L-thyroxine malabsorption due to calcium carbonate impairs blood pressure, total cholesterolemia, and fasting glycemia.

PURPOSE: Calcium carbonate was previously shown to interfere with L-thyroxine absorption. To estimate the magnitude of tablet L-thyroxine malabsorption caused by calcium carbonate, with resulting increase in serum thyrotropin (TSH), we performed a cohort study in a referral care center. METHODS: Fifty postmenopausal hypothyroid L-thyroxine-treated women (age 71.7 ± 5.1 years) who added calcium supplementation (600-1000 mg/day) were considered. They were taking L-thyroxine 45-60 min before breakfast (setting 1). After 4.4 ± 2.0 years from initiation of L-thyroxine therapy, they took calcium supplemaentation within 2 h after L-thyroxine taking (setting 2) for 2.3 ± 1.1 years. Hence, we recommended postponing calcium intake 6-8 h after L-thyroxine (setting 3). We evaluated TSH levels, the prevalence of women with elevated TSH (>4.12 mU/L), total cholesterolemia, fasting glycemia, blood pressure, and the prevalence of hypercholesterolemia, hyperglycemia, and hypertension. RESULTS: TSH levels were 3.33 ± 1.93 mU/L versus 1.93 ± 0.51 or 2.16 ± 0.54 comparing setting 2 with setting 1 or 3 (P < 0.001, both). In setting 2, 18% women had elevated TSH versus none in setting 1 or 3 (P < 0.01). Total cholesterolemia, fasting glycemia, systolic, and diastolic blood pressure were also significantly higher in setting 2 compared to settings 1 and 3. For every 1.0 mU/L increase within the TSH range of 0.85-6.9 mU/L, total cholesterolemia, glycemia, systolic, and diastolic blood pressure increased by 12.1, 3.12 mg/dL, 2.31, and 2.0 mmHg, respectively. CONCLUSIONS: Monitoring of hypothyroid patients who ingest medications that decrease L-thyroxine absorption should not be restricted to solely measuring serum TSH.

Quantification of Thyromimetic Sobetirome Concentration in Biological Tissue Samples.

Thyroid hormone is a principal regulator of essential processes in vertebrate physiology and homeostasis. Synthetic derivatives of thyroid hormone, known as thyromimetics, display desirable therapeutic properties. Thoroughly understanding how thyromimetics distribute throughout the body is crucial for their development and this requires appropriate bioanalytical techniques to quantify drug levels in different tissues. Here, we describe a detailed protocol for the quantification of the thyromimetic sobetirome using liquid chromatography tandem-mass spectrometry (LC-MS/MS).

Levothyroxine Dosing Following Bariatric Surgery.

BACKGROUND: Based on the mechanisms of drug absorption, increased levothyroxine requirements are expected after bariatric surgery. However, there are conflicting data on this topic. This review evaluates the effects of bariatric surgery on levothyroxine dosing. METHODS: Data were obtained from PubMed, Scopus, and review of published bibliographies. RESULTS: Six of 10 studies demonstrated decreased postoperative requirements. Most demonstrated correlations between weight loss and dose. Only 3 case reports and 1 case series demonstrated increased levothyroxine requirements, attributed to malabsorption. CONCLUSIONS: The loss of both fat and lean body mass may counteract malabsorptive effects from surgery, resulting in decreased postoperative levothyroxine requirements. In addition, the reversal of impaired levothyroxine pharmacokinetics and an altered set point of thyroid hormone homeostasis may also contribute to postoperative levothyroxine reductions.

[Potentiation strategies]. / Dépression résistante : les stratégies de potentialisation.

Lithium is among the most classically recommended add-on therapeutic strategy for the management of depressive patients showing unsuccessful response to standard antidepressant medications. The effectiveness of the add-on strategy with lithium requires achieving plasma levels above 0.5 mEq/L. Mood-stabilizing antiepileptic drugs such as carbamazepine, valproate derivatives or lamotrigine have not demonstrated conclusive therapeutic effects for the management of depressive patients showing unsuccessful response to standard antidepressant medications. Thyroid hormones are considered among the currently recommended add-on therapeutic strategy for the management of depressive patients showing unsuccessful response to standard antidepressant medications. The effectiveness of the add-on strategy with thyroid hormones requires achieving plasma concentration of TSH close to the lower limits at the normal range (0.4 µUI/L) or even below it. Second-generation antipsychotics such as aripiprazole or quetiapine have consistently demonstrated significant therapeutic effects for the management of depressive patients showing unsuccessful response to standard antidepressant medications. Second-generation antipsychotics however require the careful monitoring of both cardiovascular and metabolic adverse effects.

Silychristin, a Flavonolignan Derived From the Milk Thistle, Is a Potent Inhibitor of the Thyroid Hormone Transporter MCT8.

Thyroid hormones (THs) are charged and iodinated amino acid derivatives that need to pass the cell membrane facilitated by thyroid hormone transmembrane transporters (THTT) to exert their biological function. The importance of functional THTT is affirmed by the devastating effects of mutations in the human monocarboxylate transporter (MCT) 8, leading to a severe form of psychomotor retardation. Modulation of THTT function by pharmacological or environmental compounds might disturb TH action on a tissue-specific level. Therefore, it is important to identify compounds with relevant environmental exposure and THTT-modulating activity. Based on a nonradioactive TH uptake assay, we performed a screening of 13 chemicals, suspicious for TH receptor interaction, to test their potential effects on THTT in MCT8-overexpressing MDCK1-cells. We identified silymarin, an extract of the milk thistle, to be a potent inhibitor of T3 uptake by MCT8. Because silymarin is a complex mixture of flavonolignan substances, we further tested its individual components and identified silychristin as the most effective one with an IC50 of approximately 100 nM. The measured IC50 value is at least 1 order of magnitude below those of other known THTT inhibitors. This finding was confirmed by T3 uptake in primary murine astrocytes expressing endogenous Mct8 but not in MCT10-overexpressing MDCK1-cells, indicating a remarkable specificity of the inhibitor toward MCT8. Because silymarin is a frequently used adjuvant therapeutic for hepatitis C infection and chronic liver disease, our observations raise questions regarding its safety with respect to unwanted effects on the TH axis.

Effects of thyroid hormones on the heart

Thyroid hormones have a significant impact on heart function, mediated by genomic and non-genomic effects. Consequently, thyroid hormone deficiencies, as well as excesses, are expected to result in profound changes in cardiac function regulation and cardiovascular hemodynamics. Thyroid hormones upregulate the expression of the sarcoplasmic reticulum calcium-activated ATPase and downregulate the expression of phospholamban. Overall, hyperthyroidism is characterized by an increase in resting heart rate, blood volume, stroke volume, myocardial contractility, and ejection fraction. The development of "high-output heart failure" in hyperthyroidism may be due to "tachycardia-mediated cardiomyopathy". On the other hand, in a hypothyroid state, thyroid hormone deficiency results in lower heart rate and weakening of myocardial contraction and relaxation, with prolonged systolic and early diastolic times. Cardiac preload is decreased due to impaired diastolic function. Cardiac afterload is increased, and chronotropic and inotropic functions are reduced. Subclinical thyroid dysfunction is relatively common in patients over 65 years of age. In general, subclinical hypothyroidism increases the risk of coronary heart disease (CHD) mortality and CHD events, but not of total mortality. The risk of CHD mortality and atrial fibrillation (but not other outcomes) in subclinical hyperthyroidism is higher among patients with very low levels of thyrotropin. Finally, medications such as amiodarone may induce hypothyroidism (mediated by the Wolff-Chaikoff), as well as hyperthyroidism (mediated by the Jod-Basedow effect). In both instances, the underlying cause is the high concentration of iodine in this medication

Las Hormonas Tiroideas (HT) tienen un impacto significativo sobre la función cardiaca, el cual es mediado por efectos genómicos y no-genómicos. Como consecuencia, la deficiencia y el exceso de las HT origina profundos cambios en la regulación de la función cardiaca y en algunos aspectos hemodinámicos y cardiovasculares. Las HT supra-regulan la expresión de la ATPasa activada por calcio del retículo sarcoplasmático, e infra-regulan la expresión de fosfolambán. En general, el hipertiroidismo se caracteriza por un incremento en la frecuencia cardiaca en reposo, del volumen sanguíneo, de la contractilidad miocárdica y del volumen sistólico, entre otros. El desarrollo de "Falla cardiaca de alto gasto" en hipertiroidismo puede ser debido a "Cardiomiopatía mediada por taquicardia". Por otro lado; en el estado hipotiroideo, la deficiencia de HT origina bradicardia, debilidad en la contractilidad y relajación miocárdica, con prolongación del tiempo sistólico y diastólico temprano. La disminución en la precarga se debe a las alteraciones en la función diastólica; la post-carga se incrementa, y las funciones cronotrópicas e inotrópicas están disminuidas. El hipotiroidismo subclínico incrementa el riesgo de mortalidad por Enfermedad Arterial Coronaria (EAC) y de eventos por EAC, pero no aumenta el riesgo de mortalidad total. El riesgo de mortalidad por EAC y de fibrilación auricular (pero no de otros resultados) en hipertiroidismo subclínico es mayor entre pacientes con niveles muy bajos de tirotropina. Finalmente, medicamentos como la amiodarona puede inducir hipotiroidismo (mediado por el efecto de Wolff-Chaikoff, además de hipertiroidismo (mediado por el efecto de Jod-Basedow. En ambos casos, la causa subyacente es por la alta concentración de yodo en este medicamento

Placenta passage of the thyroid hormone analog DITPA to male wild-type and Mct8-deficient mice.

Monocarboxylate transporter 8 (MCT8) deficiency causes severe X-linked intellectual and neuropsychological impairment associated with abnormal thyroid function tests (TFTs) producing thyroid hormone (TH) deprivation in brain and excess in peripheral tissues. The TH analog diiodothyropropionic acid (DITPA) corrected the TFTs abnormalities and hypermetabolism of MCT8-deficient children but did not improve the neurological phenotype. The latter result was attributed to the late initiation of treatment. Therefore, we gave DITPA to pregnant mice carrying Mct8-deficient embryos to determine whether DITPA, when given prenatally, crosses the placenta and affects the serum TFTs and cerebral cortex of embryos. After depletion of the endogenous TH, Mct8-heterozygous pregnant dams carrying both wild-type (Wt) and Mct8-deficient (Mct8KO) male embryos were given DITPA. Effects were compared with those treated with levothyroxine (L-T4). With DITPA treatment, serum DITPA concentration was not different in the two genotypes, which produced equal effect on serum TSH levels in both groups of pups. In contrast, with L-T4 treatment, TSH did not normalize in Mct8KO pups whereas it did in the Wt littermates and dams despite higher concentration of serum T4. Finally, both treatments similarly modulated the expression of the TH-dependent genes Shh, Klf9, and Aldh1a3 in brain. Thus, the ability of DITPA to cross the placenta, its thyromimetic action on the expression of TH-dependent genes in brain, and its better accessibility to the pituitary than L-T4, as assessed by serum TSH, make DITPA a candidate for the prenatal treatment of MCT8 deficiency.

Regulation of adiponectin gene expression in adipose tissue by thyroid hormones

Available experimental data suggest that adiponectin and thyroid hormones have biological interaction in vivo. However, the effects of thyroid hormones on adipose adiponectin gene expression in thyroid dysfunction are unclear. We induced hyper- (HYPER) and hypothyroidism (HYPO) by daily administration of a 12 mg/l of levothyroxine and 250 mg/l of methimazole in drinking water of rats, respectively, for 42 days. The white adipose tissues and serum sample were taken on days 15, 28, 42 and also 2 weeks after treatment cessation. Analysis of adiponectin gene expression was performed by real-time PCR and 2−ÄÄct method. The levels of adipose tissue adiponectin mRNA in the HYPO rats were decreased during the 6-week treatment when compared to control rats (<0.05) and were increased significantly 2 weeks after HYPO cessation (P < 0.05). This decline in adiponectin gene expression occurred in parallel with a decrease in T3, T4, fT3 and fT4 concentrations (P < 0.05). In opposite to HYPO rats, adipose adiponectin gene expression was increased in HYPER rats during the 6-week treatment in parallel with an increase the thyroid hormones concentrations (P < 0.05), and its expression was decreased 2 weeks after HYPER cessation (P < 0.05). Adiponectin gene expression levels showed significant negative correlations with concentrations of LDL (HYPO; r = −0.806, P = 0.001 and HYPER; r = −0.749, P = 0.002), triglyceride (HYPO; r = −0.825, P = 0.001 and HYPER; r = −0.824, P = 0.001) and significant positive correlations with concentrations of glucose (HYPO; r = 0.674, P = 0.004 and HYPER; r = 0.866, P = 0.001) and HDL (HYPO; r = 0.755, P = 0.001 and HYPER; r = 0.839, P = 0.001). The current study provides evidence that adiponectin gene expression in adipose tissue is regulated by thyroid hormones at the translation level and that lipid and carbohydrate disturbances in a patient with thyroid dysfunction may be, in part, due to adiponectin gene expression changes (AU)

Intoxicación por ingesta de levotiroxina (Eutirox(R)) / Intoxication due to ingestión of levothyroxine (Eutirox(R))

La levotiroxina es el fármaco de elección en el tratamiento del hipotiroidismo. La intoxicación con levotiroxina no es muy frecuente pero puede acompañarse de complicaciones secundarias sobre todo cardiovasculares. La unión de hormonas tiroideas a proteínas plasmáticas es muy elevada (99,97%), debido a esto, la levotiroxina no se elimina por hemodiálisis ni hemoperfusión. Tiene una vida media de 7 días. Se presenta el caso de una niña de 6 años que acude a la puerta de urgencias por sospecha de ingesta de levotiroxina en cantidades desconocidas. Se valora que parámetros del seguimiento de la función tiroidea es significativo de la mejora del paciente (AU)

Levothyroxine is the drug of choice of Hypothyroidism's treatment. The poisoning (intoxication) with levothyroxine is rare, but, overcoat it can be accompanied of secondary cardiovascular complications. Binding of thyroid hormones to plasma proteins is very high (99.97%), due to this, the levothyroxine is not removed by hemodialysis or hemoperfusion. It has an average life of 7 days. We hereby present the case o a 6-year-old girl who comes at the Emergency Service for suspicion of ingestion of levothyroxine in unknown quantities. There are valued what parameters of the follow-up of the tyroid function it is significant of the improvement of the patient (AU)

Relación hepatosomática y depósito de hierro en hígado durante la instauración de anemia ferropénica nutricional / Hepatosomatic index and iron liver stores during the instauration of nutritional ferropenic anaemia

El hígado es el principal órgano de almacén de hierro en el organismo y juega un papel crucial en la homeostasis de dicho mineral. Los niveles de hierro en se consideran un fiel reflejo del estatus de hierro en el organismo, hecho que nos indujo a determinar la relación hepatosomática y el contenido de hierro en hígado durante la instauración de la anemia ferropénica nutricional inducida experimentalmente en ratas en crecimiento. Los depósitos de hierro estaban profundamente deplecionados, el peso corporal y el peso hepático fue menor en animales anémicos. Como consecuencia, la relación hepatosomática se incrementó en animales ferrodeficientes. Durante la ferrodeficiencia, varios factores reguladores de la hepcidina se alteran, aumenta la demanda eritropoyética por disminución de los parámetros hematológicos, hay un menor aporte de oxígeno a los tejidos y se deplecionan los depósitos corporales, alterándose el metabolismo de hierro, hechos que conducen a una disminución de dicha hormona, lo cual se traducirá en una menor interacción con la ferroportina 1, evitando su internalización y degradación, de manera que aumenta el flujo de salida de hierro ferroso desde los hepatocitos y consecuentemente se reduce su depósito. Por otra parte, la ferrodeficiencia afectó el peso corporal, hecho que se puede atribuir a los menores niveles de hormonas tiroideas encontrados en esta patología. Puesto que hay una clara reducción de la hemoglobina y recuento de hematíes, el suministro de oxígeno a las células se limita considerablemente e incide negativamente en la síntesis de ATP e incremento de peso(AU)

Liver is main storage organ of iron in the organism and plays a crucial role in the homeostasis of this mineral. The levels of iron are considered a routine index of the iron status in the body, fact that encouraged us to asses the hepatosomatic index and the iron content in liver, during iron-deficiency anaemia in growing rats. In rats with iron-deficiency anaemia, iron deposits were deeply depleted, body weight and hepatic weight were lower, moreover the hepatic iron deposits were lower in anaemicrats. During the iron-deficiency, several regulatory factors of the hepcidin are impaired (the erythropoietic demand increase due to the decrease of the haematological parameters, there is a minor supply of oxygen to the tissues and the body stores are depleted, being the iron metabolism altered), facts that leads to a decrease of the above mentioned hormone, which will be translated in a minor interaction with the ferroportin1, avoiding its internalization and degradation, therefore increases the outflow of ferrous iron from the hepatocytes and consistently its storage diminishes in the above mentioned organ. On the other hand, the iron-deficiency impaired the body weight, fact that can be related with the lower levels of thyroid hormones found in this pathology. Moreover, since in iron deficiency situation the haemoglobin and red blood cells count diminish drastically, the supply of oxygen to the cells limits itself considerably, which affects in a negative way to the ATP synthesis andincrease of weight(AU)

Transport of thyroid hormones is selectively inhibited by 3-iodothyronamine.

Thyroid hormone transporters are responsible for the cellular uptake of thyroid hormones, which is a prerequisite for their subsequent metabolism and action at nuclear thyroid hormone receptors. A recently discovered thyroid hormone derivative, 3-iodothyronamine (T(1)AM), has distinct biological effects that are opposite those of thyroid hormone. Here we investigate the effects of T(1)AM on thyroid hormone transporters using COS-1 cells transfected with the multispecific organic anion transporting polypeptides (OATPs) 1A2, 1B3, and 1C1, as well as the specific thyroid hormone transporters MCT8 and MCT10, and show that T(1)AM displays differential inhibition of T(3) and T(4) cellular uptake by these transporters. T(1)AM inhibits T(3) and T(4) transport by OATP1A2 with IC(50) values of 0.27 and 2.1 microM, respectively. T(4) transport by OATP1C1, which is thought to play a key role in thyroid hormone transport across the blood-brain barrier, is inhibited by T(1)AM with an IC(50) of 4.8 microM. T(1)AM also inhibits both T(3) and T(4) uptake via MCT8, the most specific thyroid hormone transporter identified to date, with IC(50) values of 95 and 31 microM, respectively. By contrast, T(1)AM has no effect on thyroid hormone transport by OATP1B3 and MCT10. Given that OATP1A2, OATP1C1, and MCT8 are all present in the brain, T(1)AM may play an important role in modulating thyroid hormone delivery and activity in specific target regions in the central nervous system.

Thyroid hormone at supra-physiological dose optimizes cardiac geometry and improves cardiac function in rats with old myocardial infarction.

Thyroid hormone (TH) is critical in cardiac cell differentiation (regulating contractile proteins and cell geometry) and this effect could be potentially exploited therapeutically in reversing the process of de-differentiation which underlies postischemic cardiac remodeling. Acute myocardial infarction was induced in male Wistar rats by ligating left coronary artery (AMI, n=8), while sham operated animals served as control (SHAM, n=8). 13 weeks after AMI, TH was administered in a group of animals for 4 weeks (AMI-THYR, n=9). TH significantly increased beta-MHC and decreased alpha-MHC expression in the myocardium. This response was accompanied by changes in cardiac geometry: sphericity index, (SI, long to short axis ratio) was found to be 1.95 (SEM, 0.02) in SHAM, 1.51(0.03) in AMI and 1.64(0.03) in AMI-THYR, p<0.05. As a consequence, cardiac function was significantly improved: left ventricular ejection fraction (EF%) was 74.5% (SEM, 2.8) in SHAM vs 29.5% (2.1) in AMI, and 40.0% in AMI-THYR, p<0.05. Furthermore, +dp/dt and -dp/dt were 4250 (127) and 2278 (55) in SHAM vs 2737(233) and 1508 (95) in AMI vs 3866 (310) and 2137(111) in AMI -THYR, respectively, p<0.05. TH treatment partially reverses cardiac dysfunction in rats with old myocardial infarction by favorably changing cardiac chamber geometry and expression of myosin isoforms. Thyroid hormone, unlike current treatments, appears to be a paradigm of therapeutic intervention which aims at restoring cardiac geometry and may prove new effective treatment for heart failure.

Gestational and lactational exposure to potassium perfluorooctanesulfonate (K+PFOS) in rats: toxicokinetics, thyroid hormone status, and related gene expression.

Perfluorooctanesulfonate (PFOS), a persistent and accumulative compound, is widely distributed in humans and wildlife. Human exposure can occur early in development, as evidenced by the detection of PFOS in umbilical cord blood and breast milk. As part of a developmental neurotoxicology study for which developmental endpoints, including those related to the developing nervous system, have been reported separately, groups of 25 pregnant Sprague Dawley rats were given daily oral doses of either vehicle control or potassium PFOS (K(+)PFOS) at 0.1, 0.3, and 1.0mg/kg-d from gestation day (GD) 0 (day positive for mating) through postnatal day (PND) 20. An additional 10 pregnant females per treatment group were treated through GD 19 and sacrificed on GD 20 in order to obtain maternal and fetal serum and tissue samples at the end of gestation. The present paper reports the results of samples of serum, liver, brain, and thyroid glands taken at various times to evaluate: (1) serum, liver, and brain PFOS concentrations by LC-MS/MS to establish the relationship between PFOS concentrations and study outcomes; (2) serum thyrotropin (TSH) concentrations by RIA; (3) thyroid follicular cell proliferation index by Ki-67 immunohistochemical staining; (4) thyroid follicle epithelial cell height and colloidal area by histomorphometric analysis; (5) selected liver mRNA transcripts by quantitative RT-PCR. PFOS concentrations in dam and pup serum, liver, and brain increased across treatment groups in approximate proportion to the proportional increases in maternal K(+)PFOS dose, and sex differences in PFOS concentrations were not apparent in pups on PND 21. In pups from K(+)PFOS maternal dose groups on PND 72, serum PFOS had decreased to about 3 and 11% of PND 21 concentrations in males and females, respectively, and liver PFOS had decreased to about 17% of PND 21 concentrations in both sexes. Liver PFOS concentrations were approximately 0.6-0.8 times serum PFOS in GD 20 fetuses, and increased to about 2-4 times serum concentrations on PND 4 and 21. GD 20 fetal and PND 4 pup brain PFOS concentrations were approximately 33% of the corresponding serum concentrations, dropping to approximately 10% by PND 21, in contrast to dam brain PFOS concentrations, which were approximately 4-9% of serum PFOS concentrations. Compared to controls, Cyp2b2 mRNA was increased (2.8-fold) in the 1.0mg/kg-d treatment-group dams on GD 20. In male pups on PND 21, Cyp4A1, ACoA, and Cyp2b2 were increased 2.1-, 1.5-, and 1.8-fold, respectively, and Cyp7A1 was decreased 3.5-fold. Serum TSH and thyroid follicular morphology were not altered by K(+)PFOS treatment. The mean number of proliferating thyroid follicular cells was increased 2.1-fold over control in GD 20 female fetuses from 1.0mg/kg-d-treated dams, yet the highest individual count was similar to that of controls (116 versus 113 in controls).

[Absorption, transport and bio-availability of iodothyronines]. / Resorption, Transport und Bioverfügbarkeit von Schilddrüsenhormonen.

The frequently prescribed classical thyroid hormones (iodothyronines) are critical dose drugs with a narrow therapeutic index. Nowadays the mechanisms of their absorption, which takes place predominantly in the jejunum and ileum, have only partly been elucidated. Bioavailability of iodothyronines whose kinetics is subject to enterohepatic circulation, is about 70 %. Several factors influence their absorption including nutrients, drugs and concomitant diseases. After being absorbed only a small fraction of thyroid hormones circulates freely in plasma, whereas the greater portion is bound to plasma proteins. This binding, too, may be influenced by numerous factors; alterations by certain diseases and physiological conditions may lead to ambiguities in differential diagnosis. Intracellular accumulation of iodothyronines is accomplished by at least ten different active and energy-dependent transporters with variable tissue distribution. Particularly in critical illness (non-thyroidal illness syndrome) alterations of protein binding and membrane transport are common. In therapy of hypothyroid patients different brand-name products lack bioequivalence and thus requiring subsequent monitoring of thyroid status after treatment has been changed among different brand-name versions.

Posibilidades terapéuticas en la resistencia hipofisaria selectiva a las hormonas tiroideas / Therapeutic possibilities in patients with selective pituitary resistance to thyroid hormones

La resistencia hipofisaria selectiva a hormonas tiroideas (RHSHT) es una forma no neoplásica de secreción inadecuada de tirotropina (TSH). La causa de esta resistencia hormonal radica en la presencia de mutaciones inactivantes en el gen del receptor de las hormonas tiroideas (RHT) beta. Estas mutaciones afectan a la zona de unión de la triyodotironina (T3) al RHT. La RHSHT se manifiesta por hipertiroidismo con bocio difuso y ausencia de lesión hipofisaria en las pruebas de imagen. Los datos analíticos muestran elevación de T3 y tiroxina libres, sin supresión de TSH y con un cociente molar de la subunidad alfa de TSH/TSH normal. No se dispone de tratamiento específico para la RHSHT. Se han empleado los bloqueadores betaadrenérgicos, como el atenolol, y los ansiolíticos como tratamiento sintomático. Entre los fármacos con capacidad de reducir la secreción de TSH se encuentran los agonistas del RHT, como el ácido triyodoacético, la D-tiroxina, el ácido 3,5,3'-triyodotiropropiónico y la L-T3

Selective pituitary resistance to thyroid hormones (SPRTH) is a non-neoplastic form of inappropriate secretion of thyrotropin (TSH). The etiology of this hormonal resistance is linked to inactivating mutations in the thyroid hormone receptor beta (TR-b) gene. These mutations affect critical portions of the receptor's triiodothyronine (T3)-binding domain. Clinically, SPRTH is characterized by hyperthyroidism with goiter and absence of pituitary mass in the morphologic study. Laboratory data show an elevation of free T3 and free thyroxine concentrations without suppression of TSH, with normal molar subunit alpha/TSH ratio. At this time, there is no specific therapy for SPRHT. Beta blockers, such as atenolol, and benzodiazepines have been used as a symptomatic therapy. Among the drugs with the capacity for reducing TSH secretion are TR agonists, such as triiodothyroacetic acid, D-thyroxine, triiodothyropropionic acid, and L-T3 (AU)

Genotype-phenotype relationship in patients with mutations in thyroid hormone transporter MCT8.

Loss-of-function mutations in thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to severe X-linked psychomotor retardation and elevated serum T(3) levels. Most patients, for example those with mutations V235M, S448X, insI189, or delF230, cannot stand, walk, or speak. Patients with mutations L434W, L568P, and S194F, however, walk independently and/or develop some dysarthric speech. To study the relationship between mutation and phenotype, we transfected JEG3 and COS1 cells with wild-type or mutant MCT8. Expression and function of the transporter were studied by analyzing T(3) and T(4) uptake, T(3) metabolism (by cotransfected type 3 deiodinase), Western blotting, affinity labeling with N-bromoacetyl-T(3), immunocytochemistry, and quantitative RT-PCR. Wild-type MCT8 increased T(3) uptake and metabolism about 5-fold compared with empty vector controls. Mutants V235M, S448X, insI189, and delF230 did not significantly increase transport. However, S194F, L568P, and L434W showed about 20, 23, and 37% of wild-type activity. RT-PCR did not show significant differences in mRNA expression between wild-type and mutant MCT8. Immunocytochemistry detected the nonfunctional mutants V235M, insI189, and delF230 mostly in the cytoplasm, whereas mutants with residual function were expressed at the plasma membrane. Mutants S194F and L434W showed high protein expression but low affinity for N-bromoacetyl-T(3); L568P was detected in low amounts but showed relatively high affinity. Mutations in MCT8 cause loss of function through reduced protein expression, impaired trafficking to the plasma membrane, or reduced substrate affinity. Mutants L434W, L568P, and S194F showed significant residual transport capacity, which may underlie the more advanced psychomotor development observed in patients with these mutations.

Mecanismos das alterações do desempenho físico na programação pelo bloqueio da prolactina ao final da lactação / Mechanisms of changes in physical performance in the programming by the blockage of prolactin at the end of lactation

Anteriormente, observamos que o uso de bromocriptina (BRO), um agonista dopaminérgico inibidor de prolactina, ao final da lactação, leva ao bloqueio da produção de leite, causando uma desnutrição moderada da prole e programando uma maior massa corporal total (MCT) e de gordura visceral (MGV) e hipofunção tireóidea na idade adulta, características que são deletérias para o adequado desempenho físico. Sendo assim, avaliamos nestes animais alguns dos mecanismos relacionados à capacidade física como o conteúdo de glicogênio (muscular e hepático), as concentrações séricas de insulina, hormônios tireóideos (HTs), a atividade da enzima glicerol-fosfato desidrogenase mitocondrial (GPDm), que é regulada por HTs, no fígado, no TAM e no músculo esquelético. Indicadores de estresse oxidativo também foram avaliados utilizando o teste de espécies reativas ao ácido tiobarbitúrico (TBARs) e capacidade antioxidante total (CAT), na prole adulta aos 90 e 180 dias de idade cujas mães receberam BRO (1 mg/dia) nos 3 dias finais da lactação. O desempenho físico foi avaliado aos 90 e 180 dias de idade pela quantificação do tempo máximo de nado (TMN) em metade dos animais de cada grupo (n=10). Os ratos foram colocados em piscina com temperatura controlada (32+-2ºC) com carga adicional presa à cauda (equivalente a 5% da MCT). Aos 90 dias a MGV foi maior no grupo BRO (+56%), enquanto que os valores de glicemia (-10%) e atividade da GPDm no músculo (-53%) e n TAM (-40%) foram menores. O conteúdo de glicogênio no músculo sóleo não apresentou diferenças em resposta ao tratamento experimental ou exercício em ambas as idades, enquanto que no EDL nós observamos uma mobilização de glicogênio nos aminais exercitados de forma similar. Os animais do grupo BRO apresentaram um maior TMN (+35%), com menor produção de lactato pós-exercício (-20%). O maior conteúdo de glicogênio hepático observado no grupo BRO aos 90 dias na condição basal (+53%), e sua maior degradação com o exercício (-57%)...

Previously, we observed that the utilization of bromocriptine (BRO) a dopaminergic agonist that inhibits prolactin, at the end of lactation causes milk production blockade, provoking a moderate malnutrition in the pups and programming a higher body mass and visceral fat mass (VFM) and thyroid hypofunction in adult age, which are deleterious conditions for adequate physical performance. Therefore, we evaluated some mechanisms related to physical performance like blood lactate, glycemia and glycogen content (muscle and liver), serum insulin and thyroid hormones (THs) concentrations, mitochondrial glycerol-phosphate dehydrogenase activity (mGPD), and enzyme regulated by thyroid hormones (THs) in liver, brown adipose tissue (BAT) and skeletal muscle. Oxidative stress indicators were also evaluated using thiobarbituric acid reactive substances (TBARs) and total antioxidant capacity (TAC) in adult pups (90 and 180 days old), whose mothers received BRO (1mg/day) at the last 3 days of lactation. Physical performance was evaluated on 90 and 180 days old animals (n=10). The rats were placed in a swimming pool with controlled temperature (89+-2ºF) with additional load attached to the tail equivalent to 5% of body mass (BM). VFM was higher in 90 days old BRO group (+56%), while glycemia (-10%) and mGPD activity in muscle (-53%) and BAT (-40%) were lower. Glycogen content in soleous muscle did not present differences in response to experimental treatment or exercise in both ages, while in EDL we observed glycogen mobilization with exercise in a similar way. BRO animals presented higher MST values (+35%), with lower post-exercise lactate production (-20%). The higher hepatic glycogen content observed in BRO group at 90 days old in the basal period (+53%), and its higher degradation (-57%) together with the higher activity of mGPD in muscle in exercised animals (+172%) could contribute to the better physical performance in that age. Additionally, the higher values...

Pseudomalabsorption of thyroid hormones: case report and review of the literature.

Many causes of thyroxine malabsorption are described in the literature, but the most common cause of failure of thyroxine therapy is poor patient compliance, or pseudomalabsorption. We describe the case of a female patient who underwent total thyroidectomy for Basedow-Graves disease. Post-operatively, several treatment regimens were employed to achieve euthyroidism, but only injectable thyroxine was found to be effective. To exclude levothyroxine malabsorption, the patient was hospitalized in a hypothyroid state while a single oral test dose of levothyroxine (1000 microg) was administered. Within 4 hours a decrease of TSH level (from 59.7 to 55.6 microUI/ml) and a significant increase in free T4 levels (from 0.8 to 15.5 pg/ml) was observed, eliminating a malabsorption problem. The cause of resistance to thyroid hormone therapy was poor patient compliance, leading to the designation of this as a case of pseudomalabsorption.