Thyroxine Treatment Research Articles

Treatment of subclinical hypothyroidism in pregnancy using fixed thyroxine daily doses of 75μg

Abstract Background and objectives Treatment of hypothyroid pregnant women is usually calculated based on weight (1 μg/kg/day) and TSH levels. This study assessed the usefulness of treating these women with a fixed dose of 75 μg/day. Patients and methods All women with pregnancy diagnosed from January to August 2012 in the Vigo Health Area (Spain) without previous diagnosis of thyroid disease or thyroxine treatment and with TSH levels over 4.5 mUI/mL were enrolled by consecutive sampling. All 116 women in the sample were treated with a fixed daily dose of thyroxine 75 μg-thyroxine levels were measured at two, four, and six months, and thyroxine dose was modified if TSH level was lower than 0.3 or higher than 4.5 mUI/mL. Results A woman had a TSH level less than 0.3 mUI/mL in a test; reduction of thyroxine dose to 50 μg/day allowed for maintaining TSH level within the desired range until delivery. Six women had TSH levels over 4.5 mUI/mL in one test; in all of them, increase in thyroxine dose to 100 μg/day allowed for maintaining the level within the desired range until delivery. Conclusions Fixed daily doses of thyroxine 75 μg allowed for achieving goal TSH levels in most of our pregnant women with subclinical hypothyroidism, irrespective of their weight and baseline TSH level.

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.

Resistance to thyroid hormone caused by a mutation in thyroid hormone receptor (TR)α1 and TRα2: clinical, biochemical, and genetic analyses of three related patients

The thyroid hormone receptor α gene (THRA) transcript is alternatively spliced to generate either thyroid hormone receptor (TR)α1 or a non-hormone-binding variant protein, TRα2, the function of which is unknown. Here, we describe the first patients identified with a mutation in THRA that affects both TRα1 and TRα2, and compare them with patients who have resistance to thyroid hormone owing to a mutation affecting only TRα1, to delineate the relative roles of TRα1 and TRα2. We did clinical, biochemical, and genetic analyses of an index case and her two sons. We assessed physical and radiological features, thyroid function, physiological and biochemical markers of thyroid hormone action, and THRA sequence. The patients presented in childhood with growth failure, developmental delay, and constipation, which improved after treatment with thyroxine, despite normal concentrations of circulating thyroid hormones. They had similar clinical (macrocephaly, broad faces, skin tags, motor dyspraxia, slow speech), biochemical (subnormal ratio of free thyroxine:free tri-iodothyronine [T3], low concentration of total reverse T3, high concentration of creatine kinase, mild anaemia), and radiological (thickened calvarium) features to patients with TRα1-mediated resistance to thyroid hormone, although our patients had a heterozygous mis-sense mutation (Ala263Val) in both TRα1 and TRα2 proteins. The Ala263Val mutant TRα1 inhibited the transcriptional function of normal receptor in a dominant-negative fashion. By contrast, function of Ala263Val mutant TRα2 matched its normal counterpart. In vitro, high concentrations of T3 restored transcriptional activity of Ala263Val mutant TRα1, and reversed the dominant-negative inhibition of its normal counterpart. High concentrations of T3 restored expression of thyroid hormone-responsive target genes in patient-derived blood cells. TRα1 seems to be the principal functional product of the THRA gene. Thyroxine treatment alleviates hormone resistance in patients with mutations affecting this gene, possibly ameliorating the phenotype. These findings will help the diagnosis and treatment of other patients with resistance to thyroid hormone resulting from mutations in THRA. Wellcome Trust, NIHR Cambridge Biomedical Research Centre, Marie Curie Actions, Foundation for Development of Internal Medicine in Europe.

Effect of Thyroxin Induction on Enzymatic and Biochemical Levels in Albino Rats

The albino Wistar rats were used to investigate the effect of thyroxine administration on the activity of citric acid, α-Amylase, creatine phosphokinase (CPK), creatinine, cholesterol and triglycerides level in blood serum and citric acid in liver and kidney. Two groups of rats were taken for the experiment. One group was injected subcutaneously with 200 μl of thyroxine/50 g of body weight, the other group served as control. The animals were vivisected with anesthesia after intervals of 24, 48, 72 and 96 hours α-Amylase and CPK levels in blood; citric acid level in liver and kidney of control and thyroxine treated rats. The results showed that the α-Amylase activity remained unaltered (100 g/h/l) throughout the experiment. However, citric acid level found to be 460 mg in the liver and 415 mg in kidney of control rats. The values slightly increased to 480 and 680 mg in respective tissues of thyroxine treated animals for 24 hr. The values decreased in 48 and 72 hours of treatment. Further the values found to be increased after 96 hours of treatment. Although the thyroxine treatment altered citric acid, Creatinine, Cholesterol, Triglycerides and CPK levels in the tissues, the serum α-Amylase was not influenced by the thyroxine. The study suggests that the thyroxine acts as a regulator all the above parameters in the cellular level.

G475(P) Management of Congenital Hypothyroidism – Our experience over a decade and the new national standards

AimTo audit the management of congenital hypothyroidism (CHT) against the recently published national standards to identify if changes in current clinical practice are required.Background:About 1 in 3000 babies born in...

Effect of Thyroxin Induction on Enzymatic and Biochemical Levels in Albino Rats

The albino Wistar rats were used to investigate the effect of thyroxine administration on the activity of citric acid, α-Amylase, creatine phosphokinase (CPK), creatinine, cholesterol and triglycerides level in blood serum and citric acid in liver and kidney. Two groups of rats were taken for the experiment. One group was injected subcutaneously with 200 μl of thyroxine/50 g of body weight, the other group served as control. The animals were vivisected with anesthesia after intervals of 24, 48, 72 and 96 hours α-Amylase and CPK levels in blood; citric acid level in liver and kidney of control and thyroxine treated rats. The results showed that the α-Amylase activity remained unaltered (100 g/h/l) throughout the experiment. However, citric acid level found to be 460 mg in the liver and 415 mg in kidney of control rats. The values slightly increased to 480 and 680 mg in respective tissues of thyroxine treated animals for 24 hr. The values decreased in 48 and 72 hours of treatment. Further the values found to be increased after 96 hours of treatment. Although the thyroxine treatment altered citric acid, Creatinine, Cholesterol, Triglycerides and CPK levels in the tissues, the serum α-Amylase was not influenced by the thyroxine. The study suggests that the thyroxine acts as a regulator all the above parameters in the cellular level.

Tratamiento del hipotiroidismo subclínico en gestantes con una dosis fija diaria de 75 μg de tiroxina

Background and objectivesTreatment of hypothyroid pregnant women is usually calculated based on weight (1μg/kg/day) and TSH levels. This study assessed the usefulness of treating these women with a fixed dose of 75μg/day. Patients and methodsAll women with pregnancy diagnosed from January to August 2012 in the Vigo Health Area (Spain) without previous diagnosis of thyroid disease or thyroxine treatment and with TSH levels over 4,5mUI/ml were enrolled by consecutive sampling. All 116 women in the sample were treated with a fixed daily dose of thyroxine 75μg-thyroxine levels were measured at two, four, and six months, and thyroxine dose was modified if TSH level was lower than 0.3 or higher than 4.5mUI/ml. ResultsA woman had a TSH level less than 0.3mUI/ml in a test; reduction of thyroxine dose to 50μg/day allowed for maintaining TSH level within the desired range until delivery. Six women had TSH levels over 4.5mUI/ml in one test; in all of them, increase in thyroxine dose to 100μg/day allowed for maintaining the level within the desired range until delivery. ConclusionsFixed daily doses of thyroxine 75μg allowed for achieving goal TSH levels in most of our pregnant women with subclinical hypothyroidism, irrespective of their weight and baseline TSH level.

Thyroid-stimulating hormone maintains bone mass and strength by suppressing osteoclast differentiation

It has been suggested that pituitary hormone might be associated with bone metabolism. To investigate the role of thyroid-stimulating hormone (TSH) in bone metabolism, we designed the present study as follows. After weaning, TSH receptor (TSHR) null mice (Tshr−/−) were randomly divided into a thyroxine treatment group (n=10) or non-treatment group (n=10); the treatment group received a dose of desiccated thyroid extract at 100ppm daily for 5 weeks. Age-matched wild-type (Tshr+/+, n=10) and heterozygote mice (Tshr+/−, n=10) served as controls. After 5 weeks, the animals were sacrificed, and the femurs were collected for histomorphometrical and biomechanical analyses. In addition, the effect of TSH on osteoclastogenesis was examined in the RAW264.7 osteoclast cell line. We found that compared with Tshr+/+ mice, Tshr−/− and Tshr+/− mice had lower bone strength. The histomorphometric results showed that trabecular bone volume, osteoid surface, osteoid thickness and osteoblast surface were significantly decreased, whereas the osteoclast surface was significantly increased in both Tshr−/− and Tshr+/− mice compared with Tshr+/+ mice. Bone resorption and formation in Tshr−/− mice were further enhanced by thyroxine replacement. bTSH inhibited osteoclast differentiation in vitro, as demonstrated by reduced development of TRAP-positive cells and down-regulation of differentiation markers, including tartrate-resistant acid phosphatase, matrix metallo-proteinase-9 and cathepsin K in RAW264.7 cells. Our results confirm that TSH increased bone volume and improved bone microarchitecture and strength at least partly by inhibiting osteoclastogenesis.

Effects of thyroxin and donepezil on hippocampal acetylcholine content and syntaxin-1 and munc-18 expression in adult rats with hypothyroidism

Adult-onset hypothyroidism induces various impairments in hippocampus-dependent cognitive function, in which numerous synaptic proteins and neurotransmitters are involved. Donepezil (DON), an acetylcholinesterase inhibitor, has been shown to be efficient in improving cognitive function. The aim of the present study was to investigate the effects of adult-onset hypothyroidism on the expression levels of the synaptic proteins syntaxin-1 and munc-18, as well as the content of the neurotransmitter acetylcholine (ACh) in the hippocampus. In addition, the study explored the effects of thyroxin (T4) and DON treatment on the altered parameters. The study involved 55 Sprague-Dawley rats that were randomly divided into five groups: Control, hypothyroid (0.05% 6-n-propyl-2-thiouracil; added to the drinking water), hypothyroid treated with T4 (6 μg/100 g body weight once daily; intraperitoneal injection), hypothyroid treated with DON (0.005%; added to the drinking water) and hypothyroid treated with a combination of the two drugs (6 μg/100 g T4 and 0.005% DON). The concentration of ACh was determined in the homogenized hippocampus of each animal by alkaline hydroxylamine colorimetry. The protein levels of syntaxin-1 and munc-18 were determined by immunohistochemistry. The results showed that the content of ACh in the hippocampi of the hypothyroid rats was significantly decreased compared with that in the controls and that T4 monotherapy and DON administration restored the ACh content to normal values. In the hippocampi of the hypothyroid group, munc-18 was expressed at significantly lower levels, while the expression levels of syntaxin-1 were increased compared with the levels in the control group. Treatment with T4 alone restored the expression of syntaxin-1 but failed to normalize munc-18 expression levels. The co-administration of T4 and DON returned the munc-18 levels to normal values. These observations indicate that adult-onset hypothyroidism induces alterations in the levels of munc-18, syntaxin-1 and ACh in the hippocampus. Syntaxin-1 and ACh levels were restored by T4 monotherapy while munc-18 levels were not. In addition, the co-administration of T4 and DON resulted in more effective restoration than either alone. The thyroid hormone has a direct effect on metabolism of hippocampal ACh in adult rats and DON is helpful for treatment of synaptic protein impairment induced by hypothyroidism.

Intergenerational effects of prenatal ethanol on glucose tolerance and insulin response

Consequences of prenatal exposure to ethanol (E) include morphological, physiological, and cognitive deficits and are collectively classified as fetal alcohol spectrum disorders. Adult prenatal E exposed offspring show insulin resistance, and given that in utero hyperglycemic environment can cause metabolic disorders in subsequent generations; we investigated the effects of grandmaternal E on functional glucose and insulin responses of the second generation. Sprague-Dawley (S) rat dams, mated with S males, received E-containing liquid diet and two different control diets between gestational days 8 and 20. Additionally, because prenatal E-induced behavioral deficits can be reversed by simultaneous thyroxine (T4) treatment, another group of dams received 0.3 mg/l T4 in their E diet. Their first-generation (F1) offspring were mated with control Brown Norway (B) males or females to produce SB and BS F2 progeny. Dams consuming E during pregnancy were hyperglycemic, and their F1 offspring showed insulin resistance in the glucose tolerance test (GTT). However, F2 responses to GTT varied based on the sex of prenatal E-exposed parent. BS F2 females, and both male and female SB F2 progeny, displayed hypoglycemic and hyperinsulinemic GTT response patterns. Although administering T4 to E dams normalized thyroid function of the F1 generation, it did not reverse their prenatal E-induced metabolic dysfunction. In contrast, administration of T4 to the alcohol-consuming grandmother reversed or alleviated the aberrant GTT responses of the F2 progeny. Prenatal E-induced dysregulation of glucose metabolism can affect the next generation, possibly via ethanol effects on the germline of the F1 fetus.

Weight Gain and Serum TSH Increase within the Reference Range after Hemithyroidectomy Indicate Lowered Thyroid Function.

Background. Weight gain is frequently reported after hemithyroidectomy but the significance is recently discussed. Therefore, the aim of the study was to examine changes in body weight of hemithyroidectomized patients and to evaluate if TSH increase within the reference range could be related to weight gain. Methods. In a controlled follow-up study, two years after hemithyroidectomy for benign euthyroid goiter, postoperative TSH and body weight of 28 patients were compared to preoperative values and further compared to the results in 47 matched control persons, after a comparable follow-up period. Results. Two years after hemithyroidectomy, median serum TSH was increased over preoperative levels (1.23 versus 2.08 mIU/L, P < 0.01) and patients had gained weight (75.0 versus 77.3 kg, P = 0.02). Matched healthy controls had unchanged median serum TSH (1.70 versus 1.60 mIU/L, P = 0.13) and weight (69.3 versus 69.3 kg, P = 0.71). Patients on thyroxin treatment did not gain weight. TSH increase was significantly correlated with weight gain (r = 0.43, P < 0.01). Conclusion. Two years after hemithyroidectomy for benign euthyroid goiter, thyroid function is lowered within the laboratory reference range. Weight gain of patients who are biochemically euthyroid after hemithyroidectomy may be a clinical manifestation of a permanently decreased metabolic rate.

Reference ranges of serum TSH, FT4 and thyroid autoantibodies in the Thai population: the national health examination survey

Data on reference intervals of thyroid functions in Southeast Asia are limited. The aim of this study was to provide reference ranges of thyroid functions and thyroid autoantibodies in Thais. Serum samples from 2545 apparently healthy non-pregnant subjects, aged ≥14 years, from the fourth Thai National Health Examination Survey were measured for TSH, FT4, antithyroperoxidase (TPO Ab), antithyroglobulin (Tg Ab) and antithyrotrophin receptor antibodies (TRAb). A reference population was selected from the disease-free population by excluding those who had thyroid autoantibodies and TSH > 20 mIU/l. For the total population, median TSH and FT4 levels were 1·94 mIU/l and 1·35 ng/dl, respectively. TSH was higher and FT4 was lower in females than in males. Based on National Academy of Clinical Biochemistry criteria, the reference intervals (2·5th-97·5th percentile) were: TSH, 0·34-5·11 mIU/l; FT4, 0·98-1·79 ng/dl; TPO Ab, 5-84·88 IU/ml; Tg Ab, 10-118·2 IU/ml; and TRAb, 0·3-1·24 IU/l. With the new reference ranges, hypothyroidism was found in 4·16% of the total population (0·78% overt and 3·38% subclinical hypothyroidism) and hyperthyroidism was found in 3·18% (0·94% overt and 2·24% subclinical hyperthyroidism). Positive TPO Ab, Tg Ab and TRAb were found in 8·96%, 12·26% and 5·93%, respectively. The upper normal limit of TSH tended to increase with age, particularly for those aged 80 years and older. The reference interval for TSH needs to be derived from each specific population. Slightly elevated TSH concentrations in the elderly could be considered acceptable, with no need for thyroxine treatment.

Approximation of A1 adenosine receptor reserve appertaining to the direct negative inotropic effect of adenosine in hyperthyroid guinea pig left atria

Hyperthyroidism elevates cardiovascular mortality by several mechanisms, including increased risk of ischemic heart disease. Therefore, therapeutic strategies, which enhance tolerance of heart to ischemia-reperfusion injury, may be particularly useful for hyperthyroid patients. One promising cardioprotective approach is use of agents that cause (directly or indirectly) A1 adenosine receptor (A1 receptor) activation, since A1 adenosinergic pathways initiate protective mechanisms such as ischemic preconditioning. However, previously we found great A1 receptor reserve for the direct negative inotropic effect of adenosine in isolated guinea pig atria. This phenomenon suggests that weakening of atria is a possible side effect of A1 adenosinergic stimulant agents. Thus, the goal of the present investigation was to explore this receptor reserve in hyperthyroidism. Our recently developed method was used that prevents the rapid intracellular elimination of adenosine, allowing sufficient time for exogenous adenosine administered for the generation of concentration-response curves to exert its effect. Our method also allowed correction for the bias caused by the consequent endogenous adenosine accumulation. Our results demonstrate that thyroxine treatment does not substantially affect the A1 receptor reserve for the direct negative inotropic effect of adenosine. Consequently, if an agent causing A1 receptor activation is administered for any indication, the most probable adverse effect affecting the heart may be a decrease of atrial contractility in both eu- and hyperthyroid conditions.

CONTROVERSIES IN ENDOCRINOLOGY: On the need for universal thyroid screening in pregnant women

There is a well-known controversy among scientific societies regarding the recommendation to screen for thyroid dysfunction (TD) during pregnancy. Although several studies have shown an association between maternal subclinical hypothyroidism and/or hypothyroxinemia with obstetric problems and/or neurocognitive impairment in the offspring, there is only limited evidence on the possible positive effects of thyroxine (T4) treatment in such cases. Despite the scarcity of this evidence, there is a widespread agreement among clinicians on the need for treatment of clinical hypothyroidism during pregnancy and the risks that could arise due to therapeutic abstention. As maternal TD is a quite prevalent condition, easily diagnosed and for which an effective and safe treatment is available, some scientific societies have proposed to assess thyroid function during the first trimester of pregnancy and ideally before week 10 of gestational age. Given the physiologic changes of thyroid function during pregnancy, hormone assessment should be performed using trimester-specific reference values ideally based on locally generated data as geographic variations have been detected. Screening of TD should be based on an initial determination of TSH performed early during the first trimester and only if abnormal should it be followed by either a free or total T4 measurement. Furthermore, adequate iodine supplementation during pregnancy is critical and if feasible it should be initiated before the woman attempts to conceive.

Hyperthyroid state or in vitro thyroxine treatment modulates TH1/TH2 responses during exposure to HSV-1 antigens

Increasingly in recent years, thyroid hormones (THs) have been considered to be important regulators of the immune system. However, their roles in host defense against viral infections are not clearly established. Therefore, this study was undertaken to examine proliferative activity and cytokine production by lymphocytes isolated from hyperthyroid and euthyroid Balb/c mice in response to herpes simplex virus-1 (HSV-1). Lymphocytes of hyperthyroid animals showed a significantly higher rate of proliferation and interferon (IFN)-γ production when compared with that by lymphocytes from euthyroid mice. In vitro thyroxine (T4) treatment was similarly effective in the potentiation of proliferation, but not IFNγ production, by euthyroid lymphocytes. Furthermore, the hyperthyroid state significantly attenuated ConA-, but not HSV-1-, induced interleukin (IL)-10 release; in vitro T4 treatment synergized this effect. These findings suggest that supra-physiologic TH levels (i.e. as occur in hyper-thyroid states) or in vitro TH treatment modulate T-helper (TH)1/TH2 lymphocyte responses and thereby amplifies host defenses against viral infections. One may also conclude that THs may have a potential application in viral immunization and/or treatment of viral infections.

Toxoplasmic Lymphadenitis Mimicking a Metastatic Thyroid Carcinoma at (18)F-FDG-PET/CT.

A 28-year-old woman underwent total thyroidectomy for a papillary thyroid carcinoma in the right thyroid lobe (pTx, pN1b). Subsequently a 131I-ablation (4.4 GBq) was performed. Four years later the patient presented increased thyroglobulin (Tg) serum levels (8.4 μg/l) during thyroxine treatment. Furthermore, enlarged hypoechoic and round-shaped bilateral cervical lymph nodes were detected at cervical ultrasonography (US). Based on laboratory and US findings suspicious for lymph nodal recurrence of thyroid carcinoma, the patient underwent an 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) to check for distant metastases [1, 2] (Fig. 1). Fig. 1 Whole-body maximum intensity projection (MIP) 18F-FDG-PET image (a), coronal 18F-FDG-PET/CT image (b), axial CT (c) and 18 F-FDG-PET/CT (d) images of the neck region revealed increased radiopharmaceutical uptake corresponding to several bilateral ... The patient underwent a US-guided fine-needle aspiration cytology on an 18F-FDG-avid cervical lymph-node. The smears were hypercellulated and consisted of numerous small- to medium-sized lymphocytes, macrophages, dendritic cells and tingible body macrophages. The cytological diagnosis was consistent with that of reactive lymphadenitis. Serological test revealed elevated IgM and IgG anti-Toxoplasma antibodies with a very low IgG-avidity, indicating an acute toxoplasmosis. Serum Tg was then measured by using heterophilic antibody blocking tubes, as previously reported [3], and serum value dropped to <0.2 μg/l. It is well known that antibody interference may falsely increase serum Tg; in particular, increased anti-Toxoplasma antibodies likely interfered to the Tg measurement in our case [4]. Additionally, activated granulocytes and macrophages may display significantly increased glucose consumption, giving false-positive results at 18F-FDG-PET/CT in oncological patients [5]. Few reports have described toxoplasmic infection mimicking malignancy at 18 F-FDG-PET/CT; these findings were found mainly in immunodepressive patients or with history of lymphoma [6–8]. Conversely, we described here a case of toxoplasmosis inducing false-positive Tg measurement, neck US and 18 F-FDG-PET/CT findings in a patient with papillary thyroid carcinoma.

Use of antiepileptic drugs and risk of hypothyroidism

This study aimed to investigate the risk of clinically significant hypothyroidism among all the currently available antiepileptic drugs (AED). The Taiwan National Health Insurance Research Database (NHIRD) from 2004 to 2010 was analyzed using a prescription sequence symmetry analysis, and thyroxine treatment was used as a proxy to identify a hypothyroidism event. A cohort of patients who have been treated with both AED and thyroxine was selected, and the chronological order of AED and thyroxine use constituted the basis of the prescription sequence symmetry analysis. A causal relationship was suspected if there was a significantly higher proportion of patients who initiated thyroxine after AED than those who initiated thyroxine before AED. The ratio of the two proportions was described as a sequence ratio. To benchmark the effect size of AEDs on thyroid function, amiodarone was selected as the reference indicator. A total of 1,878,189 AED users was found in the database, with 16,200 of them also used thyroxine. The adjusted sequence ratio of thyroxine use after each AED was 1.75 (99% confidence interval, 1.58-1.94) for phenytoin, 1.34 (1.20-1.49) for valproate, 1.25 (1.15-1.36) for phenobarbital, 1.21 (1.08-1.34) for carbamazepine, and 1.22 (1.03-1.46) for oxcarbazepine. The risk of hypothyroidism from phenytoin use within a shorter time frame was similar that associated with amiodarone use. No association was shown in most of the new generation AEDs. The results indicated an increased risk of hypothyroidism among patients using AEDs, especially phenytoin, valproate, phenobarbital, carbamazepine, and oxcarbazepine. The findings also provided strong grounds for further investigations on acute thyroid adverse effect induced by phenytoin.

Effects of thyroxine treatment during lactation on the testicular function of rats across different ages

Thyroid hormones are involved in the development of several tissues and organs and are essential for the normal growth and reproductive function. The aim of this study was to determine the effects of thyroid hormones on the development of testis and progression of spermatogenesis. Lactating mothers were treated with oral thyroxine (T4; 20 μg/100 g) for 20 days after parturition. The pups were decapitated at the age of 20, 40 and 60 days post partum. Neonatal hyperthyroidism resulted in a decrease in body and testis mass, an increase of free thyroxine and a decrease of testosterone concentrations in plasma of treated rats. The treatment was associated with a significant decrease of the diameter of seminiferous tubules and a slowdown in spermatogenesis, following a delay in the maturation of germ cells. We conclude that thyroid hormones affect the progression of postnatal spermatogenesis.

Induction of apoptosis in T lymphoma cells by long-term treatment with thyroxine involves PKCζ nitration by nitric oxide synthase

Thyroid hormones are important regulators of cell physiology, inducing cell proliferation, differentiation or apoptosis, depending on the cell type. Thyroid hormones induce proliferation in short-term T lymphocyte cultures. In this study, we assessed the effect of long-term thyroxine (T4) treatment on the balance of proliferation and apoptosis and the intermediate participants in T lymphoma cells. Treatment with T4 affected this balance from the fifth day of culture, inhibiting proliferation in a time-dependent manner. This effect was associated with apoptosis induction, as characterized through nuclear morphological changes, DNA fragmentation, and Annexin V-FITC/Propidium Iodide co-staining. In addition, increased iNOS gene and protein levels, and enzyme activity were observed. The generation of reactive oxygen species, depolarization of the mitochondrial membrane, and a reduction in glutathione levels were also observed. The imbalance between oxidants and antioxidants species is typically associated with the nitration of proteins, including PKCζ, an isoenzyme essential for lymphoma cell division and survival. Consistently, evidence of PKCζ nitration via proteasome degradation was also observed in this study. Taken together, these results suggest that the long-term culture of T lymphoma cells with T4 induces apoptosis through the increased production of oxidative species resulting from both augmented iNOS activity and the loss of mitochondrial function. These species induce the nitration of proteins involved in cell viability, promoting proteasome degradation. Furthermore, we discuss the impact of these results on the modulation of T lymphoma growth and the thyroid status in vivo.

Myocardial Rac1 Exhibits Partial Involvement in Thyroxin-induced Cardiomyocyte Hypertrophy and Its Inhibition Is Not Sufficient to Improve Cardiac Dysfunction or Contractile Abnormalities in Mouse Papillary Muscles

: Development of cardiac hypertrophy after thyroxin (T4) treatment is well recognized. Recently, we observed that T4-induced cardiac hypertrophy is associated with increased cardiac Rac1 expression and activity. Whether this Rac1 increase has a role in inducing this cardiac phenotype is, however, still unknown. Here, we showed that T4 treatment (500 µg/kg/d) for 2 weeks resulted in increased myocardial Rac1 activity with subsequent hypertension, cardiac hypertrophy, and left ventricular systolic dysfunction in vivo. Isolated right ventricular papillary muscles of T4-treated mice maintained their peak isometric active developed tension but exhibited significant decreases in their corresponding time to peak and in relaxation times. Positive inotropic responses to increasing pacing rate and β-adrenergic stimulation were also depressed in these muscles. Pravastatin (10 mg/kg/d), a Rac1 inhibitor, significantly decreased myocardial Rac1 activity, hypertension, and cardiomyocyte size in T4-treated mice but could not attenuate gross heart weight or functional cardiac changes in these mice. Our data showed that T4 could activate different signaling pathways with distinct cardiovascular outcomes. We also provide the first mechanistic evidence for the partial involvement of Rac1 activation in T4-induced cardiomyocyte hypertrophy and reveal a putative role for Rac1 in the development of T4-induced hypertension.