Propylthiouracil Treatment Research Articles

Combined Levothyroxine and Propylthiouracil Treatment in Children with Monocarboxylate Transporter 8 Deficiency: A Multicenter Case Series of 12 Patients.

Objective: To evaluate the combined administration of propylthiouracil (PTU) and levothyroxine (LT4) in managing monocarboxylate transporter 8 (MCT8) deficiency and identify optimal therapeutic dosages. Methods: This multicenter case series involved 12 male patients with MCT8 deficiency whose parents/guardians consented to PTU and LT4 treatment. Data were collected from January 2008 to June 24, 2024. The study focused on treatment safety and outcomes, analyzing baseline and last encounter biochemical, metabolic, and anthropometric parameters. Statistical analyses included Wilcoxon signed ranks tests and generalized estimated equations to assess effects on thyroid and metabolic markers, and receiver operating characteristics curves to predict optimal dose. Results: Patients showed a significant reduction in serum total triiodothyronine (TT3) concentration and TT3/TT4 ratio, with increased serum TT4 and free T4 (fT4) concentrations. The use of PTU effectively reduced TT3 concentration by 25% at an average dose of 6.8 mg/kg/day, while LT4 increased fT4 concentration by 40% from baseline at an average dose of 4.3 µg/kg/day. Thyrotropin concentration was undetectable on treatment. No statistical differences were observed in metabolic and physical parameters between baseline and last encounter overall for the group, but six of eight patients for whom these data were available had an increase in weight (z-score). There were no adverse effects on liver function or granulocyte numbers noted throughout the period of observation. Conclusion: Combined treatment with PTU and LT4 normalized serum T3, fT4, and TT4 in patients with MCT8 deficiency. Individualized dose adjustments were crucial for achieving therapeutic goals, indicating the need for personalized treatment plans.

Abstract We141: Leveraging Cardiac Gene Reprogramming at Single-Cell Resolution to Understand Heart Failure

Background: A defining characteristic of heart failure is cardiac gene reprogramming. Heart failure-induced pathological stressors activate transcription factors, including Gata4 , Tbx5 , and Mef2, required for cardiogenesis. These transcription factors activate fetal cardiac genes in the failing adult heart. The mechanism and role of such cardiac gene reprogramming in response to heart failure remain not fully characterized. Here, we leverage transcriptional reprogramming induced by thyroid hormone deficiency as a model system to understand adult heart failure at the single-cell level. Methods: We engineered a novel Myh6 / Myh7 reporter mouse line. Hypothyroidism was induced in mice with propylthiouracil (PTU). PTU treatment led to global cardiac gene reprogramming. To profile gene expression and chromatin accessibility during cardiac gene reprogramming, single nuclei multiomic sequencing was conducted. Echocardiographs on control and PTU-treated mice evaluated cardiac function changes associated with reprogramming. Cardiac tissues were collected to validate both known and newly identified candidates involved in cardiac gene reprogramming. Results: Characterization of hypothyroidic mice as a model for cardiac reprogramming revealed that the ventricles of PTU-treated hearts significantly switch from Myh6 to dominantly express Myh7 . Evaluation of echocardiographs showed that PTU-treated hearts are significantly atrophic, have chamber dilatation, and reduced cardiac function. Analysis of multiome datasets revealed a unique gene set that is differentially expressed and accessible during cardiac gene reprogramming. Upregulated and more accessible genes in PTU-treated cardiomyocytes (CM) are involved in muscle cell differentiation, muscle hypertrophy, and mitochondrion disassembly ( Tbx5 , Sox4 , Wnt2 , Rgs2 , Hey2 , Mfn2 ). Downregulated and less accessible genes in PTU-treated CMs are related to heart contraction, regulation of heart rate, and ion membrane transport ( Kcnd3 , Jarid2 , Epas1, Atp2a2 , Scn5a , Slc25a4 ). Conclusion: Induction of cardiac gene reprogramming by thyroid inhibition can be applied to understand adult heart failure mechanisms. Hypothyroidism effectively induces global remodeling in the adult heart. Single nuclei multiomic analysis reveals new mechanistic insights into cardiac gene reprogramming that alters the expression and accessibility of genes essential for heart development and maturation.

Effects of Combined Hypothyroidism and Selenium Deficiency on Selenoenzyme Glutathione Peroxidase Activity in Rats

Abstract The effects of propylthiouracil (PTU) treatment and selenium-deficient diet on selenium and thyroid status of Wistar male rats were examined in this study. Wistar male rats (n =128) were divided into four groups: (1) control group – selenium-adequate rats fed a diet supplemented with 0.334 mg Na selenite/kg feed and received regular drinking water (Se+PTU-); (2) selenium adequate rats fed a diet supplemented with 0.334 mg Na selenite/kg feed and received a dose of 150 mg/L of PTU in drinking water, (Se+PTU+); (3) selenium-deficient rats fed a diet containing 0.031 mg Na selenite/ kg and received regular drinking water (Se-PTU-); (4) selenium deficient rats fed a diet containing 0.031 mg Na selenite/kg and received 150 mg/L of PTU in drinking water (Se-PTU+). After three and seven weeks of treatment, all Se – animals had significantly lower whole blood Se concentrations and GPx1 and GPx3 activities. PTU induced a significant decrease in T4 and T3 plasma concentrations after three weeks of treatment in both PTU+ groups. Furthermore, after seven weeks, the T3 level was close to its detection limit in Se – animals. A negative correlation was spotted between GPx activity and concentration of T3 after three and seven weeks. It could indicate an inhibitory influence of thyroid hormones on the expression and/or activities of GPx enzymes related to the available Se in conditions of systemic decrease of T4 concentration. This effect was particularly pronounced in Se – animals.

OA03 Trauma secondary to a horse riding accident as a potential accelerating factor in inflammatory axial sponyloarthropathy: a case report and literature review

Abstract Introduction Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease characterised by axial involvement and sacroiliitis. The etiology of AS remains elusive, with genetic and environmental factors implicated in disease development and progression. This case report aims to investigate the potential association between trauma and the acceleration of AS in individuals positive for HLA-B27. Furthermore one purpose of this case-report is to ascertain any link between horse riding accidents in jockeys or professionals undertaking horse riding as a career choice. Is there a correlation between trauma and development of inflammatory axial spondyloarthropathy subsequently or not. Case description A 24-year-old female patient with a medical history of eczema and Graves' disease, currently undergoing propylthiouracil treatment, was referred to the rheumatology clinic due to persistent back pain for the past six to seven years following a horse riding accident. The patient had previously received physiotherapy and found relief with naproxen and co-codamol. The pain primarily affects her lower spine and radiates down her legs. While movement provides some relief, lying down exacerbates the pain. The patient experiences stiffness for approximately 30 minutes in the morning but does not exhibit peripheral joint symptoms. Exercise helps alleviate her symptoms. The patient reported a family history of psoriasis but denied any history of uveitis, inflammatory bowel disease, weight loss, night sweats, heartblock or achilles tendinitis. She also gave a history of joint hyper mobility with reduced flexion at the spine over the years. Blood tests revealed normal levels of ANA, CCP, ESR, rheumatoid factor, B12, HbA1c, and thyroid function. Ferritin levels were 30.2, and HLA B27 was positive. Joint examination did not reveal any signs of synovitis. The patient exhibited good range of motion in the spine. SLR's were positive on both sides and no tenderness over spine or sacroiliac joints. Systemic Examination was normal. BASDAI score was 4. Occiput to wall distance of 0 centimeters. Beighton score 4/9. Subsequently MRI whole spine/SI Joints were organised and results indicated a central disc protrusion at the L4-L5 level leading to critical spinal stenosis and likely impinging on the transitioning L5 and S1 nerve roots. Additionally, a disc protrusion at the L5-S1 which was impinging on the left S1 nerve root. Bilateral sacroiliitis was also observed. Patient was treated with NSAIDs and physiotherapy with good results with a view for a subsequent MRI, and escalation to biologics if symptoms were to worsen. Discussion The presented case raises the question of whether trauma accelerates the progression of ankylosing spondylitis (AS) in individuals who are positive for HLA-B27. Although this specific case involves a 24-year-old female patient with a history of back pain following a horse riding accident, additional research and studies would be required to draw definitive conclusions regarding the relationship between trauma and the development or acceleration of AS in HLA-B27 positive individuals. The question this case report poses and there is little in terms of research and case reports present, whether the involvement of the lady in question in a horse riding accident unmasked her ankylosing spondylitis given her HLA B27 positivity and the presence of sacroilitis on MRI scans. Literature review revealed a potential role of trauma accelerating the progression of ankylosing spondylitis in individuals who are also positive for HLA B-27, in addition in some cases it lead to detection and unmasking of chronic back pain which was inflammatory in nature rather than mechanical or a combination of both. This was revealed by the horse riding accident given the nature of the pain which had been constant and worsening which lead to a suspicion of a possible inflammatory component and hence further investigations were done. In conclusion this case report highlights the importance of a possible correlation between AS in HLA B27 positive individuals and raises the question whether trauma secondary to sports injuries like horseback riding accidents in our patients case, accelerates the progression of AS in individuals who are positive for HLA-B27. Key learning points This case report highlights the potential role of trauma following a sports injury as a contributing factor in the acceleration of AS in individuals positive for HLA-B27. Further investigations, including prospective studies, are warranted to elucidate the complex interplay between trauma, genetic predisposition, and disease progression in AS. The purpose of this case report is to remind sports medicine physicians of the prevalence of rheumatologic diseases in general and ankylosing spondylitis in particular and of the various ways in which spondyloarthropathies may present in athletes/sports personnel. Increased suspicion may lead to earlier diagnosis and treatment, potentially reducing illness severity and duration and improving the performance of athletes with this condition.

Levels of Antithyroid Antiperoxidase and Antithyroglobulin Antibodies in Patients with Graves Hyperthyroidism – Predictors of Initial and Sustained Remission and Consecutive Hypothyroidism

BACKGROUND: Initial and sustained remission is the principal objective in patients with Graves hyperthyroidism (GH) treated with antithyroid drugs (ATD). AIMS: Our study aimed to investigate the predictive value of antithyroid antiperoxidase (aTPO) and antithyroglobulin (aTg) levels on initial and sustained remission or consecutive hypothyroidism in subjects with GH treated with ATD. METHODS: Randomized, prospective, and longitudinal study during period 2013–2018 was performed. Eighty GH patients (thyrotropin [TSH] <0.01 mIU/L, free thyroxine [FT4] >30 pmol/L, triiodothyronine [FT3] >8 pmol/L), 59 females (73.75%), and 21 males (26.25%), aged 51 ± 12 years were included in the study. Subjects were divided into four subgroups (each with 20 patients) according to aTPO and aTg levels: Group I – no antibodies; Group II – (<500 IU/mL), Group III – (500–1000 IU/mL), and Group IV – (>1000 IU/mL). All subjects underwent 24 months of propylthiouracil treatment with follow-up of 24 months after remission (TSH >0.4 mIU/L, FT4 11–25 pmol/L, FT3 2.8–6.5 pmol/L). Blood samples were analyzed every 4 months. RESULTS: In Group I, 11 (55%) of the patients attained remission; during follow-up, 5 (45%) of them had disease relapse. In Group II, 12 (60%) attained remission and 5 (42%) had relapse. In Group III, 15 (75%) attained remission, 2 (13%) had disease relapse, and 4 (26%) developed hypothyroidism. In Group IV, 18 (90%) attained remission, 1 (5%) had disease relapse, and 9 (50%) developed hypothyroidism. Patients with values below 500 IU/mL attained remission in 60%, similar as the group without antibodies in 55% (p < 0.3). Patients in Group III and IV had significantly higher remission rates compared to Group I and II (p < 0.001). Baseline values of aTPO and aTg >1000 IU/mL were significant predictors of consecutive hypothyroidism (p < 0.05). CONCLUSION: Baseline aTPO and aTg values above 500 IU/mL were significantly prognostic for attaining and sustaining remission in GH and values above 1000 IU/mL were significant predictors of consecutive hypothyroidism.

Abstract P1146: Global Analysis Of Murine Cardiac Gene Program Regulated By Thyroid Hormone And Transcriptional Repressor Rest

Background: During adult heart failure, transcriptional reprogramming of fetal cardiac genes coincides with dysregulated heart functions. However, the underlying mechanisms remain incompletely understood. Thyroid hormone and RE1 silencing transcription factor (REST) are known regulators of cardiac gene reprogramming. Here, we report a global analysis of their co-regulatory functions. Methods: We generated a dual Myh6 and Myh7 mouse reporter line. This line was crossed with a conditional Rest allele to generate myocardial Rest knockout mice. Control and Rest null mice were treated with propylthiouracil (PTU) to inhibit thyroid hormone synthesis. PTU treatment induced heart failure and adult-to-fetal cardiac gene remodeling. Single nuclei multiomic profiling was performed, linking gene expression and gene regulatory network information from each nuclei to elucidate the impact of PTU or REST or both on cardiac gene reprogramming. Samples were collected to validate the newly identified factors involved in reprogramming. Results: Data analysis showed that PTU treatment upregulates transcription factor binding involving circadian gene expression ( Cry2 , Per2 , Per3 ). Downregulated genes are related to voltage-gated channel activity and BMP/TGFB activities involving heart development ( Myh6 , Nrg1 , Bmpr1a ) and SA node action potential ( Scn5a , Hcn2 , Ryr2 ). In contrast, Rest knockout upregulated genes are associated with arrhythmia, i.e. , cAMP catabolism ( Pde4d , Pde7a , Pde7b ), heart conduction ( Cacna1c , Gja1 , Pln ), and ion transport ( Kcnip2 , Pde4d, Esr1 ). Downregulated genes are involved in protein functions involving integrin-mediated signaling ( Itgal , Itga4 , Itga5 ), cytoskeleton organization ( Ctnna2 , Actb , Xirp1 ), and fiber organization ( Tgfb3 , Smad3 , Ptk2b ). Furthermore, a subset of genes was found to be co-regulated by thyroid hormone and REST, including Ccn2 , Myh9 , Nmrk2 , Fgr , Itga4 , Prkcb , Cspg4 which are involved in integrin signaling pathway, immune activation, and angiogenesis. Conclusion: Thyroid hormone and REST have shared function in cardiac gene reprogramming involving cardiac conduction and fibrosis as well as their own newly discovered, unique roles regulating circadian genes and cAMP catabolism, respectively.

Thyroid hormone maintains cardiac dyadic structures by regulating junctophilin-2 localization to ryanodine clusters

Overt and subclinical hypothyroidism are associated with increased risk of cardiovascular disease and mortality. In pre-clinical studies, supplementation with triiodo-L-thyronine (T3) has been shown to regulate cardiomyocyte T-tubule (TT) organization, and thereby maintain ryanodine receptor-2 and L-type Ca 2+ channel (RyR-LTCC) clusters in dyadic structures necessary for efficient excitation-contraction (EC) coupling. We hypothesized that the TT-sarcoplasmic reticulum (SR)-spanning protein Junctophilin-2 (Jph) is regulated by T3. Thyroid hormone (TH) deficiency was induced in 12 adult female Sprague-Dawley rats by oral propyl-thiouracil (PTU; 0.025%) treatment for 8 weeks. Rats were then randomized to continued PTU treatment or with T3 (10 μg/kg/day) supplementation for 2 weeks (PTU+T3). Untreated rats served as euthyroid (EU) controls. Thyroid status was confirmed by plasma T3 and T4 levels. Left ventricular cardiomyocytes (CM) were isolated by collagenase digestion for single molecule imaging of Jph2, RyR2 and LTCC proteins using 2D and 3D STORM (stochastic optical reconstruction microscopy; Oxford Nanoimager). DBSCAN algorithms for cluster analysis (Web-based programs developed by LumeVR) measured cluster size and number, nearest neighbor cluster distances, and protein co-localizations. Calcium sparks in live CMs loaded with Fluo-4 were captured by line-scanning laser microscopy (Zeiss 980) to assess spontaneous SR Ca 2+ leak. STORM imaging of normal CMs showed that ~60% of RyR clusters consisted of 10-50 RyR localizations (locs) with 100-200 Jph molecules co-localized within 210 nm radius of the cluster centroid. Although Jph locs per cluster increased proportionately with increased cluster size, PTU cells had markedly less Jph co-localized with RyR at all cluster sizes compared to EU and PTU+T3 cells. The reduction of associated Jph was most evident in super-clusters (>250 RyR locs). 3D image analysis showed nearest neighbor distances between RyR clusters that were significantly increased in the PTU CMs vs EU (749±146 nm vs 640±140 nm), which were normalized with T3-treatment (616±60 nm). Numbers of RyR clusters without associated Jph locs were significantly higher in PTU cells, and reduced with T3. RyR Ca 2+ leak as measured by spontaneous Ca 2+ sparks was increased in PTU CMs, but decreased significantly to control values in T3-treated cells. This study supports a regulatory role of T3 in maintaining TT-SR dyad structures, in part by increasing Jph co-localization with RyR clusters, thus promoting efficient interaction of RyR with LTCC channels for effective EC-coupling and cardiac output. Study funded by NIH R15HL15406 and by resources of the NYIT Imaging Center. This is the full abstract presented at the American Physiology Summit 2023 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.

Phytochemical profiling of polyphenols and thyroid stimulatory activity of Ficus religiosa leaf extract in 6-propyl-thiouracil-induced hypothyroid rats

Ethnopharmacological relevanceThe plant, Ficus religiosa (L.) from the family Moraceae, has been extensively used in Ayurveda and Unani. Traditionally this plant is known for the treatment of constipation, liver diseases and neurological disorders that are related to hypothyroidism. Aim of the studyThis study was primarily designed to evaluate the effect of Ficus religiosa leaf (FL) extract in ameliorating hypothyroidism in rats and to identify the major bioactive compounds in the test extract that might be responsible for the thyroid-altering activity. In addition, the probable mechanism underlying the thyroid regulation of the main FL constituents were analyzed by molecular docking. Materials and methodsAdult female Wistar rats were used. LC-ESI-MS/MS was performed to identify the compounds present in the extract. HPLC analysis of FL extract was also performed. A pilot study was made using 3 doses of FL extract. Out of 50, 100, and 200 mg/kg, 100 mg/kg appeared to be the most effective one as it could increase thyroid hormones and decreased TSH levels. In the final experiment, propyl-thiouracil (PTU)-induced hypothyroid rats were orally treated with FL extract (100 mg/kg) or L-thyroxine (100 μg/kg, i.p.) daily for 28 consecutive days. On 29th day, all rats were sacrificed and the serum levels of triiodothyronine (T3), thyroxine (T4), thyrotropin (TSH), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and hepatic 5′ deiodinase-1(5′D1) were estimated by ELISA. Liver marker enzymes (alanine aminotransferase, ALT and aspartate aminotransferase, AST); total cholesterol (TC) and triglycerides (TG); hepatic lipid peroxidation (LPO) and the activities of antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH) content were estimated in liver tissues. ResultsLC-MS-MS analyses of the leaf extract identified 11 compounds including the three major compounds, betulinic acid (BA), chlorogenic acid (CGA), and quinic acid (QA). While the PTU treatment decreased the levels of thyroid hormones and 5′D1 activity, it increased the TSH, ALT, AST, TNF-α, IL-6, TC, and TG levels. Furthermore, hepatic LPO significantly increased with a decrease in reduced GSH, SOD, CAT, and GPx. However, FL treatment in PTU-induced animals nearly reversed these adverse effects and improved liver function by decreasing ALT, AST, hepatic LPO and increasing the levels of antioxidants. FL not only improved the liver histology, but also suppressed the inflammatory cytokines, TNF-α and IL-6 in PTU-induced animals. A molecular docking study towards the understanding of the thyroid stimulatory mechanism of action revealed that BA, CGA, and QA might have augmented thyroid hormones by interacting with the thyroid hormone receptor (TRβ1) and TSH receptor (TSHR). ConclusionFor the first time, we report the pro-thyroidal potential of Ficus religiosa leaf extract. We postulate that its main bioactive compounds, BA, CGA, and QA involved in this action may serve as novel thyroid agonists in ameliorating hypothyroidism.

Jagged/Notch proteins promote endothelial-mesenchymal transition-mediated pulmonary arterial hypertension via upregulation of the expression of GATAs.

This study tested the hypothesis that Jagged2/Notches promoted the endothelial-mesenchymal transition (endMT)-mediated pulmonary arterial hypertension (PAH) (i.e. induction by monocrotaline [MCT]/63 mg/kg/subcutaneous injection) through increasing the expression of GATA-binding factors which were inhibited by propylthiouracil (PTU) (i.e. 0.1% in water for daily drinking since Day 5 after PAH induction) in rodent. As compared with the control (i.e. HUVECs), the protein expressions of GATAs (3/4/6) and endMT markers (Snail/Zeb1/N-cadherin/vimentin/fibronectin/α-SMA/p-Smad2) were significantly reduced, whereas the endothelial-phenotype markers (CD31/E-cadherin) were significantly increased in silenced JAG2 gene or in silenced GATA3 gene of HUVECs (all p < 0.001). As compared with the control, the protein expressions of intercellular signallings (GATAs [3/4/6], Jagged1/2, notch1/2 and Snail/Zeb1/N-cadherin/vimentin/fibronectin/α-SMA/p-Smad2) were significantly upregulated in TGF-ß/monocrotaline-treated HUVECs that were significantly reversed by PTU treatment (all p < 0.001). By Day 42, the results of animal study demonstrated that the right-ventricular systolic-blood-pressure (RVSBP), RV weight (RVW) and lung injury/fibrotic scores were significantly increased in MCT group than sham-control (SC) that were reversed in MCT + PTU groups, whereas arterial oxygen saturation (%) and vasorelaxation/nitric oxide production of PA exhibited an opposite pattern of RVW among the groups (all p < 0.0001). The protein expressions of hypertrophic (ß-MHC)/pressure-overload (BNP)/oxidative-stress (NOX-1/NOX-2) biomarkers in RV and the protein expressions of intercellular signalling (GATAs3/4/6, Jagged1/2, notch1/2) and endMT markers (Snail/Zeb1/N-cadherin/vimentin/fibronectin/TGF-ß/α-SMA/p-Smad2) in lung parenchyma displayed an identical pattern of RVW among the groups (all p < 0.0001). Jagged-Notch-GATAs signalling, endMT markers and RVSBP that were increased in PAH were suppressed by PTU.

Fluctuation of CD9/SOX2-positive cell populations during the turnover of GH- and TSH-producing cells in the adult anterior pituitary gland.

The adenohypophysis is comprised of the anterior and intermediate lobes (AL and IL, respectively). Cluster of differentiation 9 (CD9)- and sex-determining region Y-box 2 (SOX2)-positive cells are stem/progenitor hormone-producing cells in the AL. They are located in the marginal cell layer (MCL) facing Rathke's cleft between the AL and IL (primary niche) and the parenchyma of the AL (secondary niche). We previously showed that, in rats, CD9/SOX2-positive cells in the IL side of the MCL (IL-side MCL) migrate to the AL side (AL-side MCL) and differentiate into prolactin-producing cells (PRL cells) in the AL parenchyma during pregnancy, lactation, and diethylstilbestrol treatment, all of which increase PRL cell turnover. This study examined the changes in CD9/SOX2-positive stem/progenitor cell niches and their proportions by manipulating the turnover of growth hormone (GH)- and thyroid-stimulating hormone (TSH)-producing cells (GH and TSH cells, respectively), which are Pit1 lineage cells, as well as PRL cells. After induction, the isolated CD9/SOX2-positive cells from the IL-side MCL formed spheres and differentiated into GH and TSH cells. We also observed an increased GH cell proportion upon treatment with GH-releasing hormone and recovery from continuous stress and an increased TSH cell proportion upon propylthiouracil treatment, concomitant with alterations in the proportion of CD9/SOX2-positive cells in the primary and secondary niches. These findings suggest that CD9/SOX2-positive cells have the potential to supply GH and TSH when an increase in GH and TSH cell populations is required in the adult pituitary gland.

A Fine Regulation of the Hippocampal Thyroid Signalling Protects Hypothyroid Mice against Glial Cell Activation.

Adult-onset hypothyroidism is associated with learning and cognitive dysfunctions, which may be related to alterations in synaptic plasticity. Local reduced levels of thyroid hormones (THs) may impair glia morphology and activity, and promote the increase of pro-inflammatory cytokine levels mainly in the hippocampus. Given that neuroinflammation induces memory impairments, hypothyroidism-related glia dysfunction may participate in brain disorders. Thus, we investigated the mechanisms linking hypothyroidism and neuroinflammation, from a protective perspective. We induced hypothyroidism in adult C57BL/6J and wild-derived WSB/EiJ male mice by a seven-week propylthiouracil (PTU) treatment. We previously showed that WSB/EiJ mice were resistant to high-fat diet (HFD)-induced obesity, showing no neuroinflammatory response through adaptive abilities, unlike C57BL/6J. As PTU and HFD treatments are known to induce comparable inflammatory responses, we hypothesized that WSB/EiJ mice might also be protected against hypothyroidism-induced neuroinflammation. We showed that hypothyroid WSB/EiJ mice depicted no hippocampal neuroinflammatory response and were able to maintain their hippocampal thyroid signalling despite low circulatisng TH levels. In contrast, C57BL/6J mice exhibited disturbed hippocampal TH signalling, accompanied by neuroinflammation and memory impairment. Our results reinforce the preponderance of the hippocampal TH regulatory system over TH circulating levels in the hippocampal glial reactivity.

Thymoquinone improved redox homeostasis in the heart and aorta of hypothyroid rats

ABSTRACT Objectives Propylthiouracil (PTU) is a common drug that is used in medicine for treating hyperthyroidism. Furthermore, hypothyroidism can also be induced with PTU. Considering the antioxidant effects of thymoquinone (TMQ), this study was designed to find out whether TMQ could counteract the oxidative damage in the heart and aorta tissues induced by hypothyroidism in rats. Methods Animals were arranged into four groups: (1) Control, (2) PTU, (3) PTU-TMQ 5, and (4) PTU-TMQ 10. Hypothyroidism was induced in rats by giving 0.05% PTU in drinking water. PTU and TMQ (5 and 10 mg/kg, ip) treatments were done for 42 days. Finally, the animals were sacrificed and the serum of the rats was collected for thyroxine level assessment. The heart and aorta tissues were also removed for biochemical oxidative stress markers measurement. Results A lower serum thyroxine level was observed after PTU treatment compared to the control group. Hypothyroidism also was accompanied by a decrease of thiol content, and superoxide dismutase (SOD), and catalase (CAT) activities in the heart and aorta tissues while increased malondialdehyde (MDA). Furthermore, a significant reduction in oxidative damage was noted in the heart and aorta following the administration of TMQ (5 and 10 mg/kg) which was indicated by the reduction in MDA and improved activities of SOD, CAT, and thiol. Conclusion In this study, TMQ was found to improve oxidative damages in the heart and aorta tissues of hypothyroid rats.

Treatment with levothyroxine and testosterone ameliorated erectile dysfunction in a rat model of propylthiouracil-induced hypothyroidism

ABSTRACT Introduction The endocrine disease frequently interrupts sexual function, and sexual dysfunction may signal serious endocrine disease. Recent studies have claimed an association with hypothyroidism, low testosterone (T) levels and erectile dysfunction (ED), but causality is unclear. There is no study on the experimental model of hypothyroidism that was induced in rats by administration of propylthiouracil (PTU). Objective The purpose of this study was to investigate the deleterious effects of PTU-induced hypothyroidism on ED and T levels. In addition, Levothyroxine is known worldwide as the most common and least effective drug for controlling hypothyroidism. Methods Adult Sprague-Dawley rats (n = 35) were divided into five groups; control, PTU-induced hypothyroidism, PTU+ Levothyroxine, PTU+ Sustanon (a mixture of 4 types of T: propionate, phenylpropionate, isocaproate, decanoate) and PTU+ Levothyroxine + Sustanon. PTU was given in drinking water (0.05%) for 6 weeks. 4 weeks after the beginning of PTU treatment, Levothyroxine (20 mg/kg/day, oral) and Sustanon (10 mg/kg, I.M., once/week) were given for 2 weeks. Serum levels of total T, triiodothyronine (T3) and thyroxine (T4) were determined. The ratio of intracavernosal pressure (ICP) to mean arterial pressure (MAP) and total ICP were measured by cavernous nerve stimulation. The relaxant and contractile responses were evaluated on in vitro preparations of corpus cavernosum (CC) strips. The expression and localization of neuronal (nNOS), endothelial NOS (eNOS) and phosphodiesterase type 5 (PDE5​) were determined using Western blotting and immunohistochemistry. The relative area of smooth muscle to collagen was measured using Masson trichrome staining. Results The rat model of hypothyroidism showed a significant decline in serum levels of total T, T3 and T4. Levothyroxine increased T3 and T4 levels while Sustanon normalized only total T levels. In addition, combined treatment of Levothyroxine and Sustanon enhanced all hormone levels. Rats with hypothyroidism displayed the lowest ICP/MAP ratio and total ICP for 7.5 V (P &amp;lt; .001 vs controls). Combined treatment returned reduced ICP/MAP and total ICP responses, while partial amelioration was observed after Levothyroxine and Sustanon treatment alone. In vitro endothelium-dependent acetylcholine-caused relaxation at 1 nM (P &amp;lt; .001 vs controls), electrical field stimulation-induced relaxant response at 20 Hz (P &amp;lt; .001 vs controls) and sildenafil-induced relaxation at 10 µM (P &amp;lt; .05 vs controls) were decreased in the CC strips from hypothyroid rats. The treatment with Levothyroxine and Sustanon increased the reduction in relaxation responses. Decreased in the expressions of eNOS and nNOS and increased in the expressions of PDE5 in the hypothyroid group were restored by Levothyroxine and Sustanon. Mono-treatment partially enhanced reduced smooth muscle mass while combined therapy completely recovered. Conclusions These results show that hypothyroidism adversely affects T levels and erectile responses via decreasing neurogenic and endothelium-dependent relaxation responses which were reversed by the combination therapy with Levothyroxine and Sustanon. Even though the associated alterations in T levels, ED and its reversibility indicate an exact role of thyroid hormones in the erection physiology. Disclosure Work supported by industry: no.

Treatment with levothyroxine and testosterone ameliorated erectile dysfunction in rat model of propylthiouracil-induced hypothyroidism

ABSTRACT Introduction The endocrine disease frequently interrupts sexual function, and sexual dysfunction may signal serious endocrine disease. Recent studies have claimed an association with hypothyroidism, low testosterone (T) levels and erectile dysfunction (ED), but causality is unclear. There is no study on the experimental model of hypothyroidism that was induced in rats by administration of propylthiouracil (PTU). Objective The purpose of this study was to investigate the deleterious effects of PTU-induced hypothyroidism on ED and T levels. In addition, Levothyroxine is known worldwide as the most common and least effective drug for controlling hypothyroidism. Methods Adult Sprague-Dawley rats (n = 35) were divided into five groups; control, PTU-induced hypothyroidism, PTU+ Levothyroxine, PTU+ Sustanon (a mixture of 4 types of T: propionate, phenylpropionate, isocaproate, decanoate) and PTU+ Levothyroxine + Sustanon. PTU was given in drinking water (0.05%) for 6 weeks. 4 weeks after the beginning of PTU treatment, Levothyroxine (20 mg/kg/day, oral) and Sustanon (10 mg/kg, I.M., once/week) were given for 2 weeks. Serum levels of total T, triiodothyronine (T3) and thyroxine (T4) were determined. The ratio of intracavernosal pressure (ICP) to mean arterial pressure (MAP) and total ICP were measured by cavernous nerve stimulation. The relaxant and contractile responses were evaluated on in vitro preparations of corpus cavernosum (CC) strips. The expression and localization of neuronal (nNOS), endothelial NOS (eNOS) and phosphodiesterase type 5 (PDE5) were determined using Western blotting and immunohistochemistry. The relative area of smooth muscle to collagen was measured using Masson trichrome staining. Results The rat model of hypothyroidism showed a significant decline in serum levels of total T, T3 and T4. Levothyroxine increased T3 and T4 levels while Sustanon normalized only total T levels. In addition, combined treatment of Levothyroxine and Sustanon enhanced all hormone levels. Rats with hypothyroidism displayed the lowest ICP/MAP ratio and total ICP for 7.5 V (P &amp;lt; .001 vs controls). Combined treatment returned reduced ICP/MAP and total ICP responses, while partial amelioration was observed after Levothyroxine and Sustanon treatment alone. In vitro endothelium-dependent acetylcholine-caused relaxation at 1 nM (P &amp;lt; .001 vs controls), electrical field stimulation-induced relaxant response at 20 Hz (P &amp;lt; .001 vs controls) and sildenafil-induced relaxation at 10 µM (P &amp;lt; .05 vs controls) were decreased in the CC strips from hypothyroid rats. The treatment with Levothyroxine and Sustanon increased the reduction in relaxation responses. Decreased in the expressions of eNOS and nNOS and increased in the expressions of PDE5 in the hypothyroid group were restored by Levothyroxine and Sustanon. Mono-treatment partially enhanced reduced smooth muscle mass while combined therapy completely recovered. Conclusions These results show that hypothyroidism adversely affects T levels and erectile responses via decreasing neurogenic and endothelium-dependent relaxation responses which were reversed by the combination therapy with Levothyroxine and Sustanon. Even though the associated alterations in T levels, ED and its reversibility indicate an exact role of thyroid hormones in the erection physiology. Disclosure No

Efficacy of propylthiouracil in the treatment of pregnancy with hyperthyroidism and its effect on pregnancy outcomes: A meta-analysis.

Hyperthyroidism affects about 0.2%-2.7% of all pregnancies, and is generally treated with propylthiouracil (PTU). However, previous studies about the effects of propylthiouracil on maternal or foetal are contentious. This meta-analysis was carried out to investigate the safety and efficacy of propylthiouracil during pregnancy. PubMed, EBSCO, Embase, Scopus, Web of Science, Cochrane, CNKI, Wanfang and VIP database were searched from inception until August 31, 2021 for all available randomized controlled trials (RCTs) or cohort studies that evaluated the efficacy of propylthiouracil and its effects on pregnancy outcomes. Odds ratio (OR) and 95% confidence interval (CI) were used for binary variables, weighted mean difference (WMD) and 95% confidence interval (CI) were used for continuous variables. RevMan5.4 and Stata 16.0 were used for performing the meta-analysis. The researchers examined data from 13 randomized controlled trials and cohort studies involving 18948 infants. Congenital anomalies were not significantly associated with PTU in the pooled results (OR = 1.03, 95%CI: 0.84-1.25, P = 0.80, I2 = 40.3%). There were no statistically significant differences in neonatal hypothyroidism (OR = 0.55, 95%CI: 0.06-4.92, P = 0.593, I2 = 57.0%) or hepatotoxicity (OR = 0.34, 95%CI: 0.08-1.48, P = 0.151, I2 = 0.0%) exposed to PTU compared to the control group. The serum levels of FT3, FT4, TT3, and TT4 were significantly lower in the propylthiouracil group compared to the control group. This meta-analysis confirmed the beneficial effects of propylthiouracil treatment, namely the risks of adverse pregnancy outcomes were not increased, and it also proved PTU's efficacy in the treatment of pregnant women with hyperthyroidism. The findings supported the use of propylthiouracil during pregnancy with hyperthyroidism in order to improve clinical pregnancy outcomes in patients with thyroid dysfunction.

Expression of Aquaglyceroporins in Spermatozoa from Wild Ruminants Is Influenced by Photoperiod and Thyroxine Concentrations

This work identified the presence of AQPs in frozen-thawed sperm of wild ruminants and assessed the influence of the interaction between photoperiod and thyroxine on AQP expression, and on testosterone secretion. Thyroxine and melatonin were administered to ibexes. In a second experiment, performed in mouflons, circulating thyroxine was reduced via treatment with propylthiouracil (PTU), and an artificial long day (LD) photoperiod established. In the ibexes, the melatonin treatment increased the blood plasma testosterone concentration, reduced the cryoresistance ratio (CR) for sperm viability and the presence of an intact acrosome, and increased the percentage of sperm with AQP7 in the acrosome and of AQP3 and AQP10 in the midpiece. In the mouflons, neither the PTU treatment, the LD, nor the combination of both affected the CR of any sperm variable. The percentage of sperm with AQP3 increased in the post-acrosome region but decreased in the tail in the LD+PTU group. The percentage of sperm with AQP10 in the principal piece and endpiece was lower in the PTU+LD group than in the control and LD groups. The influence of photoperiod/melatonin on AQP expression might be indirectly exerted through changes in the testosterone concentration, and thus ultimately affect sperm cryoresistance.

Relationship between autoantibodies against type 2 deiodinase and antithyroid autoantibodies in Graves’ disease using antithyroid drug therapy

Background: Previously, the presence of autoantibodies against type 2 deiodinase cys- and hom-peptides was investigated in Graves’ disease with relation to thyroid function, ophthalmopathy and therapy. The new design was to reveal the relationship among antithyroid antibodies involved in hormone synthesis. Aim and scope: To demonstrate some regularity between the appearance of peptide autoantibodies and antithyroid antibodies against TSH receptor, thyroid peroxidase and thyroglobulin, the study followed the main path of hormone synthesis and the effect of antithyroid drug treatment. Has any effect of peptide autoantibodies on the titers of other autoantibodies? Methods: The methods were described in our previous papers detailed. Autoantibodies against type 2 deiodinase peptides were detected with enzyme-linked immunosorbent assay in 78 patients with Graves’ disease and 30 controls. Thyroid hormones (TSH, FT4 and FT3) and antibodies against TSH receptor, thyroid peroxidase and thyroglobulin were measured with chemiluminescence immunoassay. Results: The frequency of cys-peptide antibodies was greater in the new onset of Graves’ disease. Propylthiouracil treatment was associated with increased occurrence of cys-peptide antibodies (p&lt;0.0069). No dose-dependency in methimazole treatment could be demonstrated for cys-peptide antibody levels. Antibodies against hom-peptide or both peptides demonstrated a strong relationship with the appearance of antithyroid antibodies. No peptide antibodies were associated with anti-thyroglobulin antibody positivity (0 cases out of 11 for hom-peptide, p&lt;0.0071 and 0 cases out of 8 for both peptides, p&lt;0.0251). In contrast, all cases with TSH receptor antibody positivity were positive for peptide antibodies (all cases out of 13 for hom-peptide, p&lt;0.0139 and all cases out of 9 for both peptides, p&lt;0.0470). TSH receptor antibody levels were relevantly decreased, when hom-peptide antibodies were present [24.35(15.68-37.8) vs 11.8(8.16-17.07) IU/l, p&lt;0.0437]. Conclusion: The presence of hom-peptide antibodies was connected to the absence of antibodies against thyroglobulin and smaller anti-thyroid peroxidase antibody positivity. The presence and the high titers of TSH receptor antibodies demonstrated a close relationship with the appearance of hom-peptide antibodies. The relationship among the studied autoantibodies may depend on the alteration of thyroid hormone synthesis and the steric hindrance of targets and antithyroid drug treatment. Autoantibodies against type 2 deiodinase peptides can influence the therapeutical effectiveness

Can propylthiouracil induce autoimmune-related immunotoxicity?

Introduction. The use of propylthiouracil can be associated with mild adverse reactions, but severe complications such as agranulocytosis and vasculitis can also be seen. Direct toxicity and immune-mediated induction of anti-neutrophile cytoplasmic antibodies have been described as possible mechanisms responsible for agranulocytosis. The majority of vasculitis is antimyeloperoxidase antibodies associated, but the exact mechanism for anti-neutrophile cytoplasmic antibodies-associated vasculitis as an adverse effect of propylthiouracil treatment is still unclear. Case report. We presented a 61-year-old female patient with Graves? disease who experienced a fever and throat pain two weeks after propylthiouracil therapy was initiated. Agranulocytosis alongside basal left-sided pneumonia was noted. Propylthiouracil was discontinued, and the treatment with broad-spectrum antibiotics was started, as well as Lugol?s solution, methylprednisolone, and granulocyte-colony stimulating factor. Further course of treatment was complicated by the occurrence of a generalized erythematous-papillomatous rash. The patient was diagnosed with agranulocytosis and antimyeloperoxidase, anti-neutrophile cytoplasmic antibodies positive vasculitis as an adverse effect of propylthiouracil. Conclusion. Patients presenting with concomitant agranulocytosis and anti-neutrophile cytoplasmic antibodies-associated vasculitis as a complication of propylthiouracil therapy for Graves? disease are rare in clinical practice. Prompt discontinuation of the antithyroid drug is of great importance to reduce damage to target organs. Similarities in the pathogenesis of both conditions could be the potential explanation for these two adverse events occurring at the same time, which points out the need for a deeper understanding of this topic.

Propylthiouracil: A Well Known Cause of Agranulocytosis, but Can It Cause Aplastic Anemia?

AbstractBackground: Propylthiouracil (PTU) has been in use for more than half a century for the treatment of hyperthyroidism. While it is largely known to cause agranulocytosis, its association with aplastic anemia is generally unheard of. Our case will be the third in literature to suggest aplastic anemia as a side effect of PTU, which unfortunately culminated in the death of the patient.Case: A 67-year-old female, with recently diagnosed metastatic adenocarcinoma of the lung, developed hyperthyroidism after being started on Nivolumab and Iplimumab. After she developed atrial fibrillation, she was started on PTU to control the thyroid activity. Soon after that, she was admitted with severe neutropenia, which progressed to aplastic anemia. Despite discontinuation of PTU and aggressive treatment, she developed septic shock and multi-organ failure, leading to her death.Conclusion: Aplastic anemia has been sparingly reported as an extremely rare complication of PTU. It has not been investigated further due to the sparse events and therefore insufficient data. Further adding to the ambiguity is the unknown etiology and lack of specific therapy for the complication when attributed to PTU. The disease can carry a poor prognosis if untreated, as proven by our case, and the use of PTU being relatively commonplace, it is crucial that the complication be considered and aggressively treated. Due to the same reasons, we recommend that further investigations be done to elucidate the pathogenesis and assist with treatment of the disease when found in respect to PTU. DisclosuresNo relevant conflicts of interest to declare.

Triiodothyronine maintains cardiac transverse-tubule structure and function

Subclinical hypothyroidism and low T3 syndrome are commonly associated with an increased risk of cardiovascular disease (CVD) and mortality. We examined effects of T3 on T-tubule (TT) structures, Ca2+ mobilization and contractility, and clustering of dyadic proteins.Thyroid hormone (TH) deficiency was induced in adult female rats by propyl-thiouracil (PTU; 0.025%) treatment for 8 weeks. Rats were then randomized to continued PTU or triiodo-L-thyronine (T3; 10 μg/kg/d) treatment for 2 weeks (PTU + T3). After in vivo echocardiographic and hemodynamic recordings, cardiomyocytes (CM) were isolated to record Ca2+ transients and contractility. TT organization was assessed by confocal microscopy, and STORM images were captured to measure ryanodine receptor (RyR2) cluster number and size, and L-type Ca2+ channel (LTCC, Cav1.2) co-localization. Expressed genes including two integral TT proteins, junctophilin-2 (Jph-2) and bridging integrator-1 (BIN1), were analyzed in left ventricular (LV) tissues and cultured CM using qPCR and RNA sequencing.The T3 dosage used normalized serum T3, and reversed adverse effects of TH deficiency on in vivo measures of cardiac function. Recordings of isolated CM indicated that T3 increased rates of Ca2+ release and re-uptake, resulting in increased velocities of sarcomere shortening and re-lengthening. TT periodicity was significantly decreased, with reduced transverse tubules but increased longitudinal tubules in TH-deficient CMs and LV tissue, and these structures were normalized by T3 treatment. Analysis of STORM data of PTU myocytes showed decreased RyR2 cluster numbers and RyR localizations within each cluster without significant changes in Cav1.2 localizations within RyR clusters. T3 treatment normalized RyR2 cluster size and number. qPCR and RNAseq analyses of LV and cultured CM showed that Jph2 expression was T3-responsive, and its increase with treatment may explain improved TT organization and RyR-LTCC coupling.