[Thyroid hormone action beyond classical concepts. The priority programme "Thyroid Trans Act" (SPP 1629) of the German Research Foundation]. / Schilddrüsenhormonwirkung--jenseits klassischer Konzepte. Das Schwerpunktprogramm "Thyroid Trans Act" (SPP 1629) der Deutschen Forschungsgemeinschaft.

Thyroid hormones are of crucial importance for the function of nearly all organ systems. In case of dysfunction of thyroid hormone production and function many organ systems may be affected. The estimation of normal thyroid function is based on determination of TSH and the thyroid hormones T3 and T4. However, international conventions about the normal TSH range are still lacking which bears consequences for patient`s treatment. Hence not unexpected, many patients complain although their thyroid hormone status is in the normal range by clinical estimation. Here, more precise parameters are needed for a better definition of the healthy thyroid status of an individual. Recently, new key players in the system of thyroid hormone action were detected, like specific transporters for uptake of thyroid hormones and thyroid hormone derivatives. DFG, the German Research Foundation supports the priority program Thyroid Trans Act to find answers to the main question: what defines the healthy thyroid status of an individual. The overall aim of this interdisciplinary research consortium is to specify physiological and pathophysiological functions of thyroid hormone transporters and thyroid hormone derivative as new players in thyroid regulation in order to better evaluate, treat, and prevent thyroid-related disease.

American Thyroid Association Guide to investigating thyroid hormone economy and action in rodent and cell models.

BACKGROUND: An in-depth understanding of the fundamental principles that regulate thyroid hormone homeostasis is critical for the development of new diagnostic and treatment approaches for patients with thyroid disease. SUMMARY: Important clinical practices in use today for the treatment of patients with hypothyroidism, hyperthyroidism, or thyroid cancer are the result of laboratory discoveries made by scientists investigating the most basic aspects of thyroid structure and molecular biology. In this document, a panel of experts commissioned by the American Thyroid Association makes a series of recommendations related to the study of thyroid hormone economy and action. These recommendations are intended to promote standardization of study design, which should in turn increase the comparability and reproducibility of experimental findings. CONCLUSIONS: It is expected that adherence to these recommendations by investigators in the field will facilitate progress towards a better understanding of the thyroid gland and thyroid hormone dependent processes.

[Levothyroxine and the problem of interchangeability of drugs with narrow therapeutic index]. / Levotiroxina e o problema da permutabilidade de drogas de estreito intervalo terapêutico.

The exchange of a prescribed drug by other similar, by generic products and even by custom products has become common practice in our country, often ignoring basic tenets of bioequivalence, interchangeability, stability and characteristics of the pharmaceutical compounds. In the case of drugs of narrow therapeutic index, such as levothyroxine, these problems are intensified, putting the effectiveness of treatment and patient health at serious risk. We review the pertinent legislation, emphasizing the characteristics of levothyroxine and adverse effects that limit the interchangeability of the compound.

Levotiroxina e o problema da permutabilidade de drogas de estreito intervalo terapêutico / Levothyroxine and the problem of interchangeability of drugs with narrow therapeutic index

Tem se tornado prática comum em nosso país a troca de medicamentos prescritos por outros similares, por produtos genéricos e até mesmo por produtos manipulados, muitas vezes ignorando-se preceitos básicos de bioequivalência, permutabilidade, estabilidade e características específicas do composto farmacêutico. No caso de drogas de índice terapêutico estreito, como a levotiroxina, esses problemas se agravam colocando em sério risco a eficácia do tratamento e a saúde do paciente. Revemos a legislação pertinente ressaltando as características da levotiroxina e os efeitos adversos que limitam a permutabilidade do composto.

The exchange of a prescribed drug by other similar, by generic products and even by custom products has become common practice in our country, often ignoring basic tenets of bioequivalence, interchangeability, stability and characteristics of the pharmaceutical compounds. In the case of drugs of narrow therapeutic index, such as levothyroxine, these problems are intensified, putting the effectiveness of treatment and patient health at serious risk. We review the pertinent legislation, emphasizing the characteristics of levothyroxine and adverse effects that limit the interchangeability of the compound.

[Markers of thyroid function (II). Assessment of tissue action]. / Marcadores de función tiroidea (II). Evaluación de la acción tisular.

Advances in molecular medicine have increased our knowledge of the consequences of hormone action in target cells. We are currently able to determine to some extent the molecular thyroid hormone activity in different organs. The effects are related with a variety of factors, but their association with plasmatic hormone levels is only partially correlated. Recent advances indicate that there are several intermediate factors in thyroid tissue activity. The iodothyronine selenodeiodinases have a relevant role in this context. The clinical and biochemical methods currently available for thyroid function assessment do not permit us to explore many of these new elements. However, it is well known that thyroid hormones enhance the expression of a number of proteins, and some of these can be measured by simple methods. Accordingly, the plasmatic value of these proteins may be related with the effect of thyroid hormones in the target tissues, which is the result of thyroid function. The ability to determine the tissue activity of thyroid hormones will enable us to administrate the treatment dose more accurately, only to patients who require it, avoiding iatrogenism.

Advances in assessment, diagnosis, and treatment of hyperthyroidism in children.

The thyroid gland is responsible for regulating multiple complex metabolic processes that affect most organs. Physical growth and cognitive development are dependent on proper levels of thyroid hormone. This article will review common challenges in the diagnosis of hyperthyroidism in children, the approaches to treatment, and the nursing interventions guided toward child and family responses to thyroid disease. A comparison of signs and symptoms of hypothyroidism and hyperthyroidism is also included. The nursing interventions addressed in the article integrate the biological, psychological, social, and environmental stresses and adaptations necessary to cope with hyperthyroid disease.

Assessment of thyroid function in adult medaka (Oryzias latipes) and juvenile rainbow trout (Oncorhynchus mykiss) using immunostaining methods.

The effect of injected bovine TSH on the pattern of anti-T(4) and anti-T(3) immunostaining of the thyroid tissue was examined in rainbow trout (Oncorhynchus mykiss) and medaka (Oryzias latipes) to determine if the previously reported immunostaining of the cytoplasm of thyrocytes is due to the presence of colloid pinocytotic vesicles and is thus indicative of thyroid hormone release. We hypothesized that the number of immunostained thyrocytes should increase following a TSH challenge, and this should parallel other indicators of increased thyroid activity. In medaka, immunostained thyrocytes were only found following the TSH challenge, and were most marked after 24 to 72 hours; the immunostaining was associated with large colloid-filled cytoplasmic vesicles. In trout, the number and staining intensity of immunostained thyrocytes were increased after the TSH challenge; the immunostaining was present throughout the cytoplasm of the thyrocytes. These findings support the working hypothesis that the immunostaining of the thyrocytes is associated with the pinocytosis of thyroglobulin by the thyrocytes in parallel with an increase in release of thyroid hormone, and that this investigational approach provides a reliable indicator of thyroid hormone release activity.

Urinary cortisol metabolites in the assessment of peripheral thyroid hormone action: overt and subclinical hypothyroidism.

UNLABELLED: Biological assessment of peripheral thyroid hormone action may be important in subclinical hypothyroidism, where decision-making is often difficult. The impairment of urinary cortisol metabolites in overt hypothyroidism reflects an acquired 11 beta hydroxysteroid dehydrogenase (11 beta OHSD) deficiency, and is assessed in terms of a reduction in the tetrahydrocortisone (THE)/tetrahydrocortisol (THF) ratio or THE/THE + alpha THF ratio; the alpha THF/THF ratio reflects 5 beta reductase activity. The aim of this study was to determine if urinary cortisol metabolite ratios are a good index of peripheral thyroid hormone action in subclinical hypothyroidism. MATERIALS AND METHODS: the THE/THF, THE/THF + alpha THF and alpha THF/THF ratios were measured in 24 h urine samples from 3 groups of subjects: 1) 18 euthyroid subjects; 2) 25 patients with elevated serum TSH and low FT4 levels (overt hypothyroidism); and 3) 25 patients with increased serum TSH and normal FT4 levels (subclinical hypothyroidism. RESULTS: 7/25 overtly and 5/25 subclinically hypothyroid patients had a THE/THF + alpha THF ratio below the mean control value -2 SD, while respectively 20/25 and 11/25 patients had a THE/THF ratio below the mean control value -2 SD. The mean THE/THF + alpha THF, THE/THF and alpha THF/THF ratios were significantly different among the 3 groups (ANOVA) and were lower in the overtly hypothyroid group than in the other two groups (Fisher's test); daily urine sodium output was also significantly different between the three groups and lower in the overtly and subclinically hypothyroid groups than in the control group (Fisher's test). FT3 and FT4 both correlated with THE/THF + alpha THF in the overtly hypothyroid patients (r = 0.43; p < 0.05 and r = 0.40; p < 0.05, respectively). In the subclinically hypothyroid patients, TSH correlated with THE/THF + alpha THF (r = 0.44; p < 0.05) and THE/THF (r = 0.43; p < 0.05). FT3, FT4 and TSH levels correlated with THE/THF + alpha THF (p < 0.001), THE/THF (p < 0.001), alpha THF/THF (p < 0.001) and daily natriuresis (p < 0.05) in the whole population (patients + controls). In conclusion, urinary cortisol metabolites, although impaired in overt hypothyroidism, are not an accurate index of peripheral thyroid hormone deficiency in subclinical hypothyroidism. We also identified an increase in the alpha THF/THF ratio in overt hypothyroidism, which may be related to 5 beta reductase disturbances.

Changes in thyroid hormone economy following consumption of environmentally contaminated Great Lakes fish.

Epizootics of thyroid lesions in fish and piscivorous birds that are resident in the Great Lakes region of North America suggest that there are environmental factors present in the Great Lakes ecosystem that act as potent endocrine disruptors, and that they are transferred along the food chain. This paper examines the results of wildlife studies, as well as related studies on fish-eating human populations in the region. It also re-examines the results of experimental studies of the effects of Great Lakes fish diets on the thyroid physiology of rodents and shows that the thyroid responses of fish-fed rats and mice were essentially similar to those found in rats that had been administered specific polyhalogenated aromatic hydrocarbon (PHAH) congeners or commercial polychlorinated biphenyl mixtures. However, the responses to the Great Lakes fish diets were found at PHAH exposure levels that were commonly several orders of magnitude lower than those applied in the classical toxicology studies. These findings, together with the results of the Great Lakes piscivorous bird studies and one in which captive common seals were fed "environmentally contaminated" fish, suggest that the "environmental" PHAH mixtures accumulated in fish represent a significant threat to the thyroid hormone economy, and the effects are greater than could be predicted by virtue of the known levels of active congeners in this naturally bioaccumulated PHAH mix.

Normal age-related changes in thyroid hormone economy.

Aging is associated with significant changes in the anatomy of the thyroid gland and in the physiology of hypothalamic-pituitary-hormone thyroid axis. In addition, tissue responsiveness to thyroid hormone may also be altered with age. However, age alone should not influence the interpretation of commonly obtained thyroid function tests. The reduced thyroid hormone clearance with age explains the reduced daily replacement doses of thryoxine in hypothyroid elderly subjects.

Factors determining energy expenditure during very-low-calorie diets.

There is an important variability in short- and long-term weight loss success among obese subjects, regardless of the strategy used. It is still unclear whether this variability is a therapy-specific or a patient-specific problem. Changes in energy expenditure are probably a key factor in the phenomena of weight loss or weight regain. Factors influencing resting metabolic rate (RMR) and diet-induced thermogenesis (DIT) in obese patients are considered: age, fat mass, fat-free mass (FFM), sex and thyroid hormones are all related to the components of energy expenditure. Fat distribution estimates [expressed by waist-to-hip ratio (WHR)] seem to be related to DIT rather than to RMR. Short- and long-term effects of very-low-calorie diets (VLCDs) on RMR and DIT were investigated. Short-term weight loss by VLCD induced a significant (P less than 0.001) decrease of FFM with a concomitant decline of RMR values. A nonsignificant decreasing trend exists for thermogenesis. No further decrease of FFM was found after long-term weight loss without differences in RMR/FFM or thermogenesis. Changes in FFM are known to be the major component of changes in RMR, but other factors may be involved. Also some other factors may account for the possible changes in diet-induced thermogenesis during VLCD. Candidates for this include total fat mass, FFM, sex hormones, insulin concentrations, and fat distribution, of which insulin concentrations seem to determine RMR changes to an important extent. Fat distribution patterns per se or changes in WHR seem to account consistently (P less than or equal to 0.05) for changes in DIT during VLCD.

Intellectual assessment of hypothyroid children detected by screening.

The IQ was studied in 50 children with CH. Normal distribution of IQ was found in patients detected by neonatal screening. Close relationship was observed between subnormal IQ values (less than 90) and undetectable serum Tg levels (less than 0.3 ng/ml). The intellectual outcome in children with CH depends considerably from the intrauterine hypothyroidism.

The QKd interval in panic disorder: an assessment of end-organ thyroid hormone responsivity.

The QKd interval was utilized as a presumptive index of end-organ thyroid hormone effect to test the hypothesis that patients with panic disorder might have abnormal tissue-level responsivity to normal levels of peripherally circulating thyroid hormones. No significant differences in QKd intervals were found between 15 patients with panic disorder (230 +/- 50 msec) and 20 normal controls (224 +/- 29 msec) while drug-free. These findings suggest that patients with panic disorder have normal tissue-level responsivity to thyroid hormone.

Thyroparathyroidectomy produces a progressive escape deficit in rats.

Abnormal thyroid status and affective disorders have been associated in the human clinical literature. It has recently been shown that pretreatment with thyroid hormone can prevent escape deficits produced by inescapable shock in an animal analogue of depression. In this report we provide evidence that hypothyroid status can produce an escape deficit in rats. While sham-operated rats improved their performance on a simple escape task over three days of testing, thyroparathyroidectomized rats showed a pronounced decrease in their responses. Markov transition analysis was used to obtain conditional probabilities of escaping given a prior escape or failure to escape for the two groups. This analysis shows that the structure of the data set may be similar for the two groups. These results suggest that if intact rats learn to escape, then hypothyroid rats may learn not to escape.

The role of thyroid hormones in the control of energy expenditure.

Thyroid hormones have a direct effect on the basal or resting metabolic rate in man and a permissive effect on the adaptive thermogenesis of small animals, while altering the energy expended in exercise to the extent that patients with thyroid disorders exercise to a greater or lesser degree. The physiological concepts of energy expenditure need to be seen in the context of a new method for measuring 'thyroid thermogenesis'. Thyroid hormones seem, in evolutionary terms, to have developed a thermogenic role during the transition from poikilothermy to homeothermy; they are responsible for the increased heat production required for homeotherms to maintain body temperature above that of the environment. The potential mechanisms responsible for thyroid hormone-controlled energy expenditure are complex. Uncoupled oxidative phosphorylation is probably not responsible for thyroid hormone-controlled thermogenesis except in the special case of brown adipose tissue thermogenesis, where thyroid hormones act permissively. The concept that increased ATP generation must be coupled to ATP utilization needs to be linked with the idea that thyroid hormone-controlled thermogenesis must be through inefficient pathways of metabolism. Several of these potentially important pathways of intermediary metabolism in thyroid hormone-controlled thermogenesis can now be defined and measured, but their role in the regulation of nutritionally induced alterations in thyroid status and thermogenesis remains to be explored.

Thyroid hormones and thermogenesis: the metabolic cost of food and exercise.

To mimic plasma T3 levels observed in a previous overfeeding study, six lean healthy men received replacement amounts of L-thyroxine (200 micrograms/d) to block endogenous thyroid hormone production while consuming their habitual diet. After 4 weeks equilibration on T4, L-triiodothyronine (T3) was given (45 micrograms/d) in addition to T4, to produce mild T3-thyrotoxicosis, for another 2 weeks. At the end of this period T3 was discontinued but the subjects continued to receive T4 for another 2 weeks. Resting metabolic rate, exercise efficiency, and the thermic effect of food were measured using a ventilated hood, open circuit indirect calorimeter at the end of each phase of the experiment. There was a significant increase in the resting metabolic rate of 6% (P less than 0.01) while the subjects were mildly T3-thyrotoxic. The increase in energy expenditure however, during exercise on a bicycle ergometer or following a 500 kcal liquid-formula meal remained unaltered in the same situation. Thus, mild T3-toxicosis does not alter the efficiency of exercise or the thermic effect of food. These results suggest that the increased plasma T3 levels, observed in overfeeding, could explain corresponding increases in resting metabolic rate but not changes in the efficiency of exercise or the utilization of food.

Postnatal thyroid function in low birth weight infants: a cross-sectional assessment of free thyroxine and thyroid hormone binding globulin.

To investigate the significance of low serum thyroxine in premature infants, serum FT4, T4, TSH and TBG were measured in 7 infants with BW less than 1000 g, 8 infants with BW 1001 to 1350 g, 9 infants with BW 1351 to 2499 g, and 11 full-term infants. FT4 concentrations were lower in the LBW infants than in the FT infants. Percent FT4 values in the infants with BW less than 1000 g were the highest in the groups studied, so that FT4 concentrations in those infants did not fall proportionally with the marked T4 decrease. TBG concentrations were lower in the VLBW infants (less than BW 1350 g) than in the FT infants, and were positively correlated with BW and GA. This study suggests that in infants with lower birth weight there is a mechanism to prevent a decrease in FT4 concentrations associated with total T4 decrease. This fact may be a reason for euthroidism in small premature infants with low T4. Measurements of FT4 may be a useful adjunct to assessment of thyroid function in the VLBW infants with low T4.