In recent years, thyroid nodule diagnosis and classification have been updated by two major developments: the fifth edition of the World Health Organization (WHO) Classification of Endocrine and Neuroendocrine Tumors classification 2022), which includes thyroid neoplasms, and the third edition of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) (2023). Importantly, these classification systems converge in terminology, improving clinicopathologic correlation between fine-needle aspiration cytology (FNAC) and surgical pathology and supporting more consistent risk-based management. In parallel, molecular testing has assumed a growing role, particularly for indeterminate FNA categories, as reflected in contemporary practice recommendations. Moreover, the 2025 American Thyroid Association guidelines recalibrate postoperative risk stratification in differentiated thyroid cancer by reasserting histopathology as the cornerstone of clinical decision-making. In this review, we summarize key updates in thyroid FNAC reporting, histopathologic classification, and the practical application of molecular pathology for the evaluation and management of thyroid nodules.
With age, the incidence of stress-related pathologies, in the etiopathogenesis of which endocrine dysfunctions play an important role, increases. This review presents data on the study of age-related features in functioning of the key adaptive neuroendocrine axes (hypothalamic-pituitary-adrenal, HPA axis and hypothalamic-pituitary-thyroid, HPT axis) in individuals that differ in adaptive behavior with an emphasis on experimental studies in nonhuman primates. Studies have shown pronounced age-related differences in the functioning of HPA axis in the animals with depression-like and anxiety behavior (DAB): impairment negative feedback regulation with an increase of corticotropin and cortisol level in the afternoon - night time, a higher response to acute stress exposure, and sensitization of the hypothalamic-pituitary axis. A decrease secretion of thyroxine and its response to thyrotropin-releasing hormone (TRH) or thyrotropin administration with increased sensitivity of the adenohypophysis to TRH were identified in old DAB animals. In addition, older overweight DAB monkeys exhibited increased insulin resistance and reduced insulin and triglycerides secretion. Thus, age-related changes of HPA and HPT axes in DAB monkeys are associated with more pronounced endocrine dysfunctions as compared with young individuals, leading to hormonal imbalance that may contribute to the development of severe age-related pathology.
Neuroendocrine tumors (NETs) constitute a heterogeneous and predominantly malignant group of neuroendocrine neoplasms that arise from endocrine cells dispersed throughout the body. Their clinical presentation, biological behavior, prognosis, and therapeutic management vary considerably depending on the primary tumor location and hormonal activity. Despite substantial progress in understanding the biology of NETs, identifying reliable molecular biomarkers for diagnosis, prognosis, and prediction of treatment response remains a major challenge. Increasing attention has therefore been devoted to the molecular characterization of NETs, with particular focus on recurrent genetic alterations that may contribute to tumor initiation and progression. In this review, we summarize current knowledge and recent findings referring to certain genes involved in the tumorigenesis of pancreatic and intestinal neuroendocrine tumors. We chose the genes based on data from the COSMIC (Catalogue of Somatic Mutations in Cancer) database, which compiles somatic mutations identified across numerous human cancers. We outline the biological functions of these changes and discuss their potential prognostic and predictive role as molecular markers. We also discuss their clinical relevance in both sporadic and familial forms of NETs, alongside their implications for future research and personalized management strategies.
Paraneoplastic endocrine syndromes (PESs) are hormonal disturbances associated with malignancies that result from tumor-related production of hormone-like substances, immune-mediated mechanisms, or dysregulated signaling pathways. While they are well recognized in lung and neuroendocrine cancers, their relevance in gastrointestinal tumors remains less clearly defined. This narrative review synthesizes current knowledge on paraneoplastic endocrine manifestations in gastrointestinal malignancies, based on a structured search of the literature in major databases, including PubMed, Scopus, and Web of Science. The analysis focuses on clinically relevant syndromes such as hypercalcemia, Cushing-like manifestations, disorders of water balance, hypoglycemia, and acromegaly, with emphasis on underlying mechanisms, associated tumor types, diagnostic approaches, and therapeutic considerations. Available evidence indicates that gastrointestinal tumors can produce a range of biologically active substances, leading to diverse endocrine manifestations that may precede tumor detection and influence disease course. Among these, hypercalcemia and Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) are among the most frequently reported, while other syndromes, such as ectopic Cushing syndrome or tumor-related hypoglycemia, are less common but often associated with more severe clinical outcomes. Recognition of these manifestations has direct clinical implications, as they may support earlier diagnosis, contribute to prognostic assessment, and guide therapeutic management. Improved awareness and a multidisciplinary approach remain essential for optimizing outcomes in patients with gastrointestinal malignancies.
Short-term preoperative endocrine therapy (ET) is increasingly used in oestrogen receptor (ER)-positive, HER2-negative breast cancer as a functional test of endocrine sensitivity. We aimed to characterise histomorphological and immunophenotypic changes following preoperative ET and to identify predictors of endocrine response, defined as post-treatment Ki67 ≤ 10%. In this retrospective single-centre study, 180 patients treated with short-course preoperative ET (median duration 29 days) were compared with 151 patients undergoing primary surgery without ET. Paired biopsy and resection specimens were assessed for histological features, stromal proportion, stromal tumour-infiltrating lymphocytes (strTILs) and expression of ER, progesterone receptor (PR), HER2 and Ki67. Genomic risk was determined using the MammaPrint assay. Preoperative ET was associated with a significant reduction in tumour proliferation, with 73.9% of cases showing post-treatment Ki67 ≤ 10% compared with none in controls (P < 0.001). Histological grade decreased in 36.7% of ET-treated tumours versus 7.9% of controls (P < 0.001), predominantly reflecting reduced mitotic activity. ER expression remained stable, whereas PR expression decreased more frequently following ET (P < 0.001) and was independently associated with Ki67-defined response. HER2-low status was more frequently observed after ET (P < 0.001), but HER2 expression and microenvironmental parameters, including strTILs, were not associated with response. High genomic risk was independently associated with a lower likelihood of achieving post-treatment Ki67 ≤ 10% (P < 0.001). Short-course preoperative ET induces rapid and reproducible morphological and immunophenotypic changes in ER-positive, HER2-negative breast cancer. Ki67-defined response is associated with genomic risk and PR expression, whereas microenvironmental features appear to have limited predictive value.
Current data on neuroendocrine tumors (NETs) of the gallbladder and cystic duct (GB-NETs) are highly limited, and the available evidence, largely derived from cancer registry data, suggests that these tumors exhibit a substantially more aggressive clinical behavior than NETs arising at other anatomical sites. We analyzed 26 GB-NETs. Female-to-male ratio: 1.9:1; median age: 50 years. They were typically incidental small (median: 0.8 cm, range: 0.08-2.3 cm) tumors, with 81% classified as grade 1 (G1), either pT1 or pT2, and 38% showing a paraganglioma-like pattern at least focally. Body/fundus tumors were mostly polypoid while neck/cystic duct examples showed mural growth. Symplastic pleomorphism was found in 11%, pseudoglandular structures in 50% and psammomatous intraluminal calcifications in 15%. Pancreatic polypeptide, somatostatin, and gastrin were detected in 5/7 (71%), 5/8 (62.5%), and 4/7 (57%) tested cases, respectively. ISLET1 and ARX were diffusely expressed in all 5 tested cases. Cholesterolosis was common, and six appeared to arise within cholesterol polyps. None had any evidence of metastasis and all 12 patients with available follow-up were alive without disease after a median follow-up of 30 months. Critical review of the literature (79 bona-fide GB-NETs) showed that tumors > 2 cm and grade 3 (G3) were enriched among metastatic GB-NETs. In conclusion, GB-NETs are generally indolent neoplasms, in contrast to gallbladder neuroendocrine carcinomas. Tumor size and grade may help predict metastatic potential, while the relatively frequent paraganglioma-like morphology, often associated with diffuse somatostatin expression, can represent a diagnostic pitfall. Their frequent association with cholesterol polyps also suggests a possible etiopathogenetic link.
Declining tissue function and regenerative capacity underlie many chronic diseases. Experimentally establishing the mechanistic basis for such tissue aging presents substantial challenges, given decades-long timescales and multifactorial origins. Epigenetic alterations have been proposed to have a key etiological role, but whether they are correlative or causal remains a key unanswered question, as does their contribution to specific age-related pathologies. Here we describe an epigenetically driven accelerated aging syndrome. We demonstrate that DNMT3A gain-of-function mutations in Heyn-Sproul-Jackson syndrome recapitulate age-related gains in DNA methylation (DNAme), cause multilineage stem cell dysfunction, and phenocopy aspects of aging in humans and mice. We also show that region-specific DNA hypermethylation at lineage-specific genes can explain reduced stem cell output and lineage skewing. Hence, starting from a Mendelian disorder, we implicate DNAme-mediated stem cell dysfunction in the etiology of medically important age-related hematological, bone and metabolic pathologies, which might be targetable by future therapies.
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Male breast cancer (MBC) is uncommon, often diagnosed late and prone to distant metastases. Treating MBC is more challenging than treating female breast cancer. The present study reports a case of end-stage renal disease (ESRD) in a Chinese patient with locally advanced MBC. What distinguishes the present case from previously reported MBCs is the advanced age (90 years), the presence of ESRD with multiple complications and the locally advanced (T4b) ulcerated tumor, a triad rarely documented in the literature. A 90-year-old man presented to the hospital with an itchy, bleeding, ulcerated breast tumor. In addition to ESRD, they had hypertension and urinary retention requiring cystostomy, as well as a 5.0×4.5 cm ulcer on their left breast. A simple left mastectomy was performed as palliative surgery. Postoperative pathology confirmed invasive ductal carcinoma (unspecified type, grade III); immunohistochemistry showed strong estrogen receptor positivity (~95%) and moderate-to-strong progesterone receptor positivity (~10%). After palliative resection, the patient received adjuvant endocrine therapy as scheduled. Due to the systemic condition of the patient and their comorbidities, adjuvant endocrine therapy was chosen over radiation and chemotherapy. The quality of life of the patient improved and recovery was uneventful. In the present case, respecting the preferences of the patient was vital for this very elderly individual with a terminal illness. Striking a balance between tumor control and risk-benefit ratio within a multidisciplinary team framework was essential. A tailored approach based on endocrine and palliative medications should be adopted to improve quality of life and short-term prognosis.
Insulin and glucagon secreted by beta- and alpha-cells of the islets of Langerhans, respectively, regulate tissue glucose uptake, metabolism, and glycolysis. Islets represent around 2% of pancreatic mass but receive around 20% of the arterial blood flow; arteriolar blood entering the islet giving rise to a dense, fenestrated capillary bed enabling rapid glucose sensing and prompt hormone excretion. Local regulation of blood flow within each islet is achieved by contractile pericytes lining the capillaries. Endothelial cells and pericytes contribute to the lineage commitment and maturation of islet endocrine cells in utero, which can be disrupted by maternal under- or over-nutrition. Vascular cells generate the basement membranes juxtaposing endocrine cells and ensure optimal endocrine function. In type 2 diabetes, the intra-islet capillary density is increased but capillary walls are thickened with loss of fenestration and dysregulated hormone release. De-differentiation of pericytes to myofibroblasts causes islet fibrosis. In type 1 diabetes, this pathology is exacerbated by inflammatory cell-derived cytokine action on vascular cells. Pancreatic cancer-associated diabetes (type 3c), as seen with ductal adenocarcinoma, involves fibrotic thickening of the peri-islet basement membrane caused by tumor-derived growth factors. Conversely, insulin secretion may contribute to cancer growth. Therapeutic options to prevent or delay diabetes include maintaining islet vascular function through limiting cellular oxidative stress and inflammation.
Secondary hyperparathyroidism (SHPT) is a major component of chronic kidney disease-mineral and bone disorder (CKD-MBD), reflecting progressive disturbances in mineral metabolism, endocrine signaling, skeletal remodeling, and parathyroid-gland biology. Traditionally, preoperative parathyroid hormone (PTH) has been used primarily as a biochemical threshold for surgical referral. However, persistent PTH elevation in advanced CKD-related SHPT may reflect more than isolated endocrine activity; available evidence suggests it integrates parathyroid-gland remodeling, receptor resistance, skeletal turnover, treatment refractoriness, and systemic CKD-MBD severity. This review summarizes key molecular and cellular mechanisms of progressive SHPT, including diffuse-to-nodular hyperplastic transition, downregulation of calcium-sensing receptor (CaSR) and vitamin D receptor (VDR) signaling, disruption of the fibroblast growth factor 23 (FGF23)-Klotho axis, and activation of transforming growth factor-α (TGF-α)/epidermal growth factor receptor (EGFR) proliferative pathways. Building on this mechanistic framework, we discuss how persistent PTH elevation has been linked to glandular remodeling, resistance to calcimimetic and vitamin D therapy, high-turnover renal osteodystrophy, hungry bone syndrome, altered intraoperative PTH kinetics, postoperative endocrine-skeletal remodeling, and long-term recurrence. Severe SHPT is also increasingly recognized as a systemic CKD-MBD phenotype associated with vascular calcification, cardiovascular risk, metabolic instability, and impaired quality of life. Within this framework, preoperative PTH is best interpreted as an integrated biomarker within a broader assessment of glandular remodeling, skeletal metabolic activity, endocrine resistance, and systemic CKD-MBD biology, rather than as an isolated biochemical threshold.
Polycystic ovary syndrome (PCOS) is characterized by insulin resistance, hyperandrogenism, oxidative stress, and disrupted folliculogenesis. The present study aimed to investigate whether combined alpha-lipoic acid (ALA) and vitamin D therapy exerts synergistic effects on metabolic, oxidative, endocrine, and histomorphological parameters in a letrozole-induced rat model of PCOS. Sixty female Wistar Albino rats were randomly divided into six groups: Control, PCOS, PCOS+Metformin (500 mg/kg/day), PCOS+Vitamin D (1000 IU/kg/day), PCOS + ALA (100 mg/kg/day), and PCOS + ALA+Vitamin D. PCOS was induced with letrozole (1 mg/kg/day) for 21 days, followed by 30 days of treatment. Fasting blood glucose (FBG), insulin, and HOMA-IR were assessed to evaluate metabolic status. Ovarian oxidative stress markers (MDA, SOD, CAT, GSH), serum hormonal parameters (testosterone, LH, FSH, LH/FSH ratio), and detailed histomorphometric analyses were performed. Statistical analyses included one-way and two-way ANOVA. Letrozole administration induced persistent diestrus, hyperandrogenemia, increased ovarian weight, elevated HOMA-IR (6.61 ± 1.18 vs. 2.24 ± 0.42, p < 0.001), and marked oxidative stress (MDA: 5.84 ± 0.72 vs. 2.31 ± 0.34 nmol/mg, p < 0.001). ALA and vitamin D monotherapies significantly improved metabolic, oxidative, and endocrine parameters compared with untreated PCOS rats (p < 0.05). The combination therapy group demonstrated the most pronounced improvements, with HOMA-IR (2.43 ± 0.47), MDA (2.52 ± 0.39 nmol/mg), testosterone (1.29 ± 0.27 ng/mL), and LH/FSH ratio (1.03 ± 0.19) values approaching control levels (all p < 0.01 vs. PCOS). Histologically, combined treatment markedly reduced cystic follicles and restored granulosa and theca thickness. Two-way ANOVA revealed significant interaction effects for HOMA-IR, MDA, testosterone, and LH/FSH ratio (p < 0.05). Combined ALA and vitamin D therapy produced enhanced improvements in insulin resistance, oxidative stress, endocrine imbalance, and ovarian morphology in experimental PCOS. Simultaneous targeting of mitochondrial redox dysfunction and endocrine-metabolic signaling pathways may represent a promising multidimensional therapeutic approach in PCOS.
Granulomatosis with polyangiitis (GPA) is a systemic necrotizing vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA). Although pituitary involvement is rare, it represents a clinically relevant manifestation that may present as a sellar mass mimicking a pituitary neuroendocrine tumour (PitNET), leading to diagnostic delay and inappropriate management. We report the case of a male patient who initially presented at 24 years of age with recurrent epistaxis and nasal crusting, with histopathological evidence of chronic granulomatous inflammation of undetermined aetiology. Four years later, he developed headache, diplopia, bitemporal hemianopia, polyuria, and polydipsia. Magnetic resonance imaging revealed a pituitary mass with suprasellar extension. Endocrine evaluation demonstrated hypopituitarism and arginine vasopressin (AVP) deficiency. The patient underwent transcranial resection under the presumptive diagnosis of a non-functioning PitNET; however, postoperative imaging showed lesion progression. Further investigation revealed positive C-ANCA and systemic features consistent with GPA. Histopathological reassessment with immunohistochemistry supported the diagnosis of granulomatous hypophysitis in the context of GPA. Induction therapy with cyclophosphamide achieved initial disease control, but pituitary relapse occurred during maintenance therapy with azathioprine, prompting treatment escalation to rituximab. Rituximab led to reduction of the pituitary mass and sustained clinical stability over four years. Persistent hypopituitarism required long-term hormone replacement. Pituitary involvement in GPA is an uncommon but important diagnostic challenge and may closely mimic a PitNET. This case highlights the need for careful integration of systemic clinical features, endocrine findings, imaging, and histopathological reassessment when evaluating sellar masses. Immunosuppressive therapy with cyclophosphamide and rituximab was effective in controlling pituitary involvement, although permanent pituitary hormone deficiencies may persist despite disease control.
Intraductal papillary mucinous neoplasm (IPMN) is a rare precancerous pancreatic tumor that accounts for about 1% of pancreatic neoplasms and can impair both exocrine and endocrine function. We present the case of a woman with long-standing type 2 diabetes mellitus who developed worsening glycemic control due to pancreatic IPMN and its pathogenesis. Laboratory evaluation revealed evidence of severe pancreatic exocrine insufficiency, while imaging demonstrated a ductal lesion consistent with IPMN. Endoscopic ultrasound with biopsy confirmed a main-duct IPMN, and the patient subsequently underwent pancreaticoduodenectomy, with pathology demonstrating low-grade disease without invasion. This case highlights the connection between pancreatic structural disease and glucose metabolism. Progressive ductal obstruction and parenchymal injury from IPMN can result in combined endocrine and exocrine dysfunction, manifesting as pancreatogenic (type 3c) diabetes and malabsorption. Early recognition is critical, as it enables timely diagnostic evaluation, appropriate surgical management, and optimization of metabolic and nutritional status. Additionally, this case underscores the need for individualized diabetes management in the setting of pancreatic insufficiency and highlights ongoing uncertainties regarding the safety of certain glucose-lowering therapies in patients with premalignant pancreatic lesions.
Thyroid cancer is the most common endocrine cancer, developing in an average of 5%-7% of all nodules. In this study, we aimed to estimate the true risk, including multifocality and microcarcinomas, in patients who underwent total thyroidectomy after repeat Bethesda III cytology and in the other Bethesda groups. Three hundred patients participated in the study. Eighty-three (27.7%) of the patients were male and 217 (72.3%) were female. In the study, the diagnostic performances of the R-TIRADS (Revised Thyroid Imaging Reporting and Data System) classification used in the diagnosis of malignancy in thyroid nodules were compared with the Bethesda cytological classification. In order to compare the malignancy prediction powers, receiver operating characteristic curves were created for each system and area under the curve values were calculated. In all statistical analyses, a P-value below 0.05 was interpreted as statistically significant. A total of 150 cases (50.0%) with atypia of unknown significance (AUS) or follicular lesions of unknown significance (FLUS) were retrospectively evaluated. Histopathology results were consistent with malignancy in 103 patients. Of these patients, 27 had multifocality (26.2%), 26 had microcarcinomas (25.2%), and 22 had both multifocality and microcarcinoma (21.3%). The majority of the carcinomas (46.6%) were seen to arise in AUS with cellular and nuclear atypias. Prevalence of Bethesda category III cytologies is significantly higher than reported. A high rate of multifocality and incidental microcarcinomas in the definitive histopathology reports shows that the Bethesda classification falls short in the accuracy of risk in AUS/FLUS.
ACTH-dependent Cushing's syndrome (CS) is a rare manifestation of multiple endocrine neoplasia type 1 (MEN1). Identifying the ACTH source is challenging in MEN1 due to the frequent coexistence of multiple synchronous neuroendocrine tumors (NETs) in these patients. We describe the diagnostic dilemma in a 51-year-old male with MEN1 and severe ACTH-dependent CS. To analyze the specific diagnostic pitfalls in this population, we conducted a systematic literature review focusing exclusively on documented cases of ectopic Cushing syndrome (ECS) in MEN1 patients. The patient presented severe CS, with urinary free cortisol (UFC) at 3,188 µg/24h (exceeding 25 times the upper limit of normal). Rapid biochemical control was achieved within 10 days using a high-dose (60 mg/day) osilodrostat "block-and-replace" regimen. Imaging identified 3 potential sources: a 7x8 mm pituitary microadenoma, a small pancreatic NET, and a large thymic NET (48x62x67 mm). Despite a desmopressin stimulation test falsely suggesting a pituitary source (+118% ACTH increase), clinical severity and imaging indicated total thymectomy. Pathology confirmed a typical carcinoid tumor with ACTH expression. Postoperatively, the patient achieved complete remission. Our review of ectopic Cushing's syndrome (ECS) in MEN1 identified a total of 18 cases to date. Thymic NETs were the most frequent source (61%), followed by pancreatic NETs (28%). Notably, ectopic secretion of corticotropin-releasing hormone (CRH) was identified in 4 cases (22%), constituting a major diagnostic pitfall that led to unnecessary transsphenoidal surgery in 3 cases. ACTH-dependent CS in MEN1 is a diagnostic "perfect storm", where pituitary incidentalomas frequently mislead clinicians. Based on our review, ectopic CRH or ACTH secretion from thoracic or abdominal NETs must be systematically considered. We advocate a strategy prioritizing resection of the most suspicious lesion identified on imaging, thereby avoiding unnecessary transsphenoidal surgery.
Myotonic dystrophies (DM) are autosomal dominant, multisystemic disorders characterized by myotonia and progressive muscle weakness. Extramuscular multisystem symptoms include involvement of the respiratory, cardiac and central nervous systems, and endocrine and autoimmune alterations. While there is significant overlap in key symptoms due to a shared molecular backbone of alternative splicing, DM1 and DM2 differ in genetic origin, disease progression, and aspects of molecular pathology. Currently, DM management focuses on symptoms, and the wide clinical variation leads to long diagnostic delay. This highlights the need for reliable biomarkers to aid diagnosis, prognosis, and monitoring. As the understanding of molecular mechanisms in DM improves, new therapies are rapidly emerging, further emphasizing the need for reliable biomarkers to assess short- and long-term treatment efficacy. This review covers current biomarker research, including imaging-based, muscle-derived, and soluble liquid biopsy approaches. While established DM biomarkers are limited, with research disproportionately focused on DM1, multiple markers of alternative splicing pathology show promise. However, their reliance on invasive sampling restricts cohort size and longitudinal assessment. Consequently, efforts are shifting toward developing minimally invasive biomarkers. While some soluble markers, like muscle-specific circulating microRNAs, correlate with clinical measures, inconsistent detection, and limited evaluation of disease specificity point to the need for further research in larger, more diverse longitudinal cohorts. Future progress will depend on validating existing candidates, discovering new biomarkers addressing these limitations, and reducing the imbalance between DM1- and DM2-focused research to advance DM diagnosis, management, and therapy development.
Penile metastasis from prostate cancer is rare and is associated with a poor prognosis; however, there is currently a lack of high-level evidence to guide the management of this condition. This case report describes a 68-year-old male with prostate cancer who developed a penile metastasis during follow-up. This occurred despite stable prostate-specific antigen (PSA) levels after treatment with androgen deprivation therapy, combined with endocrine therapy and radiotherapy. Imaging studies and intraoperative frozen section pathology suggested a penile tumor. The patient subsequently underwent total penectomy combined with urinary diversion surgery. Postoperative histopathology confirmed poorly differentiated adenocarcinoma consistent with metastatic prostatic adenocarcinoma exhibiting morphological changes related to prior therapy. This case highlights the importance of maintaining clinical suspicion for penile metastasis in prostate cancer patients with stable PSA levels, especially in the context of tumor dedifferentiation, to facilitate early diagnosis and appropriate intervention.
Paclitaxel (PTX) is an effective antineoplastic agent whose clinical utility is limited by toxic effects on the male reproductive system. This study aimed to elucidate the reproductive toxicological mechanisms of PTX-induced testicular injury and to evaluate the protective effects of selenium (Se) against chemically mediated cellular and endocrine damage. Male Sprague-Dawley rats were exposed to PTX, with selenium administered at doses of 0.5 mg/kg and 1 mg/kg. Reproductive toxicity was assessed through sperm analysis and measurement of reproductive hormones, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone. Oxidative stress markers (MDA) and antioxidant enzymes (SOD, GPx), as well as pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), were quantified by ELISA. Molecular mechanisms were investigated by evaluating Keap1/Nrf2/HO-1 and HMGB1/TLR4/NF-κB signaling pathways using Western blot analysis, while RAGE and NLRP3 gene expression levels were determined by RT-PCR. Testicular damage, apoptosis, and DNA oxidation were further examined by histopathological, immunohistochemical, and immunofluorescence analyses targeting Bax, Bcl-2, caspase-3, and 8-OHdG. PTX exposure resulted in marked reproductive toxicity characterized by impaired sperm parameters, suppression of FSH, LH, and testosterone levels, increased oxidative stress, inflammatory activation, apoptotic signaling, and DNA damage in testicular tissue. Selenium treatment significantly mitigated these adverse effects in a dose-dependent manner by restoring endocrine balance, enhancing antioxidant defense, suppressing inflammatory and apoptotic pathways, and improving spermatogenesis. Collectively, these findings demonstrate that selenium exerts a protective role against PTX-induced reproductive toxicity by modulating key chemical-biological interaction pathways involved in testicular injury.
Pituitary adenomas (PA) are benign neoplasms treated by resection. Gross total resection is limited by extrasellar expansion in proximity to critical neurovascular structures. Residual tumor remains at risk of progression, with serious consequences such as optic compression or hormone hypersecretion. Adjuvant radiotherapy (RT) offers a rescue modality for both, impeding regrowth and hormonal relapse. Proton radiotherapy (PRT), owing to its favorable dose distribution and reduced exit dose through the Bragg peak, further expands the armamentarium of conventional RT modalities in cases of extrasellar macroadenomas in contact with vulnerable organs at risk. Hence, the present study provides initial evidence on the efficacy and toxicity of adjuvant PRT and offers insight into the decision-making criteria for selecting PRT over photon-based techniques. Adjuvant PRT applied for 22 residual PA including 16 non-functioning- (NFPA) and 6 functioning PA (FPA) at a large particle-therapy center, who were reviewed for local tumor control, toxicity, hormone status and visual function. Assessment of PRT response accounted for neuro-oncology criteria. After a median follow up of 65 months 5-year local tumor control rate of PA (FPA and NFPA) and hormone control rate of FPA was 100%. Secondary hypopituitarism after PRT was rare (1/22). Despite treatment escalation with PRT, stable endocrine status during follow-up enabled significant reductions in required glucocorticoid supplementation. Visual improvement was reported in 64%. Toxicity was limited, with fatigue and headache being most frequent. Adjuvant PRT for complex residual PA is efficacious and safe for treating residual disease in extrasellar expansion. Pituitary adenomas (PAs) with extrasellar extension in proximity to vulnerable neurovascular tissue or brain parenchyma carry risk of residual tumor after resection that is not amenable to further safe resection. Subsequent tumor regrowth may compress adjacent neurovascular structures resulting in frequent sequelae such as visual deterioration or central nerve palsies. Persistent hormone-secreting adenoma may further sustain endocrine dysregulation. Adjuvant radiation therapy represents an important treatment strategy to impede regrowth while minimizing toxicity to surrounding critical structures, thus achieving durable visual improvement and long-term hormonal control. Proton radiotherapy (PRT) may further improve the therapeutic ratio by exploiting its steep dose gradient and highly conformal dose distribution to enhance normal tissue sparing without compromising tumor control in selected complex PA. Therefore, the present study reports experience with adjuvant PRT for complex residual PA, demonstrating 5-year local tumor control of 100%, visual improvement in 64%, and stable hormone levels in 95%.