Menopause, particularly the consequences of severe symptoms, has become the subject of intense media interest. Reducing the prevalent stigma around women's reproductive health has allowed more women to speak openly about...Menopause, particularly the consequences of severe symptoms, has become the subject of intense media interest. Reducing the prevalent stigma around women's reproductive health has allowed more women to speak openly about their menopause experiences, the effects on their lives and the barriers they face. These effects are far-reaching and illustrate the importance of improving the understanding, management and awareness of severe menopausal symptoms. The cardinal symptoms are hot flushes (or flashes) and night sweats (vasomotor symptoms), although symptoms can vary by ethnicity. For example, some Asian women report other primary symptoms (such as bone and/or joint pain). Vasomotor symptoms affect around 70% of perimenopausal and postmenopausal women and are moderate or severe in around one-third of these women. The US Food and Drug Administration considers vasomotor symptoms to be severe if they cause the person to stop their current activity. Severe vasomotor symptoms drive treatment seeking and can affect quality of life, mental health and work ability. We review the incidence, management and potential long-term health consequences of severe vasomotor symptoms, including cardiovascular disease, diabetes mellitus, cognitive dysfunction, bone health and quality of life. We discuss potential underlying mechanisms and the efficacy of available treatments. Finally, we highlight the evidence gaps in this field and directions for future research.
BACKGROUND: Real-time continuous glucose monitoring (RT-CGM) is widely used in patients with type 1 diabetes (T1D) to improve glycemic control by reducing postprandial glucose peaks and hypoglycemic episodes. In addition...BACKGROUND: Real-time continuous glucose monitoring (RT-CGM) is widely used in patients with type 1 diabetes (T1D) to improve glycemic control by reducing postprandial glucose peaks and hypoglycemic episodes. In addition, traditional biomarkers such as glycated hemoglobin (HbA1c), glycated albumin, and fructosamine provide retrospective estimates of glucose regulation over varying timeframes. This study aimed to evaluate the correlation between these biomarkers and glycemic metrics obtained from two types of RT-CGM systems: an implantable sensor (Eversense E3) and subcutaneously inserted sensors (Dexcom G6 and Guardian 4). METHODS: We analyzed data from 35 patients with T1D: 13 used the Eversense E3 system, and 22 used Dexcom G6 or Guardian 4. Mean blood glucose (MBG) and time in range (TIR) were assessed at multiple time points and correlated with HbA1c, glycated albumin, and fructosamine levels. RESULTS: In the Eversense group, no significant correlation was observed between CGM-derived metrics and any of the biomarkers. Conversely, in the Dexcom/Guardian group, MBG and TIR demonstrated significant correlations with all biomarkers, showing large effect sizes for HbA1c and fructosamine, and medium for glycated albumin. CONCLUSIONS: These findings suggest that the Dexcom G6 and Guardian 4 systems more reliably reflect established biochemical markers of mid- to long-term glucose control, while Eversense may be less consistent in this regard. This highlights the importance of sensor selection when interpreting CGM data for clinical or research applications in diabetes management.
Growth hormone (GH) controls sexual dimorphism in hepatocyte gene expression programs governing lipid metabolism, bile acid synthesis and xenobiotic processing, which contribute to sex differences in metabolic dysfunctio...Growth hormone (GH) controls sexual dimorphism in hepatocyte gene expression programs governing lipid metabolism, bile acid synthesis and xenobiotic processing, which contribute to sex differences in metabolic dysfunction-associated steatotic liver disease (MASLD) risk. Although GH-regulated sex-specific transcription is well-studied, the functional cis-regulatory hepatocyte enhancers that orchestrate these sex-dependent metabolic programs remain largely unknown. Here, we integrated single-nucleus multiomic profiling of hepatocyte chromatin accessibility with in vivo functional enhancer assays to identify and validate GH-responsive, sex-biased hepatocyte enhancers in intact mouse liver. We constructed a tiled HDI-STARR-seq library of 23 912 reporters spanning 1839 liver ATAC regions and delivered it to liver by hydrodynamic injection, enabling enhancer activity assessment across different biological conditions. Reporters representing 840 ATAC regions showed sex-biased and/or GH-regulated enhancer activity, in many cases mirroring regulation of their accessibility in hepatocyte chromatin, validating them as functional, physiologically regulated enhancers. The regulated enhancer sequences were enriched for activating histone marks (H3K27ac, H3K4me1), and for binding sites for the STAT5-dependent, sex-specific repressors BCL6 and CUX2; whereas, STAT5 binding was enriched at both regulated and non-regulated enhancers. Motifs for HNF4A and for several novel factors identified de novo were specifically enriched at the regulated enhancers. Sex-biased and GH-regulated enhancers were linked to both MASLD-enabling and MASLD-protective genes, suggesting that GH-dependent chromatin remodeling at these loci contributes to sex-differential metabolic disease susceptibility. This integrated in vivo approach defines a validated set of GH-regulated hepatocyte enhancers through which chromatin accessibility and transcription factor binding drive sexual dimorphism in hepatic metabolism and MASLD risk.
Chen SY, Cen HH, Chao CF
… +3 more, Pepper AR, Johnson JD, Rideout EJ
Endocrinology
· 2026 Apr · PMID 41866299
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The clinical characteristics of type 2 diabetes (T2D) differ between the sexes. For example, the risk of T2D is higher in males than in premenopausal females, whereas the risk of T2D-associated cardiovascular disease is...The clinical characteristics of type 2 diabetes (T2D) differ between the sexes. For example, the risk of T2D is higher in males than in premenopausal females, whereas the risk of T2D-associated cardiovascular disease is higher in females. Notwithstanding, the sex-dependent mechanisms of T2D pathogenesis remain incompletely understood. Publicly available human islet datasets, such as HPAP and Humanislets.com, are valuable tools for uncovering the impact of biological sex on islet structure, gene expression, and function at a scale that was not previously possible. We performed integrated analyses of data from public sources to identify sex differences in baseline islet characteristics in donors without diabetes and also in donors who lived with T2D. Among donors without diabetes, female islets had a greater proportion of alpha-cells compared with male islets and showed enriched expression of ribosomal and mitochondrial pathways in both beta-cells and alpha-cells. Measurements of mitochondrial function in female islets revealed lower spare respiratory capacity compared with male islets. Male and female islets had distinct changes in gene and protein expression in the context of T2D with female islets having greater preservation of insulin content and fewer defects in islet function. Together, these data show female islets have fewer impairments in T2D. This highlights the need for detailed mechanistic studies in both sexes to support effective and sex-informed interventions for T2D.
Survodutide represents an innovative approach to obesity management and metabolic-associated fatty liver disease (MAFLD). These conditions, often closely linked with type 2 diabetes (T2DM) and cardiovascular diseases, de...Survodutide represents an innovative approach to obesity management and metabolic-associated fatty liver disease (MAFLD). These conditions, often closely linked with type 2 diabetes (T2DM) and cardiovascular diseases, demand effective treatment strategies. Survodutide acts by targeting both GLP-1 and glucagon receptors. This new dual agonist offers potential transformative benefits, with early clinical trials showcasing significant weight loss and improvements in metabolic markers. Survodutide's mechanism of action includes appetite regulation, enhanced glucose metabolism, and increased energy expenditure, making it a promising option for those struggling with obesity and related health issues. This review assesses Survodutide's pharmacology, efficacy, and safety in MASH and obesity, while also outlining its broader metabolic and cardiovascular benefits. It compares Survodutide's dual-agonist mechanism and clinical performance with single-target incretin therapies to clarify its potential role in the evolving treatment landscape. While the initial results are promising, the review emphasizes the importance of continued research to fully understand Survodutide's long-term safety and effectiveness. Ongoing trials will provide critical insights into its overall impact, side effects, patient response, and cost considerations. This article highlights Survodutide's potential in the treatment of obesity and metabolic disordersand evaluates its place in therapy for seeking improved outcomes.
Tahor M, Kuperman Y, Nahum T
… +7 more, Tsoory M, Bejar B, Regev E, Blechman J, Biran J, Chen A, Levkowitz G
Endocrinology
· 2026 Mar · PMID 41840852
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Orthopedia (Otp) transcription factor is a critical determinant in the development of the neuroendocrine hypothalamus, and its embryonic deletion results in lethality. Although Otp expression is maintained throughout lif...Orthopedia (Otp) transcription factor is a critical determinant in the development of the neuroendocrine hypothalamus, and its embryonic deletion results in lethality. Although Otp expression is maintained throughout life, its physiological function in adulthood is not well understood. Here, we generated a forebrain-specific, tamoxifen-inducible, conditional knockout mouse model to investigate the roles of Otp beyond development. Conditional deletion of Otp in 2-month-old mice resulted in impaired stress responses, characterized by increased depressive-like behavior and elevated stress-induced cortisol levels. It also led to various metabolic changes, including reduced thyroid hormone levels and body temperature, a higher percentage of fat mass and diminished responsiveness to ghrelin without affecting food intake, energy expenditure, or body weight. This composite metabolic phenotype was associated with reduced expression of hypothalamic neuropeptides TRH, AgRP, and NPY. Our findings highlight the role of Otp in adult physiological functions as a key neuroendocrine integrator of adaptive stress response and energy balance.
The lymphatic vasculature is recognized for its roles in immunity, lipid transport and fluid homeostasis, but has been ignored, until recently, for its involvement in adipose tissue metabolism, obesity and associated com...The lymphatic vasculature is recognized for its roles in immunity, lipid transport and fluid homeostasis, but has been ignored, until recently, for its involvement in adipose tissue metabolism, obesity and associated comorbidities. States of overnutrition, such as in obesity, are associated with impairment of lymphatic function, leading to localized lymphoedema, adipogenesis and insulin resistance. Conversely, compromised lymphatic vasculature integrity can induce adiposity and accelerate insulin resistance. Through the use of advanced 'omics' and bioinformatic technologies coupled with functional experiments in cells, mice and humans, we now know that the lymphatic system is more than just a transport conduit and is intimately involved in tissue and organ homeostasis, including in adipose tissue. In this Review, we summarize the interconnected causes of obesity and lymphatic dysfunction with a particular focus on delineating the underappreciated yet fundamental crosstalk between the lymphatic network and white and brown adipose tissues. We also synthesize information on lymph-directed therapeutic strategies that have the potential to transform outcomes in obesity.
Cooke M, Elyoussef Y, Abba MC
… +1 more, Kazanietz MG
Endocrinology
· 2026 Mar · PMID 41834655
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Effector kinases of the lipid second messenger diacylglycerol (DAG), including protein kinase C (PKC) and protein kinase D (PKD) isozymes, have been widely implicated in the development and progression of prostate cancer...Effector kinases of the lipid second messenger diacylglycerol (DAG), including protein kinase C (PKC) and protein kinase D (PKD) isozymes, have been widely implicated in the development and progression of prostate cancer. By acting as central hubs of growth factor-mediated signaling, these kinases integrate oncogenic signals with the androgen receptor (AR) pathway, contributing to prostate tumor growth. Distinct members of the DAG-regulated kinases contribute to the acquisition of castration-resistant prostate cancer (CRPC) and bypass AR dependence, promoting the proliferative, migratory, and invasive competencies of androgen-independent prostate cancer cells. As predicted from their coupling to signaling cascades that impact gene expression, PKC/PKD isozymes control the activation of transcription factors such as NF-κB, E2F, and STAT3, and additionally regulate epithelial-to-mesenchymal transition (EMT) transcription factors in prostate cancer cells, providing an additional layer of control in invasive signaling. The aberrant expression/activation of DAG-regulated kinases during prostate cancer progression results in pronounced deregulation and rewiring of transcriptional networks associated with cell cycle control, invasiveness, and cancer cell interactions with the tumor microenvironment (TME). The multifaceted regulation of nuclear functions by these pleiotropic kinases underscores their convoluted roles in prostate cancer development and progression, offering new opportunities for therapeutic targeting.
Amylin is a peptide hormone co-secreted with insulin from pancreatic β-cells that plays a crucial role in glucose homeostasis. Amylin by inhibiting glucagon secretion, slowing gastric emptying, and reducing food intake i...Amylin is a peptide hormone co-secreted with insulin from pancreatic β-cells that plays a crucial role in glucose homeostasis. Amylin by inhibiting glucagon secretion, slowing gastric emptying, and reducing food intake improves blood glucose and insulin sensitivity. However, emerging evidence suggests that amylin may also contribute to β-cell dysfunction and the development of insulin resistance (IR) in type 2 diabetes (T2D). This review explores the dual roles of amylin in T2D pathogenesis and management, highlighting its therapeutic and pathogenic implications. High amylin levels are associated with amyloid fibril formation, β-cell cytotoxicity, and progression of T2D complications. Conversely, amylin analogues have been shown to improve glycemic control, promote weight loss, and enhance energy balance via dual activation of amylin and calcitonin receptors in the hypothalamus. Experimental and clinical data demonstrate that both detrimental and protective effects of amylin are depending on concentration, duration, and receptor interaction. Amylin and its analogues exhibit paradoxical actions in T2D, acting as both pathogenic and protective effects. While preclinical and limited clinical studies support their role in improving metabolic control, concerns about amyloidogenic toxicity persist. Therefore, further robust clinical trials are needed to clarify amylin's long-term safety and optimize its therapeutic potential in T2D management.
Refael T, Golan G, Darsa D
… +4 more, Pnueli L, Chakravarty P, Rizzoti K, Melamed P
Endocrinology
· 2026 Apr · PMID 41823422
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A large "gene desert" located far upstream from Fshb and Kcna4 contains several gonadotrope-specific accessible chromatin sites that were seen in chromatin conformation capture to make distinct contacts with both genes....A large "gene desert" located far upstream from Fshb and Kcna4 contains several gonadotrope-specific accessible chromatin sites that were seen in chromatin conformation capture to make distinct contacts with both genes. Expression of Fshb and Kcna4 was strongly inhibited by JQ-1, which represses super-enhancer activity, and the region displays super-enhancer characteristics. The sites of open chromatin were seen, in chromatin immunoprecipitation, to bind Brd4 and Med1, most notably at a site -67 kb from the Fshb gene, as well as binding Ctcf further upstream (-123 kb), all of which were increased following activin exposure. The locus is transcribed to chromatin-associated long noncoding RNAs whose levels correlate with Fshb and Kcna4 mRNA levels in vivo and in cultured gonadotrope cells, indicating coordinated regulation. CRISPR interference confirmed distinct functions for each element and, together with the chromatin conformation capture data, indicate that the -67 kb locus mediates basal and activin-stimulated Fshb expression, whereas the site at -59 kb contributes to activin-stimulation of both genes. Single-cell multiomics revealed that the -67 kb locus is accessible in pituitary stem cells and throughout gonadotrope differentiation, preceding opening of the Fshb promoter, although it is closed in other differentiated cell types, suggesting a gonadotrope-specific factor that keeps it open at this stage. Foxl2 was found to bind this element, contributes to maintaining its chromatin accessibility, and recruits Supt16h, a component of the Facilitates Active Chromatin Transcription histone chaperone complex. These findings define a distal, Foxl2-bound super-enhancer that regulates Fshb transcription and shapes the gonadotrope regulatory landscape.
Anees M, Fugate MK, Bhasin S
… +3 more, Pandey D, Chowdhury S, Jasuja R
Endocrinology
· 2026 Mar · PMID 41817210
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BACKGROUND: Circulating estradiol is predominantly protein-bound, with human serum albumin (HSA) serving as its major carrier. While traditionally considered a carrier with low affinity and readily reversible binding at...BACKGROUND: Circulating estradiol is predominantly protein-bound, with human serum albumin (HSA) serving as its major carrier. While traditionally considered a carrier with low affinity and readily reversible binding at a single site, the molecular details and kinetics of estradiol-HSA interactions remain incompletely understood. METHODS: We employed equilibrium dialysis, steady-state and time-resolved fluorescence spectroscopy to characterize estradiol-HSA interactions. Surface plasmon resonance (SPR) was used to elucidate the kinetics of estradiol's association and dissociation with HSA. Structural and energetic features of binding were investigated using molecular docking and structure network analyses. RESULTS: Binding isotherms generated using equilibrium dialysis, steady-state and time-resolved fluorescence spectroscopy revealed nonlinear asymmetric binding with apparent Kd that varied as a function of estradiol and HSA concentrations, inconsistent with canonical model of low-affinity, single-site interaction characterized by a fixed Kd. Kinetic analyses by SPR revealed initial rapid association dynamics followed by a slower second phase. Molecular modeling identified a high-affinity estradiol-binding pocket in Sudlow's Site I and two additional low-affinity sites within a highly interconnected hub of structural blocks. Spatially coordinated conformational rearrangements accompanying estradiol partitioning into the high-affinity pocket of Sudlow's Site I and two additional moderate-affinity sites suggest an allosterically-coupled binding architecture that enables albumin to actively regulate estradiol bioavailability across a broad, physiologically relevant concentration range. CONCLUSION: Estradiol's binding to HSA is a dynamic, multi-equilibrium process driven by ligand-induced conformational rearrangements within HSA; the binding data are inconsistent with canonical model of estradiol-HSA interaction with 1:1 stoichiometry and a fixed Kd.
This narrative Review explores the role of hyperinsulinaemia as a potential independent contributor to obesity and cardiometabolic diseases. We argue that scientific discussions about the role of hyperinsulinaemia as a c...This narrative Review explores the role of hyperinsulinaemia as a potential independent contributor to obesity and cardiometabolic diseases. We argue that scientific discussions about the role of hyperinsulinaemia as a causal factor in these conditions have not sufficiently distinguished between postprandial insulin excursions and chronically elevated basal levels of insulin. We summarize findings from observational and experimental human trials, as well as preclinical models, and outline how reasonable evidence suggests that chronic (basal) exposure to elevated levels of insulin, rather than normal postprandial insulin excursions in isolation, might have a role in promoting or exacerbating the development of adiposity. We discuss the putative contributors to hyperinsulinaemia, including genetic predisposition, early-life influences, diet, environmental pollutants and physical inactivity, highlighting causality knowledge gaps relevant to the prevention of obesity and cardiometabolic diseases.
Weidner AE, Vann K, Hodowanec AI
… +5 more, Ivey D, Roy A, Sechrist ZR, Cole CL, Astapova O
Endocrinology
· 2026 Apr · PMID 41802922
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Polycystic ovary syndrome (PCOS) is a systemic endocrine disorder characterized by perturbations in both androgen and insulin signaling pathways that result in anovulatory infertility and metabolic syndrome. This study a...Polycystic ovary syndrome (PCOS) is a systemic endocrine disorder characterized by perturbations in both androgen and insulin signaling pathways that result in anovulatory infertility and metabolic syndrome. This study aimed to elucidate insulin signaling in the PCOS ovary using a mouse model that develops both the metabolic and reproductive manifestations of PCOS due to chronic postnatal dihydrotestosterone exposure. PCOS mice developed anovulation, cystic follicles, systemic insulin resistance with compensatory hyperinsulinemia and mild excess adiposity, but not hepatic steatosis, adipose inflammation or frank obesity, suggesting that hyperandrogenism is the main driver of the metabolic perturbations in this model. Insulin signaling was then assessed in the ovary, liver, and skeletal muscle from hyperinsulinemic, fasting PCOS mice. Ovarian theca and granulosa cells showed upregulated markers of insulin signaling, while the liver and skeletal muscle from the same mice showed no changes compared to controls. However, cultured primary PCOS hepatocytes were profoundly insulin resistant in vitro, while primary theca cells (TCs) and granulosa cells (GCs) isolated from the same PCOS mice were insulin sensitive. Both PCOS TCs and GCs produced significantly more steroid hormones than control cells when stimulated with insulin and gonadotropins. Our findings indicate that the PCOS ovary remains sensitive to insulin despite systemic insulin resistance and that insulin works synergistically with gonadotropins to stimulate ovarian testosterone production in PCOS. We therefore suggest that insulin resistance is not merely a byproduct of hyperandrogenism but is a disease-driving factor in PCOS and should be treated as a clinical target in PCOS management.
BACKGROUND: Male obesity-associated hypogonadism promotes a vicious cycle of sarcopenic obesity and increased cardiometabolic risk. Although tirzepatide is highly effective for weight loss, a subset of "late responders"...BACKGROUND: Male obesity-associated hypogonadism promotes a vicious cycle of sarcopenic obesity and increased cardiometabolic risk. Although tirzepatide is highly effective for weight loss, a subset of "late responders" has been reported, and treatment-induced lean body mass (LBM) depletion remains a significant clinical concern. This pilot study evaluated the efficacy of adding testosterone undecanoate (TRT) to tirzepatide in this specific population. METHODS: We enrolled 10 obese men (age range: 35-44 years; Body Mass Index [BMI] = 35.8±2.1 kg/m) with functional secondary hypogonadism after ≥3 months of treatment with tirzepatide and <5% total body weight loss (late responders). Patients were then allocated to group A (tirzepatide monotherapy, N.=5) or group B (combined tirzepatide plus testosterone undecanoate 1000 mg/im, N.=5) and re-evaluated after 6 months. DXA-derived body composition, hormonal and metabolic profiles, sexual function (International Index of Erectile Function-5, IIEF-5), and physical activity levels (Global Physical Activity Questionnaire) were evaluated. RESULTS: At 6 months, group B demonstrated significantly greater body weight and fat mass reduction compared to group A (P<0.05). Notably, while group A experienced progressive LBM loss, group B achieved significant LBM recovery (66.1±3.1 kg vs. 63.4±3.0 kg in group A, P<0.01). group B showed restored testosterone levels, leading to superior improvements in insulin sensitivity (HOMA-IR: 2.9±0.6 vs. 3.8±0.7, P<0.01) and sexual health (IIEF-5: 23.2±2.1 vs. 18.0±1.5, P<0.001). Additionally, group B exhibited nearly doubled physical activity levels (P<0.001), suggesting a synergy between hormonal restoration and increased exercise motivation. CONCLUSIONS: Our preliminary findings suggest that adding TRT to tirzepatide in late tirzepatide responders who are hypogonadal may optimize weight loss quality, prevent muscle depletion, and restore sexual and metabolic health. This dual pharmacological approach represents a promising precision medicine strategy for managing complex phenotypes of male obesity-associated hypogonadism.
Baak R, Westland D, de Lange E
… +2 more, Houtman R, Kalkhoven E
Endocrinology
· 2026 Apr · PMID 41793069
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Full text
Missense mutations in nuclear receptor (NR) transcription factors cause a number of genetic disorders, including PPARG mutations that result in familial partial lipodystrophy type 3 (FPLD3). Experimental assessment is es...Missense mutations in nuclear receptor (NR) transcription factors cause a number of genetic disorders, including PPARG mutations that result in familial partial lipodystrophy type 3 (FPLD3). Experimental assessment is essential to establish a newly identified mutation as disease-causing, as accurately predicting the effect of a new mutation in silico remains challenging due to the multifunctional and modular nature of these proteins. However, deep structure-function characterization often requires specialized and technically demanding approaches, which may not be readily available. Therefore, we established a simple and robust experimental framework based on 4 complementary reporter assays that independently assess (1) ability of the full-length receptor to activate transcription; (2) integrity of the ligand-binding domain; (3) heterodimerization potential; and (4) DNA-binding capacity. As a proof of concept, we analyzed 3 uncharacterized FPLD3-associated loss-of-function variants and 2 bladder cancer-associated gain-of-function variants. Together, the 4 complementary assays showed unique functional phenotypes for all 5 mutants that were further supported by coregulator profiling. We therefore conclude that this framework provides a simple and robust first-line approach to identify functional alterations in peroxisome proliferator-activated receptor γ mutants with mechanistic resolution. This framework is broadly applicable across NRs and offers a scalable path to systematic variant interpretation both in research and clinical contexts.