Thyroid Hormone Dysregulation Research Articles

A Prospective Observational Analysis of Endometrial Cancer Risk Associated with Thyroid Hormone Dysregulation

This prospective observational study investigated the relationship between thyroid dysfunction and the risk of developing endometrial cancer in a cohort of 100 patients diagnosed with endometrial cancer. Patient data including demographics, medical history, thyroid function tests (T3, T4, TSH levels), and comorbidities (diabetes mellitus and hypertension) were collected. Thyroid dysfunction was defined as T3, T4, or TSH levels outside the reference ranges (T3: 0.8-2.0 ng/mL, T4: 5.1-14.1 ug/dL, TSH: 0.27-4.2 uIU/mL). Logistic regression analyses were performed to evaluate the association between thyroid dysfunction and endometrial cancer risk, adjusting for potential confounders. The study population had a mean age of 55.9 years (range: 35-82 years). Out of 100 patients, 28 (28%) exhibited hypothyroidism (low T3 or T4, or high TSH), and 12 (12%) exhibited hyperthyroidism (high T3 or T4, or low TSH). Univariate logistic regression analysis revealed a significant association between hypothyroidism and endometrial cancer risk (OR = 2.14, 95% CI: 1.22-3.76, p = 0.008). After adjusting for age, diabetes, and hypertension, the multivariate logistic regression analysis showed that hypothyroidism remained an independent risk factor for endometrial cancer (OR = 1.92, 95% CI: 1.07-3.45, p = 0.029). However, the association between hyperthyroidism and endometrial cancer risk was not statistically significant (OR = 1.34, 95% CI: 0.64-2.82, p = 0.439). This study provides evidence for a significant association between hypothyroidism and increased risk of endometrial cancer, independent of age, diabetes, and hypertension. Further research is needed to understand the underlying mechanisms and explore the potential implications for screening and management strategies

Caloric Restriction Improves Hepatic Thyroid Hormone Signaling During Metabolic Syndrome

Thyroid hormone dysregulation has been associated with metabolic syndrome (MetS) risk factors: hypertension, atherogenic dyslipidemia, obesity, and glucose intolerance. Several pathways are regulated by thyroid hormones such as the insulin signaling pathway, lipid metabolism, and antioxidant production among others. Impairment of thyroid hormone production causes dysregulation of these pathways. Caloric restriction (CR) is a form of non-pharmaceutical approach that has been shown to ameliorate MetS cluster factor conditions. However, caloric restriction's effects on thyroid hormone signaling during MetS remains unclear. A cohort of 11-week-old Otsuka Long Evan Tokushima Fatty (OLETF) and lean-strain control Long Tokushima Evans Otsuka (LETO) rats were fed chow ad libitium for 4 weeks. At 15 weeks, the animals were fed a 50% CR diet (compared to their control) for 10 days and assigned to four groups: (1) LETO (n=14), (2) LETO CR (n=14), (3) OLETF (n=14), and (4) OLETF CR (n=14). After the CR period, 7 animals from each group were then refed at pre-CR levels for 7 days and assigned to four groups: (1) LETO (n=7), (2) LETO post-recovery (LETO PR; n=7), (3) OLETF (n=7), and (4) OLETF PR (n=7). Mean body mass decreased 12% and 14% in LETO and OLETF, respectively, during the CR period compared to their ad lib controls. Hepatic deiodinase 1 (Dio1) protein expression was reduced by 41% in the OLETF compared to LETO. Dio1 protein expression was increased by 150% during CR and 88% by PR in OLETF. Deiodinase 2 (Dio2) showed a decreasing trend in OLETF rats compared to LETO and an increasing trend in the OLETF CR group compared to its ad lib control. Both free (fT4) and total T4 (tT4) had increasing trends in OLETF compared to LETO. CR induced a decreasing trend in fT4 and tT4 in OLETF compared to ad lib OLETF controls. These findings demonstrate that caloric restriction induces changes in hepatic thyroid hormone signaling that can improve impaired metabolism induced by MetS. Doctoral fellowship UC MEXUS-CONACYT 440553 National Institute on Minority Health and Health Disparities grant 9T37-MD001480 American Heart Association 23DIVSUP1066372. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Challenges of Cutaneous Care in Hyperthyroidism: A Case Report

Cutaneous manifestations of thyroid disease are one of the first notable signs of thyroid hormone dysregulation. Skin changes in hyperthyroidism vary from individual to individual. In dark skinned Africans it may be challenging to detect these dermatoses and care for the patients with these dermatoses if they arise. Making the actual cutaneous diagnosis in hyperthyroidism may be impaired by co-morbidities, drug-drug interactions, hypersensitive reactions, unusual presentation of common diseases, immunosuppression that may result to opportunistic infections and similar presentations of dermatoses. There may be dermatoses that may co-exist with other dermatoses within the same site. The peculiarity of our case report is that we present three females with hyperthyroidism that cut across different age groups with different cutaneous lesions. This case report aims to present the challenges of making accurate skin diagnosis and challenges that arise in actually caring for them. Counselling the patient on the appropriate care and prognosis of these skin lesions would help in improvement of quality of life and unwanted expectations

Dose Response, Dosimetric, and Metabolic Evaluations of Replacement PFAS Perfluoro-(2,5,8-trimethyl-3,6,9-trioxadodecanoic) Acid (HFPO-TeA).

Few studies are available on the environmental and toxicological effects of perfluoroalkyl ether carboxylic acids (PFECAs), such as GenX, which are replacing legacy PFAS in manufacturing processes. To collect initial data on the toxicity and toxicokinetics of a longer-chain PFECA, male and female Sprague Dawley rats were exposed to perfluoro-(2,5,8-trimethyl-3,6,9-trioxadodecanoic) acid (HFPO-TeA) by oral gavage for five days over multiple dose levels (0.3-335.2 mg/kg/day). Clinically, we observed mortality at doses >17 mg/kg/day and body weight changes at doses ≤17 mg/kg/day. For the 17 mg/kg/day dose level, T3 and T4 thyroid hormone concentrations were significantly decreased (p < 0.05) from controls and HFPO-TeA plasma concentrations were significantly different between sexes. Non-targeted analysis of plasma and in vitro hepatocyte assay extractions revealed the presence of another GenX oligomer, perfluoro-(2,5-dimethyl-3,6-dioxanonanoic) acid (HFPO-TA). In vitro to in vivo extrapolation (IVIVE) parameterized with in vitro toxicokinetic data predicted steady-state blood concentrations that were within seven-fold of those observed in the in vivo study, demonstrating reasonable predictivity. The evidence of thyroid hormone dysregulation, sex-based differences in clinical results and dosimetry, and IVIVE predictions presented here suggest that the replacement PFECA HFPO-TeA induces a complex and toxic exposure response in rodents.

Exploring thyroxine binding globulin structural changes and its release from human hepatoblastoma cells upon interaction with silica particles: A prelude to unrevealing the mechanism of thyroid hormone dysregulation

Endocrine dysregulation in the presence of environmental chemical risk factors is a global adverse health concern. The aim of this investigation was to explore the structural changes and binding affinity of thyroxine (T4) binding protein (TBG) upon interaction with SiO2 particles as the second largest mineral in the Earth's crust and one of the most important constituents of rock, soil, and dust. Therefore, the interaction of TBG with SiO2 particles was assessed by fluorescence quenching, molecular docking, ANS and synchronous fluorescence, and far-UV CD analyses. Also, the release of TBG from human hepatoblastoma cell line, Hep G2, was assessed by ELISA assay. The results displayed that the value of stoichiometry of binding site (n) of TBG for T4 was approximately equal to one, which was reduced to 0.36 in the presence of SiO2 particles. Also, the binding affinity (Kb) values revealed that the binding affinity between T4 and TBG was strong (97.90 × 105 L/mol), while the presence of SiO2 particles resulted in the calculation of a Kb around 0.00159 × 105 L/mol, which was significantly lower than that of the absence of SiO2 particles. This data was also verified by molecular docking analyses which indicated that SiO2 particles interacted with the T4 binding pocket of TBG. Moreover, further studies exhibited that although the equimolar concentration of T4 to TBG resulted in the superior stability of TBG-T4 complex relative to free TBG, the presence of SiO2 particles with the same concentration led to denaturation of the secondary structure of TBG. Furthermore, it was seen that the amount of released TBG in the cell culture medium of Hep G2 was about 2.21 ng/mL protein, whereas this amount in SiO2 particles-treated cell group was significantly reduced to 1.71 ng/mL protein (*P < 0.05). In conclusion, this study implies that SiO2 particles show the potential to result in inhibition of TBG release, TBG denaturation, and interfere with TBG binding affinity which may lead to dysregulation of the thyroid hormone transport and associated signaling pathways.

Body Mass Index (BMI) Related Morbidity with Thyroid Surgery.

The increase in incidence of thyroid cancer correlates with strict increases in body mass index (BMI) and obesity in the United States. Thyroid hormone dysregulation has been shown to precipitate circulatory volume, peripheral resistance, cardiac rhythm, and even cardiac muscle health. Theoretically, thyroid surgery could precipitate injury to the cardiopulmonary system. The American College of Surgery National Quality Improvement Program database was queried for thyroidectomy cases in the 2007-2020 Participant User files. Continuous and categorical associations between BMI and cardiopulmonary complications were investigated as reported in the database. The query resulted 186,095 cases of thyroidectomy procedures in which the mean age was 51.3 years and sample was 79.3% female. No correlation was evident in univariate and multivariate analyses between BMI and the incidence of postoperative stroke or myocardial infarction. The incidence of complications was extremely low. However, risk of deep venous thrombosis correlated with BMI in the categorical, univariate, and multivariate (OR 1.036, CI 1.014-1.057, p < 0.01) regression analysis. Additionally, increased BMI was associated with increased risk of pulmonary embolism (PE) (OR 1.050 (1.030, 1.069), p < 0.01), re-intubation (OR 1.012 (1.002, 1.023), p = 0.02), and prolonged intubation (OR 1.031 (1.017, 1.045), p < 0.01). Despite the rarity of cardiopulmonary complications during thyroid surgery, patients with very high BMI carry a significant risk of deep venous thrombosis, PE, and prolonged intubation. 3 Laryngoscope, 133:2823-2830, 2023.

Dermatologic manifestations of thyroid disease: a literature review.

Thyroid hormone is considered one of the key regulatory hormones for skin homeostasis. Multiple organs are affected by the release of peripheral thyroid hormones (T4 and T3) further regulating various functions at a cellular level. Specifically, skin is considered an important target organ in which the thyroid hormone has a significant impact. Multiple skin diseases are associated with thyroid hormone dysregulation. However, other striking dermatologic manifestations are seen in nails and hair as well. Hypothyroidism, hyperthyroidism, and thyroid cancer can have an array of cutaneous manifestations, and we present the recent updates in this field. A PubMed search was performed for updates in any new skin disease findings and treatments between 2010 and 2022. Research published in the past decade and previously known foundational skin findings associated with thyroid disease were presented in this review. Cutaneous manifestations of thyroid disease is one of the first notable signs of thyroid hormone dysregulation. This article reviews the recent updates on the thyroid and skin interplay, and it further discusses overt visible findings and various available treatment modalities.

Association between polychlorinated biphenyl exposure and thyroid hormones: a systematic review and meta-analysis

Purpose: To conduct a comprehensive meta-analysis investigating the association between polychlorinated biphenyl (PCB) exposure and serum thyroid hormone levels among adults. Methods: Eleven studies met inclusion criteria for analysis following systematic search of PubMed, Embase, and Scopus databases. Of these, 7 studies measured exposure by the total sum of PCB congeners (∑PCB), 1 study measured individual PCB congener levels, and 3 studies measured both ∑PCB levels and PCB congener levels. Correlation coefficients (r) were extracted from each study. Summary estimates were calculated for ∑PCB levels and PCB congeners reported by 2 or more studies: PCB 28, 52, 101, 105, 118, 138, 153, and 180, using random effects model. Results: Significant negative correlation was found between ∑PCBs and T3 (r: −0.09; 95% CI: −0.17, −0.02) and FT3 (r: −0.24; 95% CI: −0.36, −0.12). Congener-specific analysis found T3 to be negatively correlated with PCB-153 (r: −0.19; 95% CI: −0.34, −0.03) and PCB-180 (r: −0.14; 95% CI: −0.26, −0.01), whereas TSH was positively correlated with PCB-105 (r: 0.15; 95% CI: 0.02, 0.28). Conclusions: The present study is the first meta-analysis to investigate the association between PCB exposure and thyroid hormone dysfunction among adults. Results suggest a significant association between PCB exposure and thyroid hormone dysregulation.

Transcriptome Profile of Thyroid Glands in Bile Duct Ligation Mouse Model.

Thyroid hormone (TH) contributes to multiple cellular mechanisms in the liver, muscle cells, adipose tissue, and brain, etc. In particular, the liver is an important organ in TH metabolism for the conversion of thyronine (T4) into triiodothyronine (T3) by the deiodinase enzyme. TH levels were significantly decreased and thyroid-stimulating hormone (TSH) levels were significantly increased in patients with liver failure compared with normal subjects. Among liver failure diseases, hepatic encephalopathy (HE) deserves more attention because liver damage and neuropathologies occur simultaneously. Although there is numerous evidence of TH dysregulation in the HE model, specific mechanisms and genetic features of the thyroid glands in the HE model are not fully understood. Here, we investigated the significantly different genes in the thyroid glands of a bile duct ligation (BDL) mouse model as the HE model, compared to the thyroid glands of the control mouse using RNA sequencing. We also confirmed the alteration in mRNA levels of thyroid gland function-related genes in the BDL mouse model. Furthermore, we evaluated the increased level of free T4 and TSH in the BDL mouse blood. Thus, we emphasize the potential roles of TH in liver metabolism and suggest that thyroid dysfunction-related genes in the HE model should be highlighted for finding the appropriate solution for an impaired thyroid system in HE.

Abstract #994791: An Unusual Presentation of Amiodarone-Induced Thyroid Hormone Dysregulation

Abstract #994791: An Unusual Presentation of Amiodarone-Induced Thyroid Hormone Dysregulation

Effects of thyroid hormone on ovarian cell apoptosis in the rat.

Follicle development is a complicated process regulated by thyroid hormone (TH). TH dysregulation is associated with reproductive disorders; however, the mechanism underlying these relationships remains unclear. Glucose-related protein 78 (GRP78) is a well-characterised endoplasmic reticulum stress protein related to ovarian cell apoptosis. To clarify whether GRP78 is regulated by TH and the involvement of GRP78 in follicle development, we established rat models of hypothyroidism and hyperthyroidism and investigated the effects of TH dysregulation on levels of GRP78, C/EBP homologous protein (CHOP) and cleaved caspase-3. TH dysregulation decreased levels of GRP78 and increased those of CHOP and cleaved caspase-3 in both rat models. However, treatment with equine chorionic gonadotrophin reversed these effects, as well as granulosa cell apoptosis induced by TH dysregulation. Together, these results provide evidence that TH dysregulation alters the GRP78 expression profile, triggering the apoptotic signalling pathway, and suggest that GRP78 is a novel mediator of TH in follicle development.

PBDEs Concentrate in the Fetal Portion of the Placenta: Implications for Thyroid Hormone Dysregulation.

During pregnancy, the supply of thyroid hormone (TH) to the fetus is critically important for fetal growth, neural development, metabolism, and maintenance of pregnancy. Additionally, in cases where maternal and placental TH regulation is significantly altered, there is an increased risk of several adverse pregnancy outcomes. It is unclear what may be disrupting placental TH regulation; however, studies suggest that environmental contaminants, such as polybrominated diphenyl ethers (PBDEs), could be playing a role. In this study, Wistar rats were gestationally exposed to a mixture of PBDEs for 10 days. THs and PBDEs were quantified in paired maternal serum, dissected placenta, and fetuses, and mRNA expression of transporters in the placenta was assessed. Significantly higher concentrations of PBDEs were observed in the fetal portion of the placenta compared with the maternal side, suggesting that PBDEs are actively transported across the interface. PBDEs were also quantified in 10 recently collected human maternal and fetal placental tissues; trends paralleled observations in the rat model. We also observed an effect of PBDEs on T3 levels in dam serum, as well as suggestive changes in the T3 levels of the placenta and fetus that varied by fetal sex. mRNA expression in the placenta also significantly varied by fetal sex and dose. These observations suggest the placenta is a significant modifier of fetal exposures, and that PBDEs are impacting TH regulation in a sex-specific manner during this critical window of development.

Effect of thyroid dysfunction on NOS expression in the female rat

Thyroid hormones (THs) are vital for normal reproductive function and dysregulation of TH impairs follicular development. Although the functions of THs on female reproduction are of great interest, the mechanisms still remain unclear. Many studies have shown that NO plays important roles in female reproduction. In the present study, we investigate the effects of TH dysregulation on nitric oxide synthase types (NOS) expression in rats. Propylthiouracil (PTU) and L-thyroxine were administered to rats to induce hypo- and hyperthyroidism, respectively. Ovarian histology was detected by immunohistochemistry (IHC) and protein or mRNA content was analyzed by Western blotting or RT-PCR, respectively. The results showed that NOS1, NOS2 and NOS3 expressions were detected in the oocyte, granulosa cell and theca cell in all follicular stages, which were up-regulated by eCG treatment. NOS1 protein content was increased in both PTU and L-thyroxine treatments. There were no significant differences in NOS2 levels between the treatment and the control group. However, NOS3 was only increased in the hyperthyroid group. These results were consistent with the IHC staining. The present study provides evidence that TH dysregulation alters NOSs profiles, which suggests that NOSs/nitric oxide (NO) is possibly involved in the regulation of female reproduction.

Effects of Thyroid Dysfunction on Reproductive Hormones in Female Rats.

Thyroid hormones (THs) play a critical role in the development of ovarian cells. Although the effects of THs on female reproduction are of great interest, the mechanism remains unclear. We investigated the effects of TH dysregulation on reproductive hormones in rats. Propylthiouracil (PTU) and L-thyroxine were administered to rats to induce hypo- and hyperthyroidism, respectively, and the reproductive hormone profiles were analyzed by radioimmunoassay (RIA). Ovarian histology was evaluated with hematoxylin and eosin (H&E) staining, and gene protein level or mRNA content was analyzed by western blotting or reverse transcription polymerase chain reaction (RT-PCR). The serum levels of gonadotropin releasing hormone (GnRH) and follicle stimulating hormone (FSH) in both rat models were significantly decreased on day 21, although there were no significant changes at earlier time points. There were no significant differences in luteinizing hormone (LH) or progesterone (P4) levels between the treatment and the control groups. Both PTU and L-thyroxine treatments downregulated estradiol (E2) concentrations; however, the serum testosterone (T) level was increased only in hypothyroid rats at day 21. In addition, the expression levels of FSH receptor, cholesterol side-chain cleavage enzyme (P450scc), and steroidogenic acute regulatory protein (StAR) were decreased in both rat models. Moreover, the onset of puberty was significantly delayed in the hypothyroid group. These results provide evidence that TH dysregulation alters reproductive hormone profiles, and that the initiation of the estrous cycle is postponed in hypothyroidism.

Expression levels of interferon-ɣ and type 2 deiodinase in patients diagnosed with recurrent depressive disorders.

Thyroid hormones (TH) are involved in modulation of the immune system and inflammation. TH dysregulation is associated with depressive disorders. The iodothyronine deiodinases (DIOs), the key enzymes for TH synthesis, can be affected and induced by pro-inflammatory cytokines. We aimed to investigate the levels of and correlation between type 2 DIO (DIO2) and interferon-gamma (IFN-ɣ) in patients with recurrent depressive disorders (rDD). Data from 91 rDD patients and 105 healthy controls were analyzed. The diagnoses are based on the ICD-10 criteria (F33.0-F33.8). Expression levels of DIO2 and IFN-ɣ were estimated using the method based on the polymerase chain reaction and the enzyme-linked immunosorbent assay (ELISA). The DIO2 expression on mRNA/protein levels in rDD patients (both female and males) was reduced as compared with the control subjects. No correlation between DIO2 and IFN-ɣ expression was observed. This is the first study to reveal that one may cautiously suggest that DIO2 may be involved in the development and/or progression of rDD. The mechanisms of TH regulation on depression, however, need further investigation.

Transcriptional profiling of male F344 rats suggests the involvement of calcium signaling in the mode of action of acrylamide-induced thyroid cancer

Acrylamide (AA) exposure in 2-year cancer bioassays leads to thyroid, but not liver, adenomas and adenocarcinomas in rats. Hypothesized modes of action (MOAs) include genotoxicity/mutagenicity, or thyroid hormone dysregulation. To examine the plausibility of these two or any alternative MOAs, RNA-sequencing was performed on the thyroids and livers of AA-exposed rats, in parallel with measurement of genotoxicity (blood micronucleus and Pig-a mutant frequency) and serum thyroid hormone levels, following the exposure of male Fischer 344/DuCrl rats to 0.0, 0.5, 1.5, 3.0, 6.0, or 12.0 mg AA/kg bw-day in drinking water for 5, 15, or 31 days. Differentially expressed genes in both tissues provided marginal support for hormonal and genotoxic MOAs, which was consistent with negative/equivocal genotoxicity assay and marginal changes in thyroid hormone levels. Instead, there was a pronounced effect on calcium signaling/cytoskeletal genes in the thyroid. Benchmark dose modeling of RNA-sequencing data for the calcium signaling pathway suggests a point of departure (POD) of 0.68 mg/kg bw-day, which is consistent with a POD of 0.82 mg/kg bw-day derived from the thyroid 2-year cancer bioassay data. Overall, this study suggests a novel MOA for AA-induced thyroid carcinogenicity in male rats centered around perturbation of calcium signaling.

Genomics and CSF analyses implicate thyroid hormone in hippocampal sclerosis of aging

We report evidence of a novel pathogenetic mechanism in which thyroid hormone dysregulation contributes to dementia in elderly persons. Two single nucleotide polymorphisms (SNPs) on chromosome 12p12 were the initial foci of our study: rs704180 and rs73069071. These SNPs were identified by separate research groups as risk alleles for non-Alzheimer's neurodegeneration. We found that the rs73069071 risk genotype was associated with hippocampal sclerosis (HS) pathology among people with the rs704180 risk genotype (National Alzheimer's Coordinating Center/Alzheimer's Disease Genetic Consortium data; n=2113, including 241 autopsy-confirmed HS cases). Furthermore, both rs704180 and rs73069071 risk genotypes were associated with widespread brain atrophy visualized by MRI (Alzheimer's Disease Neuroimaging Initiative data; n=1239). In human brain samples from the Braineac database, both rs704180 and rs73069071 risk genotypes were associated with variation in expression of ABCC9, a gene which encodes a metabolic sensor protein in astrocytes. The rs73069071 risk genotype was also associated with altered expression of a nearby astrocyte-expressed gene, SLCO1C1. Analyses of human brain gene expression databases indicated that the chromosome 12p12 locus may regulate particular astrocyte-expressed genes induced by the active form of thyroid hormone, triiodothyronine (T3). This is informative biologically, because the SLCO1C1 protein transports thyroid hormone into astrocytes from blood. Guided by the genomic data, we tested the hypothesis that altered thyroid hormone levels could be detected in cerebrospinal fluid (CSF) obtained from persons with HS pathology. Total T3 levels in CSF were elevated in HS cases (p<0.04 in two separately analyzed groups), but not in Alzheimer's disease cases, relative to controls. No change was detected in the serum levels of thyroid hormone (T3 or T4) in a subsample of HS cases prior to death. We conclude that brain thyroid hormone perturbation is a potential pathogenetic factor in HS that may also provide the basis for a novel CSF-based clinical biomarker.

Age-Dependent Changes of Monocarboxylate Transporter 8 Availability in the Postnatal Murine Retina.

The thyroid hormones (TH) triiodothyronine (T3) and its prohormone thyroxine (T4) are crucial for retinal development and function, and increasing evidence points at TH dysregulation as a cause for retinal degenerative diseases. Thus, precise regulation of retinal TH supply is required for proper retinal function, but knowledge on these mechanisms is still fragmentary. Several transmembrane transporters have been described as key regulators of TH availability in target tissues of which the monocarboxylate transporter 8 (MCT8), a high affinity transporter for T4 and T3, plays an essential role in the central nervous system. Moreover, in the embryonic chicken retina, MCT8 is highly expressed, but the postnatal availability of MCT8 in the mammalian retina was not reported to date. In the present study, spatiotemporal retinal MCT8 availability was examined in mice of different age. For this purpose, we quantified expression levels of Mct8 via Real-Time Reverse-Transcriptase PCR in mouse eyecups (C57BL/6) of juvenile and adult age groups. Additionally, age-dependent MCT8 protein levels were quantified via Western blotting and localized via immunofluorescence confocal microscopy. While no difference in Mct8 expression levels could be detected between age groups, MCT8 protein levels in juvenile animals were about two times higher than in adult animals based on Western blot analyses. Immunohistochemical analyses showed that MCT8 immunoreactivity in the eyecup was restricted to the retina and the retinal pigment epithelium. In juvenile mice, MCT8 was broadly observed along the apical membrane of the retinal pigment epithelium, tightly surrounding photoreceptor outer segments. Distinct immunopositive staining was also detected in the inner nuclear layer and the ganglion cell layer. However, in adult specimens, immunoreactivity visibly declined in all layers, which was in line with Western blot analyses. Since MCT8 was abundantly present in juvenile and about twofold lower in adult retinae, our findings suggest a pivotal role of MCT8 especially during postnatal maturation. The present study provides novel insights into age-dependent retinal TH supply, which might help to understand different aspects regarding retinal development, function, and disorders.

Effect of adult onset hypothyroidism on behavioral parameters and acetylcholinesterase isoforms activity in specific brain regions of male mice

Thyroid hormones (TH) are essential for normal development and function of mammalian central nervous system (CNS); TH dysregulation has been implicated in several cognitive and behavioral deficits related to dysfunctions of neurotransmitter systems. In the present study, we investigated the effects of adult onset hypothyroidism on the activity of acetylcholinesterase (AChE) and on related behavioral parameters. For this purpose we used adult male Balb/cJ mice that were divided randomly into euthyroid and hypothyroid animal groups. Animals were rendered hypothyroid through administration of 1% w/v KClO4 in their drinking water for 8weeks. At the end of the treatment, learning/memory procedures were examined through step-through passive avoidance task while fear/anxiety was assessed using elevated plus-maze (EPM) and open-field (OF) tests. AChE activity was determined colorimetrically in two different fractions, salt-soluble fraction (SS) (containing mainly the G1 isoform) and detergent-soluble fraction (DS) (containing mainly the G4 isoform) in cerebral cortex, cerebellum, midbrain, hippocampus and striatum. Our results indicate that adult onset hypothyroidism caused significant memory impairment and increased fear/anxiety. Moreover, the activity of both isoforms of AChE was reduced in all brain regions examined in a brain region- and isoform-specific manner.

Dysthyroidism and heart failure: from clinical case to pathophysiology

Dysthyroidism affects cardiovascular function in many ways and can cause heart failure. The physiopathological mechanisms underlying the development of heart failure involve both direct intranuclear transcriptional effects of thyroid hormones and specific haemodynamic consequences of vascular modifications induced by dysthyroidism. Phospholamban regulatory action on diastolic ventricular function appears to play a pivotal role in mediating both direct T3 action and adrenal effects on myocardial contractility, possibly explaining the way dysthyroidism mimics sympathoadrenergic alterations on cardiovascular function. Therapeutical approach to cardiovascular disorders in dysthyroidism should focus on both thyroid hormones dysregulation and sympathoadrenergic activity, to attempt a reversal of the associated derangements.