Menopause marks the end of a woman's reproductive life, and the transition to this stage is accompanied by profound physiological and metabolic changes. These include alterations in lipoproteins and various metabolites, such as lipids, fatty acids, and amino acids, resulting in a more atherogenic profile and, in some cases, an increased risk in cardiovascular disease (CVD). CVD remains the leading cause of death among women, and lipid profiles change substantially in postmenopause, representing a key sex-specific risk factor. Thus, elucidating the metabolic pathways affected during menopause is crucial to reducing the burden of menopause-related conditions. However, the underlying molecular mechanisms of this increased metabolic burden remain incompletely understood. Recent advances in metabolomic technologies, including mass spectrometry (MS), nuclear magnetic resonance (NMR), and computational tools, have greatly improved our ability to characterize these metabolic shifts. This review summarizes current knowledge on the metabolic changes associated with menopause and their implications for CVD development.

Growth and differentiation factor 15 (GDF-15) is a stress-responsive hormone secreted by various cell types in response to cellular stress. To regulate ingestive behaviour, suppress food intake, and induce nausea and vomiting during cellular stress, GDF-15 signals via a brainstem-restricted receptor, GFRAL. Elevated circulating GDF-15 levels serve as a biomarker of cellular stress and are increased in a wide range of diseases. GDF-15 has recently been established as a causal factor in cancer cachexia and GDF15-GFRAL antagonism is being pursued as a therapeutic strategy. Recent studies have highlighted a dynamic interplay between GDF-15 and the hypothalamus-pituitary-adrenal (HPA) axis, suggesting that GDF-15 acts as a sentinel hormone in stress responses. Here, we review the canonical role of GDF-15 in stress-related conditions and its potential impact on circadian regulation and HPA axis dysregulation. The review explores the potential activation of the HPA axis by GDF-15 and discuss the hypothesis that downstream glucocorticoid signalling may contribute to some of the cardiovascular, metabolic, immune, and musculoskeletal changes reported for GDF-15. Additionally, the review discusses the potential role of GDF-15 in adrenal insufficiency and its treatment and in adrenocortical carcinoma. In summary, this review aims to elucidate the role of GDF-15 in glucocorticoid homeostasis and adrenal disease in the context of the stress response.

Primary aldosteronism (PA), characterised by autonomous aldosterone excess, accounts for a substantial proportion of patients with hypertension, particularly those with resistant disease. Current clinical management is largely guided by a binary classification into unilateral and bilateral PA; however, accumulating clinical, pathological, and molecular evidence indicates that this framework inadequately captures the underlying biological heterogeneity. Variable surgical outcomes, biochemical recurrence following adrenalectomy, and refined aldosterone synthase (CYP11B2)-based histopathological classifications highlight PA as a disease spectrum driven by disrupted adrenal zonation, cellular plasticity, and diverse aldosterone-driving somatic mutations. Despite major advances in defining the molecular basis of PA over the past decade, most insights have been derived from bulk genetic analyses of surgically excised tissue, limiting resolution of cellular heterogeneity and disease evolution. In this review, we integrate current understanding of PA pathophysiology with recent advances in single-cell and spatial technologies that have transformed adrenal research. We outline key methodological approaches enabling high-resolution interrogation of adrenal development, tumour heterogeneity, and the adrenal microenvironment. Finally, we discuss the translational implications of single-cell insights for PA, including improved patient stratification, identification of pre-operative biomarkers, and the development of mechanism-based, genotype-informed therapies beyond conventional mineralocorticoid receptor antagonism. Collectively, these advances support a paradigm shift from lateralisation-based management toward precision approaches targeting the cellular and molecular drivers of aldosterone excess.

The medical management of obesity has been transformed by the introduction of obesity medicines (OMs), based on the actions of glucagon-like peptide-1 and other nutrient-stimulated hormones, enabling the achievement of unprecedented weight reduction through pharmacotherapy. Here we review our current understanding of key issues surrounding obesity treatment, weight reduction, and improving health for people living with obesity. Key gaps in our knowledge of fundamental aspects of energy homeostasis are identified with a focus on their translational importance for improving outcomes. We discuss the utility of weight and health metrics, heterogeneity in achievement of clinical outcomes, individualization of treatment targets and goals, strengths and limitations of clinical trial, observational and real-world data (RWD), opportunities for improving the joint use of lifestyle management and OMs, gaps in our understanding of the long-term safety and side effects of current and emerging medicines, and the potential negative effects of losing weight. Collectively, while not intended as guidance for treatment, this document highlights the considerable progress and new research opportunities for interrogating basic and clinical science with the goal of translating advances in endocrine science into optimized outcomes for a broad range of individuals along the continuum of the weight journey.

Conventional management of classic congenital adrenal hyperplasia (CAH) relies on glucocorticoid (GC) therapy, both to replace the cortisol deficiency and to reduce the production of upstream cortisol precursors and subsequent metabolites. To attenuate the disinhibited hypothalamic-pituitary-adrenal (HPA) axis under endogenous cortisol deficiency, GCs are often administered at supraphysiological doses and at non-physiological timings, particularly to blunt the HPA axis activation in the early morning before awakening. Long-term studies of adults with CAH show increased risk of co-morbidities, which are often associated with chronic excessive GC exposures. To maintain disease control and to mitigate the adverse effects of conventional therapy, alternative approaches have been trialed. Circadian delivery of hydrocortisone with modified-release preparations or continuous subcutaneous infusion achieves better control at the same or lower daily dose than hydrocortisone tablets. GC-sparing therapies, the first being the corticotropin-releasing factor type 1 receptor antagonist crinecerfont, offer a block-and-replace approach, with near-physiologic dosing of GCs and a second agent to reduce precursor accumulation. The melanocortin type 2 (ACTH) receptor antagonist atumelnant and the anti-ACTH antibody asedebart are in trials. This article reviews the historical background, genetics, pharmacology, and data supporting the use of alternative strategies, as well as the practical implications and limitations of these approaches in routine patient care. A new era of CAH management has arrived, and we provide a perspective on the path forward using new tools to address the remaining unsolved challenges.

Obesity is a growing global health challenge associated with major cardiometabolic complications. While bariatric surgery remains the most effective treatment for severe obesity, recent advances in incretin-based pharmacotherapy, multi-receptor agonists, and endoscopic bariatric procedures have substantially expanded therapeutic options. Beyond mechanical restriction, these interventions exert their effects through complex hormonal and neurophysiological mechanisms involving gut-brain signaling, gastric motility, and enteroendocrine adaptations. Gut-derived hormones, including ghrelin, glucagon-like peptide-1 (GLP-1), peptide YY (PYY), amylin, and leptin, play a central role in the regulation of hunger, satiation, and satiety by integrating nutrient sensing, vagal afferent signaling, and central hypothalamic pathways. Surgical procedures such as laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass induce profound and durable hormonal remodeling, whereas endoscopic sleeve gastroplasty primarily modulates gastric physiology with more modest and heterogeneous endocrine effects. Intragastric balloons induce a transient delay in gastric emptying and achieve moderate short-term weight loss, although their metabolic and weight-loss effects appear limited in durability. In parallel, GLP-1 receptor agonists and emerging multi-agonist therapies reproduce several post-bariatric hormonal adaptations and achieve clinically meaningful weight loss. In this review, we summarize current knowledge on digestive hormone physiology and provide an updated overview of the hormonal mechanisms underlying pharmacologic, endoscopic, and surgical bariatric interventions, highlighting their respective roles within a continuum of obesity treatment strategies.

Human development begins with the fusion of sperm and oocyte, yet the maternal genome plays a far more active and essential role than traditionally appreciated. This review critically examines the influence of maternal genetic integrity on embryogenesis and offspring health, emphasizing that the maternal genome is not merely a passive donor of half the DNA, but a vital architect of early life. We explore the role of maternal effect genes (MEGs) in orchestrating early zygotic development, detailing their functions in epigenetic regulation, mitochondrial dynamics, DNA repair, and cell division. A curated reference of MEGs, spanning mouse models and human pathogenic variants, is presented to support future research and clinical diagnostics. Beyond early embryonic development, maternal genetic integrity has lasting implications for offspring well-being. Errors in DNA replication and repair machinery within the maternal germline can lead to de novo variants (DNVs)-spontaneous germline variants that can be passed on to the offspring and impact their health at different ages. We highlight an underappreciated contribution of maternally derived DNVs to a growing list of sporadic disorders and present the first comprehensive catalogue of associated diseases. We further examine DNVs compatible with multigenerational transmission, investigating how maternal age and mutational processes-such as recombination errors and epigenetic drift-influence both disease risk and evolutionary outcomes. By integrating insights from developmental biology, genomics, and reproductive medicine, this review reframes the maternal genome as a dynamic and fragile foundation upon which life depends-offering new directions for understanding fertility, sporadic disease, and intergenerational health.

Immune checkpoint molecules (ICMs) are a class of surface proteins predominantly expressed on immune cells that play a key role in maintaining immune homeostasis by regulating the functions of T cells and other immune cells. Beyond their established immunoregulatory roles, emerging evidence indicates that ICMs are also involved in metabolic regulation. Within the tumor microenvironment (TME), tumour-derived ICMs have been shown to modulate glucose, amino acid, and lipid metabolism in infiltrating T cells, thereby influencing their metabolic reprogramming and functional states. Certain ICMs expressed on immune cells may directly regulate systemic metabolism through cell-intrinsic, immune-independent mechanisms. Moreover, specific ICMs are constitutively expressed in key metabolic tissues, such as pancreatic islets, liver, and adipose tissue, where they are thought to contribute to the maintenance of systemic metabolic homeostasis. Clinically, host metabolic status can affect the efficacy of immune checkpoint inhibitor (ICI) therapies. Conversely, ICI treatment can lead to metabolism-related adverse effects, such as ICI-associated diabetes (ICI-DM), which may extend beyond classic autoimmune insulin-dependent diabetes. Accumulating evidence suggests that ICMs can exert direct regulatory roles in metabolism independent of their canonical immune functions. Elucidating how ICMs regulate metabolism could, on the one hand, improve ICI therapy by maintaining metabolic homeostasis and preventing T cell exhaustion, and on the other hand, facilitate the development of novel therapeutic strategies for metabolic diseases that simultaneously target metabolic and inflammatory pathways. This review synthesises current knowledge on the metabolic roles and regulatory mechanisms of ICMs.

The prevalence of obesity is steadily increasing worldwide. Obesity profoundly alters the composition, structure, and function of adipose tissue (AT), the largest endocrine organ in the body. Adipose-derived mesenchymal stem cells (ASCs) are central to AT plasticity and become dysfunctional in obesity. In this review, we outline the molecular regulation of ASCs in self-renewal and differentiation, and their roles in regulating AT expansion, modulating immune and inflammatory response, and remodeling the extracellular matrix (ECM), positioning ASCs as decisive homeostatic regulators of AT. By integrating recent findings from cutting-edge studies and performing extensive bioinformatic analyses, we delineate ASC differentiation trajectories and propose a fundamentally revised view of ASCs with a heterogeneous hierarchy of functionally distinct subpopulations. Obesity impairs ASC subsets in their self-renewal and differentiation, driving fibro-inflammatory phenotypes that promote maladaptive immune response, ECM stiffening and fibrosis, and premature cellular senescence, acting as central hubs of obesity-associated tissue dysfunction. These alterations likely arise from reprogrammed ASC epigenomic landscapes and obesogenic niches characterized by an inflammatory milieu, toxic metabolites, and oxidative stress. Interestingly, substantial weight loss attenuates fibro-inflammatory stromal states and partially restores ASC pools, whereas fibrosis-associated transcriptional programs and niche memory persist, indicating incomplete reversal of obesity-induced stromal remodeling. Drawing on human, mouse, and experimental single-cell datasets, we provide mechanistic insights into the ASC-immune cell-ECM regulatory network, highlighting how obesity reshapes ASC identity, lineage trajectories, and niche signaling. Finally, we propose that therapeutic restoration of ASC plasticity may represent a promising strategy to reestablish AT homeostasis and limit the progression of metabolic disease.

Obesity is an alarmingly growing global epidemic strongly associated with type 2 diabetes, cardiovascular disease, metabolic syndrome, and chronic kidney disease. Metabolic dysfunction-associated steatotic liver disease (MASLD) is considered an important contributor within this interconnected spectrum, representing a new component of the broader cardio-kidney-metabolic (CKM) syndrome, now more aptly labelled as the cardio-kidney-liver-metabolic (CKLM) syndrome. This narrative review synthesizes evidence from epidemiological studies, clinical trials, and ongoing scientific research to explore the multifaceted associations, complex interplay and shared pathophysiological mechanisms among these disorders. The clinical implications of this interplay are substantial, underscoring the need for a holistic approach encompassing early detection, comprehensive risk assessment, and multi-targeted interventions. Therapeutic strategies discussed include lifestyle modification, anti-diabetic, anti-obesity, lipid-lowering agents, and bariatric surgery. Given MASLD's potential role in the CKLM spectrum, future research should deepen the understanding of shared mechanisms and develop integrated clinical management strategies to improve outcomes and reduce their global burden.

Congenital pituitary hormone deficiency (CH) is a rare disorder that usually involves deficient production of growth hormone (GH) and other pituitary hormones. Many cases are syndromic, affecting other aspects of craniofacial development and sometimes other organs. There are many genes implicated in congenital pituitary hormone deficiency, and some of them also cause more severe disorders like septo-optic dysplasia (SOD) and holoprosencephaly (HPE). It is not clear why mutations in the same gene can cause such variable clinical features. In addition, the molecular etiology of many cases is not identified with current genetic testing approaches. To realize the promise of the human genome project, more genetic causes need to be identified, and the basis for variable clinical presentations needs to be better understood. In this review we provide information about the overlapping genetic causes of this spectrum of disorders in humans, discuss the influence of genetic background and environment on presentations, and highlight animal models that expand our understanding of how genetic and environmental factors can synergize to generate diverse phenotypes. Evidence for genetic and environmental contributions to this spectrum of disorders is strong.

The textbook view of the regulation of calcium homeostasis centers on parathyroid hormone, calcitriol, and calcitonin. While this paradigm has long dominated the field, it represents only part of a broader evolutionary and physiological landscape. This article focuses on Stanniocalcin 1 (STC1), a calciotropic hormone originally discovered in bony fish. Since its discovery in the 1970s, our understanding of STC1 has evolved from a "fish-specific" hormone to a member of a multifunctional glycoprotein family with deep roots in metazoan evolution. Recent studies in zebrafish show that STC1 inhibits calcium uptake through two mechanisms: it reduces TRPV6-dependent calcium influx and limits the proliferation of calcium-transporting ionocytes. Mechanistically, STC1 suppresses local insulin-like growth factor (IGF) signaling by binding pappalysin-family IGF-binding protein (IGFBP) proteases, thereby modulating IGFBP processing and downstream IGF activity. This STC1-Pappalysin-IGFBP-IGF axis has recently been positioned as a central node in an organ-brain communication pathway that links calcium uptake to brain function and animal behavior. In humans and other mammals, STC1 is expressed in many tissues locally and exerts local actions in a paracrine fashion. Dysregulation of STC1 expression has been associated with chronic kidney diseases and multiple cancer types. Recent studies have uncovered a novel role for STC1 in tumor immune evasion as a phagocytosis checkpoint and a "don't eat me" signal. This review integrates recent findings on the multifunctional roles of STC1 in regulating calcium homeostasis, IGF signaling, and cancer immunity, and to highlight the therapeutic potential of targeting STC1 in kidney diseases and cancer immunotherapy.

Cardiovascular-kidney-metabolic (CKM) syndrome represents an intricate and interdependent nexus among metabolic risk factors, such as diabetes and obesity, chronic kidney disease (CKD), and cardiovascular disease (CVD), collectively exerting a profound impact on global morbidity and mortality. The rising prevalence of type 2 diabetes (T2D) underscores the urgent need for therapeutic strategies that transcend glycemic control to target the intricate pathophysiology underlying these conditions. This review examines the expanding role of novel antidiabetic drug classes, including sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dual or triple-incretin agonists, across the CKM continuum. These agents have demonstrated significant benefits in reducing major adverse cardiovascular events (MACEs), attenuating CKD progression, and enhancing metabolic health, independent of their glucose-lowering properties. Across the CKM continuum, we prioritize weight-centric incretin therapy (GLP-1RAs or dual incretins) in stage 0-1 (obesity/prediabetes), SGLT2 inhibitors first for albuminuric CKD and/or heart failure risk in stage 2 (with early addition of GLP-1RAs when CVD/obesity predominates), and layered combination therapy in stage 3, typically SGLT2 inhibitor + GLP-1RA/dual incretin (± finerenone for persistent albuminuria), to maximize cardiovascular and kidney protection. By synthesizing evidence from pivotal clinical trials, evaluating emerging combination therapies, and delineating the evolving treatment paradigm, this review aims to provide a comprehensive perspective on how these antidiabetic therapies influence CKM syndrome management. As research advances, an integrated, multifaceted approach to diabetes care leveraging these agents may lead to substantial improvements in cardiovascular, kidney, and metabolic outcomes.

Endocrine tissues must continuously adjust their structure and function in response to circadian cues, metabolic state, and physiological stress. Within these dynamic systems, stem cells contribute not only to tissue maintenance and repair but also to functional plasticity. The hypothalamic-pituitary-adrenal (HPA) axis exemplifies this integration of local stem cell regulation with systemic endocrine control. In this Review, we highlight the shared regulatory principles and tissue-specific adaptations of stem cell populations across the hypothalamus, anterior pituitary and adrenal gland. We discuss tanycytes as hypothalamic stem cells, SOX2+ stem cells as key regulators of pituitary plasticity, and multipotent and lineage-restricted progenitors that sustain adrenal cortical and medullary renewal. Across HPA axis organs, conserved signaling pathways and multiple modes of cell-cell communication, including paracrine and feedback mechanisms, coordinate stem cell behavior with endocrine output. Importantly, we present growing evidence that endocrine stem cells influence organ function beyond direct cell replacement, shaping tissue responsiveness, and adaptation to physiological demand. Disruption of these processes contributes to endocrine dysfunction and tumorigenesis. Integrating insights from genetic models, human single-cell and spatial atlases, we outline how viewing the HPA axis as an integrated stem cell system provides a framework for understanding endocrine plasticity and identifies emerging opportunities and challenges for regenerative and therapeutic strategies.