Endocrines, Volume 7, Issue 1 (March 2026) – 12 articles

Background: Risk stratification of indeterminate thyroid nodules (Bethesda III–IV) remains difficult and often triggers unnecessary procedures. Ultrasound-based ACR TI-RADS and the 2023 Bethesda System are widely used, but the incremental value of combining them and the role of size thresholds needs prospective validation. Objective: The objective of this study was to prospectively compare the diagnostic performance of ACR TI-RADS and the 2023 Bethesda System, alone and in combination, for predicting malignancy in thyroid nodules, with dedicated analyses of indeterminate lesions (Bethesda categories III–IV), including subtypes of Bethesda III (nuclear atypia vs. other atypia), and the impact of nodule size. Methods: Histopathology was available for 131 nodules. Diagnostic metrics (sensitivity, specificity, PPV, NPV), ROC curves (DeLong comparison), and Youden indices were calculated for individual and combined thresholds; a 16 mm size cut-off was explored. Results: Malignancy was confirmed in 105/131 nodules (80.2%). Bethesda outperformed TI-RADS (AUC 0.87 vs. 0.69; DeLong p = 0.041). Malignancy rates rose with higher categories (e.g., TI-RADS 5: 93.6%; Bethesda category V: 100%; Bethesda category VI: 100%) and were markedly elevated in the histologically confirmed subset for Bethesda category III (32/41; 78.0%) and IV (6/8; 75.0%). The combined requirement of TI-RADS ≥ 4 and Bethesda ≥ 4 maximized specificity (96.2%) and PPV (98.4%) with a high Youden J (0.552), supporting a rule-in strategy in category IV of Bethesda. Size alone was a weak discriminator (AUC 0.66); within Bethesda III–IV nodules, malignancy did not differ significantly by the 16 mm threshold (p = 1.00). ROC using continuous tumor size yielded AUC = 0.66; the ROC-derived optimal cut-off was 16 mm. Applying this split produced sensitivity 0.80 and specificity 0.50. Conclusions: Integrating ACR TI-RADS with Bethesda cytology significantly improves specificity and PPV for indeterminate thyroid nodules, supporting a morphology-driven approach over traditional size-based thresholds. Incorporation of combined sonographic–cytologic criteria into management algorithms may reduce unnecessary interventions and optimize patient care. Full article

Background/Objectives: The aim of this study is to describe sex- and age-specific patterns of HbA1c in adults with type 2 diabetes (T2D) mellitus across three temporal cohorts from Southern Italy (2012, 2017, and 2024), and to assess whether glycemic differences between men and women persist, narrow, or evolve over time. Methods: We analyzed three independent cohorts of adults with T2D, including 1249 patients in 2012 and 1125 patients in both 2017 and 2024. HbA1c values were summarized as medians and interquartile ranges within sex- and age-stratified groups. Temporal variation in cohort-specific median HbA1c was examined across timepoints within each sex and age category, and sex differences were assessed within each cohort year. Results: At the population level, median HbA1c values remained within a narrow range across all three cohorts, indicating overall temporal stability of glycemic control. No significant sex differences were observed in 2012 or 2024, and only one age stratum (≥80 years) showed a significant sex difference in 2017, with men exhibiting slightly higher median HbA1c. Age-stratified analyses revealed heterogeneous temporal patterns. In older adults (≥70 years), HbA1c medians were remarkably stable in both sexes (approximately 7.2–7.4% in women and 7.2–7.6% in men). In midlife (40–59 years), women tended to show modest increases or partial reversals in HbA1c, whereas men displayed worsening between 2012 and 2017 followed by stabilization thereafter. The youngest adults (18–29 and 30–39 years) showed the highest HbA1c levels in 2017 and the largest subsequent improvements between 2017 and 2024 in both sexes, with median values decreasing toward approximately 7.1–7.6%. Conclusions: Despite well-described biological and social sex differences in T2D, median HbA1c values in this real-world setting were broadly comparable between men and women and largely stable over a 12-year period. Sex differences were small, inconsistent, and age-dependent, with age, and not sex, emerging as the primary determinant of HbA1c over time. These findings suggest that sex-related disparities in glycemic control may be better understood through a dynamic, life-course perspective rather than static cross-sectional comparisons. Full article

Background/Objectives: Migraine is a leading cause of disability in women and is intricately linked to hormonal fluctuations and systemic health. This review aims to unravel the complex relationship between migraine, cardiovascular disease, and metabolic syndrome throughout the female reproductive lifespan. Methods: A comprehensive narrative review was conducted using the PubMed database for studies published between January 1988 and December 2025. Keywords included “migraine”, “cardiovascular risk”, “metabolic syndrome”, “pregnancy”, and “hormonal therapy”. Articles were selected to synthesize the latest pathophysiological evidence and clinical guidelines. Results: Migraine prevalence in women is two to threefold higher than in men, peaking during fertile age. Hormonal milestones, particularly estrogen withdrawal, trigger menstrual migraine. Metabolic syndrome is significantly more common in migraineurs than the general population. Obesity and insulin resistance have been associated with higher migraine attack frequency and severity. Experimental evidence suggests that hyperinsulinemia may sensitize TRPV1 receptors on trigeminal neurons and enhance CGRP release, potentially lowering the activation threshold for migraine attacks; however, direct confirmation of this pathway in humans remains limited. Furthermore, migraine with aura is linked to a doubled risk of ischemic stroke and increased risk of cardiovascular events. In pregnancy, migraine is an independent risk factor for stroke, myocardial infarction, and spontaneous coronary artery dissection. Conclusions: Migraine is a critical marker for cardiovascular and metabolic risk, necessitating routine screening and multidisciplinary management. Clinicians must prioritize cardiovascular counselling, metabolic evaluations, and careful monitoring in these patients, especially during pregnancy. Hormonal therapy choices should be individualized, preferring progestin-only contraceptives for those with aura and transdermal routes for hormone replacement therapy to minimize cardiometabolic impact. Full article

Background: Cardiovascular complications are a leading cause of death in patients with type 2 diabetes (T2D). The GLP-1 receptor agonist (GLP-1RA) semaglutide has shown cardiometabolic benefits in individual studies, but a comprehensive analysis of its effects in both oral and subcutaneous formulations is lacking. Objective: This study aimed to systematically evaluate the impact of semaglutide, in oral and subcutaneous formulations, on major adverse cardiovascular events (MACE) in patients with T2D. Methods: This review adhered to the PRISMA guidelines and included a comprehensive search of PubMed, MEDLINE, and Google Scholar from November 2016 to June 2025. High-quality randomized controlled trials (RCTs) comparing semaglutide with placebo in patients with T2D were included. The primary endpoint was MACE, defined as cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. Hazard ratio (HR) and 95% confidence intervals (CIs) were pooled using a random-effects model. Results: Of the 127 articles screened, 3 trials involving 16,130 participants met the inclusion criteria. The pooled HR for MACE across the SOUL, SUSTAIN-6, and PIONEER-6 trials was 0.83 (95% CI: 0.76–0.92; I² = 25%), indicating a 17% relative risk reduction with low heterogeneity. Adverse event profiles were comparable between the semaglutide and placebo groups. Conclusions: Semaglutide use was associated with a significant and consistent reduction in MACE in patients with T2D, supporting its role as a valuable therapeutic option for combined glycemic control and cardiovascular risk reduction. Full article

Background: Older patients with type 2 diabetes mellitus (T2DM) are often undertreated because of concerns regarding hypoglycaemia and clinical heterogeneity. Although the evidence base for oral semaglutide is growing, data specifically in older adults remain relatively limited, particularly regarding long-term effectiveness and tolerability in routine practice. Methods: This observational study included 81 patients aged ≥65 years with T2DM treated with oral semaglutide for 12 months. Changes in glycaemic, anthropometric and cardiometabolic parameters were evaluated. The primary endpoint was the achievement of HbA1c < 7% at 12 months. Multivariable logistic regression was performed to identify baseline predictors of response. Results: HbA1c decreased from 7.75 ± 1.01% to 6.80 ± 0.88% after 12 months (p < 0.00001). Significant reductions were observed in body weight (−4.09 ± 4.42 kg, p < 0.00001), BMI (−1.50 ± 1.55 kg/m², p < 0.00001) and waist circumference (−5.83 ± 4.71 cm, p < 0.00001). Improvements were also detected in lipid profile, blood pressure and visceral adiposity indices. No hypoglycaemic events were reported during follow-up. In multivariable analysis, baseline age, diabetes duration, baseline HbA1c and baseline VAI were not independently associated with the achievement of HbA1c < 7%; therefore, these baseline factors did not discriminate responders within our cohort (hypothesis-generating). Greater absolute HbA1c reductions were observed in patients with higher baseline HbA1c. Conclusions: In older patients with T2DM, oral semaglutide is associated with effective glycaemic control without hypoglycaemia and with a response largely independent of baseline clinical characteristics, supporting its use in elderly and clinically heterogeneous populations. Full article

Background/Objectives: The co-existence of Type 2 Diabetes Mellitus (T2DM) and cancer presents complex self-management challenges due to competing health demands. This study aimed to evaluate and compare self-care activities and adherence to medical recommendations between T2DM patients with cancer and a non-cancer T2DM control group. Additionally, it investigated the impact of sociodemographic and clinical characteristics on treatment adherence. Methods: A cross-sectional study was conducted in a general hospital in Thessaloniki, Greece, using convenience sampling. The sample consisted of 62 participants: 29 patients with T2DM and cancer and 33 controls with T2DM only. Data were collected using the “Diabetes Self-Care Activities Questionnaire”, analyzing subscales for self-care activities and adherence to medical orders. Results: The cancer group was notably older, with a mean age of 69.8 years compared to 60.3 years in the control group (p < 0.001). While overall adherence scores were comparable between groups, significant disparities existed in specific domains. The cancer group demonstrated a critical neglect of foot care recommendations compared to controls (p < 0.001), with a very large effect size (d = 1.60). Conversely, cancer patients reported significantly stricter adherence to dietary recommendations (p = 0.001, d = 0.96). Within the cancer group, older age and lower education were unexpectedly associated with better foot care adherence (p < 0.05). Conclusions: The results suggest a distinct prioritization among cancer patients, whereby they reported maintaining strict dietary adherence while potentially deprioritizing preventative foot care. Clinical practice should consider transitioning to an integrated model where oncology healthcare professionals actively reinforce diabetic foot surveillance to prevent complications. Full article

Background: The interplay between obesity and thyroid dysfunction is complex, characterized by adaptive hyperthyrotropinemia and peripheral hormone resistance. Metabolic and Bariatric surgery (MBS) has emerged not only as a weight-loss (WL) intervention but also as a potent modulator of the thyroid–gut axis. Methods: We conducted a narrative review of the literature (2015–2025), synthesizing data from prospective cohorts, meta-analyses, and mechanistic studies to evaluate the impact of MBS on thyroid function, autoimmune dynamics, and drug pharmacokinetics. Discussion: Current evidence suggests that MBS promotes a recalibration of the thyroid axis. Post-operative WL is independently associated with a significant reduction in serum thyroid-stimulating hormone (TSH) and free triiodothyronine (fT3) levels, reversing obesity-induced peripheral resistance. Concurrently, the reduction in systemic inflammation (NOD-like receptor protein 3 (NLRP3) inflammasome deactivation) may dampen lymphocytic infiltration, while the amelioration of gut dysbiosis and intestinal permeability is hypothesized to reduce cross-reactivity mechanisms (molecular mimicry), leading to decreased antibody titers in Hashimoto’s thyroiditis. However, these benefits are counterbalanced by altered drug absorption mechanisms. While most hypothyroid patients benefit from reduced Levothyroxine (L-T4) requirements due to decreased lean mass, malabsorptive procedures (Roux-en-Y Gastric Bypass, One Anastomosis Gastric Bypass) can precipitate refractory hypothyroidism due to bypassed absorptive surfaces and altered gastric pH. Conclusions: MBS offers a dual benefit of functional restoration and modulation of autoimmune markers. However, post-surgical management requires a tailored approach. Clinicians must distinguish between the physiological decline in TSH (adaptive) and iatrogenic malabsorption, advocating for liquid L-T4 formulations in complex malabsorptive phenotypes. Full article

Objectives: This study aimed to evaluate adherence to therapy in hypoparathyroidism and related endocrine–metabolic disorders and to assess its association with biochemical outcomes, hypocalcemia episodes, and health-related quality of life (HRQoL). Methods: In accordance with PRISMA 2020 guidelines, PubMed, Scopus, Google Scholar, and the Cochrane Library were searched until September 2025. The eligible studies were randomized controlled trials, cohort, case–control studies, cross-sectional, and observational studies that reported adherence to calcium/vitamin D or recombinant parathyroid hormone therapy. Results: twenty-three studies were included in the qualitative synthesis, and 11 studies were included in the quantitative meta-analysis. Pooled medication adherence compliance was 70–82% and improved with simplified regimens and the use of recombinant PTH. Additionally, this was also associated with an improvement in HRQoL (p < 0.0001) and a lower risk of hypocalcemia (p < 0.0001). Conversely, multifactorial regulation was observed as the level of adherence had no significant effect on serum calcium levels (p = 0.7116). Sensitivity analyses demonstrate the strength of findings and indicate no significant publication bias. Conclusions: Medication adherence is a key factor in determining patient-centered outcomes in hypoparathyroidism. Better adherence is linked to a higher quality of life and fewer episodes of hypocalcemia, while its effect on biochemical parameters seems minimal. Educational programs, simple treatment regimens, and wider access to rhPTH therapy can be used to improve patient management of the disease over time. Full article

Diabetic foot complications represent a major global health burden and arise from a multifactorial interaction between neuropathy, ischemia, infection, and impaired wound repair. Increasing evidence suggests that, beyond traditional vascular and metabolic risk factors, endocrine dysregulation plays a central role in shaping vascular dysfunction and tissue vulnerability in patients with diabetes. This narrative review provides an updated overview of the endocrine–vascular axis in the development, progression, and healing of diabetic foot ulcers (DFUs), integrating evidence from experimental and clinical studies identified through targeted searches of PubMed, Embase, and Scopus. We examine how alterations in insulin signaling, relative glucagon excess, adipokine imbalance, dysregulation of stress hormones, and thyroid dysfunction interact with chronic hyperglycemia, dyslipidemia, mitochondrial dysfunction, and low-grade inflammation to impair endothelial homeostasis. These disturbances promote oxidative stress, reduce nitric oxide bioavailability, and compromise microvascular perfusion, thereby creating a pro-ischemic and pro-inflammatory tissue environment that limits angiogenesis, extracellular matrix (ECM) remodeling, immune coordination, and effective wound repair. By linking pathophysiological mechanisms to clinical relevance, this review highlights potential biomarkers of endocrine–vascular dysfunction, implications for risk stratification, and emerging therapeutic perspectives targeting metabolic optimization, endothelial protection, and hormonal modulation. Finally, key knowledge gaps and priority areas for future translational and clinical research are discussed, supporting the development of integrated endocrine-based strategies aimed at improving DFU prevention, healing outcomes, and long-term limb preservation in patients with diabetes. Full article

Background: Papillary thyroid cancer (PTC) incidence is rising, particularly among Adolescents and Young Adults (AYA, 15–39 years). However, data on PTC characteristics in the AYA population, especially from the Middle East, remain limited. This study aims to describe the clinicopathological features of PTC in AYA patients treated at a large tertiary center in Qatar. Methods: A retrospective chart review was conducted for AYA patients diagnosed with PTC between May 2015 and December 2020 at Hamad General Hospital, Qatar. Data on demographics, tumor characteristics, histopathology, staging, risk stratification, and treatment were extracted and analyzed. We stratified the cohort based on sex. Results: We studied 326 AYA patients (mean age 33.0 ± 5.2 years); the majority were females (72.7%) and were mostly of Asian origin (51.5%). Most patients underwent total thyroidectomy (77.6%), while 22.4% underwent partial thyroidectomy. Histologically, classic PTC was most common (83.38%), followed by the follicular variant (16.00%). Capsule invasion occurred in 21.04%, vascular invasion in 11.76%, and lymphatic invasion in 14.38%. Most patients were at low ATA risk (68.61%), with intermediate (20.06%) and high risk (11.33%) less common. Distant metastases were rare (0.3%), and 59.1% received Radioactive iodine (RAI). Compared to females, males had larger tumors (mean 2.65 cm vs. 2.01 cm, p = 0.0009), higher rates of vascular invasion (22.4% vs. 7.7%, p < 0.001), affected lymph nodes (mean 4.2 vs. 2.4, p = 0.0223), and ATA high-risk proportions (23.5% vs. 7.0%, p < 0.001). Conclusions: This study provides the first detailed characterization of PTC in AYA patients from Qatar. While confirming female predominance, males exhibited more aggressive features (larger tumors, higher LN involvement, and ATA risk). These findings emphasize the need to consider gender-specific differences in managing PTC within the AYA population. Full article

Introduction: We previously showed that baboon offspring born to mothers deprived of estrogen during the second half of gestation exhibited insulin resistance prior to and after the onset of puberty. Moreover, the size of skeletal muscle myofibers and the number of microvessels important for delivery of insulin/glucose to myofibers were lower in near-term fetuses deprived of estrogen during pregnancy, and myofiber capillarization remained reduced in post-pubertal offspring deprived of estrogen in utero. However, it remains to be determined whether skeletal muscle size is restored to normal in animals deprived of estrogen in utero after the onset of puberty/gonadal estrogen production. Methods: To answer this question, the current study quantified the size and number of slow and fast fibers in biopsies of vastus lateralis skeletal muscle obtained from post-pubertal female baboon offspring 9–12 years old, born to mothers who were untreated (n = 7) or treated during the second half of gestation with letrozole (n = 6; suppressed maternal and fetal estrogen by >90%) or letrozole plus estradiol benzoate (n = 3). Results: Results indicated that skeletal muscle slow and fast fiber growth in female offspring appeared to occur by hypertrophy and that respective size of fibers after the onset of puberty was similar in offspring born to mothers who were untreated or deprived of estrogen in utero. Conclusions: Postnatal myofiber hypertrophy likely reflects the impact of the pubertal surge in and continued exposure of offspring myofibers to ovarian estrogen and is restored to normal in post-pubertal female offspring deprived of estrogen in utero. Full article