Impact of methimazole-induced hypothyroidism on postnatal swine.

Thyroid hormones regulate metabolic rate, nutrient utilization, growth, and development. Swine are susceptible to thyroid suppression in response to disease or environmental conditions, but the physiological impact of such disruption has not been established. The objective of this study was to evaluate the impact of hypothyroidism induced with the antithyroid medication methimazole (MMI). 10 mg/kg MMI significantly decreased circulating triiodothyronine (T3) for the duration of treatment but had only a transient effect on circulating thyroxine (T4). Thyroid tissue weight was significantly increased by more than 3.5-fold in response to MMI treatment. Histologically, the eosinophilic colloid was largely absent from the thyroid follicle which displayed a disorganized columnar epithelium consistent with goiter. MMI induced hypothyroidism has no effect on growth rate over 28 days. Hepatic expression of genes associated with thyroid metabolism (DIO1, DIO2, and DIO3), lipid utilization (CD36, FASN, and ACACA), apoptosis (TP53, PERP, SIVA1, and SFN) and proliferation (CDK1, CDK2, CDK4, and CDKN1A) were unaffected by treatment. Collectively these results demonstrate that MMI induces mild systemic hypothyroidism and pronounced goiter, indicating a strong homeostatic central regulation within the hypothalamic pituitary thyroid axis. This combined with limited peripheral effects, indicates resilience to hypothyroidism in modern swine.

Lactose intolerance and levothyroxine malabsorption: a review of the literature and report of a series of patients treated with liquid L-T4 without lactose.

In hypothyroid patients needing large doses of levothyroxine (L-T4) (>1.7-2 µg/kg/day) to reach euthyroidism, lactose intolerance (LI) needs to be excluded, owing to the high prevalence in the population. If LI is present, a lactose-free diet decreases the rate of L-T4 malabsorption. However, an increased requirement of L-T4 is described in patients with LI, which can be beneficially treated using lactose-free L-T4 formulation. The lactose-free liquid L-T4 formulation is able to circumvent LI malabsorption leading to the normalization of thyroid-stimulating hormone (TSH) in patients with subclinical hypothyroidism and long-term stable TSH levels.

Thyroid hormone deprival and TSH/TSHR signaling deficiency lead to central hypothyroidism-associated intestinal dysplasia.

BACKGROUND: Central hypothyroidism (CH) is characterized by low T4 levels and reduced levels or bioactivity of circulating TSH. However, there is a lack of studies on CH-related intestinal maldevelopment. In particular, the roles of TH and TSH/TSHR signaling in CH-related intestinal maldevelopment are poorly understood. Herein, we utilized Tshr-/- mice as a congenital hypothyroidism model with TH deprival and absence of TSHR signaling. METHODS: The morphological characteristics of intestines were determined by HE staining, periodic acid-shiff staining, and immunohistochemical staining. T4 was administrated into the offspring of homozygous mice from the fourth postnatal day through weaning or administrated after weaning. RT-PCR was used to evaluate the expression of markers of goblet cells and intestinal digestive enzymes. Single-cell RNA-sequencing analysis was used to explore the cell types and gene profiles of metabolic alternations in early-T4-injected Tshr-/- mice. KEY FINDINGS: Tshr deletion caused significant growth retardation and intestinal maldevelopment, manifested as smaller and more slender small intestines due to reduced numbers of stem cells and differentiated epithelial cells. Thyroxin supplementation from the fourth postnatal day, but not from weaning, significantly rescued the abnormal intestinal structure and restored the decreased number of proliferating intestinal cells in crypts of Tshr-/- mice. Tshr-/- mice with early-life T4 injections had more early goblet cells and impaired metabolism compared to Tshr+/+ mice. SIGNIFICANCE: TH deprival leads to major defects of CH-associated intestinal dysplasia while TSH/TSHR signaling deficiency promotes the differentiation of goblet cells and impairs nutrition metabolism.

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.

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.

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.

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.

Probiotics and Prebiotics in Subclinical Hypothyroidism of Pregnancy with Small Intestinal Bacterial Overgrowth.

Evaluating efficacy of probiotics combined with prebiotics in small intestinal bacterial overgrowth (SIBO) in subclinical hypothyroidism (SCH) in the second trimester. We collected data from 78 pregnant women with SCH (SCH group) and 74 normal pregnant women (control group) in second trimester, compare the differences in high sensitivity C-reactive protein (hsCRP), result of lactulose methane-hydrogen breath test and gastrointestinal symptoms assessed by GSRS scale between two groups. In SCH group, 32 patients with SIBO were selected as intervention group. Treatment with probiotics + prebiotics for 21 days; The differences of lipid metabolism, hsCRP, thyroid function level, methane-hydrogen breath test results and GSRS scores before and after treatment were compared to evaluate the therapeutic effect. (1) The positive rate of SIBO and methane, hsCRP levels in SCH group were higher than those in control group (P < 0.05), the total score of GSRS scale, mean score of indigestion syndrome, and constipation syndrome in SCH group were higher (P < 0.05). (2) The mean abundance of hydrogen and methane were higher in SCH group. (3) After treatment, serum levels of thyrotropin(TSH), total cholesterol(TC), triglyceride(TG), low-density lipoprotein (LDL), and hsCRP in intervention group were decreased, and high-density lipoprotein (HDL) was increased compared with before treatment (P < 0.05). (4) After treatment, methane positive rate, total score of GSRS scale, mean score of diarrhea syndrome, dyspepsia syndrome, and constipation syndrome were decreased (P < 0.05). (5) The average abundance of methane and hydrogen were lower. Probiotics combined with prebiotics are effective in the treatment of SIBO in pregnant SCH patients.Clinical Trial Registration Number: ChiCTR1900026326.

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.

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.

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.

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.