Cushing's syndrome in older adults is uncommon but clinically consequential. The diagnostic tests are largely the same as in younger adults, yet the clinical threshold for testing, the interpretation of biochemical results, and the therapeutic endpoint often differ. Older patients may lack classic cushingoid features and instead present with poorly controlled diabetes or hypertension, recurrent falls, rapid bone loss, proximal weakness, venous thromboembolism, cognitive decline, or an adrenal incidentaloma. These features overlap with common age-related disorders and create a dual risk: missing clinically important hypercortisolism or overdiagnosing mild biochemical abnormalities with limited clinical relevance. A practical approach begins by excluding exogenous glucocorticoid exposure, identifying progressive and discriminatory features, and selecting screening tests that account for renal function, sleep pattern, drug interactions, and the probability of non-neoplastic hypercortisolism. Late-night salivary cortisol is convenient but should be repeated and interpreted cautiously in patients with diabetes, sleep disturbance, or acute illness; urinary free cortisol may be falsely low in chronic kidney disease; and dexamethasone suppression testing requires careful review of interacting medications and, in selected cases, dexamethasone levels. Management should be based on etiology and functional status rather than chronological age. Fit older adults should generally be offered standard curative therapy, whereas vulnerable or frail patients may benefit more from staged, less invasive, or symptom-directed treatment. Preservation of mobility, cognition, independence, and quality of life should be explicit treatment goals.
CONTEXT:Survival after pediatric hematologic malignancies has improved substantially, increasing concern regarding endocrine sequelae. While gonadotoxic effects on germ cells are characterized in adult survivors, the early impact of cancer and chemotherapy on hypothalamic-pituitary-testicular axis during childhood and adolescence remains insufficiently studied. DESIGN:We conducted a prospective longitudinal cohort study including 63 boys and adolescents with acute lymphoblastic leukemia, acute myeloid leukemia, or non-Hodgkin lymphoma treated at a tertiary pediatric center in Argentina between 2013 and 2019. Hormonal markers of Sertoli cell (AMH, inhibin B, FSH) and Leydig cell function (testosterone, LH) were serially assessed from diagnosis, throughout chemotherapy, and up to 3 years after treatment completion. RESULTS:In prepubertal boys, Sertoli cell function was mildly impaired at diagnosis, with reduced AMH and FSH levels. AMH increased during induction chemotherapy, fluctuated during treatment, and normalized thereafter, remaining stable up to 3 years post-treatment. Transient FSH suppression coincided with exposure to high-dose corticosteroids. Boys entering puberty during follow-up showed persistently elevated AMH relative to pubertal stage, suggesting delayed Sertoli cell maturation. In pubertal patients, a transient seminiferous tubular dysfunction, reflected by increased FSH and decreased inhibin B occurred, with recovery by 3 years after treatment. Mild compensated Leydig cell dysfunction persisted, characterized by elevated LH despite normal testosterone concentrations. CONCLUSIONS:Testicular dysfunction associated with pediatric hematologic malignancies is mostly reversible. However, delayed Sertoli cell maturation and persistent compensated Leydig cell insufficiency indicate residual testicular vulnerability, underscoring the importance of long-term endocrine surveillance during and after the end of chemotherapy.
CONTEXT:Theranostics has emerged as a precision medicine paradigm in neuroendocrine tumors (NETs), integrating receptor-based imaging with targeted radionuclide therapy to individualize treatment. This approach is particularly valuable in functional and biologically heterogeneous NETs, where hormonal control and variable clinical behavior dominate therapeutic priorities. CASE DESCRIPTION:We present a three-case series illustrating the application of theranostics across diverse NET contexts. Case 1 describes a patient with metastatic insulinoma with refractory hypoglycemia, in whom multimodal therapy, including locoregional intervention, was sequenced to prioritize hormonal control, with somatostatin receptor (SSTR) imaging ultimately enabling peptide receptor radionuclide therapy (PRRT) and durable glycemic response. Case 2 discusses a patient with metastatic pancreatic NET who, after prior benefit from PRRT, underwent successful retreatment guided by persistent SSTR expression and appropriate clinical selection, with individualized dosimetry used to optimize safety and efficacy. Case 3 describes metastatic small-intestinal NET grade 3 with carcinoid syndrome, where dual-tracer PET (SSTR and FDG) revealed biologic heterogeneity that informed sequencing of systemic and locoregional therapies alongside PRRT, in the setting of competing priorities including carcinoid heart disease. CONCLUSIONS:These cases highlight theranostics as a clinical framework that integrates tumor biology, functional imaging, and patient-specific priorities to guide management of NETs. Optimal care requires multidisciplinary coordination across endocrinology, oncology, nuclear medicine, and interventional and surgical specialties, particularly when hormonal morbidity and tumor progression compete in driving treatment decisions. Receptor-based imaging identifies candidates for targeted therapies and provides insight into tumor behavior, enabling sequencing of systemic and locoregional interventions to achieve biochemical and oncologic control.
INTRODUCTION:Glucose tolerance abnormalities can be detected in preschool and school-age children with cystic fibrosis. There is limited data on the impact of CFTR modulator elexacaftor/tezacaftor/ivacaftor (ETI) on their trajectories. We examined CGM metrics before and after ETI initiation across different pediatric age groups. METHODS:We included participants from the French MODUL-CF real world study aged 2-18 years with at least 24 hours of CGM data before initiation of ETI and a 2nd CGM 12±3 months following ETI start. The cohort was stratified in 3 groups based on the age at ETI initiation: <6, 6-12 and >12 years. CGM derived glucose metrics were compared before and after ETI. RESULTS:98 patients with CF were enrolled, including 13 preschool children, 55 school age children and 32 adolescents. At baseline, participants displayed a time in tight glucose range (TITR) of 89.8%(84.1, 93.4) with 34% of the whole cohort spending >10% of time>140mg/dL (TA140). Following treatment, TITR increased of ∼2%(+1.8[-1.8, +6.0]%) (p=0.004). This was associated with a 0.4% reduction of mild-hyperglycemia (>140mg/dL) and a lower CV (21.5%(19.0, 24.7) vs 19.6%(17.0, 22.6), p<0.001). Those with TA140≤10% at baseline displayed greater weight gain and improvement of lung function respect to the group with TA140>10%. CONCLUSION:ETI is associated with improvement of CGM glucose in children and adolescents with CF. TA140 before ETI initiation may impact the trajectory of clinically relevant outcomes.
CONTEXT:Type 2 diabetes mellitus (DM) is a major risk factor for cognitive decline, whereas physical activity (PA) is associated with better cognitive health. We examined associations of DM status and PA level with cognitive impairment and hippocampal volume. DESIGN AND SETTING:This cross-sectional study included 1,615 community-dwelling older adults from the Bunkyo Health Study. PA was assessed using the International Physical Activity Questionnaire and classified as moderate-or-higher or low. Participants were categorized into 4 groups according to PA level and DM status. Cognitive impairment was defined as a Montreal Cognitive Assessment score ≤22, and hippocampal volume was measured by 0.3-T magnetic resonance imaging. Multivariable logistic regression and analysis of covariance were used to evaluate associations with cognitive impairment and hippocampal volume. RESULTS:Mean age was 73.1 ± 5.4 years, and 57.7% were women. Cognitive impairment prevalence was 15.6%, 19.7%, 20.4%, and 38.1% in the non-DM/high PA, non-DM/low PA, DM/high PA, and DM/low PA groups, respectively. Higher odds of cognitive impairment were observed only in the DM/low-PA group versus the non-DM/high-PA group (OR, 2.51; 95% CI, 1.40-4.49). Adjusted hippocampal volume was lower in the DM/low-PA group than in the non-DM groups. The DM × PA interaction did not reach statistical significance for either outcome. CONCLUSIONS:Individuals with both DM and low PA had the highest prevalence of cognitive impairment and lower hippocampal volume. Neither interaction reached statistical significance; however, a moderate interaction for cognitive impairment could not be excluded, and the hippocampal findings should be interpreted cautiously.
CONTEXT:Catecholamine-secreting pheochromocytomas and paragangliomas (PPGLs) can be difficult to stabilize before surgery or during follow-up. Somatostatin receptor expression provides a rationale for octreotide therapy, but clinical evidence is limited. OBJECTIVE:To evaluate biochemical, clinical, hemodynamic, metabolic, and perioperative outcomes associated with octreotide treatment in catecholamine-secreting PPGLs. METHODS:We retrospectively studied 27 consecutive patients with PPGLs treated with octreotide at two referral centers in Muscat, Oman between January 2012 and March 2026. Primary outcomes were clinical, hemodynamic and biochemical responses; secondary outcomes included glycemic, surgical, and follow-up outcomes. RESULTS:Twenty-seven patients were included (70.4% female; mean age, 50.3 ± 22.2 years); 14 had paraganglioma and 13 pheochromocytoma. All received long-acting octreotide, and 10 also received short-acting octreotide. Median plasma norepinephrine decreased from 6,723 to 1,901 pmol/L (P < 0.0001). Epinephrine, dopamine, and chromogranin A also decreased significantly. Mean blood pressure decreased from 154.8/93.5 to 123.0/75.3 mmHg (n = 16; P = 0.0003 for systolic and P = 0.0006 for diastolic pressure), and mean HbA1c decreased from 8.6 ± 2.4% to 6.2 ± 0.8% among patients with diabetes (n = 11; P = 0.005). Seventeen patients underwent surgical resection. During a median follow-up of 3 years, one non-PPGL-related death occurred. CONCLUSIONS:Octreotide treatment was associated with biochemical, hemodynamic, and metabolic improvement and may serve as a useful adjunct in selected patients, particularly as a bridge to surgery and during perioperative preparation.
CONTEXT:Adrenarche involves maturation of the adrenal zona reticularis (ZR), but its molecular regulation is poorly understood. MicroRNAs (miRNAs) may contribute to adrenal development. OBJECTIVE:To investigate whether circulating miRNAs are associated with ZR maturation during adrenarche and to characterize the functional role of candidate miRNAs in adrenal steroidogenesis. DESIGN AND SETTING:Prospective cohort study was nested within the population-based PANIC study with longitudinal follow-up at ages 7, 9, and 15 years, combined with experimental analyses in the human adrenocortical NCI-H295R cell model. PARTICIPANTS:A total of 34 children (20 girls) with clinical and/or biochemical signs of adrenarche at age 9 as cases, and 24 age-matched controls (11 girls). INTERVENTIONS:None. MAIN OUTCOME MEASURES:Longitudinal serum miRNA expression and in vitro effects of candidate miRNAs on adrenal steroidogenesis and gene expression. RESULTS:Serum miR-1-3p levels were higher in cases compared to controls at age 7 years (fold change 2, p < 0.001), preceding clinical adrenarche. In both groups, miR-1-3p levels declined during adrenarchal and pubertal development. In vitro, miR-1-3p overexpression increased steroidogenic activity (approximately 1.5-fold on average) without altering the expression of canonical steroidogenic enzyme genes. Transcriptomic analysis identified 208 upregulated and 140 downregulated genes, including PRKCA, encoding protein kinase C (PKC), enriched in the ZR and involved in steroidogenic signaling. CONCLUSIONS:Elevated circulating miR-1-3p precedes clinical adrenarche and enhances steroidogenesis in vitro. The temporal decline of circulating miR-1-3p levels and the identification of PKC support a model in which miR-1-3p may contribute to functional maturation of the ZR through modulation of non-canonical intracellular signaling pathways.
CONTEXT:Thyroid dysfunction and menopause both affect cardiovascular risk, but the specific influence of the menopausal transition on thyroid function independent of aging remains unclear. OBJECTIVE:To examine longitudinal changes in thyroid function across the menopausal transition among a large cohort of healthy midlife women. DESIGN:Longitudinal cohort study (2004-2024) using annual health checkup data and interrupted time-series analyses within mixed-effects linear models. SETTING:Annual health screening program at St. Luke's International Hospital, Tokyo, Japan. PARTICIPANTS:7,644 Japanese women who experienced natural menopause and had at least one health checkup both before and after menopause. Those with hormone therapy or surgical menopause were excluded. MAIN OUTCOME MEASURES:Serum TSH and free thyroxine (fT4) levels. Secondary outcomes included abnormal TSH categories (>4.5, >10.0, <0.4, and <0.1 mIU/L) and self-reported thyroid disorders. RESULTS:Over a median 13.7-year follow-up (86,967 visits), TSH increased by 0.014 mIU/L per year (95% CI, 0.010 to 0.019) before menopause, with no significant slope change at menopause (additional change, -0.006 mIU/L per year [CI, -0.012 to 0.000]). fT4 levels decreased by 0.005 ng/dL per year (CI, -0.006 to -0.005) before menopause and stabilized thereafter (additional slope change, +0.005 ng/dL per year [CI, 0.004 to 0.005]). The prevalence of abnormal TSH and thyroid disorders increased with age, but there were no distinct changes at menopause. CONCLUSIONS:Menopause was not associated with clinically meaningful changes in thyroid function beyond aging. Age-related factors, rather than the menopausal transition, may largely explain increasing thyroid abnormalities in midlife women.
Achieving pregnancy in females with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is one of the major challenges in the care of adult female patients. Although females across all phenotypes of CAH due to 21OHD are generally fertile, multiple factors contribute to markedly reduced fertility rates compared with the general population. These factors include urogenital malformations, psychosexual issues and most importantly hormonal imbalances. While the prevailing perception today is that pregnancy rates among women with CAH approach those of the general population and that most women who wish to conceive eventually succeed, it was shown that even in specialized centres the latency to pregnancy is substantially prolonged irrespective of the phenotype. Herein we demonstrate how pregnancy in women with CAH can be achieved as well as how treatment during pregnancy should be monitored. The crucial step is normalization of preconception progesterone concentrations in the follicular phase. To achieve this, not only the glucocorticoid (GC) dose but also the timing of hormone replacement is crucial.
Diabetes is highly heterogeneous, rendering traditional type 1 and type 2 classification insufficient for optimizing treatment strategy. This mini-review examines data-driven clustering-categorizing adult-onset diabetes into five subtypes: SAID (severe autoimmune), SIDD (severe insulin-deficient), SIRD (severe insulin-resistant), MOD (moderate obesity-related), and MARD (mild age-related)-within the context of East Asian populations. East Asians exhibit a distinct "Asian phenotype" characterized by impaired insulin secretion and visceral fat accumulation at lower body mass index levels. Meta-analyses reveal a significantly higher proportion of the SIDD subtype in East Asians compared to Caucasians, driven by ancestry-specific genetic variants affecting β-cell function and tissue-specific gene expression. Furthermore, complication risks differ between regions; while the SIRD cluster remains the primary risk for metabolic dysfunction-associated steatotic liver disease (MASLD) and nephropathy across populations, East Asian SIDD patients face significantly higher risks of chronic kidney disease and sarcopenia than their Caucasian counterparts. These findings emphasize that while clustering provides a robust framework for risk stratification, clinical application in East Asians requires modifications accounting for unique body compositions and pathophysiology. Integrating subtype-guided strategies-such as early intensive insulin therapy for SIDD and multifaceted insulin sensitivity improvement for SIRD-represents a critical step toward personalized medicine to eradicate diabetes complications in East Asians.
BACKGROUND:Helicobacter pylori (H. pylori) infection has been associated with insulin resistance and metabolic syndrome, particularly in East Asian populations. Whether these associations are independent or explained by socioeconomic and lifestyle confounding remains unclear. We examined this relationship in a large European cohort using rigorous confounder adjustment and Bayesian sensitivity analyses. METHODS:This cross-sectional study included 4,681 asymptomatic adults (2007-2020), with H. pylori status determined by gastric biopsy. The primary outcome was insulin resistance (HOMA-IR > 2.5); secondary outcomes included HOMA2 model parameters and metabolic syndrome (ATP III criteria). Poisson regression estimated incidence rate ratios (IRR) with sequential adjustment for age, sex, education, alcohol, smoking, and diet. Bayesian analyses quantified the probability of clinically meaningful effects. RESULTS:Of 4,681 participants (median age 57; 52% male), 868 (18.5%) were H. pylori-positive. Infected individuals had lower education, higher BMI, and higher alcohol consumption. Crude insulin resistance prevalence was higher in H. pylori-positive participants (31% vs. 27%; P = 0.015). In unadjusted regression, H. pylori was associated with insulin resistance (IRR 1.15, 95% CI 1.01-1.32), but this association disappeared after full adjustment (IRR 1.12, 95% CI 0.95-1.31; P = 0.176). No association with metabolic syndrome was found (IRR 1.03; P = 0.681). Bayesian analysis showed an 87.9% probability of practical equivalence, arguing strongly against a clinically meaningful independent effect. CONCLUSIONS:The association between H. pylori and insulin resistance is fully explained by socioeconomic and lifestyle confounding. H. pylori acts as a marker of adverse metabolic risk rather than a causal factor, and eradication cannot be recommended for metabolic syndrome prevention.
Advances in research enable precision medicine for rare metabolic diseases. The approval of therapies as melanocortin-4 receptor (MC4R) agonists for the treatment of hyperphagia and obesity in monogenic disorders (POMC, PCSK1, and LEPR deficiencies) and Bardet-Biedl syndrome (BBS), affecting fewer than 1 in 20,000 (BBS) to fewer than 1 in 1,000,000 individuals, represents a major advance. These therapies have transformative potential but introduce new responsibilities due to limited patient numbers and lack of long-term data. Equitable access to diagnosis and treatment, expert care and structured monitoring systems facilitate efficient use of resources and can address gaps in knowledge. This article outlines a European expert consensus recommending the designation of centers of expertise to coordinate the diagnosis and treatment of patients with monogenic obesity. The need for structured care protocols based on continued analysis of real-world databases to optimize therapy in a responsible manner is emphasized. The goals are (1) early and precise diagnosis; (2) access for eligible patients to therapy; (3) continuous evaluation of treatment response allowing discontinuation without no measurable clinical benefit and (4) provision of clinical care by trained and experienced professionals.
BACKGROUND:Androgen-dependent prostate pathology, including prostate cancer and benign prostatic hyperplasia, differs in prevalence and phenotype across races/ethnicities. Adrenal-derived 11-oxygenated C19 steroids (11-oxyandrogens) are relevant to several androgen-dependent pathologies, but data on their race/ethnic variations are lacking. METHODS:Male participants in the multiethnic cross-sectional Dallas Heart Study-2 were included. Serum androstenedione, testosterone, and 11-oxyandrogens were quantified simultaneously using liquid chromatography-tandem mass spectrometry, and were compared across races, adjusting for age, BMI, and comorbidities. RESULTS:Of 1,025 men (mean age 51 ± 10 years), 478 (47%) were Black, 375 (37%) White, 141 (14%) Hispanic, and 31 (3%) other races. Androgen concentrations varied with race/ethnicity: testosterone medians [interquartile ranges]: 338 [248-465], 347 [287-428], and 307 [232-422] ng/dL; and 11-ketotestosterone: 27 [16-46], 24 [15-41], and 21 [13-36] ng/dL in Black, Hispanic, and White men, respectively (P < 0.01 for both). Compared with White men with similar age and BMI, Black men had higher concentrations of testosterone (β = 47.06 ± 13.05 ng/dL), 11-ketotestosterone (β = 7.30 ± 1.90 ng/dL), androstenedione, and 11-oxy-androstenedione; while Hispanic men had higher 11-ketoandrostenedione and 11-ketotestosterone P < 0.05 for all). Race- and age-adjusted concentrations of testosterone and androstenedione decreased with BMI, whereas all 11-oxyandrogens increased with BMI (P < 0.05). After adjusting for race and BMI, 11β-hydroxyandrostenedione increased with age (P < 0.001), while all other androgens remained stable across ages. CONCLUSION:Circulating 11-ketotestosterone concentrations were higher in Black and Hispanic men than in White men with similar age and BMI. Interethnic variability in systemic androgens might contribute to differences in androgen-related pathologies.
PURPOSE:To assess the results of patient-reported outcome measures (PROMs) in a national cohort of females with a prolactinoma by disease activity. METHODS:Females with prolactinoma included in the PRolaCT or ProlaC study were assessed cross-sectionally, comparing patients with active (prolactin above upper limit of normal (ULN)) and controlled (prolactin<ULN) disease. Disease and treatment characteristics were reported. Patients completed PROMs on symptoms (modified PRO-CTCAE), health-related quality of life (HR-QoL) (SF-36), anxiety and depressive symptoms (Hospital Anxiety and Depression Scale (HADS)), and disease burden (Leiden Bother and Needs Questionnaire for patients with Pituitary disease (LBNQ-Pituitary)). RESULTS:Four hundred and fifty females with a prolactinoma were included (active: n=223, controlled: n=227), most were treated with dopamine agonists (DAs) (97.0%). Fatigue was the most prevalent symptom in both patients with active and controlled disease (92.6%, and 86.4%, respectively) followed by concentration problems (79.0%, and 64.5%, respectively) (modified PRO-CTCAE, LBNQ-Pituitary). Anxiety and depressive symptoms were worse in patients with active compared to controlled disease (HADS-Anxiety: 8.0 ± 4.5 vs 6.4 ± 4.5 p<0.001. HADS-Depression: 6.4 ± 5.0 vs 4.7 ± 4.4 p<0.001). Disease burden was higher in patients with active compared to controlled disease (LBNQ-Pituitary: Total Bother 24.4 ± 22.9 vs 16.4 ± 17.9 (p<0.001). CONCLUSIONS:Females with a prolactinoma were most affected by fatigue and cognitive complaints. Although patients with active disease perceived more burden than patients with controlled disease, symptoms including fatigue, psychological and cognitive complaints were prevalent despite disease control. Therefore, improvement of treatment and rehabilitation strategies is needed.
INTRODUCTION:Current tools to evaluate fracture risk in children with Osteogenesis Imperfecta (OI) are limited and bone mineral density (BMD) has limitations and is not widely available for children under 5 years. We hypothesized that the Bone Health Index (BHI), evaluating the average cortical thickness of the three middle metacarpal bones, adjusted for bone width and length, could be a useful tool in the assessment of fracture risk, particularly in infants. METHODS:The service at Great Ormond Street Hospital (London, UK) follows a cohort of over 277 children with classical OI and keeps a detailed and accurate record of confirmed fractures. We reviewed their BHI (analysed using the latest version of BoneXpert® software) at presentation (n = 123), the lumbar BMD (n = 47) taken on the same day where available, the subsequent two years fracture history and annual lateral spine X-rays. RESULTS:In multivariable logistic regression, each 1-SD decrease in BHI SDS was independently associated with a 5.3-fold higher odds of incident fracture within two years (OR 5.26, 95% CI 2.4-11.1, p < 0.001), while DXA BMD and BMAD Z-scores were not independent predictors. ROC analysis showed good discriminatory performance for BHI SDS (AUC 0.84), superior to DXA BMD Z-score (AUC 0.60) and BMAD Z-score (AUC 0.51). CONCLUSIONS:Our study indicates that lower BHI SDS values are associated with increased fracture risk in children with classical OI. In the available DXA subgroup, BHI demonstrated stronger discriminatory performance than DXA-derived measures. BHI may represent a clinically useful complementary tool for fracture risk stratification in young children with OI, particularly where DXA is unavailable or technically limited, including infancy.
CONTEXT:Androgen excess in polycystic ovary syndrome (PCOS)/polyendocrine metabolic ovarian syndrome (PMOS) is classically attributed to ovarian steroids, yet adrenal-derived 11-oxygenated androgens are potent contributors whose regulation and treatment responsiveness in PMOS remains poorly characterized. OBJECTIVE:To quantify classic and 11-oxygenated androgens across PMOS phenotypes versus controls and to evaluate their responses to oral contraceptive pills (OCPs), metformin, or lifestyle modification (LSM). DESIGN:Secondary analysis of residual serum samples from three trials: OWL-PCOS (16-week OCP vs LSM), COMET-PCOS (24-week OCP vs metformin), and AMIGOS (controls). SETTING:Two academic medical centers. PATIENTS OR OTHER PARTICIPANTS:276 with Rotterdam-defined PMOS and 97 controls. INTERVENTION(S):Low dose OCPs (4-6 months), metformin (2000mg/day for 6 months), or LSM (4 months). MAIN OUTCOME MEASURE(S):Serum concentrations of 11β-hydroxytestosterone (11-OHT), 11-ketotestosterone (11-KT), 11-ketoandrostenedione (11-KA4), and 11β-hydroxyandrostenedione (11-OHA4) measured by LC-MS/MS, and total testosterone (TT), at baseline and end of study. RESULTS:Adjusting for age and BMI, women with PCOS/PMOS had higher median 11-OHT (11.0 vs 7.8 ng/dL; P = 0.01) and 11-KT (31.9 vs 25.6 ng/dL; P = 0.03) than controls. Elevations were phenotype-specific: biochemical hyperandrogenism showed broad increases, whereas clinical hyperandrogenism with normal TT found no significant differences compared to controls. OCPs suppressed 11-KT, 11-KA4, and 11-OHT (all P < 0.001), comparable to TT reductions. Metformin produced modest reductions in 11-OHT and 11-KT (P < 0.05), while LSM had no effect. Changes were independent of BMI, glycemia, and HOMA-IR. CONCLUSIONS:11-oxygenated androgens are elevated in PMOS in a phenotype-specific manner and are strongly suppressed by OCPs, with modest response to metformin and no short-term effect from LSM, supporting their utility in phenotyping and treatment monitoring.
As the global burden of cirrhosis shifts toward metabolic dysfunction-associated steatotic liver disease (MASLD), diabetes and metabolic syndrome act as key upstream drivers of liver injury. At the same time, diabetes is increasingly recognized even in cirrhosis of non-metabolic etiologies, including viral hepatitis, reflecting both shared risk factors and cirrhosis-related disturbances in glucose homeostasis. This coexistence amplifies morbidity, mortality, and therapeutic complexity, while conventional diabetes paradigms often prove inadequate in management of cirrhosis. This review synthesizes current evidence and proposes a pragmatic framework for managing diabetes across the full spectrum of cirrhosis. We examine the evolving concept of hepatogenous diabetes, limitations of HbA1c in advanced liver disease, and the complementary roles of oral glucose tolerance testing and continuous glucose monitoring in improving diagnostic accuracy. The pharmacologic landscape is critically evaluated, integrating contemporary diabetes guidelines with hepatic stage-specific considerations. Metformin remains the backbone of therapy in compensated cirrhosis. Among newer agents, GLP-1 receptor agonists and SGLT2 inhibitors show promise in compensated disease, particularly in patients with MASLD and cardio-renal comorbidities. In contrast, sulfonylureas, insulin secretagogues, and agents associated with fluid retention require caution or avoidance as hepatic reserve declines. Insulin therapy remains the cornerstone in decompensated cirrhosis and during hospitalization, where conservative dosing and dynamic titration are essential to minimize hypoglycemia. The review emphasizes nutritional optimization, frequent reassessment, and coordinated hepatology-endocrinology care. As diabetes in cirrhosis increasingly reflects the convergence of two metabolic disorders, management must prioritize hepatic safety, metabolic stability, and individualized outcomes over rigid glycemic targets.
CONTEXT:Temple syndrome (TS14) is an imprinting disorder caused by abnormalities at chromosome 14q32.2. Its phenotype overlaps with Silver-Russell (SRS) and Prader-Willi (PWS) syndromes, contributing to under-recognition and delayed diagnosis. Its endocrine manifestations remain incompletely characterised. OBJECTIVE:To report the largest TS14 cohort to date to define the endocrine and clinical phenotype, evaluate management, response to growth hormone (GH) therapy, and develop a novel TS14-specific clinical score. DESIGN:Multicentre cohort study. SETTING:Specialist centres in United Kingdom and The Netherlands. PATIENTS:Seventy-one individuals with TS14. MAIN OUTCOME MEASURE:Endocrine and growth-related phenotypes, metabolic complications, and diagnostic performance of a scoring system. RESULTS:Genetic subtypes included maternal uniparental disomy (52%), hypomethylation (41%) and deletion (6). Most patients were born small for gestational age (68%). 73% had short stature at age 1-3 years, improving to 15% at age 11-14 years, with a greater improvement in those treated with GH. Baseline IGF-1 concentrations were ≥-2 SDS in all patients, while GH deficiency (GHD) was confirmed in 27%. Early feeding difficulties affected 87%, 47% developed obesity, and 20% had hyperphagia. Dyslipidaemia was present in 38% and central precocious puberty in 62%. Only 56.5% fulfilled ≥3 criteria of the Netchine-Harbison scoring system. We present a scoring system to identify which patients should be tested for TS14. CONCLUSION:The endocrine phenotype of TS14 encompasses growth failure, GHD, precocious puberty and disordered appetite, and requires age-specific management. Response to GH therapy was promising. A TS14-specific scoring system could enable earlier diagnosis and endocrine intervention, potentially improving outcomes.
