Antioxidant effects of α-lipoic acid against epididymal oxidative damage in adult offspring rats exposed to maternal hypothyroidism stress.

It is well known that the epididymis promotes post-testicular sperm maturation events. However, its malfunction during congenital hypothyroidism is relatively less understood as compared to the testis. The present study evaluated the probable effect of α-lipoic acid on epididymal oxidative stress parameters in rats exposed to antithyroid drug, carbimazole during fetal period. Time-mated pregnant rats in unexposed and carbimazole (1.35 mg/Kg body weight exposed were allowed to deliver pups and weaned. At postnatal day 100, the F1 male pups were assessed for epididymal endpoints. Among the epididymal regions, significant elevation of lipid peroxidation levels, superoxide anion, and hydrogen peroxide contents with a concomitant reduction in the activity levels of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and reduced glutathione levels were observed in cauda epididymis of carbimazole exposed rats over controls. Significant elevation in sperm DNA fragmentation (comet assay), accelerated cauda epididymal sperm transit time and reduction in epididymal sialic acid content was observed in carbimazole exposed rats. RT-qPCR studies revealed that embryonic exposure to carbimazole resulted in down regulation of androgen receptor, nuclear factor eryrthoid 2 like 2, 5α-reducatse 1 mRNA levels, while up regulation of caspase 3 mRNA was observed in epididymal regions of rats. In addition, fetal exposure to carbimazole resulted in disorganization of cauda epididymal architecture in rats. Conversely, supplementation of α-lipoic acid (70 mg/Kg bodyweight) during PND 3 to 14 restored epididymal functions in carbimazole exposed rats and the ameliorative effects of lipoic acid could be attributed to its antioxidant and steroidogenic effects.

Chronic Excess Iodine Intake Inhibits Bone Reconstruction Leading to Osteoporosis in Rats.

BACKGROUND: Although iodine modulates bone metabolism in the treatment of thyroid disease, the effect of iodine intake on bone metabolism remains less known. OBJECTIVE: This study evaluated the effect of excess iodine intake in rats on bone reconstruction in the 6th and 12th month of intervention. METHOD: Rats were treated with different doses of iodinated water: the normal group (NI, 6.15 µg/d), 5-fold high iodine group (5HI, 30.75 µg/d), 10-fold high iodine group (10HI, 61.5 µg/d), 50-fold high iodine group (50HI, 307.5 µg/d), and 100-fold high iodine group (100HI, 615 µg/d). Thyroid hormone concentrations were determined by a chemiluminescent immunoassay. Morphometry and microstructure of bone trabecula were observed by hematoxylin and eosin staining and microcomputed tomography, respectively. Alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) staining were performed to evaluate the activity of osteoblasts and osteoclasts, respectively. RESULTS: The 24-h urine iodine concentration increased with iodine intake. The rats in the HI groups had higher serum thyroid-stimulating hormone and decreased serum free thyroxine concentrations in the 12th month than the NI group (all P < 0.05). The percentage of the trabecular bone area and osteoblast perimeter in the 100HI group were significantly lower than those in the NI group (P < 0.05). Increased structure model index was observed in the 50HI and 100HI groups compared with the NI group in the 6th month and increased trabecular separation in the 12th month (all P < 0.05). ALP and TRAP staining revealed osteoblastic bone formation was reduced, and the number of TRAP+ multinucleated cells decreased with increasing iodine intake. CONCLUSIONS: Excess iodine intake may increase the risk of hypothyroidism in rats. Chronic excess iodine intake can lead to abnormal changes in skeletal structure, resulting in reduced activity of osteoblasts and osteoclasts, which inhibits the process of bone reconstruction and may lead to osteoporosis.

Differentiation and Treatment of Hypothyroidism, Functional Hypothyroidism, and Functional Metabolism.

Less than optimal thyroid effects can occur for many reasons, including lack of production, excessive binding, reduced conversion to the active form of thyroid, poor intracellular transport, poor receptor response, or autoimmune and toxicity issues. Differentiation of where the problem or problems causing the symptoms of hypothyroidism to occur is a key to the return to optimal thyroid response and successful treatment outcome. The concept of hypothyroidism, functional hypothyroidism, and functional hypometabolism as an alternative method to describe classical subclinical hypothyroidism symptoms according to the source of the malfunction are discussed in this article. The author also presents a unique method of using standard thyroid measurements to determine the areas of dysfunction and discusses the possible reasons for low production, excessive binding, poor conversion, and suboptimal receptor response. Appropriate treatment options for each area are discussed, including nutritional requirements. Thyroid replacement therapy options are presented and individualization of therapy based on need established with use of the thyroid gradient levels is discussed. Individualization of thyroid therapy will often require the use of compounded T3 or T4/T3 combination therapy. Compounding thyroid replacement allows for avoiding fillers that can interfere with absorption, unwanted diluents, unknown or nonstandardized ingredients from animal sources, providing more sustained action with less side effects, and individualizing the ratio of T4 and T3 initially, and as improvements are made in the patient's ability to convert T4 to T3.

Kisspeptin-10 Improves Testicular Redox Status but Does Not Alter the Unfolded Protein Response (UPR) That Is Downregulated by Hypothyroidism in a Rat Model.

Hypothyroidism compromises the testicular redox status and is associated with reduced sperm quality and infertility in men. In this regard, studies have demonstrated the antioxidant potential of kisspeptin in reproductive and metabolic diseases. In this study, we evaluate the effects of kisspeptin-10 (Kp10) on the testicular redox, as well as mediators of the unfolded protein response (UPR) in adult rats with hypothyroidism. Adult male Wistar rats were randomly separated into the Control (n = 15), Hypo (n = 13) and Hypo + Kp10 (n = 14) groups, and hypothyroidism was induced with 6-propyl-2-thiouracil (PTU) for three months. In the last month, half of the hypothyroid animals received Kp10. Testis samples were collected for enzymatic, immunohistochemical and/or gene evaluation of mediators of oxidative stress (TBARs, lipid hydroperoxides (LOOH), ROS, peroxynitrite, SOD, CAT and GPX), endoplasmic reticulum stress (GRP78, ATF6, PERK, CHOP, HO-1 and sXBP1) and antiapoptocytes (BCL-2). Hypothyroidism increased apoptosis index, TBARS and LOOH concentrations, and reduced testicular gene expression of Sod1, Sod2 and Gpx1, as well as the expression of Grp78, Atf6, Ho1 and Chop. Treatment with Kp10, in turn, reduced testicular apoptosis and the production of peroxynitrite, while increased SOD1 and GPX ½ expression, and enzymatic activity of CAT, but did not affect the lower expression of UPR mediators caused by hypothyroidism. This study demonstrated that hypothyroidism causes oxidative stress and dysregulated the UPR pathway in rat testes and that, although Kp10 does not influence the low expression of UPR mediators, it improves the testicular redox status, configuring it as an important antioxidant factor in situations of thyroid dysfunction.

Thyrotropin induces atherosclerosis by upregulating large conductance Ca2+-activated K+ channel subunits.

Hypothyroidism is associated with elevated levels of serum thyrotropin (TSH), which have been shown to promote abnormal proliferation of vascular smooth muscle cells and contribute to the development of atherosclerosis. However, the specific mechanisms underlying the TSH-induced abnormal proliferation of vascular smooth muscle cells remain unclear. The objective of this study was to investigate the role of TSH in the progression of atherosclerosis. Our research findings revealed that hypothyroidism can trigger early atherosclerotic changes in the aorta of Wistar rats. In alignment with our in vitro experiments, we observed that TSH induces abnormal proliferation of aortic smooth muscle cells by modulating the expression of α and ß1 subunits of large conductance Ca2+-activated K+ (BKCa) channels within these cells via the cAMP/PKA signaling pathway. These results collectively indicate that TSH acts through the cAMP/PKA signaling pathway to upregulate the expression of α and ß1 subunits of BKCa channels, thereby promoting abnormal proliferation of arterial smooth muscle cells. These findings may provide a basis for the clinical prevention and treatment of atherosclerosis caused by elevated TSH levels.

Impact of metformin on hypothalamic-pituitary-thyroid axis activity in women with autoimmune and non-autoimmune subclinical hypothyroidism: a pilot study.

BACKGROUND: Metformin reduces plasma TSH levels if these levels are elevated. No study has investigated whether the hormonal effects of metformin are impacted by thyroid autoimmunity. The current study aimed to compare the effect of metformin on hypothalamic-pituitary-thyroid axis activity between subjects with mild hypothyroidism of different origins. METHODS: The study population consisted of two groups of women with prediabetes and mildly elevated TSH levels, matched by age, insulin sensitivity, TSH, and thyroid hormone levels. Group A included 26 women with autoimmune thyroiditis, while group B enrolled 26 individuals with hypothyroidism of non-autoimmune origin. Both groups were treated with metformin (2.55-3 g daily). Circulating levels of TSH, total and free thyroid hormones, glucose, insulin, prolactin, high-sensitivity C-reactive protein (hsCRP) and 25-hydroxyvitamin D, concentrations of thyroid antibodies, and structure parameters of thyroid homeostasis were assessed at baseline and 6 months later. RESULTS: All patients completed the study. At baseline, both groups differed in concentrations of thyroid peroxidase antibodies, thyroglobulin antibodies, hsCRP, and 25-hydroxyvitamin D. The drug reduced TSH and Jostel's index, with no difference between the study groups. The improvement in insulin sensitivity, observed in both groups, was more pronounced in group B than in group A. In women with autoimmune hypothyroidism, the drug increased SPINA-GT and decreased hsCRP levels. The remaining markers did not change throughout the study. CONCLUSIONS: The obtained results suggest that, despite differences in thyroid output, the impact of metformin on TSH levels is similar in hypothyroid women with and without thyroid autoimmunity.

Hypothalamic Thyroid Hormone Receptor α1 Signaling Controls Body Temperature.

Background: The importance of thyroid hormones (THs) for peripheral body temperature regulation has been long recognized, as medical conditions such as hyper- and hypothyroidism lead to alterations in body temperature and energy metabolism. In the past decade, the brain actions of THs and their respective nuclear receptors, thyroid hormone receptor α1 (TRα1) and thyroid hormone receptor beta (TRß), coordinating body temperature regulation have moved into focus. However, the exact roles of the individual TR isoforms and their precise neuroanatomical substrates remain poorly understood. Methods: Here we used mice expressing a mutant TRα1 (TRα1+m) as well as TRß knockouts to study body temperature regulation using radiotelemetry in conscious and freely moving animals at different ambient temperatures, including their response to oral 3,3',5-triiodothyronine (T3) treatment. Subsequently, we tested the effects of a dominant-negative TRα1 on body temperature after adeno-associated virus (AAV)-mediated expression in the hypothalamus, a region known to be involved in thermoregulation. Results: While TRß seems to play a negligible role in body temperature regulation, TRα1+m mice had lower body temperature, which was surprisingly not entirely normalized at 30°C, where defects in facultative thermogenesis or tail heat loss are eliminated as confounding factors. Only oral T3 treatment fully normalized the body temperature profile of TRα1+m mice, suggesting that the mutant TRα1 confers an altered central temperature set point in these mice. When we tested this hypothesis more directly by expressing the dominant-negative TRα1 selectively in the hypothalamus via AAV transfection, we observed a similarly reduced body temperature at room temperature and 30°C. Conclusion: Our data suggest that TRα1 signaling in the hypothalamus is important for maintaining body temperature. However, further studies are needed to dissect the precise neuroanatomical substrates and the downstream pathways mediating this effect.

Thyroid Hormones Regulate the Thermoregulatory Mechanisms of the Body: Review.

Thyroid hormones (TH) play a critical role in metabolism, energy balance and thermogenesis. The mechanisms whereby thyroid hormone increases heat production have been analyzed with emphasis in more recent developments. Thyroid hormone increases obligatory thermogenesis as a result of the stimulation of numerous metabolic pathways involved in the development, remodeling and delivery of energy to the tissues. In this section, alterations in primary hyperthyroidism and hypothyroidism will be contrasted with the physiological characteristics of TH-dependent regulation in response to fasting and exposure to cold. The current review will discuss the situation with regard to regional thyroid hormones in the Central Nervous System (CNS) and more specifically, in peripheral cells. When caused by exposure to cold or fasting, local anomalies in the CNS are distinct from peripheral compartments, in contrast to hyperthyroidism and hypothyroidism, which differ when similar changes are observed. Lower hypothalamic TH concentrations are associated with cold exposure, although higher peripheral TH levels. The TH tendency is reversed by fasting. Primary hypothyroidism and hyperthyroidism impair them. The current study aims to trace the various mechanisms used by the thyroid gland to regulate the body's energy production process.

Transcriptomic and lipid profiling analysis reveals a functional interplay between testosterone and growth hormone in hypothyroid liver.

Preclinical and clinical studies suggest that hypothyroidism might cause hepatic endocrine and metabolic disturbances with features that mimic deficiencies of testosterone and/or GH. The absence of physiological interactions between testosterone and GH can be linked to male differentiated liver diseases. Testosterone plays relevant physiological effects on somatotropic-liver axis and liver composition and the liver is a primary organ of interactions between testosterone and GH. However, testosterone exerts many effects on liver through complex and poorly understood mechanisms. Testosterone impacts liver functions by binding to the Androgen Receptor, and, indirectly, through its conversion to estradiol, and cooperation with GH. However, the role of testosterone, and its interaction with GH, in the hypothyroid liver, remains unclear. In the present work, the effects of testosterone, and how they impact on GH-regulated whole transcriptome and lipid composition in the liver, were studied in the context of adult hypothyroid-orchiectomized rats. Testosterone replacement positively modulated somatotropic-liver axis and impacted liver transcriptome involved in lipid and glucose metabolism. In addition, testosterone enhanced the effects of GH on the transcriptome linked to lipid biosynthesis, oxidation-reduction, and metabolism of unsaturated and long-chain fatty acids (FA). However, testosterone decreased the hepatic content of cholesterol esters and triacylglycerols and increased fatty acids whereas GH increased neutral lipids and decreased polar lipids. Biological network analysis of the effects of testosterone on GH-regulated transcriptome confirmed a close connection with crucial proteins involved in steroid and fatty acid metabolism. Taken together, this comprehensive analysis of gene expression and lipid profiling in hypothyroid male liver reveals a functional interplay between testosterone and pulsed GH administration.

Hypothyroidism increases angiotensinogen gene expression associated with vascular smooth muscle cells cholesterol metabolism dysfunction and aorta remodeling in Psammomys obesus.

It has been previously shown that clinical cardiovascular manifestations can be caused by mild changes in thyroid function. However, the implication of angiotensinogen (Agt) and vascular smooth muscle cells (VSMCs) dysfunction in the pathophysiology of cardiovascular manifestations in hypothyroidism have not yet been investigated. We induced experimental hypothyroidism in Psammomys obesus by administering carbimazole for five months. At the end of the experiment, the animals were sacrificed and histopathological analysis was performed using Masson's trichrome staining of the aorta and thyroid gland. The expression of the Agt gene and the genes implicated in cholesterol metabolism regulation in the liver and VSMCs was determined by qRT-PCR. Histological observations revealed profound remodeling of the aorta structure in animals with hypothyroidism. In addition, Agt gene expression in the liver was significantly increased. In vitro study, showed that VSMCs from hypothyroid animals overexpressed 3-hydroxy-3-methylglutaryl coenzyme A reductase (Hmgcr) and Acyl CoA:cholesterol acyltransferase (Acat) 1, with failure to increase the efflux pathway genes (ATP-binding cassette subfamily G member (Abcg) 1 and 4). These results suggest that hypothyroidism leads to vascular alterations, including structural remodeling, VSMCs cholesterol metabolism dysfunction, and their switch to a synthetic phenotype, together with hepatic Agt gene overexpression.

Thyroid-stimulating hormone may participate in insulin resistance by activating toll-like receptor 4 in liver tissues of subclinical hypothyroid rats.

BACKGROUND: Thyroid-stimulating hormone (TSH) is an independent risk factor of and closely associated with metabolic disorders. In the present study, we explored the potential mechanism and adverse effects of TSH on insulin resistance in the liver of subclinical hypothyroidism models in vivo. METHODS: The mean glucose infusion rate (GIR), free fatty acids (FFAs), the homeostatic model assessment for insulin resistance (HOMA-IR), fasting plasma insulin (FINS), the TLR4 signal pathway and its intracellular negative regulator-toll-interacting protein (Tollip), and the modulators of insulin signaling were evaluated. RESULTS: Compared to the normal control group (NC group), the subclinical hypothyroidism rat group (SCH group) showed decreases in GIR and increases in FFAs, FINS, and HOMA-IR. The levels of TLR4 and of its downstream molecules like p-NF-κB, p-IRAK-1, IL-6 and TNF-α were evidently higher in the SCH group than in the NC group. Conversely, the level of Tollip was significantly lower in the SCH group than in the NC group. Compared to the NC group, the levels of phosphorylated IRS-1-Tyr and GLUT2 were decreased in the SCH group. Macrophage infiltration was higher in the SCH group than in the NC group. CONCLUSION: TSH may participate in aggravating inflammation by increasing macrophage infiltration; furthermore, it may activate the TLR4-associated inflammatory signaling pathway, thus interfering with insulin signals in liver tissues. Targeting TSH may have therapeutic benefits against metabolic disorders.

Kisspeptin treatment reverses high prolactin levels and improves gonadal function in hypothyroid male rats.

We evaluated whether the administration of kisspeptin-10 (Kp10) is capable of restoring gonadal function in hypothyroid male rats. Hypothyroidism was induced with 6-propyl-2-thiouracil (PTU) for three months. In the last month, half of the hypothyroid animals were treated with Kp10. Hypothyroidism reduced testicular and sex gland mass, decreased the proliferation of the seminiferous epithelium, and compromised sperm morphology, motility, and vigor. A decrease in plasma LH and testosterone levels and an increase in prolactin secretion were observed in the hypothyroid rats. Hypothyroidism reduced Kiss1 and Kiss1r protein and gene expression and Star and Cyp11a1 mRNA levels in the testis. Furthermore, it reduced Lhb, Prl, and Drd2 and increased Tshb and Gnrhr expression in the pituitary. In the hypothalamus, hypothyroidism increased Pdyn and Kiss1r while reducing Gnrh1. Kp10 treatment in hypothyroid rats restored testicular and seminal vesicle morphology, improved sperm morphology and motility, reversed high prolactin levels, and increased LH and testosterone levels. In addition, Kp10 increased testicular expression of Kiss1, Kiss1r, Fshr, and Nr5a1 and pituitary Kiss1 expression. Our findings describe the inhibitory effects of hypothyroidism on the male gonadal axis and sperm quality and demonstrate that Kp10 treatment reverses high prolactin levels and improves gonadal function and sperm quality in hypothyroid rats.

Preventive Effect of Molecular Iodine in Pancreatic Disorders from Hypothyroid Rabbits.

Pancreatic alterations such as inflammation and insulin resistance accompany hypothyroidism. Molecular iodine (I2) exerts antioxidant and differentiation actions in several tissues, and the pancreas is an iodine-uptake tissue. We analyzed the effect of two oral I2 doses on pancreatic disorders in a model of hypothyroidism for 30 days. Adult female rabbits were divided into the following groups: control, moderate oral dose of I2 (0.2 mg/kg, M-I2), high oral dose of I2 (2.0 mg/kg, H-I2), oral dose of methimazole (MMI; 10 mg/kg), MMI + M-I2,, and MMI + H-I2. Moderate or high I2 supplementation did not modify circulating metabolites or pancreatic morphology. The MMI group showed reductions of circulating thyroxine (T4) and triiodothyronine (T3), moderate glucose increments, and significant increases in cholesterol and low-density lipoproteins. Acinar fibrosis, high insulin content, lipoperoxidation, and overexpression of GLUT4 were observed in the pancreas of this group. M-I2 supplementation normalized the T4 and cholesterol, but T3 remained low. Pancreatic alterations were prevented, and nuclear factor erythroid-2-related factor-2 (Nrf2), antioxidant enzymes, and peroxisome proliferator-activated receptor gamma (PPARG) maintained their basal values. In MMI + H-I2, hypothyroidism was avoided, but pancreatic alterations and low PPARG expression remained. In conclusion, M-I2 supplementation reestablishes thyronine synthesis and diminishes pancreatic alterations, possibly related to Nrf2 and PPARG activation.

Effect of Combined Levothyroxine (L-T4) and 3-Iodothyronamine (T1AM) Supplementation on Memory and Adult Hippocampal Neurogenesis in a Mouse Model of Hypothyroidism.

Mood alterations, anxiety, and cognitive impairments associated with adult-onset hypothyroidism often persist despite replacement treatment. In rodent models of hypothyroidism, replacement does not bring 3-iodothyronamine (T1AM) brain levels back to normal. T1AM is a thyroid hormone derivative with cognitive effects. Using a pharmacological hypothyroid mouse model, we investigated whether augmenting levothyroxine (L-T4) with T1AM improves behavioural correlates of depression, anxiety, and memory and has an effect on hippocampal neurogenesis. Hypothyroid mice showed impaired performance in the novel object recognition test as compared to euthyroid mice (discrimination index (DI): 0.02 ± 0.09 vs. 0.29 ± 0.06; t = 2.515, p = 0.02). L-T4 and L-T4+T1AM rescued memory (DI: 0.27 ± 0.08 and 0.34 ± 0.08, respectively), while T1AM had no effect (DI: -0.01 ± 0.10). Hypothyroidism reduced the number of neuroprogenitors in hippocampal neurogenic niches by 20%. L-T4 rescued the number of neuroprogenitors (mean diff = 106.9 ± 21.40, t = 4.99, pcorr = 0.003), while L-T4+T1AM produced a 30.61% rebound relative to euthyroid state (mean diff = 141.6 ± 31.91, t = 4.44, pcorr = 0.004). We performed qPCR analysis of 88 genes involved in neurotrophic signalling pathways and found an effect of treatment on the expression of Ngf, Kdr, Kit, L1cam, Ntf3, Mapk3, and Neurog2. Our data confirm that L-T4 is necessary and sufficient for recovering memory and hippocampal neurogenesis deficits associated with hypothyroidism, while we found no evidence to support the role of non-canonical TH signalling.

Effects of maternal hypothyroidism on postnatal cardiomyocyte proliferation and cardiac disease responses of the progeny.

Maternal hypothyroidism (MH) could adversely affect the cardiac disease responses of the progeny. This study tested the hypothesis that MH reduces early postnatal cardiomyocyte (CM) proliferation so that the adult heart of MH progeny has a smaller number of larger cardiac myocytes, which imparts adverse cardiac disease responses following injury. Thyroidectomy (TX) was used to establish MH. The progeny from mice that underwent sham or TX surgery were termed Ctrl (control) or MH (maternal hypothyroidism) progeny, respectively. MH progeny had similar heart weight (HW) to body weight (BW) ratios and larger CM size consistent with fewer CMs at postnatal day 60 (P60) compared with Ctrl (control) progeny. MH progeny had lower numbers of EdU+, Ki67+, and phosphorylated histone H3 (PH3)+ CMs, which suggests they had a decreased CM proliferation in the postnatal timeframe. RNA-seq data showed that genes related to DNA replication were downregulated in P5 MH hearts, including bone morphogenetic protein 10 (Bmp10). Both in vivo and in vitro studies showed Bmp10 treatment increased CM proliferation. After transverse aortic constriction (TAC), the MH progeny had more severe cardiac pathological remodeling compared with the Ctrl progeny. Thyroid hormone (T4) treatment for MH mothers preserved their progeny's postnatal CM proliferation capacity and prevented excessive pathological remodeling after TAC. Our results suggest that CM proliferation during early postnatal development was significantly reduced in MH progeny, resulting in fewer CMs with hypertrophy in adulthood. These changes were associated with more severe cardiac disease responses after pressure overload.NEW & NOTEWORTHY Our study shows that compared with Ctrl (control) progeny, the adult progeny of mothers who have MH (MH progeny) had fewer CMs. This reduction of CM numbers was associated with decreased postnatal CM proliferation. Gene expression studies showed a reduced expression of Bmp10 in MH progeny. Bmp10 has been linked to myocyte proliferation. In vivo and in vitro studies showed that Bmp10 treatment of MH progeny and their myocytes could increase CM proliferation. Differences in CM number and size in adult hearts of MH progeny were linked to more severe cardiac structural and functional remodeling after pressure overload. T4 (synthetic thyroxine) treatment of MH mothers during their pregnancy, prevented the reduction in CM number in their progeny and the adverse response to disease stress.

Primary Hypothyroidism and Alzheimer's Disease: A Tale of Two.

Hypothyroidism (HPT) HPT could be a risk factor for the development and progression of Alzheimer's disease (AD). In addition, progressive neurodegeneration in AD may affect the metabolism of thyroid hormones (THs) in the brain causing local brain HPT. Hence, the present review aimed to clarify the potential association between HPT and AD. HPT promotes the progression of AD by inducing the production of amyloid beta (Aß) and tau protein phosphorylation with the development of synaptic plasticity and memory dysfunction. Besides, the metabolism of THs is dysregulated in AD due to the accumulation of Aß and tau protein phosphorylation leading to local brain HPT. Additionally, HPT can affect AD neuropathology through various mechanistic pathways including dysregulation of transthyretin, oxidative stress, ER stress, autophagy dysfunction mitochondrial dysfunction, and inhibition of brain-derived neurotrophic factor. Taken together there is a potential link between HPT and AD, as HPT adversely impacts AD neuropathology and the reverse is also true.

Is periventricular heterotopia a useful endpoint for developmental thyroid hormone system disruption in mouse toxicity studies?

In rats, hypothyroidism during fetal and neonatal development can disrupt neuronal migration and induce the formation of periventricular heterotopia in the brain. However, it remains uncertain if heterotopia also manifest in mice after developmental hypothyroidism and whether they could be used as a toxicological endpoint to detect TH-mediated effects caused by TH system disrupting chemicals. Here, we performed a mouse study where we induced severe hypothyroidism by exposing pregnant mice (n = 3) to a very high dose of propylthiouracil (PTU) (1500 ppm) in the diet. This, to obtain best chances of detecting heterotopia. We found what appears to be very small heterotopia in 4 out of the 8 PTU-exposed pups. Although the incidence rate could suggest some utility for this endpoint, the small size of the ectopic neuronal clusters at maximum hypothyroidism excludes the utility of heterotopia in mouse toxicity studies aimed to detect TH system disrupting chemicals. On the other hand, parvalbumin expression was manifestly lower in the cortex of hypothyroid mouse offspring demonstrating that offspring TH-deficiency caused an effect on the developing brain. Based on overall results, we conclude that heterotopia formation in mice is not a useful toxicological endpoint for examining TH-mediated developmental neurotoxicity.

Melissa officinalis extract suppresses endoplasmic reticulum stress-induced apoptosis in the brain of hypothyroidism-induced rats exposed to γ-radiation.

The purpose of this study was to demonstrate the neuroprotective effect of Melissa officinalis extract (MEE) against brain damage associated with hypothyroidism induced by propylthiouracil (PTU) and/or γ-radiation (IR) in rats. Hypothyroidism induction and/or exposure to IR resulted in a significant decrease in the serum levels of T3 and T4 associated with increased levels of lipid peroxidation end product, malondialdehyde (MDA), and nitrites (NO) in the brain tissue homogenate. Also, hypothyroidism and /or exposure to IR markedly enhance the endoplasmic reticulum stress by upregulating the gene expressions of the protein kinase RNA-like endoplasmic reticulum kinase (PERK), activated transcription factor 6 (ATF6), endoplasmic reticulum-associated degradation (ERAD), and CCAAT/enhancer-binding protein homologous protein (CHOP) in the brain tissue homogenate associated with a proapoptotic state which indicated by the overexpression of Bax, BCl2, and caspase-12 that culminates in brain damage. Meanwhile, the PTU and /or IR-exposed rats treated with MEE reduced oxidative stress and ERAD through ATF6. Also, the MEE treatment prevented the Bax and caspase-12 gene expression from increasing. This treatment in hypothyroid animals was associated with neuronal protection as indicated by the downregulation in the gene expressions of the microtubule-associated protein tau (MAPT) and amyloid precursor protein (APP) in the brain tissue. Furthermore, the administration of MEE ameliorates the histological structure of brain tissue. In conclusion, MEE might prevent hypothyroidism-induced brain damage associated with oxidative stress and endoplasmic reticulum stress.

Levothyroxine Dosing in Older Adults: Recommendations Derived From The Baltimore Longitudinal Study of Aging.

OBJECTIVE: As thyroid hormone metabolism slows with advancing age, treatment dosing requirements change. Guidelines recommend titration from a low starting dose for older adults with hypothyroidism while providing weight-based estimates for younger populations. However, rapid replacement may be appropriate with acute onset of overt hypothyroidism. Therefore, a weight-based recommendation specific to older adults is needed. METHODS: We determined mean levothyroxine dose using actual and ideal body weight (IBW) ratios for the outcome of euthyroid on therapy relative to assay-specific and proposed age-specific ranges for independently living participants aged ≥65 years in the Baltimore Longitudinal Study of Aging. We examined risk factors to identify those at highest risk of overtreatment using regression analyses adjusted for potential covariables and clustering to account for multiple visits per individual. RESULTS: One hundred eighty-five participants aged ≥65 years were on levothyroxine at 645 eligible visits. At euthyroid visits, participants were on an average dose of 1.09 µg/kg (1.35 µg/kg IBW), with 84% of euthyroid individuals on a dose of <1.6 µg/kg. Average euthyroid dose did not differ by sex using either actual body weight (ABW) or IBW. For obese individuals, mean euthyroid dose was lower if calculated using ABW (0.9 µg/kg vs 1.14 µg/kg; P < .01) but similar if calculated using IBW (1.42 vs 1.32 µg/kg IBW; P = .41) compared with those with a body mass index of <30. CONCLUSION: Thyroid hormone dose per body weight estimates for replacement in older adults (1.09 µg/kg ABW or 1.35 µg/kg IBW) are one-third lower than current weight-based dose recommendations for younger populations.

Distinct Cardiac Connexin-43 Expression in Hypertrophied and Atrophied Myocardium May Impact the Vulnerability of the Heart to Malignant Arrhythmias. A Pilot Study.

Our and other studies suggest that myocardial hypertrophy in response to hypertension and hyperthyroidism increases propensity of the heart to malignant arrhythmias, while these are rare in conditions of hypothyroidism or type-1 diabetes mellitus associated with myocardial atrophy. One of the crucial factors impacting the susceptibility of the heart to life-threatening arrhythmias is gap junction channel protein connexin-43 (Cx43), which ensure cell-to-cell coupling for electrical signal propagation. Therefore, we aimed to explore Cx43 protein abundance and its topology in hypertrophic and hypotrophic cardiac phenotype. Analysis were performed in left ventricular tissue of adult male spontaneously hypertensive rat (SHR), Wistar Kyoto rats treated for 8-weeks with L-thyroxine, methimazol or strepotozotocin to induce hyperthyroid, hypothyroid and type-1 diabetic status as well as non-treated animals. Results showed that comparing to healthy rats there was a decrease of total myocardial Cx43 and its variant phosphorylated at serine368 in SHR and hyperthyroid rats. Besides, enhanced localization of Cx43 was demonstrated on lateral sides of hypertrophied cardiomyocytes. In contrast, total Cx43 protein and its serine368 variant were increased in atrophied left ventricle of hypothyroid and type-1 diabetic rats. It was associated with less pronounced alterations in Cx43 topology. In parallel, the abundance of PKCepsilon, which phosphorylates Cx43 at serine368 that stabilize Cx43 function and distribution was reduced in hypertrophied heart while enhanced in atrophied once. Findings suggest that differences in the abundance of cardiac Cx43, its variant phosphorylated at serine368 and Cx43 topology may explain, in part, distinct propensity of hypertrophied and atrophied heart to malignant arrhythmias.