Propylthiouracil Induced Rat Model Reflects Heterogeneity Observed in Clinically Non-Obese Subjects with Nonalcoholic Fatty Liver Disease.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing, affecting up to 30% of the population, with approximately 20% of cases occurring in non-obese individuals. The recent shift to the term metabolic dysfunction-associated steatosis liver disease (MASLD) highlights the disease's heterogeneity. However, there are no well-established animal models replicating non-obese NAFLD (NO-NAFLD). This study aimed to evaluate the relevance of the high-fat diet (HFD) combined with the propylthiouracil (PTU)-induced rat model in mimicking the histopathology and pathophysiology of NO-NAFLD. We first analyzed metabolic and clinical parameters between NO-NAFLD patients (Average BMI = 21.96 kg/m2) and obese NAFLD patients (Average BMI = 29.7 kg/m2). NO-NAFLD patients exhibited significantly higher levels of carnitines, phospholipids, and triglycerides. In the animal model, we examined serum lipid profiles, liver inflammation, histology, and transcriptomics. Hepatic steatosis in the HFD+PTU model at week 4 was comparable to that of the HFD model at week 8. The HFD+PTU model showed higher levels of carnitines, phospholipids, and triglycerides, supporting its relevance for NO-NAFLD. Additionally, the downregulation of lipid synthesis-related genes indicated differences in lipid accumulation between the two models. Overall, the HFD+PTU-induced rat model is a promising tool for studying the molecular mechanisms of NO-NAFLD.

The Downregulation of the Liver Lipid Metabolism Induced by Hypothyroidism in Male Mice: Metabolic Flexibility Favors Compensatory Mechanisms in White Adipose Tissue.

In mammals, the maintenance of energy homeostasis relies on complex mechanisms requiring tight synchronization between peripheral organs and the brain. Thyroid hormones (THs), through their pleiotropic actions, play a central role in these regulations. Hypothyroidism, which is characterized by low circulating TH levels, slows down the metabolism, which leads to a reduction in energy expenditure as well as in lipid and glucose metabolism. The objective of this study was to evaluate whether the metabolic deregulations induced by hypothyroidism could be avoided through regulatory mechanisms involved in metabolic flexibility. To this end, the response to induced hypothyroidism was compared in males from two mouse strains, the wild-derived WSB/EiJ mouse strain characterized by a diet-induced obesity (DIO) resistance due to its high metabolic flexibility phenotype and C57BL/6J mice, which are prone to DIO. The results show that propylthiouracil (PTU)-induced hypothyroidism led to metabolic deregulations, particularly a reduction in hepatic lipid synthesis in both strains. Furthermore, in contrast to the C57BL/6J mice, the WSB/EiJ mice were resistant to the metabolic dysregulations induced by hypothyroidism, mainly through enhanced lipid metabolism in their adipose tissue. Indeed, WSB/EiJ mice compensated for the decrease in hepatic lipid synthesis by mobilizing lipid reserves from white adipose tissue. Gene expression analysis revealed that hypothyroidism stimulated the hypothalamic orexigenic circuit in both strains, but there was unchanged melanocortin 4 receptor (Mc4r) and leptin receptor (LepR) expression in the hypothyroid WSB/EiJ mice strain, which reflects their adaptability to maintain their body weight, in contrast to C57BL/6J mice. Thus, this study showed that WSB/EiJ male mice displayed a resistance to the metabolic dysregulations induced by hypothyroidism through compensatory mechanisms. This highlights the importance of metabolic flexibility in the ability to adapt to disturbed circulating TH levels.

The Effects of Anti-thyroid Drugs on Lipoproteins and Insulin Resistance in Graves' Disease: A Randomized Clinical Trial.

Objective: Graves' disease (GD) is characterized by thyroid overactivity. Anti-thyroid drugs (ATDs), such as propylthiouracil (PTU) and methimazole (MMI), are commonly used for GD treatment, and studies have suggested a link between these drugs and elevated lipoprotein levels. However, data on their effects on lipoproteins, insulin resistance, or low-density lipoprotein receptor (LDL-R) levels are lacking, both in Indonesia and in other countries. This study investigated changes in lipoproteins, LDL-R, and insulin resistance markers with ATD treatment. Methods: This study is a secondary analysis of a randomized clinical trial entitled "The Differential Effects of Propylthiouracil and Methimazole as Graves' Disease Treatment on Vascular Atherosclerosis Markers" conducted in Jakarta, Indonesia. Thirty-seven newly diagnosed GD patients received MMI or PTU for 3 months. Results: After 3 months of ATD treatment, LDL-R levels significantly decreased compared to baseline (197 vs. 144 ng/mL, p<0.001), while most lipoproteins, including TC, LDL-C, HDL-C, non-HDL-C, the cholesterol ratio, and the LDL-C/HDL-C ratio, increased. Unexpectedly, neither the PTU nor MMI groups showed an increased dyslipidemia prevalence. Although body mass index increased significantly and fasting plasma glucose decreased slightly, no significant post-treatment change in insulin resistance was observed. The study received ethical approval from the Ethics Committee of the Faculty of Medicine, Universitas Indonesia (ref KET-784/UN.2.F1/ETIK/PPM.00.02/2019) and was registered on clinicaltrials.gov (NCT05118542). Conclusion: ATD treatment for GD led to a significant increase in total cholesterol, LDL-cholesterol, and high-density lipoprotein-cholesterol levels, along with a reduction in LDL-R levels. Both PTU and MMI showed similar effects. These findings provide valuable insights into the effects of ATDs on lipoproteins and insulin resistance in GD patients. Trial Registration: ClinicalTrials.gov Identifier: NCT05118542.

Comparison of drug-induced liver injury risk between propylthiouracil and methimazole: A quantitative systems toxicology approach.

Propylthiouracil (PTU) and methimazole (MMI), two classical antithyroid agents possess risk of drug-induced liver injury (DILI) with unknown mechanism of action. This study aimed to examine and compare their hepatic toxicity using a quantitative system toxicology approach. The impact of PTU and MMI on hepatocyte survival, oxidative stress, mitochondrial function and bile acid transporters were assessed in vitro. The physiologically based pharmacokinetic (PBPK) models of PTU and MMI were constructed while their risk of DILI was calculated by DILIsym, a quantitative systems toxicology (QST) model by integrating the results from in vitro toxicological studies and PBPK models. The simulated DILI (ALT >2 × ULN) incidence for PTU (300 mg/d) was 21.2%, which was within the range observed in clinical practice. Moreover, a threshold dose of 200 mg/d was predicted with oxidative stress proposed as an important toxic mechanism. However, DILIsym predicted a 0% incidence of hepatoxicity caused by MMI (30 mg/d), suggesting that the toxicity of MMI was not mediated through mechanism incorporated into DILIsym. In conclusion, DILIsym appears to be a practical tool to unveil hepatoxicity mechanism and predict clinical risk of DILI.

An Unusual Presentation of Propylthiouracil-Induced Immunoglobulin A Vasculitis With Positive Anti-proteinase-3 and Anti-myeloperoxidase Antibodies.

Propylthiouracil (PTU) has been identified as a known cause of anti-neutrophil cytoplasmic antibodies-associated vasculitis. However, the association between PTU and immunoglobulin A (IgA) vasculitis remains uncertain due to its rarity and diverse clinical presentation. Here, we report the case of a 57-year-old female with a past medical history of chronic leukopenia and Graves' disease treated with PTU that presented with pancytopenia and widespread non-blanching ecchymoses on the bilateral legs. A punch biopsy of the medial leg demonstrated IgA vasculitis and autoimmune antibody analysis revealed increased levels of anti-proteinase 3 antibodies compared to anti-myeloperoxidase antibodies. These findings led to the diagnosis of PTU-induced IgA vasculitis. Following the discontinuation of PTU, there was marked improvement in the appearance of the patient's cutaneous manifestations and hematological indices.

Diagnostic Dilemma of a Complex Case of Cerebral Vasculitis: A Rare Probable Drug-Induced Antineutrophil Cytoplasmic Antibody-Associated Vasculitis With Large Vessel Involvement.

A case of a 43-year-old male with a history of Graves' disease treated with propylthiouracil was investigated for vasculitis and lymphoproliferative disease. However, his clinical picture was complicated by recurrent episodes of neurological symptoms resembling stroke syndrome, which widened the breadth of the diagnostic workup. Extensive investigations, including imaging and biopsies, excluded other possibilities. The patient was treated as probable cerebral vasculitis after identifying new narrowing in the left middle cerebral artery and was treated with pulsed intravenous methylprednisolone, followed by high-dose oral prednisolone and cyclophosphamide. Repeated brain imaging showed further narrowing of the large vessels, which reaffirmed the likelihood of vasculitis necessitating continuation of induction therapy with further maintenance treatment, which led to stabilization of neurological burden and symptom recovery. This case elucidates complexities in reaching the diagnosis of drug-induced antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, which can present heterogeneously and mimic other clinical entities such as stroke.

Propylthiouracil-Induced Anti-Neutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis Presenting with Multiple Sterile Abscesses, Mononeuritis Multiplex, and Splenic Vein Thrombosis: A Case Report and Literature Review.

Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) represents a rare group of disorders, that traditionally includes diseases like granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA), and microscopic polyangiitis (MPA). However, AAV can also be triggered by medications such as propylthiouracil (PTU). This article focuses on the subset of drug-induced AAV. We examine how certain medications, notably PTU, can provoke an AAV response, detailing the pathophysiological mechanisms and clinical implications. A 72-year-old female being treated with PTU presented with bilateral hand abscesses, generalized weakness, and frequent falls. Despite initial treatments, her condition worsened, prompting consideration of AAV secondary to PTU. Following appropriate diagnostic procedures and initiation of treatment, including steroids, heparin, and rituximab, the patient showed significant improvement. PTU-induced AAV is a serious, albeit rare, side effect characterized by anti-neutrophil cytoplasmic autoantibodies, with the potential for varied organ involvement and generally a better prognosis than primary AAV. The atypical presentation in this case underscores the importance of clinician vigilance and awareness, ensuring timely diagnosis and appropriate management of this complex condition.

Dose-dependent incidence of agranulocytosis in patients treated with methimazole and propylthiouracil.

Agranulocytosis is a serious adverse effect of methimazole (MMI) and propylthiouracil (PTU), and although there have been reports suggesting a dose-dependent incidence in relation to both drugs, the evidence has not been conclusive. The objective of our study was to determine whether the incidences of agranulocytosis induced by MMI and PTU exhibit dose-dependency. The subjects were 27,784 patients with untreated Graves' disease, 22,993 of whom were on an antithyroid drug treatment regimen for more than 90 days. Within this subset, 18,259 patients had been treated with MMI, and 4,734 had been treated with PTU. The incidence of agranulocytosis according to dose in the MMI group was 0.13% at 10 mg/day, 0.20% at 15 mg/day, 0.32% at 20 mg/day, and 0.47% at 30 mg/day, revealing a significant dose-dependent increase. In the PTU group, there were 0 cases of agranulocytosis at doses of 125 mg/day and below, 0.33% at 150 mg/day, 0.31% at 200 mg/day, and 0.81% at 300 mg/day, also revealing a significant dose-dependent increase. The incidence of agranulocytosis at MMI 15 mg and PTU 300 mg, i.e., at the same potency in terms of hormone synthesis inhibition, was 0.20% and 0.81%, respectively, and significantly higher in the PTU group. Our findings confirm a dose-dependent increase in the incidence of agranulocytosis with both drugs, but that at comparable thyroid hormone synthesis inhibitory doses PTU has a considerably higher propensity to induce agranulocytosis than MMI does.

Differential Activation of TAS2R4 May Recover Ability to Taste Propylthiouracil for Some TAS2R38 AVI Homozygotes.

Bitterness from phenylthiocarbamide and 6-n-propylthiouracil (PROP) varies with polymorphisms in the TAS2R38 gene. Three SNPs form two common (AVI, PAV) and four rare haplotypes (AAI, AAV, PVI, and PAI). AVI homozygotes exhibit higher detection thresholds and lower suprathreshold bitterness for PROP compared to PAV homozygotes and heterozygotes, and these differences may influence alcohol and vegetable intake. Within a diplotype, substantial variation in suprathreshold bitterness persists, and some AVI homozygotes report moderate bitterness at high concentrations. A second receptor encoded by a gene containing a functional polymorphism may explain this. Early work has suggested that PROP might activate TAS2R4 in vitro, but later work did not replicate this. Here, we identify three TAS2R4 SNPs that result in three diplotypes-SLN/SLN, FVS/SLN, and FVS/FVS-which make up 25.1%, 44.9%, and 23.9% of our sample. These TAS2R4 haplotypes show minimal linkage disequilibrium with TAS2R38, so we examined the suprathreshold bitterness as a function of both. The participants (n = 243) rated five PROP concentrations in duplicate, interleaved with other stimuli. As expected, the TAS2R38 haplotypes explained ~29% (p < 0.0001) of the variation in the bitterness ratings, with substantial variation within the haplotypes (AVI/AVI, PAV/AVI, and PAV/PAV). Notably, the TAS2R4 diplotypes (independent of the TAS2R38 haplotypes) explained ~7-8% of the variation in the bitterness ratings (p = 0.0001). Given this, we revisited if PROP could activate heterologously expressed TAS2R4 in HEK293T cells, and calcium imaging indicated 3 mM PROP is a weak TAS2R4 agonist. In sum, our data are consistent with the second receptor hypothesis and may explain the recovery of the PROP tasting phenotype in some AVI homozygotes; further, this finding may potentially help explain the conflicting results on the TAS2R38 diplotype and food intake.

Development and validation of UPLC-MS/MS method for 5-Fluorouracil quantification in dried blood spot.

5-Fluorouracil is an antimetabolite drug indicated for cancer treatment. Therapeutic drug monitoring of 5-Fluorouracil is necessary because 5-Fluorouracil has narrow therapeutic window and its concentration in blood is affected by individual conditions, like gene polymorphisms. Dried Blood Spot (DBS) is one of the biosampling methods used for therapeutic drug monitoring. Asides from reducing patients' discomfort, the use of DBS can increase 5-Fluorouracil stability by stopping the enzymes activity in blood. Therefore, this research developed a method to monitor 5-Fluorouracil levels in DBS using ultra-high performance liquid chromatography-tandem mass spectrometry. Sample preparation was carried out by extracting DBS using 2-Propanol: ethyl acetate (16:84). Reconstituted samples were analyzed using ultra high performance liquid chromatography equipped with Acquity® UPLC BEH C18 column (2.1 × 100 mm; 1.7 µm). The ionization process was carried out in negative electrospray ionization mode. Multiple Reaction Monitoring (MRM) values were set at m/z 128.97 > 41.82 for 5-Fluorouracil and 168.97 > 57.88 for propylthiouracil as the internal standard. Optimum analytical conditions were obtained with acetonitrile-ammonium acetate 1 mM (95:5) as mobile phase, flow rate of 0.15 mL/min, and column temperature of 40 °C. The lowest level of quantification obtained from this method was 0.1 µg/mL with a calibration curve range of 0.1 µg/mL-60 µg/mL. This method was proven to be valid according to the requirements set by the US Food and Drug Administration and the European Medicines Agency.

Ameliorative effect of ferulic acid on thyroid dysfunction against propyl-thiouracil induced hypothyroid rats.

PURPOSE: Hypothyroidism is an endocrine disorder characterised by decreased T3, T4 and increased TSH levels. This study aims to examine the potential effects of Ferulic acid (FA) on rats with hypothyroidism induced by propylthiouracil through the estimation of biochemical parameters and histopathological studies. METHODS: Twenty-five female wistar rats were allocated into five groups: Control group [1% CMC, p.o.], Disease group [PTU-50 mg/kg, p.o.], [Levothyroxine (LT4) group - 20 µg/kg, p.o. + PTU-50 mg/kg, p.o.], [FA -25 mg/kg, p.o. + PTU-50 mg/kg, p.o.] and [FA 50 mg/kg, p.o. + PTU-50 mg/kg, p.o.]. On 15th day blood was collected and serum was separated for estimation of biochemical parameters, liver and kidney homogenate was utilised for the estimation of oxidative stress markers and the thyroid gland was dissected to examine histological features. RESULTS: PTU administration for 14 days showed a substantial decline in T3 and T4 and increases in TSH levels. PTU-administered rats significantly increased TC, TG and LDL levels, and decreased HDL levels. AST, ALT, urea, creatinine, and IL-6 were determined and these levels were significantly altered in PTU-induced hypothyroid group. In hypothyroid rats MDA, NO, GSH and SOD levels were significantly altered. However, treatment with FA for 14 days attenuated PTU-induced alterations. Furthermore, FA improves the histological changes of the thyroid gland. CONCLUSION: In conclusion, FA treatment showed a protective effect against hypothyroidism by stimulating the thyroid hormones through the activation of thyroid peroxidase enzyme and improving thyroid function. In addition, FA diminished the increase in lipids, liver and kidney markers, oxidative stress and inflammation.

An Autopsy Case of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Induced by Propylthiouracil.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a complication caused by antithyroid drugs, particularly propylthiouracil (PTU). Most patients experience organ failure due to the affects of the treatment regimen. We herein report the case of an 89-year-old woman whose severe AAV induced by PTU resulted in various instances of organ failure that eventually led to death after 9 years of PTU therapy. During autopsy, we identified five types of organ failure. As AAV is a potentially fatal disease, the development of various vasculitis symptoms during PTU therapy should therefore be carefully monitored.

Influence of taste sensitivity on preference and sensory perception of mezcal.

The perception of orosensory stimuli, which includes flavor, can vary between individuals. These individual variations in oral sensations can be due to genetic factors and it would appear that they can predict food liking and consumption. The most studied source of variation is related to bitter taste perception associated with 6-n-propylthiouracil (PROP) responsiveness. In this context, humans can be classified as non-tasters (NT), medium tasters (MT) and supertasters (ST). Evidence suggests that genetic variation in bitter taste perception contributes to differences in the level of irritation caused by alcohol perception in solutions. The aim of this investigation was to study the bitter taste sensitivity among a group of mezcal consumers and its relationship with sensory perception and preference through PROP taster status. The tests were carried out in the state of Oaxaca in Mexico. A total of 83 mezcal consumers were classified by their PROP taster status and were asked to provide sensory descriptors for five mezcal samples and rate them according to the level of liking. The three-solution test was used to classify the subjects as NT, MT, and ST, while a Multiple Factor Analysis (MFA) was used to visualize the sensory descriptors provided by these three groups. The proportion of MT subjects was 16%, while the proportion of NT and ST was 34 and 51%, respectively. The MT provided higher liking ratings for at least three mezcal samples. According to MFA, the mezcal samples were organized in a similar configuration along the two dimensions. However, NT mentioned a limited number of simple terms (strong flavor, tasteless, burning in the mouth) to describe the samples, whereas ST used a more complex vocabulary (astringent, smoky, scratchy aftertaste). These data suggest that the preference for mezcal samples was similar for non-taster and supertasters, but there are indications that the sensory perception of mezcal differs between groups.

Propylthiouracil-Induced Antineutrophil Cytoplasmic Antibody-Associated Vasculitis with Overlap IgA Nephropathy: A Case Report.

Background: The anti-thyroid medication propylthiouracil (PTU) is a recognised cause of drug-induced antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Pauci-immune crescentic glomerulonephritis is the characteristic feature of this condition on renal biopsy. We present a case of PTU-induced AAV with the unusual histological finding of overlap IgA nephropathy (IgAN) in a young female with treatment-resistant Graves' disease. Case Report: A 26-year-old female presented with an acute kidney injury, macroscopic haematuria, and proteinuria 14 months after starting PTU for Graves' disease. She had a history of established thyroid eye disease and a previous severe adverse reaction to carbimazole. Her autoantibodies were strongly positive for myeloperoxidase-ANCA (199 U/mL). Renal biopsy demonstrated both necrotising crescentic glomerulonephritis and prominent (3+) mesangial deposition of IgA. She was treated with glucocorticoids and rituximab with sustained improvement in her renal function but persisting mild proteinuria and microscopic haematuria. PTU was ceased following a dose of radioactive iodine (RAI). Twelve months post-RAI, her Graves' orbitopathy remained stable, and her thyroid function was gradually normalising. Conclusion: This was a case of drug-induced AAV with histological features of overlap IgAN. We suggest that this patient had pre-existing subclinical IgAN and then developed AAV secondary to PTU. The management of her thyroid disease was complex given the PTU-induced vasculitis, previous reaction to carbimazole, the risks of a thyroidectomy on immunosuppression, and the possible worsening of her eye disease with RAI. The glucocorticoids and Rituximab prescribed for vasculitis may have prevented the progression of her Graves' orbitopathy after RAI.

Intermittent Fasting and Vitamin E Supplementation Attenuates Hypothyroidism-Associated Ophthalmopathy.

Visualization is a complex-integrated procedure of the eyes and brain that allows to see this colorful world. Hypothyroidism-associated ophthalmopathy (HAO), often known as dry eyes, swelling around the eyes, blurred vision, glaucoma, and cataracts, are some eye-related issues caused by hypothyroidism. Yet there is no permanent cure for hypothyroidism; taking medicine throughout life is the only solution to keep its harmful effects under control. This study used intermittent fasting (IF) and vitamin E (Vit.E) supplementation to prevent hypothyroidism-associated ophthalmopathy. This study hypothesized that intermittent fasting-like diet regimens and vitamin supplementation should reduce the propagation of HAO by its antioxidant potential. In the present study, experimental animals are divided into five groups: normal, hypothyroidism control, dual, Vit. E, and IF. Hypothyroidism is generated in the experimental groups by taking propylthiouracil (PTU) for 24 days while also taking IF and Vit. E supplements. The hypothyroid-induced experimental animals demonstrated an increase in IOP and lipid peroxidation while thyroid hormone levels depicted a massive decline which is a clear denotation of the effects of the thyroid on eyes and lifestyle. Ancient Ayurveda inspires these proposed therapies and has successfully reduced all the damage to the thyroid gland and the eye.

Comparison of agranulocytosis and anti-neutrophil cytoplasmic antibody-associated vasculitis caused by two antithyroid drugs: A pharmacovigilance study using the WHO international database.

BACKGROUND: Methimazole (MMI) and propylthiouracil (PTU) are commonly used for patients with thyrotoxicosis. Agranulocytosis and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is associated with high morbidity and mortality, requiring appropriate interventions. In this study, we compared adverse drug effects associated with MMI and PTU using a real-world large pharmacovigilance database. METHODS: We searched all Individual Case Safety Reports reported to be associated with MMI and PTU, from VigiBase between 1967 and June 2, 2021. We conducted disproportionality analysis (case/non-case analysis) to analyze the difference in reported adverse drug reactions (ADRs) between antithyroid drugs (case) and the entire database (non-cases). We further analyzed information for the cases of agranulocytosis and AAV. RESULTS: Among 11 632 cases of ADRs reported after MMI intake, agranulocytosis occurred in 1633 cases and AAV occurred in 41 cases. For 5055 cases of ADRs reported after PTU intake, agranulocytosis occurred in 459 cases and AAV occurred in 110 cases. Agranulocytosis occurred after a median of 28 days after PTU intake and 33 days after MMI intake. More than 95% of the agranulocytosis cases were classified as serious, but most of them (65.1% for PTU and 70.4% for MMI) were reported to have recovered after dechallenge actions; mostly drug withdrawal. AAV occurred after a median of 668 days after PTU intake, and 1162 days after MMI intake. CONCLUSIONS: This is a pharmacoepidemiological study investigating agranulocytosis and AAV caused by MMI and PTU. Through this research, we could provide more specific insights into a safe prescription of antithyroid drugs in a real-world setting.

Selenium protects against nesfatin-1 modulation of the hypothalamic-pituitary-testicular axis during hypothyroidism in male rats.

Normal gonadal function can be disrupted by hypothyroidism. Hypothyroidism disturbs testicular function directly and centrally by affecting the hypothalamic-pituitary-testicular axis with unclear mechanism. As nesfatin-1 neurons co-localized with TRH and GnRH neurons in the hypothalamus, it could play a role in centrally hypothyroidism induced testicular dysfunction. Selenium (Se), by affecting thyroid iodide supply, could relieve these disturbances. So, we aim to identify the role of nesfatin-1 as a link between testicular dysfunction and hypothyroidism through modulating the MAPK/ERK pathway while discussing the possible role of Se in alleviating hypothyroidism and associated testicular damage. Forty male rats were divided equally into: Control: distilled water, Se: Se orally, Propylthiouracil (PTU): PTU orally, PTU + Se: Se with PTU orally. Serum thyroid function, gonadal hormones, nesfatin-1, testicular redox status, sperm analysis, brain tissue GnRH, nucleobindin 2-derived polypeptide, pMAPK/ERK gene expression, histological changes and immunohistochemical expression of testicular proliferating cell antigen (PCNA) were done. PTU induced hypothyroidism and reduction of gonadal hormones which both were correlated with reduced nesfatin-1. There was testicular stress with reduced GnRH, NUCB2, pMAPK/ERK gene expression, and PCNA immunopositive cells. These parameters were reversed by Se. Nesfatin-1 could be the central link between hypothyroidism and disturbances of the hypothalamic pituitary testicular axis.

Carbimazole-Resistant Grave's Thyrotoxicosis is a Diagnostic and Therapeutic Dilemma, Case Report with Literature Review.

Background: Carbimazole (CBZ) (or methimazole) is the most used drug inducing and maintaining remission in thyrotoxicosis, especially Grave's disease (GD). Rarely, situations arise when patients do not respond to recommended or even supratherapeutic doses of CBZ. It poses a challenge to diagnose drug resistance and ultimately manage hyperthyroidism, which can otherwise be fatal if left untreated. Propylthiouracil (PTU) has been used as an alternative in such patients amid increased side effect risks. Additionally, definitive therapy has been recommended with ablation or surgery. However, the best modality of inducing euthyroidism in drug-resistant patients is yet to be established. On literature search, twenty similar cases were found in the literature search. This study summarizes the past literature with addition of a new case of anti-thyroid drug resistant (ATDR) GD. Case Presentation: A 34-year-old female presented with a 5-day history of progressively worsening fatigue, heat intolerance, sweating, and palpitations. She was diagnosed with GD based on her thyroid function tests (TFTs) and started on CBZ and propranolol. Despite being compliant with CBZ 20 mg once daily and then twice daily, her TFTs remained unchanged for 4 months. However, patient revisited the emergency with continued thyrotoxicosis and unchanged TFTs. Her dose was eventually increased to 20 mg thrice daily, and administration under supervision did not improve her TFTs. The patient was shifted to PTU 150 mg thrice daily with steroids, with minimal improvement. The patient eventually underwent thyroidectomy to avoid long-term PTU use. Conclusion: ATDR GD is rare and remains a diagnostic and therapeutic challenge. Optimal management should focus on carefully excluding other possibilities and shared decision-making in its management. Most patients may require definitive therapy; hence, arrangements should be made timely with simultaneous attempts to reduce the thyrotoxic state, which otherwise poses a continued threat to patients' life with potentially serious complications.

Therapeutic Management and Long-Term Outcome of Hyperthyroidism in Patients with Antithyroid-Induced Agranulocytosis: A Retrospective, Multicenter Study.

BACKGROUND: Antithyroid drug-induced agranulocytosis (AIA) (neutrophils <500/µL) is a rare but serious complication in the treatment of hyperthyroidism. METHODOLOGY: Adult patients with AIA who were followed up at 12 hospitals in Spain were retrospectively studied. A total of 29 patients were studied. The etiology of hyperthyroidism was distributed as follows: Graves' disease (n = 21), amiodarone-induced thyrotoxicosis (n = 7), and hyperfunctioning multinodular goiter (n = 1). Twenty-one patients were treated with methimazole, as well as six patients with carbimazole and two patients with propylthiouracil. RESULTS: The median (IQR) time to development of agranulocytosis was 6.0 (4.0-11.5) weeks. The most common presenting sign was fever accompanied by odynophagia. All of the patients required admission, reverse isolation, and broad-spectrum antibiotics; moreover, G-CSF was administered to 26 patients (89.7%). Twenty-one patients received definitive treatment, thirteen patients received surgery, nine patients received radioiodine, and one of the patients required both treatments. Spontaneous normalization of thyroid hormone values occurred in six patients (four patients with amiodarone-induced thyrotoxicosis and two patients with Graves' disease), and two patients died of septic shock secondary to AIA. CONCLUSIONS: AIA is a potentially lethal complication that usually appears around 6 weeks after the initiation of antithyroid therapy. Multiple drugs are required to control hyperthyroidism before definitive treatment; additionally, in a significant percentage of patients (mainly in those treated with amiodarone), hyperthyroidism resolved spontaneously.

Curcumin exerts protective effects on the thyroid gland in propylthiouracil-treated rats.

INTRODUCTION: Among the plant ingredients, some compounds interfere with the functions of the thyroid gland. However, there is limited research on the effect of curcumin (CMN) on the functions of this gland. The aim of this study was to analyze the effect of CMN on morphology, histochemical reactivity of cytochrome c oxidase (CCO) and secretion functions of the thyroid gland under conditions of hypothyroidism induced by propylthiouracil (PTU). MATERIAL AND METHODS: The rats were treated for 30 days by gavage with CMN (100 mg/kg b.w.) and/or PTU (1 mg/kg b.w.). Control rats received vehicle only. Histomorphometric tests were performed on the thyroid glands, cytochrome c oxidase activity was visualized using the histochemical method, and the levels of thyroid hormones were measured using the radioimmunoassay method. RESULTS: Rats receiving PTU showed compensatory changes in their thyroid glands, including a significant increase in thyroid epithelium height, a decrease in colloid volumen density, a decrease in the percentage of small follicles, an increase in medium-sized follicles compared to the control group, as well as a significant increase in CCO histochemical reactivity in the columnar epithelium and a decrease in FT4 serum level compared to the control group. The administration of CMN reversed these adverse changes caused by PTU. The PTU + CMN group exhibited a significant decrease in the height of the thyroid follicle epithelium compared to the PTU group. The percentage of small and medium-size follicles in the CMN + PTU group did not differ from the control group. Furthermore, CCO reactivity in the cubic epithelium and serum FT4 levels increased compared to the PTU group. Administration of CMN alone resulted in a significant increase in FT4 levels compared to the control group. CONCLUSIONS: The administration of CMN to rats with induced hypothyroidism resulted in a reduction of hyperplasia, hypertrophy, and increase in secretory activity of the thyroid gland. These findings suggest the protective effect of CMN against induced hypothyroidism.