Polycystic ovary syndrome (PCOS) is a common, heterogeneous condition that is tightly linked to obesity, visceral adiposity and insulin resistance. Lifestyle intervention and off-label use of metformin provide only modest and unsustained weight loss, insufficient to reverse obesity-driven pathophysiology in most women with PCOS and obesity. Incretin-based anti-obesity medications, including glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonists (dual GIP/GLP-1RAs), offer a biologically plausible way to target adipose dysfunction, hyperinsulinemia and chronic inflammation that drive PCOS in a large subset of patients. In this narrative, product-segmented review, we map the evidence for liraglutide, semaglutide and tirzepatide in PCOS across mechanistic, clinical, and safety domains, and highlight key evidence gaps that limit current practice. Liraglutide has the densest PCOS-specific evidence, demonstrating reproducible weight loss across small and heterogeneous cohorts, reductions in visceral adiposity and hepatic fat, improved glycemia and inflammatory markers, and early signals for androgen and fertility benefits in selected phenotypes. Semaglutide data remain sparse but conceptually rich, demonstrating weight-loss efficacy and mechanistic insights, alongside preliminary signals of increased likelihood of natural conception. Tirzepatide currently has no PCOS-specific evidence and cannot be recommended beyond extrapolation from obesity and diabetes trials. Across all agents, reproductive outcomes, periconceptional and pregnancy safety, adolescent use, long-term cardiovascular–kidney–metabolic trajectories, obstructive sleep apnea, musculoskeletal health and phenotype-stratified response remain major evidence gaps. We propose a multidimensional, metabolic high-risk PCOS phenotype as the most rational current target for incretin therapy, while emphasizing that well-designed, PCOS-specific trials are essential before these drugs can be viewed as PCOS-modifying therapies rather than powerful, but still adjunctive, weight-loss agents.

Indolent systemic mastocytosis (ISM) is an under-recognised cause of secondary osteoporosis, and skeletal fragility may be the only presenting feature, delaying diagnosis. We describe four adults referred to a tertiary endocrinology service for unexplained osteoporosis or low-trauma fractures, in whom systemic mastocytosis (SM) was identified during work-up. All had elevated basal serum tryptase (41.4-87.0 µg/L), bone-marrow biopsy showing atypical mast cells and the KIT D816V variant; cutaneous lesions were absent in every case. Three patients fulfilled WHO 2022 criteria for ISM. The fourth had coexistent JAK2 V617F-positive post-essential-thrombocythaemia myelofibrosis and was classified as SM with associated haematological neoplasm (SM-AHN); his mast cell clone (tryptase 43.7 µg/L; KIT D816V VAF 0.391%) behaved indolently and contributed clinically through osteoporosis alone, illustrating that an indolent mast cell component can be overlooked when a chronic myeloid neoplasm dominates the picture. Presentations ranged from an isolated low-energy L5 fracture in a 55-year-old man, to multiple vertebral compression fractures despite denosumab in a 71-year-old woman with primary hyperparathyroidism, to severe wasp-sting anaphylaxis in a 43-year-old man. After multidisciplinary review, all received intravenous zoledronic acid with vitamin D repletion; KIT-targeted therapy is under consideration in selected patients. Although causal inferences cannot be drawn from four retrospectively identified cases, the series illustrates how ISM may be missed in unexplained or treatment-refractory osteoporosis-particularly in younger men, those with prior severe anaphylaxis, and those fracturing on antiresorptive therapy-and supports combining basal serum tryptase with high-sensitivity peripheral-blood KIT D816V testing, in line with the WHO/ICC/AIM-ECNM 2022-2024 criteria. Prospective studies are needed.

BACKGROUND:Patients with adult growth hormone deficiency (AGHD) show accelerated atherosclerosis. While growth hormone replacement therapy (GHRT) may help mitigate this process, the mechanisms driving atherosclerosis progression in GHRT-treated patients with AGHD remain unclear. METHODS:Thirty-one patients with AGHD on daily GHRT for ≥5 years were assessed in this crosssectional study. Carotid intima-media thickness (cIMT) was evaluated by ultrasound. Reactive hyperemia index (RHI) was measured using peripheral arterial tonometry. Associations between vascular measures and clinical, pituitary, treatment, body composition, and laboratory parameters were evaluated. RESULTS:cIMT correlated with body mass index (r=0.584, p=0.001) and visceral adipose tissue area (r=0.791, p<0.001), while demonstrating nominally significant associations with triglyceride levels, insulin resistance index, smoking history, and arterial hypertension. Neither the current nor the 5-year mean insulin-like growth factor 1 standard deviation score directly correlated with vascular parameters. Median cIMT was higher in adult-onset compared with child-onset AGHD (0.70 vs. 0.58 mm; p=0.020), while median RHI was lower in genetic than structural etiology (1.58 vs. 2.18; p=0.010); however, both associations were nominally significant. DISCUSSION:Several of the identified cardiovascular risk factors associated with cIMT are unlikely to be sufficiently controlled through GHRT. Pituitary disease characteristics may play a role in atherogenesis; however, the subgroups defined by disease onset timing and etiology were small and not fully comparable. CONCLUSION:In long-term GHRT-treated patients, cIMT is linked to well-established cardiovascular risk factors rather than features of the pituitary disorder and its management, highlighting the need for targeted cardiovascular risk management alongside GHRT in AGHD.

Tirzepatide has been associated with significant reductions in body weight in randomized clinical trials. However, real-world evidence evaluating the multisystemic effects of tirzepatide across the cardio-metabolic-kidney (CKM) continuum remains limited. The aim of this study was to assess the real-world persistence-driven cumulative benefits of tirzepatide beyond weight reduction in adults with obesity but without type 2 diabetes mellitus (T2DM). This single-center observational cohort study evaluated in the United Arab Emirates adults with obesity (body mass index [BMI] ≥ 30 kg/m2) treated with tirzepatide. Participants were stratified by treatment persistence: ≤ 1 year (short-term) and > 1 year (long-term). Anthropometric, glycemic, lipid, hepatic, and renal outcomes were assessed at baseline and follow-up. One hundred participants (25 women; mean age 37.6 ± 10.0 years; baseline BMI 35.0 [33.0–39.0] kg/m2) were included. Median weight reduction was − 8.1

The understanding of obesity is evolving from a perceived lifestyle-related condition to a chronic, biologically driven disease. Perception of obesity as a disease among health care professionals is important for effective evidence-based obesity care. Nurses have the most sustained patient contact and play an important role in obesity prevention and management, yet their role in this context remains underexplored. We therefore assessed the perceptions and attitudes towards obesity and obesity care in a Slovenian nursing care cohort. Non-interventional, descriptive, cross-sectional study collecting data via an online survey system was distributed to nationwide membership of the Nurses and Midwives Association of Slovenia via their digital communication channels. The online questionnaire was active for three months. Data was integrated with previously obtained responses from physicians, to enable cross-professional comparison. The majority of respondents agreed that obesity is a disease (82.7

Second-generation incretin-based therapies have transformed the pharmacological management of obesity by inducing substantial and sustained weight loss. The weight-reducing effects are primarily mediated through appetite suppression, reduced energy intake, and modulation of eating behavior. While therapeutically beneficial, these mechanisms may also influence dietary quality, micronutrient exposure, and overall nutritional status, particularly in individuals with obesity, a population already characterized by a high prevalence of baseline nutritional inadequacy. This narrative review is intended to inform clinicians, clinical nutrition specialists and researchers involved in obesity management by summarizing baseline micronutrient vulnerability in obesity, synthesizing available evidence on dietary intake, biochemical micronutrient status, and nutrition-related clinical outcomes during incretin-based therapy, discussing plausible mechanisms linking these therapies to micronutrient risk, and outlining approaches to risk-stratified nutritional monitoring in clinical practice.

INTRODUCTION:Pregnancy concurrent with incretin-based medications is contraindicated due to unknown risk of teratogenicity, as is breastfeeding. The aim of this systematic scoping review was to investigate potential risks and benefits of incretin-based medications in relation to preconception, pregnancy, and postnatal health, and to propose expert guidelines for clinical practice. METHODS:An international expert multidisciplinary group was formed. Research questions relevant to women's reproductive health and incretin-based medications were refined collaboratively, utilizing a lifecourse approach. A systematic search was undertaken on July 23, 2025, across several databases and grey literature sources. Primary data from human studies were prioritized above animal studies. Titles, abstracts, and full text articles were screened independently by two authors. Data were extracted by two people independently using a pre-defined proforma and synthesized narratively. Consensus recommendations were made. RESULTS:Thirty-four articles were included in the evidence synthesis: 11 randomized trials, nine observational studies, two pharmacovigilance reviews, nine case reports/series, two animal studies, and one ex vivo study. No qualitative studies were identified. Evidence was found for 18/32 (56.3%) research questions. Most studies related to preconception or pregnancy usage; two addressed contraception, and one was about lactation. The sample size of exposed pregnancies ranged from 1 to 4267. Three studies reported exposure throughout pregnancy. Three studies investigated postpartum usage. One (animal) study had offspring data beyond birth. No studies reported an increase in congenital anomalies. CONCLUSION:Clinical practice and research recommendations were made based on current available evidence and evidence gaps, encompassing contraception, preconception, nutritional, pregnancy monitoring, lactation, and longer-term outcomes.

OBJECTIVE:We evaluated the efficacy of somapacitan in a 24-week, randomized, active-controlled study in patients with growth hormone deficiency (GHD) who experienced fatigue from daily growth hormone (GH) injections. METHODS:Twenty-nine adult patients with GHD, pretreated with daily GH for ≥5 years, who had reported treatment-related fatigue, were randomized to somapacitan or daily GH. Outcome measures were changes in treatment satisfaction assessed by Treatment Satisfaction Questionnaire for Medication-9, insulin-like growth factor-1 (IGF-1) standard deviation score, glucose and lipid parameters, body composition, bone mineral density (BMD), carotid intima media thickness, and reactive hyperaemia index, from baseline to week 24. RESULTS:The difference in change in Treatment Satisfaction Questionnaire for Medication-9 score for convenience was significant, in favor of somapacitan (estimated difference, somapacitan-daily GH [95% CI]:23.2 [7.9; 38.4] points, P = .004). No differences between treatment arms in estimated changes from baseline to study-end were observed for IGF-1 levels, glucose and lipid profile, visceral adipose tissue, fat mass (%), lean body mass, and vascular parameters. There was significant difference in BMD of the lumbar spine (estimated difference, somapacitan-daily GH [95% CI] -0.036 (-0.064, -0.009) gr/cm2, P = .011). CONCLUSION:In AGHD patients who were fatigued from the long-term daily GH injections, somapacitan was reported to be more convenient than daily GH. It was effective in maintaining IGF-1 levels and body composition, glucose, lipids, and vascular parameters, comparable to daily GH. Nonsignificant decrease in BMD with somapacitan could reflect a favorable increase in bone metabolic units, as previously observed in naïve patients with GHD during the initial 6-month period of GH therapy.

We report the case of a female patient with spinal muscular atrophy type 3c, low bone mineral density and multiple fragility fractures, successfully treated with teriparatide. She sustained a vertebral fracture at age 35 years while treatment naïve, and additionally, one vertebral fracture as well as an intertrochanteric right hip fracture during the 5-year treatment with oral bisphosphonates. A sequential 2-year treatment with teriparatide followed by a one-year treatment with oral bisphosphonate risedronate resulted in an overall 11-year fracture-free period and stable bone mineral density. Teriparatide is an osteoanabolic medication that effectively reduces vertebral and nonvertebral fractures in postmenopausal, male and glucocorticoid-induced osteoporosis, particularly in individuals at very high risk of fracture. In the context of neuromuscular disease, teriparatide proved effective in the treatment of osteoporosis in Duchenne muscular dystrophy. In contrast, the data for patients with spinal muscular atrophy are lacking. Further studies are needed to assess its role in this population.

IntroductionPrader-Willi syndrome (PWS) is the most prevalent cause of syndromic obesity. Obesity development in PWS is driven by dysfunction in neural pathways involved in satiety and reward, dysregulation in hormones regulating satiety and food intake, altered body composition and reduced energy expenditure, as well as the presence of various hormone deficiencies. As hyperphagia, satiety dysfunction and consequent food-seeking behaviors are intrinsic to PWS, obesity management can be challenging.Case seriesWe present a long-term follow-up of treatment with GLP-1 receptor agonist (GLP-1 RA) semaglutide in three patients with PWS without diabetes, one of whom had previously undergone metabolic surgery. Semaglutide treatment at dosages from 0.5 mg to 2 mg weekly demonstrated variable efficacy, from preventing further weight gain in patient 1, to achieving weight loss of up to 14.4% and 11% relative to baseline, in Patient 2 and Patient 3. It was well tolerated, even after metabolic surgery.ConclusionLong-term randomized placebo-controlled trials with larger sample sizes are needed to provide stronger evidence on the long-term efficacy and safety of semaglutide for obesity treatment in PWS as well as explore the potential synergistic effects of GLP-1 RA treatment combined with other therapeutic interventions.

Obesity is rising among women of reproductive age and significantly contributes to subfertility. If conception occurs, maternal obesity is associated with increased risks for both maternal and neonatal complications, with potential long-term effects on the offspring's health. Current clinical guidelines emphasize the importance of preconception weight optimization in women with obesity to reduce maternal and fetal risks. Amid the rising use of incretin-based anti-obesity medications, particularly among young women, their potential role in preconception care is receiving growing clinical and research interest. With unplanned pregnancies remaining common, incidental exposure during early pregnancy is becoming more likely. In parallel, there is increasing interest in the potential of these agents to support preconception weight loss and enhance fertility outcomes in women with obesity. This narrative review examines the current human evidence on GLP-1 and dual GLP-1/GIP receptor agonists approved for obesity treatment, focusing on their potential role in preconception care and addressing key safety considerations and challenges related to their use during the preconception period, as well as inadvertent exposure in early pregnancy.

CONTEXT:Relationship between obesity and the sense of taste is complex, with many inconsistent and conflicting findings that are largely methodology dependent. The impact of glucagon-like peptide-1 analogues on taste remains largely unaddressed. METHODS:In this 16-week, single-blinded, placebo-controlled study, 30 women with polycystic ovary syndrome (PCOS), aged 33.7 ± 6.1 years with a body mass index of 36.4 ± 4.4 kg/m2 were randomized to semaglutide 1.0 mg once weekly or placebo. Change in taste recognition was assessed by 16 strips impregnated with 4 different concentrations of the 4 basic tastes. Tongue biopsies were performed for gene expression analysis. Brain responses to visual cues of sweet and savory foods and to sweet solution dripping on the tongue were evaluated by functional magnetic resonance imaging. RESULTS:Semaglutide improved overall taste recognition score from 11.9 ± 1.9 points to 14.4 ± 1.0 points, with an estimated treatment difference of 2.5 points (95% CI, 1.7-3.3). The genes EYA, PRMT8, CRLF1, and CYP1B1, which are associated with taste signaling transduction pathways, neural plasticity, and renewal of taste buds, showed differential RNA expression by a multi-tiered analytical pipeline. Semaglutide decreased activation of putamen in response to visual food cues and increased activity in the angular gyrus of the parietal cortex in response to sweet solution after meal intake (semaglutide vs placebo, P < .001). CONCLUSION:In women with obesity and PCOS, semaglutide improved an overall taste recognition score, altered RNA expression in the tongue and modified brain activity in response to sweet and savory food cues and to tasting sweet solution.

The distinctive effects of maintaining the upper- (0-2) versus lower-normal (-2-0) range of IGF-1 SDS in adult growth hormone deficiency (AGHD) remain understudied. We conducted a cross-sectional study on 31 patients with AGHD receiving growth hormone replacement therapy (GHRT) with daily GH for >5 years, with a 2-year mean IGF-1 SDS ranging between -2 and +2. Patients were categorized into the upper- or lower-normal range IGF-1 SDS groups according to their 2-year mean. Associations of clinical characteristics, anthropometric parameters, laboratory tests, and vascular markers of subclinical atherosclerosis with the 2-year IGF-1 SDS range and 5-year mean IGF-1 SDS were explored. Long-term maintenance of upper-normal IGF-1 SDSs was more common in men and in patients with a longer duration of GHRT. Patients with tumor-related AGHD had a lower 5-year mean IGF-1 SDS. Long-term maintenance of IGF-1 SDS in the upper-normal range was associated with lower high-sensitivity C-reactive protein (hs-CRP) levels (median (25-75% range): 0.8 (0.6-1.1) vs. 1.8 (0.8-4.6); p = 0.005). Moreover, a negative correlation was identified between a hs-CRP and the 5-year mean IGF-1 SDS. The association between the upper-normal IGF-1 SDS range and lower body fat percentage lost significance after adjusting for sex, due to the higher proportion of male patients in the upper-normal IGF-1 SDS group. In conclusion, long-term maintenance of upper-normal IGF-1 SDSs was associated with male sex and reduced low-grade inflammation. Randomized controlled studies are needed to evaluate the long-term and sex-specific effects of targeting the upper- vs. lower-normal IGF-1 range in AGHD.

Arginine-vasopressin peptide (AVP) plays a critical role in water balance and osmoregulation. However, emerging evidence suggests that AVP’s actions may expand beyond its traditional role, significantly influencing metabolic regulation, including glucose homeostasis, insulin sensitivity, lipid metabolism and energy balance. Elevated AVP levels are seen in various metabolic conditions, such as insulin resistance, metabolic syndrome, type 2 diabetes (T2D) and obesity, further highlighting its potential role as a metabolic regulator. As AVP levels are regulated by hydration status, studies have proposed that chronic hypohydration and persistently elevated AVP levels may contribute to metabolic dysfunction, where increased hydration and therefore AVP suppression may lead to potential metabolic improvements. By analyzing data from animal studies, human observational research and interventional trials, this review evaluates the current evidence on the potential causal relationships and impact of AVP on metabolic regulation, as well as exploring the role of hydration in AVP-mediated metabolic outcomes.

Obesity is a complex disease marked by excessive, dysfunctional adipose tissue accumulation. Recent research underscores the pivotal role of brown adipose tissue (BAT) in metabolic health and its potential as a therapeutic target for obesity management. Emerging preclinical and clinical evidence suggests that second-generation anti-obesity drugs, especially dual agonists such as tirzepatide, may enhance BAT activity. Additionally, beige adipose tissue, derived from white adipose tissue (WAT), may contribute significantly to whole-body thermogenesis, yet its role remains underexplored. This investigator-initiated, randomized, placebo-controlled clinical trial aims to evaluate the effects of tirzepatide on BAT activity and WAT browning in premenopausal women with obesity. Thirty-four participants will be randomized 1:1 to receive either tirzepatide or a placebo for 24 weeks. Primary outcomes include changes in BAT volume and activity, assessed using 18F-FDG-PET/CT, MRI, and infrared thermography, as well as the induction of WAT browning, evaluated through changes in mRNA expression patterns and histomorphometric alterations in subcutaneous adipose tissue samples. Secondary outcomes will involve the assessment of whole-body composition, resting energy expenditure, and various metabolic health markers, correlated with thermogenic adipose tissue changes. Comparative analysis of BAT assessment methods will refine protocols for research and clinical use. This study is the first to systematically explore the potential of pharmacological obesity management to enhance BAT activity and induce WAT browning. Results may establish thermogenic adipose tissue augmentation as a novel mechanism of action for second-generation anti-obesity medications. ClinicalTrials.gov NCT06893211. Registered on 2025 March 25.