesized that thyroid hormone status modulates ERK activity and that administration of thyroid hormone could alter the activity of this kinase in cardiac hypertrophy induced by pressure overload. ERK is activated by phosphorylation; accordingly, we investigated phosphorylation of ERK in hearts of control, hypothyroid, and hyperthyroid mice. In addition, the effect of T3 treatment on ERK phosphorylation in hypertrophied hearts from transverse aortic-constricted (TAC) mice was investigated. Results showed that phosphorylated ERK (p-ERK) was decreased by 25% in hyperthyroid mice. In contrast, hypothyroid mice presented increased p-ERK by 80%. TAC mice presented a greater than fourfold increase of p-ERK compared with control mice. Interestingly, T3 administration dramatically canceled TAC-induced ERK phosphorylation (36% lower compared with control). Raf-1 is upstream of the ERK pathway. TAC mice presented a 45% increase in phospho-Raf-1 (Ser338). T3 treatment inhibited this effect of pressure overload and further decreased p-Raf-1 (Ser338) by 37%, compared with control. Overexpression of thyroid hormone receptor-α in cultured cardiomyocytes potentiated the inhibitory effect of T3 on ERK phosphorylation. We concluded that thyroid hormone has an inhibitory effect on the Raf-1/ERK pathway. Furthermore, treatment of TAC mice with T3 inhibited Raf-1/ERK pathway by a thyroid hormone receptor-dependent mechanism.

A Physiological Systems Model for Iodine for Use in Radiation Protection

This paper summarizes the biokinetic database for iodine in the human body and proposes a biokinetic model for systemic iodine for use in dose assessments for internally deposited radioiodine. The model consolidates and extends existing physiological systems models describing three subsystems of the iodine cycle in the body: circulating inorganic iodide, thyroidal iodine (trapping and organic binding of iodide and synthesis, storage and secretion of thyroid hormones), and extrathyroidal organic iodine. Thyroidal uptake of inorganic iodide is described as a function of stable iodine intake (Y, µg day(-1)) and thyroidal secretion of hormonal iodine (S, µg day(-1)). Baseline parameter values are developed for reference adults with typical iodine intake. Compared with the current systemic biokinetic model of the International Commission on Radiological Protection (ICRP) for occupational intake of radioiodine, the proposed model predicts higher absorbed doses to the thyroid per unit uptake to blood for very short-lived iodine isotopes, similar absorbed doses to thyroid for iodine isotopes with half-life of at least a few hours, and substantially higher estimates of absorbed dose to stomach wall, salivary gland and kidneys for most iodine isotopes. Absorbed dose estimates for intravenous administration of radioiodine-labeled thyroid hormones based on the proposed model differ substantially in some cases from current ICRP values.

Thyroid hormone can favorably remodel the diabetic myocardium after acute myocardial infarction

It has been previously shown that regulators of physiological growth such as thyroid hormone (TH) can favorably remodel the post ischaemic myocardium. Here, we further explored whether this effect can be preserved in the presence of co-morbidities such as diabetes which accelerates cardiac remodeling and increases mortality after myocardial infarction. Acute myocardial infarction (AMI) was induced by left coronary ligation in rats with type I diabetes (DM) induced by streptozotocin administration (STZ; 35mg/kg; i.p.) while sham-operated animals served as controls (SHAM). AMI resulted in distinct changes in cardiac function and geometry; EF% was significantly decreased in DM-AMI [37.9±2.0 vs. 74.5±2.1 in DM-SHAM]. Systolic and diastolic chamber dimensions were increased without concomitant increase in wall thickness and thus, wall tension index [WTI, the ratio of (Left Ventricular Internal Diameter at diastole)/2*(Posterior Wall thickness)], an index of wall stress, was found to be significantly increased in DM-AMI; 2.27±0.08 versus 1.70±0.05. 2D-Strain echocardiographic analysis showed reduced systolic radial strain in all segments, indicating increased loss of cardiac myocytes in the infarct related area and less compensatory hypertrophy in the viable segments. This response was accompanied by a marked decrease in the expression of TRα1 and TRβ1 receptors in the diabetic myocardium without changes in circulating T3 and T4. Accordingly, the expression of TH target genes related to cardiac contractility was altered; β-MHC and PKCα were significantly increased. TH (L-T4 and L-T3) administration prevented these changes and resulted in increased EF%, normal wall stress and increased systolic radial strain in all myocardial segments. Acute myocardial infarction in diabetic rats results in TH receptor down-regulation with important physiological consequences. TH treatment prevents this response and improves cardiac hemodynamics.

New insights into the role of thyroid hormone in cardiac remodeling: time to reconsider?

Chronic ischemia or pressure overload decreases thyroid hormone (TH) signaling and activates the fetal gene program in the heart. While these features are of physiologic importance in the developing heart, their respective roles in the postnatal heart are debated. Administration of TH can prevent the changes of the fetal gene program and rebuild the heart after an "index event" such as ischemia. TH affects cardiac remodeling by limiting reperfusion injury, and, at later states, by inducing distinct changes in cardiac chamber geometry in a time-dependent manner. Furthermore, administration of TH can convert pathologic to physiologic hypertrophy. These effects are the result of favorable cellular remodeling. While preliminary clinical studies provide encouraging results, the potential and efficacy of TH in the treatment of heart disease still await evaluation in large clinical trials.

Skull Base Metastasis From Follicular Thyroid Carcinoma -Two Case Reports-

A 58-year-old woman and a 71-year-old woman presented with extremely rare skull base metastases from follicular thyroid carcinoma (FTC). Surgical removal and external radiotherapy were performed followed by iodine-131 ((131)I) brachytherapy and thyroid hormone administration. The metastatic tumors in the skull base were well controlled. Treatment for skull base metastasis from FTC includes surgical debulking of the metastatic lesion, as well as complete resection of the thyroid gland, followed by internal irradiation with (131)I, external irradiation, and administration of thyroid hormone to prevent tumor growth by suppression of endogenous thyroid-stimulating hormone. Skull base metastases may be the initial clinical presentation of FTC, with silent primary sites. The possibility of skull base metastasis from FTC should be considered in patients with clinical symptoms of cranial nerve dysfunction and radiological findings of bone destruction.

Cytoprotective and suicidal signaling in oxidative stress

Oxidative stress is an imbalance between pro-oxidants and antioxidants in favor of the pro-oxidants, leading to different responses depending on the level of pro-oxidants achieved and the duration of exposure. In this article, we discuss the cytoprotective or suicidal signaling mechanisms associated with oxidative stress by addressing: (i) the development of an acute and mild pro-oxidant state by thyroid hormone administration eliciting the redox upregulation of the expression of proteins affording cell protection as a preconditioning strategy against ischemia-reperfusion liver injury; and (ii) the role of prolonged and severe oxidative stress and insulin resistance as determinant factors in the pathogenesis of non-alcoholic fatty liver disease associated with obesity.

Administration of thyroid hormone increases reelin and brain-derived neurotrophic factor expression in rat hippocampus in vivo

Thyroid hormones play important roles in the maturation and function of the central nervous system. However, the underlying mechanism behind thyroid hormone-regulated gene expression in the adult brain is not well understood. Two genes critical for neuronal plasticity and implicated in psychiatric disorders, reelin and brain-derived neurotrophic factor (BDNF), were investigated in the present study. Triiodothyronine (T3), the active form of thyroid hormone was administered to young adult rats in two different manners: systemic injection or local brain infusion. Real time RT-PCR results revealed that T3 administration lead to a significant increase in reelin, total BDNF and exon-specific BDNF mRNA expression in the hippocampus. Furthermore, the association of transcriptional coactivators (including steroid receptor coactivator-1 (SRC-1), cAMP response element binding protein-binding protein (CBP), and thyroid hormone receptor associated protein 220 (TRAP 220)) and RNA polymerase II (RNA Pol II), with reelin and BDNF genes in the rat hippocampus displayed a distinct process following thyroid hormone administration. These findings suggest that association of transcriptional coactivators and RNA Pol II with gene promoters may be a possible mechanism explaining T3-induced reelin and BDNF expression in the hippocampus of young adult rats.

Pilot study on the assessment of the setpoint of the hypothalamus–pituitary–thyroid axis in healthy volunteers

To determine the log-linear relationship between TSH and free thyroxine in healthy subjects, and the variation in baseline TSH/free thyroxine (FT(4)) combination in each individual. Twenty-one healthy volunteers (nine males and 12 females; mean age 60 years, range 51-74) were randomized to receive at 2300 h with 2-week intervals a single dose of placebo, 125 microg T(4) and 250 microg T(4) (arm 1, n=10), or placebo, 25 microg triiodothyronine (T(3)) and 50 microg T(3) (arm 2, n=11). Blood samples were taken in the morning (0800-1100 h) before and following the administration of the drug for the assessment of TSH, FT(4) and T(3). Intra- and inter-individual variation and the individuality index of the four baseline serum samples were respectively 21.6%, 41.9% and 0.52 for TSH; 9.9%, 16.5% and 0.60 for FT(4); and 9.3%, 16.0% and 0.58 for T(3). Substantial differences existed in the location of individual working points within the reference range. T(4) administration increased FT(4) (but not T(3)) and decreased TSH, resulting in a log-linear relationship (log TSH=1.50-0.059xFT(4), P<0.05) for the whole group. T(3) administration increased T(3) and decreased TSH (but not FT(4)), resulting in a log-linear relationship (log TSH=0.790-0.245xT(3), P<0.001) for the whole group. Log-linear relationships were not always significant when assessed for each subject separately. Individuality indices of TSH, FT(4) and T(3) are all <or=0.6, thereby limiting the usefulness of the population-based reference values. Accurate assessment of individual setpoints of the HPT axis was not possible with the applied single doses of T(4) or T(3), and will require either prolonged administration or higher single doses of thyroid hormone.

Thyroid state and tolerance of mammalian myocardium to hypoxia

Thyroid hormone is known to affect myocardial glycogen stores and thereby possibly limit anaerobic performance of mammalian cardiac muscle. Thyroid hormone administration (3,5,3'-triiodo-L-thyroxine, 300 microg/kg/day, sc) for 10 days decreased left ventricle (LV) glycogen concentration relative to euthyroid animals (2.78+/-0.46 vs. 4.28+/-0.29 mg/g of LV (mean+/-SEM)) while increasing the percent of V(1) myosin isozyme, contractile activity and cardiac mass. In contrast, thyroidectomy increased myocardial glycogen stores (8.50+/-0.56 mg/g of LV) and shifted the myosin isozyme toward V(3), prolonged contractile activity and decreased LV mass. Thyroxine administration for 3, 7 and 10 days to thyroidectomized animals progressively decreased contractile duration and increased LV mass. Thyroxine administration for 3 or 7 days to thyroidectomized rats did not reduce glycogen stores (7.75+/-1.02 and 9.62+/-1.16 mg/g of LV, respectively), whereas myocardial glycogen declined to 3.30+/-0.58 mg/g of LV after 10 days of treatment. During hypoxia, cardiac muscle from thyroidectomized rats maintained greater active force and developed less contracture relative to euthyroid and, to a greater extent, than hyperthyroid rats. Removal of glucose from the bath decreased anaerobic performance and impaired recovery; however, myocardium from thyroidectomized rats remained more tolerant to hypoxia than the euthyroid group. Overall, the intrinsic LV glycogen content was positively correlated to anaerobic performance. These data demonstrate that the thyroid state profoundly affects myocardial growth, contractility and anaerobic performance of rat myocardium. Although energy demand may affect function during hypoxia, anaerobic substrate reserve (cardiac glycogen concentration) appears to be the primary factor determining tolerance to hypoxic stress.

Osteoporosis and Thyrotropin-Suppressive Therapy: Reduced Effectiveness of Alendronate

Many reports of the effect of exogenous thyroxine therapy on bone mineral density (BMD) show a relationship between excess thyroid hormone administration and osteoporosis. The aim of this study was to evaluate the effect of antibone resorptive agents, in particular alendronate (ALN) on BMD in postmenopausal osteoporotic women with thyroid carcinoma who were receiving long-term thyrotropin (TSH)-suppressive therapy with thyroxine. Seventy-four postmenopausal women with low BMD (T-score < or =-2.5) and differentiated thyroid carcinoma on long-term TSH-suppressive therapy (TSH > or =0.05 and < or =0.1 microU/mL) for about 3-9 years were selected for the study. The patients were divided into three groups according to the length of levothyroxine (LT(4)) treatment prior to the beginning of the study: group A (TSH-suppressive therapy for about 3 years), group B (for about 6 years), and group C (for about 9 years). These patients were compared with 74 matched women not taking LT(4). All patients and controls were treated with bisphosphonates, calcium, and vitamin D for 2 years and evaluated. After 24 months of treatment group A showed a 7.8% increase in lumbar BMD; group B, a 4.6% increase; and group C, a 0.86% increase. In the control group BMD increased 8.2%. A significant difference was found in both lumbar and femoral BMD increase among the three groups: group C had a lower BMD increase than group A (p < 0.001) and B (p < 0.001). In postmenopausal women who were receiving adequate amounts of calcium and vitamin D in their diet ALN was less effective for those who were also receiving TSH-suppressive doses of LT(4) for either 6 or 9 years. The positive effect of ALN on BMD was less for longer periods of LT(4) treatment. It seems likely that other bisphosphonates would also be less effective in increasing BMD in postmenopausal women receiving TSH-suppressing doses of LT(4).

Expression of Nkx2.5 in Wild Type, Cardiac Mutant, and Thyroxine-Induced Metamorphosed Hearts of the Mexican Axolotl

Nkx2.5, a homeodomain-containing transcription factor, is known to be necessary for normal heart development in vertebrates. It is one of the earliest lineage-restricted genes expressed in cardiovascular progenitor cells and knowledge of its expression patterns has important therapeutic implications for damaged cardiomyocytes. Mexican axolotl is a unique system to study heart development for two reasons: the presence of a mutant phenotype lacking organized myofibrils due to sarcomeric tropomyosin deficiency and the ability to induce metamorphosis by administration of exogenous thyroid hormone. In this study, we cloned and sequenced the as yet uncharacterized Nkx2.5 cDNA from normal and cardiac mutant axolotl heart RNA. Comparison of cDNA sequences of Nkx2.5 from normal and mutant axolotl hearts did not show differences suggesting that loss of function mutation in Nkx2.5 is not responsible for the mutant phenotype. However, quantitative studies show higher expression of Nkx2.5 in mutant hearts raising the possibility that increased expression of Nkx2.5 may contribute to the mutant phenotype. We also evaluated quantitative changes in expression of Nkx2.5 in axolotl hearts during embryonic and postembryonic heart development induced by exogenous thyroid hormone. There is an apparent increase in Nkx2.5 transcript levels in metamorphosed hearts.