Medicine and Pharmacology

Abstract: Primary hyperparathyroidism (PHPT) is definitively treated by parathyroidectomy (PTx), with surgical cure conventionally defined by sustained normocalcemia. However, some patients develop elevated parathyroid hormone (PTH) concentrations despite normal postoperative calcium levels. This heterogeneous condition may reflect vitamin D insufficiency, reduced calcium availability, skeletal remineralization, or renal dysfunction, but may occasionally indicate persistent parathyroid autonomy or precede biochemical recurrence. Fibroblast growth factor 23 (FGF23), an osteocyte-derived regulator of phosphate excretion and calcitriol synthesis, occupies a central position within the bone–kidney–parathyroid axis and may participate in metabolic adaptation after PTx. This narrative review examines FGF23 regulation, circulating concentrations, clinical associations, and perioperative dynamics in PHPT. A structured search of PubMed/MEDLINE, Scopus, and Web of Science identified 11 original clinical studies directly evaluating FGF23 in PHPT. Findings were discordant: some studies reported increased preoperative concentrations and a postoperative decline, whereas others found normal levels or no significant change after surgery. Differences in disease phenotype, renal function, vitamin D status, assay methodology, supplementation, and sampling time may partly explain this heterogeneity. Notably, no study related perioperative FGF23 changes to subsequent PTH trajectories, and studies of postoperative eucalcemic PTH elevation did not measure FGF23. FGF23 cannot currently be considered a diagnostic or prognostic biomarker in PHPT. Nevertheless, serial assessment alongside conventional mineral-metabolism parameters may clarify endocrine adaptation after PTx and determine whether biologically distinct postoperative phenotypes exist.

Abstract: Background: Tissue hypoxia and dysregulated hypoxia-inducible factor-1α (HIF-1α) signaling recur across diabetic complications, yet a circulating determinant linking chronic hyperglycemia to organ oxygen stress remains incompletely defined. Glycohypoxia proposes that impaired erythrocyte oxygen unloading constitutes an additional systemic pressure superimposed on tissue-specific microvascular and metabolic vulnerability. Evidence synthesis: In T2DM, increasing HbA1c was associated with lower P₅₀ (27.0 ± 0.5 to 26.2 ± 0.7 mmHg) and 2,3-bisphosphoglycerate (2,3-BPG; 4.8 ± 0.4 to 4.2 ± 0.5 μmol/g Hb) despite preserved arterial PO₂, while modeling predicted a 1.5–3.9% cumulative unloading deficit across HbA1c 6–9%. Independent mechanistic models demonstrate that ADORA2B–AMPK–BPGM, SphK1–S1P–Band 3/glycolytic, and ENT1–AMPD3–purine/redox signaling dynamically regulate erythrocyte 2,3-BPG/P₅₀ and tissue oxygenation. During hypoxia, SphK1-dependent adaptation increased P₅₀ by approximately 20% in humans; genetic failure of erythrocyte unloading increased renal and myocardial hypoxia, whereas AMPK activation restored BPGM/2,3-BPG signaling and reduced tissue hypoxia. Downstream, oxygen availability interfaces with PHD–VHL/FIH–HIF signaling, but diabetes can uncouple hypoxia from effective adaptation. Methylglyoxal promotes HIF-1α degradation through Hsp40/Hsp70–CHIP and disrupts HIF-1α–p300 transcriptional competence, while diabetic myocardial fatty-acid metabolism limits succinate-dependent PHD inhibition. Accordingly, diabetic kidney, retina, myocardium, peripheral nerve, and wounds exhibit distinct combinations of tissue hypoxia, HIF dysregulation, VEGF signaling, metabolic remodeling, fibrosis, and defective repair. Conclusions: Glycohypoxia is therefore best considered a mechanistically grounded but unproven systemic oxygen-delivery modifier whose expression depends on organ-specific reserve. Definitive validation requires within-subject linkage of P₅₀/2,3-BPG to directly measured tissue oxygenation, PHD/FIH–HIF state, and organ dysfunction independently of glycemia, hemoglobin concentration, arterial oxygenation, and perfusion.

Abstract: Obesity is a heterogeneous chronic disease in which cardiometabolic and functional risks are influenced not only by total body fat but also by its anatomical distribution, ectopic fat accumulation, and skeletal muscle quality. Traditional anthropometric measurements, such as body mass index and waist circumference, fail to capture these biological differences. Point-of-care ultrasound provides a portable, radiation-free, repeatable, and widely available bedside tool for assessing multiple adipose and muscular compartments, yet a broadly standardized framework integrating these measurements into a multiorgan obesity phenotype remains lacking. We propose OBESUS (OBESity UltraSound), a pragmatic multiorgan point-of-care ultrasound framework for structured obesity phenotyping. To facilitate competency-based and stepwise implementation, OBESUS comprises two complementary tiers: OBESUS-Core evaluates abdominal subcutaneous adiposity, preperitoneal fat thickness, hepatic steatosis, and rectus femoris muscle quality, whereas OBESUS-Plus incorporates epicardial and perirenal adipose tissue as additional cardiorenal ectopic fat depots. Rather than generating a numerical score, the framework integrates these findings into four non-mutually exclusive ultrasound-derived phenotypes: metabolic, myosteatotic, epicardial adiposity, and perirenal adiposity. This narrative review describes the conceptual basis, standardized acquisition methodology, pragmatic reference thresholds, and potential clinical applications of OBESUS. The framework is intended to provide a foundation for prospective evaluation of its reproducibility, clinical validity, prognostic significance and potential utility for longitudinal monitoring.

Abstract: Adult-onset Langerhans cell histiocytosis (LCH) is an uncommon disease. Central nervous system involvement, particularly the hypothalamic–pituitary complex, can provoke severe endocrine and neurological complications. We report the case of a 39-year-old female patient with a history of pulmonary LCH, who developed central diabetes insipidus (CDI), anterior pituitary dysfunction, and severe hypothalamic syndrome, accompanied by adipsia, thermoregulatory dysfunction, and cognitive impairment. Brain magnetic resonance imaging revealed a hypothalamic mass with peritumoral edema. Following ineffective corticosteroid therapy, cladribine was administered. Although the tumor size and edema significantly decreased, it caused prolonged grade 4 bone marrow suppression, necessitating treatment discontinuation. Despite the marked radiological improvement, panhypopituitarism, cognitive impairment, and irreversible hypothalamic dysfunction persisted. Furthermore, concomitant adipsic CDI and thermoregulatory failure provoked severe dehydration, complicating clinical management. Ultimately, the patient died of sudden cardiac arrest, secondary to extreme hypernatremia (170 mEq/L). This case highlights the possible devastating consequences of hypothalamic involvement in adult multisystem LCH. While cladribine is effective at reducing the tumor burden, it fails to reverse established neuroendocrine and neurodegenerative damage. Early therapeutic and further lifelong interventions, specifically for adipsic CDI, are crucial to prevent fatal outcomes and maintain quality of life.

Abstract: The global obesity epidemic continues despite intensive research, in part because the dominant conceptual framework remains the energy balance model. This paradigm has struggled to reconcile the high heritability of body mass index (40–70 %) [1] with the small effect sizes of common variants identified by genome-wide association studies (GWAS), which collectively explain only a few percent of BMI variance [2–4]. Here I argue that the missing heritability of obesity is, to a substantial degree, an artifact of phenotype resolution. GWAS has asked which genes regulate energy balance; the genes regulate mass balance. The body possesses no receptors for calories or joules. It senses the mass and molecular identity of specific nutrients. Reframing the three canonical obesity genes through the mass balance model (MBM) yields a complete account of macronutrient partitioning: FTO regulates nitrogen mass balance, MC4R regulates carbon mass partitioning, and leptin regulates lipid mass clearance. These three genes describe the three mass fluxes that constitute body-weight regulation. The framework generates precise, falsifiable predictions and identifies new GWAS endpoints – most importantly the mass-clearance parameter k – that lie closer to the immediate targets of gene action than BMI. Measuring k, rather than a coarse anthropometric surrogate, offers the most direct route to recovering the missing heritability.

Abstract: Preferential loss of visceral adipose tissue is clinically desirable because of its strong association with cardiometabolic risk. Hall and Hallgreen (2008) showed that VAT loss is allometrically related to total fat mass loss, with a single dimensionless exponent k ≈ 1.3 describing data from 37 studies and more than 1400 individuals. This relationship is the correct null hypothesis for any claim of selective VAT targeting. The present commentary accepts that foundation and asks whether a mass-balance perspective can both explain it and indicate how to move beyond it. The decisive distinction is between the allometric exponent – an emergent property of the system – and the compartment-specific clearance coefficient – a physiological parameter. Within the mass balance model, VAT's higher clearance coefficient produces the observed preferential early loss under a Torricelli-type relationship between mass and clearance rate. Because the coefficient is modifiable, interventions that alter carbon and lipid mass fluxes may improve the VAT-to-total-fat loss ratio above the allometric baseline. The framework yields six testable predictions, identifies the condition under which the coefficient becomes resistant to change, and provides practical priorities for maximizing visceral fat reduction while preserving lean mass.

Abstract: Background: Hyperprolactinemia, characterized by serum prolactin levels >20 ng/mL, is a rare comorbidity in diabetes mellitus, potentially exacerbating insulin resistance and glycemic dysregulation via JAK/STAT signaling. This case series analysis examines five rare cases to elucidate clinical patterns, molecular mechanisms, and therapeutic outcomes, aiming to inform precision endocrine management. Methods: Five cases were curated from PubMed and Scopus (1999–2025), focusing on hyperprolactinemia in diabetes (type 1, type 2, or insipidus). Data on demographics, symptoms, laboratory findings (prolactin, insulin, C-peptide), imaging (MRI), and treatment outcomes were extracted. Results: The cohort included 3 females and 2 males (mean age: 26.2 years, range: 7–33). Prolactin levels ranged from 145–3,177 ng/mL, with 2/5 cases (40%) having type 1 diabetes, 1/5 (20%) type 2, 1/5 (20%) diabetes insipidus, and 1/5 (20%) factitious hypoglycemia. Presentations included hypogonadism (3/5, 60%), galactorrhea (2/5, 40%), and hypoglycemia (2/5, 40%). MRI revealed microadenomas (2/5, 40%), a macroadenoma (1/5, 20%), or normal pituitary (2/5, 40%). Cabergoline or medication withdrawal normalized prolactin in 4/5 (80%), reducing levels (e.g., 3,177 to 321 ng/mL in one case) and improving glycemic control (fewer hypoglycemic episodes) in 3/5 (60%). Prolactin activates JAK2/STAT5, inducing SOCS3 to inhibit IRS-1/PI3K/Akt, impairing glucose uptake. Conclusion: Hyperprolactinemia, whether tumoral or non-tumoral, disrupts metabolic homeostasis in diabetes. Routine prolactin screening is recommended for patients with reproductive or glycemic anomalies, emphasizing targeted therapies like dopamine agonists to optimize outcomes.

Abstract: Background: The C3 epimer of 25-hydroxyvitamin D₃ [3-epi-25(OH)D₃] is measurable in maternal and neonatal circulation, but its developmental relevance is unknown. Objective: To evaluate, using prospectively collected data from the KLOTHO birth cohort, whether cord blood 3-epi-25-hydroxyvitamin D₃ [3-epi-25(OH)D₃] is associated with autism-related trait domains at age 10 years. Methods: This exploratory secondary analysis used prospectively collected data from the KLOTHO birth cohort. Vitamin D metabolites were quantified by liquid chromatography–tandem mass spectrometry at delivery. Parent-reported autism-related traits were assessed with the Australian Scale for Asperger’s Syndrome. Record-level integrity checks preceded analysis. Spearman correlations, sex-stratified analyses, and supportive ordinary least-squares regression models were used. False-discovery-rate adjustment was applied to 13 unique bivariate tests. Results: A total of 87 offspring, including 41 boys and 46 girls, had available cord 3-epi-25(OH)D₃ and cognitive-domain data at age 10 years. Higher cord 3-epi-25(OH)D₃ was associated with a lower cognitive-domain score (Spearman ρ = −0.412; p < 0.001; Benjamini–Hochberg q = 0.001). The crude linear estimate was also inverse (B = −0.285; SE = 0.087; 95% CI, −0.458 to −0.112; p = 0.002), but it attenuated after adjustment, and the adjusted confidence intervals included the null. The rank-correlation estimate was larger in boys (n = 41; ρ = −0.611; p < 0.001) than in girls (n = 46; ρ = −0.304; p = 0.040), although the between-sex difference was not statistically significant (Fisher z = −1.78; p = 0.075). The stricter record-linkage sensitivity analysis remained significant (n = 84; ρ = −0.350; p = 0.001). Conclusions: Cord 3-epi-25(OH)D₃ showed an inverse rank association with cognitive autism-related traits at age 10 years that remained significant after multiplicity correction and in the stricter record-linkage sensitivity analysis. The crude linear estimate was directionally concordant, but the adjusted estimates included the null. The overall domain pattern was not uniform, and the formal between-sex comparison was not statistically significant. These findings remain exploratory and do not support causal or sex-specific conclusions.

Abstract: Resistance training produces hypertrophy that decelerates as muscle mass increases. Disuse produces atrophy that decelerates as muscle mass decreases. These two trajectories are routinely attributed to separate biological mechanisms – anabolic resistance, sarcopenia, saturation of signaling, adaptive downregulation of proteolysis. The present commentary argues that neither requires a direction-specific explanation for its baseline trajectory. Both follow from a single geometric constraint: protein synthesis capacity scales with the surface area available for the synthetic machinery, while protein maintenance scales with volume. As a myofiber grows, its surface-to-volume ratio falls, and synthesis capacity per unit mass declines. As it shrinks, the ratio rises, and degradation capacity per unit mass falls. The two trajectories are mirror images of the same relation. Muscle memory is presented as the natural empirical test of the framework: myonuclei retained after atrophy constitute a residual that accelerates regrowth beyond the geometric baseline. Geometry sets the baseline; adaptive physiology explains the residual. The argument extends the mass-balance framework previously developed for whole-body mass change to the cellular level, and generates quantitative predictions that distinguish geometric necessity from biological regulation.

Abstract: Oxyntomodulin (OXM), an endogenous proglucagon-derived peptide with dual glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) agonism, provides a physiological precedent for contemporary multi-receptor pharmacology. Recognition that GCGR signaling regulates not only hepatic glucose production but also amino acid turnover, lipid metabolism, substrate oxidation, and energy expenditure prompted the development of engineered GLP-1R/GCGR co-agonists, including cotadutide, mazdutide, survodutide, and pemvidutide. Retatrutide extends this strategy by integrating GIPR, GLP-1R, and GCGR agonism within a single long-acting peptide and has produced substantial improvements in body weight, glycemic control, and cardiometabolic parameters in phase 2 and phase 3 trials. This review examines the evolutionary and structural relationships of the proglucagon–Class B1 GPCR system, OXM biosynthesis and receptor pharmacology, the mechanistic rationale for therapeutic GCGR agonism, and the molecular and clinical development of dual and triple agonists. We further address receptor balance, the GIPR agonism–antagonism paradox, and the unresolved attribution of clinical effects to individual receptor components. Finally, we propose an Activity–Exposure–Context framework for interpreting polyagonist pharmacology and discuss prospective enteroinsular phenotyping using standardized mixed-meal testing as a testable strategy to investigate interindividual variability in therapeutic response.

Abstract: A recent modeling analysis by Hall attributes the attenuated weight loss observed in patients with type 2 diabetes treated with GLP-1 receptor agonists primarily to reductions in urinary glucose excretion (UGE) and energy expenditure that accompany improved glycemic control. The analysis is conducted entirely within an energy-balance framework. This commentary identifies two elementary but consequential problems. First, glucose excreted in urine is mass leaving the body. Hall’s own equation computes UGE as a mass flux; its subsequent treatment as an “energy sink” is a category error that adds unnecessary assumptions without adding information. Second, the model converts an inferred energy imbalance into an expected mass change via assumed tissue energy densities, and then compares this prediction with observed mass change. Because the energy-to-mass conversion is partly calibrated on the same type of data being predicted, the comparison has limited independent confirmatory power. A mass-balance formulation avoids both problems, supplies a simpler account of the same clinical phenomenon, and generates testable predictions that distinguish the two frameworks.

Abstract: Once the decelerating trajectory of human mass change is recognized as a geometric consequence of surface-area scaling, a substantial fraction of what has historically been labelled metabolic adaptation is removed from the explanatory burden of biology. What remains is a residual: any systematic deviation of observed mass or energy trajectories from the geometric baseline. This residual – not the raw deceleration – is the proper object of physiological investigation. The present paper outlines a framework for isolating and modelling it. Geometry supplies a baseline that is entailed by its premises and is direction-symmetric; biology is responsible only for what cannot be accounted for by that baseline. Distinguishing the two levels prevents the continued misattribution of geometric entailment to regulatory physiology and opens the way to more precise, less confounded models of true adaptive responses.

Abstract: Recent analysis has shown that the progressive slowing of human mass loss under energy restriction follows from a mass reservoir whose outflow scales with surface area. The same geometry operates in the opposite direction. When mass increases, surface area increases, net outflow rises, and the rate of further accretion declines. Decelerating mass gain, like decelerating mass loss, therefore requires no direction-specific adaptive mechanism for its baseline trajectory. For fixed intake, the system approaches an equilibrium mass M* where intake equals outflow; gain from below and loss from above are mirror images of the same relation. Geometry accounts for the direction-symmetric component of deceleration; adaptive physiology, if present, must be inferred from the residual beyond that baseline. Literature's near-exclusive focus on adaptation during loss, while largely ignoring the corresponding deceleration during gain, is itself suggestive of an unevenly distributed explanatory burden. Geometry does not choose direction.

Abstract: Background: Longitudinal changes in estimated cardiovascular risk vary across indi-viduals with type 2 diabetes. We investigated whether baseline clinical data predict a relative decrease of at least 10% in the DIAL2-derived calibrated one-year cardiovascular risk estimate (P1Y) over two years. Methods: This single-centre observational prediction analysis used data collected at ASST Mantova. Of 332 source records, 324 had valid P1Y estimates at baseline (T0) and two years (T2). Elastic net logistic regression and random forest were assessed with three repetitions of nested stratified five-fold cross-validation. We assessed discrimination, average precision, Brier score, and calibration of held-out predictions. Results: The response criterion was met in 135 of 324 patients (41.7%). Mean test-fold area under the receiver operating characteristic curve (AUROC) was 0.788 (fold SD 0.043) with elastic net and 0.780 (0.047) with random forest. Average precision was 0.755 and 0.740, and Brier score was 0.183 and 0.190. Elastic net without treatment group yielded AUROC 0.783. Averaged held-out elastic net predictions had AUROC 0.792 and calibration slope 0.978. At fixed baseline age, 230/324 (71.0%) met the reduction criterion; a separately validated elastic net had mean AUROC 0.751. Outcomes were changes in a computed risk estimate, not observed cardiovascular events. Conclusions: Baseline characteristics discriminated individuals with a two-year reduction in estimated annual risk in internal validation. Endpoint status was sensitive to the age term in DIAL2. These findings require validation in an independent cohort; model outputs cannot establish the effect of any therapy on clinical cardiovascular outcomes.

Abstract: The progressive slowing of weight loss during caloric restriction is routinely ascribed to metabolic adaptation. This interpretation treats the deceleration as a biological adjustment whose magnitude must be estimated after the fact. The present analysis shows that the decelerating trajectory is required by geometry. The human body is a mass reservoir. Net mass outflow occurs across surfaces whose aggregate area scales with retained mass. When outflow is an increasing function of surface area, and surface area is an increasing function of mass, the rate of mass loss must decline as mass declines. This relation follows directly from the continuity equation and the geometry of surface-to-volume scaling; it does not require empirical calibration to be true in principle. Once the geometric term is acknowledged, a large fraction of what has been labelled metabolic adaptation ceases to require biological explanation. The phenomenon that has most persistently disordered obesity research is, to first order, the ordinary behaviour of a draining reservoir.

Abstract: Prader–Willi syndrome (PWS) is an imprinting disorder characterized by severe hypotonia, poor suck, failure to thrive and hypogonadism\hypogenitalism noted during infancy with hyperphagia, severe obesity, and metabolic dysregulation onset in early childhood. Inhibition of methionine aminopeptidase 2 (METAP2) using Beloranib, a fumagillin analog inhibits angiogenesis and associated with decreased adiposity, reduced appetite and body weight in clinical trials of obese individuals with and without PWS. However, clinical trials using Beloranib were discontinued following reports of thromboembolic events and deaths. To better characterize the biological mechanisms underlying METAP2 and related METAP1, we performed a comprehensive silico analysis of genetic and curated protein interactive networks with initial observations from STRING and compared with Pathway Commons and BioGRID interactive gene and protein web-based programs. The studies revealed that METAP2 is centrally embedded within networks governing cytoplasmic translation, ribosomal biogenesis, post-translational protein maturation, ubiquitin-mediated proteostasis, and lipid biology. METAP2 showed strong associations with ribosomal proteins, deubiquitinating enzymes and sphingolipids, as components of the vascular wall, along with metabolic regulation. Identification of risk factors and use of next-generation METAP2 inhibitors such as ZGN-1061with improved safety profiles and combined careful thrombotic risk identification and stratification with monitoring would be critical in the future for selected patient populations.

Abstract: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C) levels and early cardiovascular disease. Despite intensive lipid-lowering therapy, achieving target LDL-C levels remains challenging, and many patients require lifelong LDL apheresis. We report a 33-year-old Mexican–Lebanese woman with confirmed HoFH and multiple comorbidities, including systemic lupus erythematosus. Severe hypercholesterolemia was evident from early childhood, with total cholesterol levels of approximately 800 mg/dL and development of xanthomas at age 3. The patient underwent long-term multimodal therapy, including statins, ezetimibe, PCSK9 inhibitors, and LDL apheresis initiated at age 9 and continued for approximately 20 years, achieving only partial lipid control. Evinacumab, an angiopoietin-like protein 3 (ANGPTL3) inhibitor, was initiated in adulthood as adjunctive therapy. Within two months, significant and sustained LDL-C reduction was achieved, allowing complete discontinuation of LDL apheresis. Follow-up demonstrated stable LDL-C levels between 180–225 mg/dL. This case highlights the clinical effectiveness of Evinacumab in patients with HoFH, demonstrating its potential to achieve sustained lipid reduction and eliminate the need for invasive apheresis. ANGPTL3 inhibition may represent a transformative strategy for improving long-term management and quality of life in this high-risk population, particularly in settings with limited access to apheresis.

Abstract: Cellular stress is not inherently detrimental; its biological consequences depend on intensity, duration, context, and the capacity for recovery. This narrative review proposes the Burn-ON/Burn-OUT paradigm as a hypothesis-generating framework describing the transition from adaptive cellular activation to progressive loss of cellular resilience. A structured literature search was conducted for English-language articles published between 2021 and 2026 in PubMed, Web of Science, and Scopus, focusing on cellular stress adaptation, mitochondrial dysfunction, integrated stress response, autophagy and mitophagy, redox signaling, inflammasome activation, metabolic flexibility, senescence, and nutritional modulation. In the proposed model, Burn-ON represents a state of increased cellular demand in which mitochondrial adaptation, stress-response signaling, autophagic quality control, redox homeostasis, and metabolic flexibility remain sufficiently preserved to sustain function and allow recovery. With persistent or repetitive stress, these adaptive mechanisms may progressively lose reversibility, defining a potential tipping point toward Burn-OUT. Burn-OUT is characterized conceptually by impaired mitochondrial quality control, reduced energetic reserve, defective autophagic flux, persistent inflammatory signaling, redox imbalance, metabolic inflexibility, and loss of functional recovery, with senescence or regulated cell death representing possible downstream outcomes. Nutrition and lifestyle may modulate this continuum by influencing nutrient sensing, substrate load, mitochondrial metabolism, autophagy, and inflammatory pathways. The Burn-ON/Burn-OUT model frames cellular stress as a double-edged biological process, in which adaptation and dysfunction represent different positions along a dynamic continuum. Longitudinal studies are needed to determine whether recovery kinetics and multidimensional biomarker profiles can distinguish these proposed states.

Abstract: Background: Hair loss is a prevalent but underaddressed consequence of the menopausal transition, reflecting the simultaneous decline of estrogen, progesterone, and the protective estrogen:androgen ratio that governs scalp follicular biology. Methods: Following SANRA guidelines, a systematic literature search was conducted across PubMed/MEDLINE and EMBASE (January 2000–September 2026) using MeSH and free-text terms encompassing female pattern hair loss (FPHL), menopause, sex steroids, hormone replacement therapy (HRT), 5-alpha-reductase, and dihydrotestosterone (DHT), among others.[25] Key Findings: Estrogen loss shortens anagen duration and amplifies follicular DHT accumulation through three converging mechanisms. Progesterone withdrawal removes an underappreciated anti-androgenic buffer via competitive 5-alpha-reductase inhibition. Testosterone, though gradually declining with age, becomes relatively more androgenic as estrogenic modulation of its conversion is lost. For eligible women, systemic transdermal estradiol combined with a hair-favorable progestogen — micronized progesterone or drospirenone — provides the most comprehensive follicular protection. Topical scalp estradiol constitutes a distinct hair-directed local modality. A structured hormonal panel including the testosterone:DHT ratio guides antiandrogen selection and treatment monitoring; serum DHT measured by LC-MS/MS functions as a pharmacodynamic marker, not a standalone diagnostic test for female pattern hair loss. Conclusions: Integrating hormonal hair assessment into routine gynecological-endocrinological practice — with attention to progestogen androgenicity, route of estrogen delivery, and the role of hormone replacement therapy as an adjunctive rather than primary hair indication — can meaningfully reduce the undertreatment of this prevalent dimension of menopausal women's health.

Abstract: Background: Permanent postoperative hypoparathyroidism (p-HypoPT) is a major long-term complication of thyroid surgery; however, its incidence remains uncertain because reported rates are influenced by heterogeneous case mix and variable follow-up. We assessed the burden and determinants of p-HypoPT in patients undergoing surgery for differentiated thyroid cancer (DTC) with long-term endocrine follow-up. Methods: We retrospectively analysed prospectively collected data from 518 consecutive adults with DTC enrolled in a dedicated longitudinal endocrine follow-up programme between 2013 and 2022. p-HypoPT was operationally defined as the persistent requirement for oral calcium and/or active vitamin D supplementation at ≥12 months after surgery. Independent associations were assessed by means of multivariable logistic regression. Rates were also explored across the 2015 and 2025 American Thyroid Association (ATA) risk categories. Results: p-HypoPT occurred in 60/518 patients (11.6%). Median follow-up was 10.8 years (IQR 8.0–12.8), and all patients with p-HypoPT remained on calcium and/or active vitamin D supplementation at their latest available follow-up. Central neck dissection was associated with p-HypoPT in multivariable analysis (adjusted OR 2.94, 95% CI 1.55–5.57; P&lt;0.001). Under the 2025 ATA classification, p-HypoPT frequencies differed across categories in unadjusted analysis (P=0.005), with the highest frequency in the high–intermediate-risk group (23.9%). This association was attenuated after adjustment for central and lateral neck dissection and was no longer statistically significant (global P=0.566). Conclusions: Permanent hypoparathyroidism represents a relevant long-term burden after DTC surgery. Its assessment should account for both the duration of postoperative surveillance and the extent of surgery, moving beyond aggregate rates derived from heterogeneous thyroidectomy cohorts. More granular, procedure-specific and risk-adjusted estimates may ultimately support meaningful quality comparisons and provide a more individualised assessment of long-term functional risk.