Prohormone T4 Research Articles

Two synchronous paraneoplastic endocrine syndromes in a 53-year-old male with broadly metastatic widely invasive Hürthle cell carcinoma.

Unlike medullary thyroid carcinomas, follicular cell-derived thyroid malignancies have rarely been associated with paraneoplastic endocrine syndromes. An ultrarare case of a middle-aged man with heavily treated broadly metastatic radioactive iodine-refractory widely invasive Hürthle cell carcinoma (HCC) of the thyroid with two synchronous paraneoplastic endocrine syndromes, T3 thyrotoxicosis and hypercalcemia of malignancy, is discussed here. The levothyroxine-induced T3 thyrotoxicosis was a gradual process that became more noticeable as the tumor burden, refractory to different modalities of therapy, expanded. The 1,25-dihydroxyvitamin-D-mediated hypercalcemia, on the other hand, developed in a manner of weeks, as it usually happens. It is important to emphasize that in patients with metastatic Hürthle cell and follicular carcinomas of the thyroid, on TSH suppressive therapy, the unexplained and progressive decline in FT4 and rise in FT3 levels, resulting in an elevated FT4/FT3 ratio, could be an indication of augmented type 1 (D1) and/or type 2 (D2) deiodinase expression in tumoral tissue, causing an increased conversion from the prohormone T4 into the active metabolite T3 via outer ring deiodination. Albeit extremely rare, some patients with thyroid cancer can present with more than one concomitant paraneoplastic syndrome. Although medullary thyroid carcinoma is the thyroid malignancy that is usually associated with paraneoplastic endocrine syndromes, follicular cell-derived thyroid cancers have been rarely described as being the culprit. In patients with metastatic Hürthle cell and follicular thyroid carcinomas, the unexplained and progressive decline in FT4 and rise in FT3 levels could be an indication of augmented type 1 (D1) and/or type 2 (D2) deiodinase expression in tumoral tissue, causing an increased conversion from T4 into T3 leading to T3 thyrotoxicosis.

Deiodinases control local cellular and systemic thyroid hormone availability.

Iodothyronine deiodinases (DIO) are a family of selenoproteins controlling systemic and local availability of the major thyroid hormone l-thyroxine (T4), a prohormone secreted by the thyroid gland. T4 is activated to the active 3,3'-5-triiodothyronine (T3) by two 5'-deiodinases, DIO1 and DIO2. DIO3, a 5-deiodinase selenoenzyme inactivates both the prohormone T4 and its active form T3. DIOs show species-specific different patterns of temporo-spatial expression, regulation and function and exhibit different mechanisms of reaction and inhibitor sensitivities. The main regulators of DIO expression and function are the thyroid hormone status, several growth factors, cytokines and altered pathophysiological conditions. Selenium (Se) status has a modest impact on DIO expression and translation. DIOs rank high in the priority of selenium supply to various selenoproteins; thus, their function is impaired only during severe selenium deficiency. DIO variants, polymorphisms, SNPs and rare mutations have been identified. Development of DIO isozyme selective drugs is ongoing. A first X-ray structure has been reported for DIO3. This review focusses on the biochemical characteristics and reaction mechanisms, the relationships between DIO selenoproteins and their importance for local and systemic provision of the active hormone T3. Nutritional, pharmacological, and environmental factors and inhibitors, such as endocrine disruptors, impact DIO functions.

Selenoproteins in brain development and function.

Expression of selenoproteins is widespread in neurons of the central nervous system. There is continuous evidence presented over decades that low levels of selenium or selenoproteins are linked to seizures and epilepsy indicating a failure of the inhibitory system. Many developmental processes in the brain depend on the thyroid hormone T3. T3 levels can be locally increased by the action of iodothyronine deiodinases on the prohormone T4. Since deiodinases are selenoproteins, it is expected that selenoprotein deficiency may affect development of the central nervous system. Studies in genetically modified mice or clinical observations of patients with rare diseases point to a role of selenoproteins in brain development and degeneration. In particular selenoprotein P is central to brain function by virtue of its selenium transport function into and within the brain. We summarize which selenoproteins are essential for the brain, which processes depend on selenoproteins, and what is known about genetic deficiencies of selenoproteins in humans. This review is not intended to cover the potential influence of selenium or selenoproteins on major neurodegenerative disorders in human.

SECISBP2L-Mediated Selenoprotein Synthesis Is Essential for Autonomous Regulation of Oligodendrocyte Differentiation.

Thyroid hormone (TH) controls the timely differentiation of oligodendrocytes (OLs), and its deficiency can delay myelin development and cause mental retardation. Previous studies showed that the active TH T3 is converted from its prohormone T4 by the selenoprotein DIO2, whose mRNA is primarily expressed in astrocytes in the CNS. In the present study, we discovered that SECISBP2L is highly expressed in differentiating OLs and is required for DIO2 translation. Conditional knock-out (CKO) of Secisbp2l in OL lineage resulted in a decreased level of DIO2 and T3, accompanied by impaired OL differentiation, hypomyelination and motor deficits in both sexes of mice. Moreover, the defective differentiation of OLs in Secisbp2l mutants can be alleviated by T3 or its analog, but not the prohormone T4. The present study has provided strong evidence for the autonomous regulation of OL differentiation by its intrinsic T3 production mediated by the novel SECISBP2L-DIO2-T3 pathway during myelin development.SIGNIFICANCE STATEMENT Secisbp2l is specifically expressed in differentiating oligodendrocytes (OLs) and is essential for selenoprotein translation in OLs. Secisbp2l regulates Dio2 translation for active thyroid hormone (TH) T3 production in the CNS. Autonomous regulation of OLs differentiation via SECISBP2L-DIO2-T3 pathway.

Thyroid Hormone Action in Muscle Atrophy.

Skeletal muscle atrophy is a condition associated with various physiological and pathophysiological conditions, such as denervation, cachexia, and fasting. It is characterized by an altered protein turnover in which the rate of protein degradation exceeds the rate of protein synthesis, leading to substantial muscle mass loss and weakness. Muscle protein breakdown reflects the activation of multiple proteolytic mechanisms, including lysosomal degradation, apoptosis, and ubiquitin–proteasome. Thyroid hormone (TH) plays a key role in these conditions. Indeed, skeletal muscle is among the principal TH target tissue, where TH regulates proliferation, metabolism, differentiation, homeostasis, and growth. In physiological conditions, TH stimulates both protein synthesis and degradation, and an alteration in TH levels is often responsible for a specific myopathy. Intracellular TH concentrations are modulated in skeletal muscle by a family of enzymes named deiodinases; in particular, in muscle, deiodinases type 2 (D2) and type 3 (D3) are both present. D2 activates the prohormone T4 into the active form triiodothyronine (T3), whereas D3 inactivates both T4 and T3 by the removal of an inner ring iodine. Here we will review the present knowledge of TH action in skeletal muscle atrophy, in particular, on the molecular mechanisms presiding over the control of intracellular T3 concentration in wasting muscle conditions. Finally, we will discuss the possibility of exploiting the modulation of deiodinases as a possible therapeutic approach to treat muscle atrophy.

Testing the short-and long-term effects of elevated prenatal exposure to different forms of thyroid hormones.

Maternal thyroid hormones (THs) are known to be crucial in embryonic development in humans, but their influence on other, especially wild, animals remains poorly understood. So far, the studies that experimentally investigated the consequences of maternal THs focused on short-term effects, while early organisational effects with long-term consequences, as shown for other prenatal hormones, could also be expected. In this study, we aimed at investigating both the short- and long-term effects of prenatal THs in a bird species, the Japanese quail Coturnix japonica. We experimentally elevated yolk TH content (the prohormone T4, and its active metabolite T3, as well as a combination of both hormones). We analysed hatching success, embryonic development, offspring growth and oxidative stress as well as their potential organisational effects on reproduction, moult and oxidative stress in adulthood. We found that eggs injected with T4 had a higher hatching success compared with control eggs, suggesting conversion of T4 into T3 by the embryo. We detected no evidence for other short-term or long-term effects of yolk THs. These results suggest that yolk THs are important in the embryonic stage of precocial birds, but other short- and long-term consequences remain unclear. Research on maternal THs will greatly benefit from studies investigating how embryos use and respond to this maternal signalling. Long-term studies on prenatal THs in other taxa in the wild are needed for a better understanding of this hormone-mediated maternal pathway.

Inhibition of Type 1 Iodothyronine Deiodinase by Bisphenol A.

Plastics are ubiquitously present in our daily life and some components of plastics are endocrine-disrupting chemicals, such as bisphenol A and phthalates. Herein, we aimed to evaluate the effect of plastic endocrine disruptors on type 1 and type 2 deiodinase activities, enzymes responsible for the conversion of the pro-hormone T4 into the biologically active thyroid hormone T3, both in vitro and in vivo. Initially, we incubated rat liver type 1 deiodinase and brown adipose tissue type 2 deiodinase samples with 0.5 mM of the plasticizers, and the deiodinase activity was measured. Among them, only BPA was capable to inhibit both type 1 and type 2 deiodinases. Then, adult male Wistar rats were treated orally with bisphenol A (40 mg/kg b.w.) for 15 days and hepatic type 1 deiodinase and brown adipose tissue type 2 deiodinase activities and serum thyroid hormone concentrations were measured. In vivo bisphenol A treatment significantly reduced hepatic type 1 deiodinase activity but did not affect brown adipose tissue type 2 deiodinase activity. Serum T4 levels were higher in bisphenol A group, while T3 remained unchanged. T3/T4 ratio was decreased in rats treated with bisphenol A, reinforcing the idea that peripheral metabolism of thyroid hormone was affected by bisphenol A exposure. Therefore, our results suggest that bisphenol A can affect the metabolism of thyroid hormone thus disrupting thyroid signaling.

SAT-LB095 The Role of Type 2 Deiodinase in Interactions Between Muscle Stem Cells and Endothelial Cells

Thyroid hormone (TH) is a major muscle target and is required for muscle homeostasis, function, and regeneration. T3, the biologically active TH, is locally produced in muscle from the prohormone T4 by type 2 deiodinase (D2). An increase in D2, and the subsequent T3 generated, is required for normal muscle stem cell (MuSC) differentiation during muscle repair [1]. Interestingly, crosstalk between MuSC and endothelial cells via vascular endothelial growth factor (VEGF) is critical for proper muscle regeneration. It is unknown if local T3 generation by D2 influences interactions between MuSCs and endothelial cells. We hypothesized that D2-deficiency in MuSCs will affect crosstalk with endothelial cells. To study this, we deleted D2 in a myoblast cell line (D2KO C2C12) and explored interactions between C2C12 and human umbilical vein endothelial cells (HUVECs). Initially, we induced differentiation of wild-type (WT) C2C12 and D2KO C2C12 by serum withdrawal and assessed gene expression. We found that VEGF expression increased with differentiation, peaking at day 4. Strikingly, this was 2.3-fold higher in WT than D2KO C2C12 (p< 0.0001). Consistent with mRNA changes, both intracellular and secreted VEGF were increased in a time-dependent manner during differentiation. Notably, secreted VEGF from WT C2C12 was significantly higher than D2KO C2C12 (2.5-fold, p < 0.0001). Further, VEGF expression in differentiated WT C2C12 cells was increased 1.5-fold (p=0.03) with T3-treatment, suggesting VEGF is a T3-responsive gene. VEGF has proangiogenic effects during muscle injury [2]. To assess the functional consequences of decreased VEGF production by D2KO C2C12 cells, HUVECs were incubated with WT and D2KO C2C12-derived conditioned media collected during differentiation. We found that angiogenesis and chemotaxis of HUVECs were enhanced after culture with WT C2C12 conditioned media. In contrast, these parameters were blunted when HUVECS were cultured with D2KO C2C12 conditioned media, consistent with lower VEGF. Our results suggest that local D2-mediated increase in T3 regulates VEGF production during myoblast differentiation, promoting endothelial cell migration and angiogenesis.

SAT-564 The Role Of Se Recycling In Regulating Iodothyronine-deiodinases In The Skeletal Muscle

T3 action is locally modulated by the intracellular type 2 (D2) and type 3 (D3) iodothyronine-deiodinases which convert the prohormone T4 to active T3, and inactivate T4 and T3, respectively. The synchronized expression of D3 followed by D2 is necessary for proper muscle development and regeneration. D2 and D3 are selenoproteins containing selenium (Se) at their active site in the form of the rare amino acid selenocysteine (Sec) which is incorporated during translation by the recoding of an UGA stop codon. Consequently, dietary Se is essential for TH metabolism. During times of Se deficiency, selenocysteine lyase (Scly) decomposes Sec to Se allowing it to be recycled into new selenoproteins. We hypothesized that Scly is involved in preserving the production of the deiodinases and other selenoproteins when dietary Se levels are low. During the neonatal period when muscle is maturing, and deiodinase expression is high, we found that between P1 and P15 Scly expression increases 2-fold in soleus and 15-fold in the extensor digitalis longus (EDL) muscle. Further, we found that Scly mRNA expression was 2.5-fold higher in the adult slow oxidative soleus muscle versus the fast glycolytic EDL. Next, we fed male WT and Scly knockout (Scly-/-) mice a Se adequate or deficient diet and evaluated gene expression in the soleus and EDL via qPCR. In WT soleus, low Se diet decreased expression of many selenoproteins, likely in part due to nonsense-mediated decay of the non-translated UGA containing transcripts. In contrast, the expression of these selenoproteins was unchanged in the EDL. Scly-/- mice fed a Se adequate diet demonstrated a trend towards increased Dio2, SelenoN, SelenoM, SelenoP, Txnrd1, and Sephs2 expression in soleus when compared to WT mice on the same diet, but this was abolished under low Se conditions. In the soleus, diet had no effect on SelenoH in WT mice, while notably, SelenoH was significantly decreased in Scly-/- mice fed a low Se diet. In the EDL, expression of SelenoW and SelenoH was unchanged under low Se conditions in WT mice, but was decreased in Scly-/-. This suggests that the expression of a subset of genes relies upon the Se provided by Scly recycling when Se is limiting. Finally, to investigate the possible role of Scly in muscle differentiation, we induced the murine myoblast C2C12 cell line to differentiate via serum withdrawal in the presence of 100 nM total Se to control for the effects of decreased serum on Se levels. Scly mRNA expression reached peak induction by 48h after differentiation. Dio2, Gpx3, SelenoP, SelenoM, SelenoN, and the selenoprotein synthesis factor SBP2 exhibited similar expression profiles. Our results suggest a role for Scly in skeletal muscle development, differentiation, and adult muscle homeostasis. Further, expression of some muscle selenoproteins, including Dio2, appears to be sensitive to low dietary Se when Scly mediated Se recycling is impaired. Funding: NIH-NIDDK

Marked improvement of thyroid function and autoimmunity by Aloe barbadensis miller juice in patients with subclinical hypothyroidism

Some natural compounds decrease serum levels of thyroid autoantibodies, but results are inconsistent and thyroid function has been evaluated infrequently; moreover, the effects of Aloe on thyroid autoimmunity and function have been examined in very few studies. This study stems from the observation of one co-author, who has Hashimoto’s thyroiditis (HT)-related subclinical hypothyroidism (SCH). Upon checking her biochemical thyroid panel when taking daily Aloe barbardensis Miller juice (ABMJ) for thyroid-unrelated reasons, she noticed a decrease in serum thyroperoxidase autoantibodies (TPOAb) and thyrotropin (TSH) and an increase in serum free thyroxine (FT4). Based on this observation, we enrolled 30 consecutive HT women with levothyroxine-untreated SCH and high TPOAb levels. All of them took ABMJ (50 ml daily) for nine months and were tested for serum TSH, FT4, free triiodothyronine (FT3) and TPOAb. Measurements were performed at baseline and at months 3 and 9. TSH, FT4 and TPOAb improved significantly already at month 3 and further (−61%, +23% and −56%) at month 9. However, FT3 decreased significantly at month 3 (−16%) with no further decrease at month 9, so that the FT4:FT3 ratio increased significantly (+33% and + 49%). At baseline, 100% of women had TSH > 4.0 mU/L and TPOAb > 400 U/ml, but frequencies fell to 0% and 37%, respectively, at month 9. In contrast, a control group (namely, 15 untreated SCH women of comparable age and baseline levels of TSH, FT4, FT3 and TPOAb) had no significant changes in any index. We conclude that the daily intake of 100 ml ABMJ for 9 months in women with HT-related SCH decreases the burden of thyroid autoimmune inflammation. In addition, ABMJ rescues thyrocyte function, with decreased need for conversion of the prohormone T4 into the more active T3 through ABMJ-induced inhibition of T4 deiodination.

An Essential Physiological Role for MCT8 in Bone in Male Mice.

T3 is an important regulator of skeletal development and adult bone maintenance. Thyroid hormone action requires efficient transport of T4 and T3 into target cells. We hypothesized that monocarboxylate transporter (MCT) 8, encoded by Mct8 on the X-chromosome, is an essential thyroid hormone transporter in bone. To test this hypothesis, we determined the juvenile and adult skeletal phenotypes of male Mct8 knockout mice (Mct8KO) and Mct8D1D2KO compound mutants, which additionally lack the ability to convert the prohormone T4 to the active hormone T3. Prenatal skeletal development was normal in both Mct8KO and Mct8D1D2KO mice, whereas postnatal endochondral ossification and linear growth were delayed in both Mct8KO and Mct8D1D2KO mice. Furthermore, bone mass and mineralization were decreased in adult Mct8KO and Mct8D1D2KO mice, and compound mutants also had reduced bone strength. Delayed bone development and maturation in Mct8KO and Mct8D1D2KO mice is consistent with decreased thyroid hormone action in growth plate chondrocytes despite elevated serum T3 concentrations, whereas low bone mass and osteoporosis reflects increased thyroid hormone action in adult bone due to elevated systemic T3 levels. These studies identify an essential physiological requirement for MCT8 in chondrocytes, and demonstrate a role for additional transporters in other skeletal cells during adult bone maintenance.

Permanent Deiodinase Type 2 Deficiency Strongly Perturbs Zebrafish Development, Growth, and Fertility.

Iodothyronine deiodinases are selenocysteine-containing enzymes that activate or inactivate thyroid hormones (THs). Deiodinase type 2 (Dio2) catalyzes the conversion of the prohormone T4 into the transcriptionally active T3 and is the predominant activating deiodinase in zebrafish. Using zinc finger nucleases, we generated two different dio2(-/-) mutant zebrafish lines to investigate the physiological function of this TH activator. The first line contains a deletion of 9 bp, resulting in an in-frame elimination of three conserved amino acids. The other line is characterized by an insertion of 4 bp, leading to the introduction of a premature stop-codon. Both lines completely lack Dio2 activity, resulting in a strong reduction of T3 abundancy in all tissues tested. Early development is clearly perturbed in these animals, as shown by a diverse set of morphometric parameters, defects in swim bladder inflation, and disturbed locomotor activity tested between 1 and 7 days after fertilization. Permanent Dio2 deficiency also provokes long-term effects because growth and especially fertility are severely hampered. Possible compensatory mechanisms were investigated in adult dio2(-/-) mutants, revealing a down-regulation of the inactivating deiodinase Dio3 and TH receptor transcript levels. As the first nonmammalian model with permanent Dio2 deficiency, these mutant zebrafish lines provide evidence that Dio2 is essential to assure normal development and to obtain a normal adult phenotype.

Characterization of Chicken Thyroid Hormone Transporters.

Thyroid hormone (TH) transmembrane transporters are key regulators of TH availability in target cells where correct TH signaling is essential for normal development. Although the chicken embryo is a valuable model for developmental studies, the only functionally characterized chicken TH transporter so far is the organic anion transporting polypeptide 1C1 (OATP1C1). We therefore cloned the chicken L-type amino acid transporter 1 (LAT1) and the monocarboxylate transporters 8 (MCT8) and 10 (MCT10), and functionally characterized them, together with OATP1C1, in JEG3, COS1, and DF-1 cells. In addition, we used in situ hybridization to study their mRNA expression pattern during development. MCT8 and OATP1C1 are both high affinity transporters for the prohormone T4, whereas receptor-active T3 is preferably transported by MCT8 and MCT10. The latter one shows lower affinity but has a high Vmax and seems to be especially good at T3 export. Also, LAT1 has a lower affinity for its preferred substrate 3,3'-diiodothyronine. Reverse T3 is transported by all 4 TH transporters and is a good export product for OATP1C1. TH transporters are strongly expressed in eye (LAT1, MCT8, MCT10), pancreas (LAT1, MCT10), kidney, and testis (MCT8). Their extensive expression in the central nervous system, especially at the brain barriers, indicates an important role in brain development. In conclusion, we show TH transport by chicken MCT8, MCT10, and LAT1. Together with OATP1C1, these transporters have functional characteristics similar to their mammalian orthologs and are interesting target genes to further elucidate the role of THs during embryonic development.

Thyroid Hormone Signaling in Male Mouse Skeletal Muscle Is Largely Independent of D2 in Myocytes.

The type 2 deiodinase (D2) activates the prohormone T4 to T3. D2 is expressed in skeletal muscle (SKM), and its global inactivation (GLOB-D2KO mice) reportedly leads to skeletal muscle hypothyroidism and impaired differentiation. Here floxed Dio2 mice were crossed with mice expressing Cre-recombinase under the myosin light chain 1f (cre-MLC) to disrupt D2 expression in the late developmental stages of skeletal myocytes (SKM-D2KO). This led to a loss of approximately 50% in D2 activity in neonatal and adult SKM-D2KO skeletal muscle and about 75% in isolated SKM-D2KO myocytes. To test the impact of Dio2 disruption, we measured soleus T3 content and found it to be normal. We also looked at the expression of T3-responsive genes in skeletal muscle, ie, myosin heavy chain I, α-actin, myosin light chain, tropomyosin, and serca 1 and 2, which was preserved in neonatal SKM-D2KO hindlimb muscles, at a time that coincides with a peak of D2 activity in control animals. In adult soleus the baseline level of D2 activity was about 6-fold lower, and in the SKM-D2KO soleus, the expression of only one of five T3-responsive genes was reduced. Despite this, adult SKM-D2KO animals performed indistinguishably from controls on a treadmill test, running for approximately 16 minutes and reached a speed of about 23 m/min; muscle strength was about 0.3 mN/m·g body weight in SKM-D2KO and control ankle muscles. In conclusion, there are multiple sources of D2 in the mouse SKM, and its role is limited in postnatal skeletal muscle fibers.

Thyroid hormone function in the rat testis.

Thyroid hormones are emerging regulators of testicular function since Sertoli, germ, and Leydig cells are found to express thyroid hormone receptors (TRs). These testicular cells also express deiodinases, which are capable of converting the pro-hormone T4 to the active thyroid hormone T3, or inactivating T3 or T4 to a non-biologically active form. Furthermore, thyroid hormone transporters are also found in the testis. Thus, the testis is equipped with the transporters and the enzymes necessary to maintain the optimal level of thyroid hormone in the seminiferous epithelium, as well as the specific TRs to execute thyroid hormone action in response to different stages of the epithelial cycle of spermatogenesis. Studies using genetic models and/or goitrogens (e.g., propylthiouracil) have illustrated a tight physiological relationship between thyroid hormone and testicular function, in particular, Sertoli cell differentiation status, mitotic activity, gap junction function, and blood–testis barrier assembly. These findings are briefly summarized and discussed herein.

A novel role for the thyroid hormone-activating enzyme type 2 deiodinase in the inflammatory response of macrophages.

Deiodinase type 2 (D2) is a thyroid hormone-activating enzyme converting the prohormone T4 into the active hormone T3. In the present study, we show for the first time that D2 is up-regulated in the mouse liver during acute and chronic inflammation, in close correlation with the proinflammatory cytokine IL-1β and independently of serum T3. Inflammation-induced D2 expression was confirmed in macrophages, in conjunction with selective thyroid hormone transporter (monocarboxylate transporter 10) and thyroid hormone receptor (TR)α1 stimulation, and was absent in hepatocytes. Moreover, D2 knockdown in macrophages resulted in a clear attenuation of the lipopolysaccharide (LPS)-induced IL-1β and GM-CSF expression, in addition to aberrant phagocytosis. Locally produced T3, acting via the TRα, may be instrumental in this novel inflammatory response, because LPS-treated TRα(0/0) mice showed a markedly decreased LPS-induced GM-CSF mRNA expression. We now propose that hepatic D2 favors the innate immune response by specifically regulating cellular thyroid hormone levels in macrophages.

Moderate Weight Loss Is Sufficient to Affect Thyroid Hormone Homeostasis and Inhibit Its Peripheral Conversion

Thyroid hormones are important determinants of energy expenditure, and in rodents, adipose tissue affects thyroid hormone homeostasis via leptin signaling. The relationship between thyroid hormones and nutritional status in humans has been assessed primarily in drastic dietary or bariatric surgery interventions, while limited information is available on serial assessment of this axis during moderate, prolonged dietary restriction. To evaluate the effects of moderate dietary restriction on thyroid hormone homeostasis, 47 subjects with a body mass index (BMI) of 25-45 kg/m(2) were enrolled in a longitudinal intervention study; 30 nonoverweight volunteers were also enrolled as controls. Overweight and obese subjects underwent a 12-month individualized dietary intervention aimed at achieving a 5-10% weight loss. The intervention resulted in a 6.3±0.9 kg (6.5±1.0%) weight loss. At baseline, thyrotropin (TSH) and T3 concentrations correlated significantly with fat mass (R=0.257, p=0.024 and R=0.318, p=0.005, respectively). After weight loss, T3 decreased significantly (from 112.7±3.1 to 101.8±2.6 ng/dL, p<0.001) in the absence of significant changes in TSH or free T4 (fT4). The decrease in serum T3 correlated with the decrease in weight (R=0.294, p<0.001). The T3:fT4 ratio decreased significantly (p=0.02) in individuals who lost >5% body weight. T3 concentration closely correlates with individual nutritional status, and moderate weight loss results in a decrease in T3 with minimal changes in other thyroid hormone homeostasis parameters. The data suggest that a decrease in peripheral conversion of the prohormone T4 into its hormonally active metabolite T3 is at least in part responsible for the observed changes in thyroid hormone homeostasis.

Thyroid Hormones and Antioxidant Systems: Focus on Oxidative Stress in Cardiovascular and Pulmonary Diseases

In previous works we demonstrated an inverse correlation between plasma Coenzyme Q10 (CoQ10) and thyroid hormones; in fact, CoQ10 levels in hyperthyroid patients were found among the lowest detected in human diseases. On the contrary, CoQ10 is elevated in hypothyroid subjects, also in subclinical conditions, suggesting the usefulness of this index in assessing metabolic status in thyroid disorders. A Low-T3 syndrome is a condition observed in several chronic diseases: it is considered an adaptation mechanism, where there is a reduction in pro-hormone T4 conversion. Low T3-Syndrome is not usually considered to be corrected with replacement therapy. We review the role of thyroid hormones in regulation of antioxidant systems, also presenting data on total antioxidant capacity and Coenzyme Q10. Published studies suggest that oxidative stress could be involved in the clinical course of different heart diseases; our data could support the rationale of replacement therapy in low-T3 conditions.

Antithyroid agents and QSAR studies: inhibition of lactoperoxidase-catalyzed iodination reaction by isochromene-1-thiones

Thyroxine, the main secretory hormone of thyroid gland, is produced from thyroglobulin by thyroid peroxidase/hydrogen peroxide/iodide system. The prohormone T4 is then converted to its potent form T3 by a selenocysteine-containing enzyme iodothyronine deiodinase. Autoantibodies which activate thyroid-stimulating hormone receptor are not under the pituitary feedback control system, and therefore, the uncontrolled production of thyroid hormones leads to a condition called “hyperthyroidism.” The overproduction of T4 and T3 can be controlled by specific inhibitors, which either block the synthesis of thyroid hormone or reduce the conversion of T4–T3. Unique classes of such inhibitors are thiourea drugs, methimazole (MMI), 6-n-propyl-2-thiouracil, and carbimazole suggesting that thione moiety exhibit excellent antithyroid activity. We have carried out biomimetic studies by HPLC assay, which suggested that isochromene-1-thiones exhibit significant antithyroid activity by inhibiting the lactoperoxidase (LPO)-catalyzed iodination, comparable with MMI, and that the inhibitory effects of some of them were found to be much superior to those of MMI. Kinetic studies demonstrate that isochromene-1-thiones inhibit LPO irreversibly. Our inhibition studies suggest that isochromene-1-thiones might be another promising candidate with potential for developing therapeutics for hyperthyroidism. The quantitative structure–activity relationship (QSAR) was developed between the LPO-inhibitory activities of isochromene-1-thiones and their physiochemical properties. The statistical measures, such as r2 (0.81), r2adj (0.79), q2 (0.73), and F-ratio (39.05), were found to be within the acceptable range.

Rapid Induction of Hypothalamic Iodothyronine Deiodinase Expression by Photoperiod and Melatonin in Juvenile Siberian Hamsters (Phodopus sungorus)

Production of T(3) in the mediobasal hypothalamus is critical for regulation of seasonal reproductive physiology. Type 2 iodothyronine deiodinase (DIO2) and DIO3 enzymes catalyze the prohormone T(4) into biologically-active T(3) and biologically-inactive rT(3), respectively. In several seasonally-breeding vertebrates, DIO2 and DIO3 expression is implicated in photoperiod signal transduction in adulthood. These experiments tested the hypothesis that juvenile Siberian hamsters, which are highly responsive to photoperiod at weaning (postnatal day [PND]18), exhibit rapid and sustained changes in hypothalamic dio3 mRNA expression during photoperiod-induced and photoperiod-inhibited puberty. Hypothalamic dio2 and dio3 expression was measured via quantitative PCR in hamsters born and reared in a long-day photoperiod (15L:9D) and weaned on PND18 into short-day photoperiods (9L:15D). In SD males, hypothalamic dio3 mRNA was elevated 2.5-fold within 3 days (PND21) and continued to increase (>20-fold) through PND32; changes in dio3 mRNA preceded inhibition of gonadotropin (FSH) secretion and gonadal regression in SD. Females exhibited comparable dio3 responses to SD. In LD males, dio3 remained low and invariant from PND18-PND32. In contrast, dio2 mRNA rose conspicuously on PND21, independent of photoperiod, returning to basal levels thereafter. In LD, a single afternoon melatonin (MEL) injection on PND18 or PND20 was sufficient to increase hypothalamic dio3 mRNA, and dio3 increased in proportion to the number of successive days of MEL treatment. SD photoperiods and MEL exert rapid, sustained, and additive effects on hypothalamic dio3 mRNA, which may play a central role in inhibiting maturation of the peripubertal hypothalamo-pituitary-gonadal axis.