Changes In Thyroid Hormone Economy Research Articles

The 5′-Deiodinases Are Not Essential for the Fasting-Induced Decrease in Circulating Thyroid Hormone Levels in Male Mice: Possible Roles for the Type 3 Deiodinase and Tissue Sequestration of Hormone

Fasting in rodents is characterized by decreases in serum T4 and T3 levels but no compensatory increase in serum TSH level. The types 1 and 2 deiodinases (D1 and D2) are postulated to play key roles in mediating these changes. However, serum T4 and T3 levels in fasted 5'-deiodinase-deficient mice decreased by at least the same percentage as that observed in wild-type mice, whereas serum TSH level was unaffected. D3 activity was increased in kidney, muscle, and liver up to 4-fold during fasting, and the mean serum rT3 level was increased 3-fold in fasted D1-deficient mice, compared with fed animals. In wild-type mice, the tissue contents of T4 and T3 in liver, kidney, and muscle were unchanged or increased in fasted animals, and after the administration of [(125)I]T4 or [(125)I]T3, the radioactive content in the majority of tissues from fasted mice was increased 2- or 4-fold, respectively. These findings suggest that the observed fasting-induced reductions in the circulating T3 and T4 levels are mediated in part by increased D3 activity and by the sequestration of thyroid hormone and their metabolites in tissues. Studies performed in D3-deficient mice demonstrating a blunting of the fasting-induced decrease in serum T4 and T3 levels were consistent with this thesis. Thus, the systemic changes in thyroid hormone economy as a result of acute food deprivation are not dependent on the D1 or D2 but are mediated in part by sequestration of T4 and T3 in tissues and their enhanced metabolism by the D3.

The case of thyroid hormones: how to learn physiology by solving a detective case

Thyroid diseases are prevalent among endocrine disorders, and careful evaluation of patients' symptoms is a very important part in their diagnosis. Developing new pedagogical strategies, such as problem-based learning (PBL), is extremely important to stimulate and encourage medical and biomedical students to learn thyroid physiology and identify the signs and symptoms of thyroid dysfunction. The present study aimed to create a new pedagogical approach to build deep knowledge about hypo-/hyperthyroidism by proposing a hands-on activity based on a detective case, using alternative materials in place of laboratory animals. After receiving a description of a criminal story involving changes in thyroid hormone economy, students collected data from clues, such as body weight, mesenteric vascularization, visceral fat, heart and thyroid size, heart rate, and thyroid-stimulating hormone serum concentration to solve the case. Nevertheless, there was one missing clue for each panel of data. Four different materials were proposed to perform the same practical lesson. Animals, pictures, small stuffed toy rats, and illustrations were all effective to promote learning, and the detective case context was considered by students as inviting and stimulating. The activity can be easily performed independently of the institution's purchasing power. The practical lesson stimulated the scientific method of data collection and organization, discussion, and review of thyroid hormone actions to solve the case. Hence, this activity provides a new strategy and alternative materials to teach without animal euthanization.

Neonatal Thyroid Function

Postnatal changes in thyroid hormone economy reflect the adjustment of the fetus to the extrauterine environment. Thyroid-stimulating hormone (TSH) surges soon after birth, resulting in thyroxine (T4) concentrations that are higher in the first postnatal week than at any other time of life and in circulating triiodothyronine (T3) concentrations that are three to four times higher than in the fetus. In preterm infants born after 31 weeks' gestation, the pattern is similar, although less pronounced; in younger infants, a decrease in TSH may be seen, accompanied by a low T4 concentration. Usually the free T4 concentration is less affected than the total T4. Thyroid hormone synthesis is critically dependent on an adequate prenatal and postnatal supply of iodine, which can paradoxically suppress T4 secretion when present in excess, especially in preterm infants and in the presence of iodine deficiency. Maternal T4 is a critical source of thyroid hormone when the fetus is hypothyroid. Postnatal thyroid function also can be affected by maternally or postnatally administered drugs, maternal TSH receptor antibodies (Abs), and acute illness. Because of the vital role of thyroid hormone in brain development and the importance of early, adequate therapy when thyroid function is impaired, knowledge of normal thyroid function in the neonatal period and factors affecting it are critical for physicians caring for newborns.

Thyroid hormone metabolism in heart failure: iodothyronine deiodinases in focus

Heart disease is the leading cause of death worldwide and no efficient treatment against this threatening condition exists. Based on their recognized regulatory action on cardiovascular system, thyroid hormones emerged as a good alternative for patients with heart disease. Although many studies have shown beneficial effects of thyroid hormone replacement in patients with heart failure, many questions are still unsolved. Thus, the purpose of this review was to discuss changes in thyroid hormone economy with special emphasis on thyroid hormone metabolism in models of heart failure. Severe illness, such as heart failure, is characterized by changes in thyroid hormone economy, characterized by decreased serum T3 and increased serum rT3, a condition called the 'low T3-syndrome'. Unlike other animal models of thyroid status derangement during systemic illness, some clinical and experimental studies have observed compensatory stimulation of the hypothalamus-pituitary-thyroid axis in patients and models of heart failure. In this context, induction of type 3 deiodinase is the main cause of decreased T3. This is uniquely reminiscent of the pathophysiology of the 'consumptive hypothyroidism', which has previously been described in patients with large D3-expressing tumors. Tight regulation of cardiac T3 levels occurs in heart failure and understanding the pathophysiology of this phenomenon might support future researches to find new efficient strategies to treat heart failure.

Thyroid dysfunction in pregnancy: optimizing fetal and maternal outcomes

Recent decades have seen a growing awareness of the threat posed by thyroid dysfunction in pregnancy on maternal, fetal and neonatal well-being. Uncontrolled hypothyroidism and hyperthyroidism are associated with adverse obstetrics and fetal outcomes and also affect neurointellectual development in the offspring. Excellent outcomes are, however, achievable with appropriate management. An understanding of the changes in thyroid hormone economy in pregnancy is crucial to the evaluation of thyroid status in pregnant patients with thyroid dysfunction. Furthermore, a balance must be maintained between the control of maternal disease and the requirements of the developing fetus. Careful monitoring of patients in a multidisciplinary care setting, and appropriate adjustments of treatment, is essential throughout pregnancy and the puerperium. In this special report we summarize best practice in the management of thyroid dysfunction in pregnancy.

Effects of energy restriction on thyroid hormone metabolism in chickens

Energy restriction induces changes in thyroid hormone economy in the form of a complex adaptation mechanism, in order to conserve energy storage and protein reserves. In the present work, thyroid hormone serum concentrations, hepatic deiodinase enzyme activities and hepatic deiodinase mRNA expression were examined after feed restriction and fasting. We demonstrate that during energy restriction, T 3 concentration is lowered due to a decreased T 4 activation and increased T 3 inactivation. We show that hepatic type-I deiodinase (D1) is not affected by energy restriction, however, hepatic D2 is decreased on both transcriptional and enzyme activity levels. Furthermore, hepatic D3 is increased after feed restriction in the liver. We also show that the hypothalamic feedback is not involved in the changes in serum T 3 and T 4 concentrations. Our data indicate that D2 enzyme contributes to the special hormone-exporting role of the chicken liver and this enzyme can be modulated by feed restriction.

Tissue-specific deiodinase regulation during food restriction and low replacement dose of leptin in rats

The relationship between thyroid function and leptin has been extensively studied; however, the mechanisms underlying the changes in thyroid hormone economy that occur during caloric deprivation remain elusive. Our goal was to evaluate the thyroid function of rats submitted to 40% food restriction after chronic leptin replacement. Caloric restriction for 25 days led to significantly reduced serum leptin, thyroid-stimulating hormone (TSH), thyroxine (T(4)), and triiodothyronine (T(3)) and increased serum corticosterone, while liver, kidney, and thyroid type I deiodinase (D1) and brown adipose tissue (BAT) type II deiodinase (D2) activities were decreased and hypothalamic D2 was significantly increased. Interestingly, thyroid iodide uptake was unchanged by caloric restriction, but thyroperoxidase (TPO) activity was significantly reduced. Leptin replacement for the last 10 days of caloric restriction normalized serum leptin and TSH levels, but serum T(4) and T(3) levels and thyroid D1 and TPO activities were not reestablished. Also, a negative effect of leptin administration on Na(+)-I(-) symporter function was detected. Liver and kidney D1 and hypothalamic and BAT D2 were normalized by leptin, while pituitary D2 was significantly decreased. In conclusion, a tissue-specific modulation of deiodinases might be implicated in the normalization of thyroid function during leptin replacement in food-restricted rats. Although leptin restores the hypothalamus-pituitary axis during food restriction, it exerts a direct negative effect on the thyroid gland; thus normalization of serum thyroid hormones might depend on changes in deiodinase activities and the long-term thyroid stimulation by TSH to counterbalance the direct negative effects of leptin on the thyroid gland.

Asymptomatic Hyperthyroidism in Older Adults

Hyperthyroidism is the result of increased serum free thyroid hormone levels and is associated with a well recognized set of clinical signs and symptoms. However, older patients who develop hyperthyroidism tend to have fewer hyperadrenergic signs and an increased incidence of weight loss, cardiac arrhythmias and, occasionally, apathetic mood. This article highlights the paucity of clinical signs and symptoms of hyperthyroidism in older people and reviews the potential biochemical changes in thyroid hormone physiology that may account for an altered clinical presentation in older people with hyperthyroidism. First, a brief vignette from our own clinical practice is described to highlight an unusual presentation of hyperthyroidism in an older woman. The subject is then reviewed on the basis of relevant articles identified through a MEDLINE search of the English literature, using the key words 'hyperthyroidism' and 'aging'. The available evidence indicates that the clinical syndrome of asymptomatic hyperthyroidism in older adults appears to be distinct from the more widely recognized syndromes of apathetic hyperthyroidism or thyroid hormone resistance. Age-related changes in thyroid hormone economy and reduced cellular uptake of thyroid hormone as well as changes in thyroid hormone regulation of gene expression may account for reduced manifestations of hyperthyroidism in older adults. Thus, in addition to the well known changes in thyroid gland anatomy and function with aging, there may be an age-related resistance to thyroid hormone action. Asymptomatic hyperthyroidism may well be a syndrome that is currently under-diagnosed.

Targeted Disruption of the Type 1 Selenodeiodinase Gene (Dio1) Results in Marked Changes in Thyroid Hormone Economy in Mice

The type 1 deiodinase (D1) is thought to be an important source of T3 in the euthyroid state. To explore the role of the D1 in thyroid hormone economy, a D1-deficient mouse (D1KO) was made by targeted disruption of the Dio1 gene. The general health and reproductive capacity of the D1KO mouse were seemingly unimpaired. In serum, levels of T4 and rT3 were elevated, whereas those of TSH and T3 were unchanged, as were several indices of peripheral thyroid status. It thus appears that the D1 is not essential for the maintenance of a normal serum T3 level in euthyroid mice. However, D1 deficiency resulted in marked changes in the metabolism and excretion of iodothyronines. Fecal excretion of endogenous iodothyronines was greatly increased. Furthermore, when compared with both wild-type and D2-deficient mice, fecal excretion of [125I]iodothyronines was greatly increased in D1KO mice during the 48 h after injection of [125I]T4 or [125I]T3, whereas urinary excretion of [125I]iodide was markedly diminished. From these data it was estimated that a majority of the iodide generated by the D1 was derived from substrates other than T4. Treatment with T3 resulted in a significantly higher serum T3 level and a greater degree of hyperthyroidism in D1KO mice than in wild-type mice. We conclude that, although the D1 is of questionable importance to the wellbeing of the euthyroid mouse, it may play a major role in limiting the detrimental effects of conditions that alter normal thyroid function, including hyperthyroidism and iodine deficiency.

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.

Triiodothyronine (T3) reflects renal graft function after renal transplantation.

Abnormalities in thyroid function are observed in patients with end stage renal disease. However, there are no data available evaluating sequential changes of thyroid function after renal transplantation. Therefore, we have studied thyroid hormone function in the immediate post-operative period after renal transplantation in order to determine the relationship between improving renal function and changes in thyroid hormone economy. Thyroid function was evaluated in 22 patients before and on days 1, 3, 7 and 15 after renal transplantation. All patients received prednisone and cyclosporin as immunosuppressive therapy. Twelve patients with normal renal function undergoing comparable surgical procedures served as a control group. Serum creatinine and thyroid hormone parameters (total T4, total T3, free T4, free T3, thyroxin binding globulin (TBG), reverse T3, T3 sulphate and TSH) were measured. According to post-operative kidney function after renal transplantation, patients could be subdivided into three groups: five patients had primary graft function (group I); seven patients had delayed graft function because of acute renal failure (group II); 10 patients had delayed graft function requiring high doses of prednisone and some also of OKT3 because of acute rejection (group III). There was a significant fall in T3 and T4 concentrations with a concomitant rise in reverse T3 in all patients up to 3 days after renal transplantation. However, only patients in group I reached pre-operative values on day 15 after renal transplantation (serum creatinine 167 +/- 52 microM), whereas patients in group II (creatinine 609 +/- 118 microM) and group III (creatinine 839 +/- 71 microM) continued to have T3 concentrations well in the hypothyroid range (group I, 1.68 +/- 0.28 nM) vs 0.87 +/- 0.09 nM in group II and 0.76 +/- 0.10 nM in group III; P < 0.01). Serum T4 concentrations were also low in group III (47.7 nM vs 100.2 nM in group I; P < 0.05) 15 days after renal transplantation. These changes were accompanied by a concomitant fall in T3/TBG ratio and in free T3. Elevated reverse T3 returned to normal values in all groups on the 15th day after renal transplantation. TSH fell significantly on the first post-operative day, but did not return to pre-operative values in renal transplantation patients. In the control group, TSH did not change during the study period. T3 sulphate, known to be elevated in chronic renal failure, remained above normal in all patients irrespective of graft function during this study period. T3 concentrations reflect renal graft function after renal transplantation. T3 is below normal in patients with delayed graft function (acute renal failure or acute rejection). The post-operative period (up to 3 days after renal transplantation) is associated with a low T3 syndrome. TSH does not return to pre-operative values even in patients with primary graft function. This might be due to the administration of prednisone. T3-sulphate is elevated before and after renal transplantation irrespective of graft function.

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.

Fasting-induced changes in thyroid hormone economy in normal and acromegalic subjects.

To study whether high growth hormone (GH) milieu may counteract fasting-induced changes in thyroid hormone economy, we measured basal and TRH-stimulated TSH concentrations as well as thyroxine (total, TT4 and free, FT4), total triiodothyronine (TT3) and total reverse T3 (TrT3) before and after a 6-day fast in 6 healthy men and in 8 patients with acromegaly. Baseline values for all parameters were similar in both groups. Fasting induced similar increases in TT4 and TrT3 concentrations and a similar decline in TT3 concentrations in both groups. The TT3/TT4 and TrT3/TT4 ratios changed identically in both groups. We conclude that high GH is incapable of altering fasting-induced changes in thyroid hormone economy.

Assessment of thyroid function during pregnancy.

Assessment of a woman's thyroid function often is necessary during pregnancy, since either uncorrected hypothyroidism or hyperthyroidism can adversely affect pregnancy outcome. Pregnancy-induced changes in thyroid hormone economy, particularly the major alterations in thyroid hormone binding to serum proteins, change the results of some commonly used thyroid hormone measurements. In vivo isotopic testing, including scintiscanning and thyroid radioiodine uptakes, cannot be used. Because of advances in assay technology, the best strategy for thyroid function assessment is now based on a high sensitivity serum thyroid-stimulating hormone (S-TSH) measurement as the first-line test. When S-TSH levels are high, indicating hypothyroidism, follow-up tests include serum free T4 and, if appropriate, antithyroid antibody measurements. The great majority of cases of hypothyroidism are due to Hashimoto's thyroiditis or prior thyroid ablation for hyperthyroidism or thyroid cancer. When S-TSH levels are low, suggesting hyperthyroidism, confirmatory tests are serum free T4 and free T3 measurements. Graves' disease is by far the most common cause of hyperthyroidism during pregnancy. Other causes, including those mediated by high hCG levels, can be distinguished from Graves' disease by careful clinical evaluation.

Thyroid Hormone Economy in Pregnant Rats Near Term: A “Physiological” Animal Model of Nonthyroidal Illness?*

We have studied the changes in thyroid hormone economy that occur in normal pregnant rats between 17-22 days of gestation. T4 and T3 decreased in all extrathyroidal tissues studied, namely plasma, liver, kidney, lung, heart, and skeletal muscle. The exception is the concentration of T3 in cerebral cortex, which remains unchanged, possibly as a consequence of an increase in type II 5'-iodothyronine deiodinase activity. The marked decrease observed in most T4 and T3 pools was not accompanied by a commensurate increase in circulating TSH levels, which at 21 days gestation were either unchanged or actually decreased. The TSH response to TRH appeared to be prolonged. alpha-Glycerophosphate dehydrogenase activity was decreased in the liver, in accordance with its thyroid hormone deficiency. Hepatic type I 5'-iodothyronine deiodinase activity, however, did not decrease, but was slightly increased. Thus, thyroid hormone economy in the pregnant rat near term shows striking similarities with several (but not all) of the changes described in patients with nonthyroidal illness and in several animal models used to study this condition. It is suggested that attenuation of the negative feedback response to the decrease in thyroid hormone pools, leading to low levels of thyroid hormones in most tissues, is the normal physiological response to situations where preservation of energy (and protein) represents a distinct adaptive advantage, as in the case of the pregnant rat and her conceptus.