Endocrinology[JOURNAL]
Sun
200 papers
Advances in diagnosing and treating diabetic retinopathy.
Sivaprasad S, Vujosevic S
Nat Rev Endocrinol · 2026 May · PMID 42115318 · Publisher ↗
Diabetic retinopathy has traditionally been defined as a microvascular complication of diabetes mellitus; however, advances in retinal imaging, digital technologies and mechanistic insights have challenged this narrow vi...
Diabetic retinopathy has traditionally been defined as a microvascular complication of diabetes mellitus; however, advances in retinal imaging, digital technologies and mechanistic insights have challenged this narrow view. Increasing evidence indicates that neuronal and glial dysfunction and degeneration, neuroinflammation, capillary non-perfusion and metabolic dysregulation can occur early in the disease process and can precede or coexist with clinically apparent vascular abnormalities. These insights support the emerging concept of diabetic retinal disease (DRD), which encompasses the full spectrum of diabetes mellitus-related retinal pathology, with or without visible microvascular lesions. In this Review, we summarize the evolution of disease classification and advances made within the past 10 years in diagnostic imaging that enable more precise phenotyping and risk stratification of DRD. We also present a framework for a digitally enabled care pathway spanning screening, diagnosis, treatment and post-treatment follow-up. Finally, we discuss current therapies alongside emerging preventive and personalized treatment strategies that target both vascular and neuroretinal components across the full DRD disease continuum.
Obesity-cancer convergence in the destiny of an adipocyte.
Malara N, Aversa A, Riva F
Minerva Endocrinol (Torino) · 2026 May · PMID 42099193 · Publisher ↗
Abstract loading — click title to view on PubMed.
Acidic extracellular pH-induced PTH secretion in male mouse parathyroids is OGR1-dependent.
Yang Y, Chen M, Cui M … +2 more , Lashbrooks E, Wang B
Endocrinology · 2026 May · PMID 42089253 · Full text
The role of extracellular acidity in regulating PTH secretion in cultured mouse parathyroid glands (PTGs) has not been studied to date, largely because of the technical difficulty of isolating mouse PTGs. We hypothesized...
The role of extracellular acidity in regulating PTH secretion in cultured mouse parathyroid glands (PTGs) has not been studied to date, largely because of the technical difficulty of isolating mouse PTGs. We hypothesized that acidic extracellular pH directly stimulates PTH secretion through activation of a proton-sensing receptor, specifically ovarian cancer G protein-coupled receptor 1 (OGR1, also known as GPR68). To test this, we developed a method to reliably identify and isolate PTGs from male mice by administering 5-aminolevulinic acid, which induced selective fluorescence in these glands. Using this model, we demonstrate that acidic extracellular pH significantly stimulates PTH secretion in cultured mouse PTGs. Mechanistically, we identify OGR1 as the primary proton sensor mediating this response, as PTGs from OGR1 knockout mice failed to increase PTH secretion under acidic conditions, with no evidence of compensatory upregulation of other proton-sensing receptors. In addition, we found that low extracellular Ca2+ not only stimulates PTH secretion but also promotes extracellular acidification. Notably, low Ca2+ and acidic pH act synergistically to enhance PTH secretion in wild-type PTGs, an effect markedly attenuated in OGR1-deficient glands. Together, these findings establish a direct, OGR1-dependent mechanism by which extracellular acidity regulates PTH secretion and reveal an interaction between calcium and pH signaling in this process. This work provides a robust ex vivo model for studying PTG physiology and offers new insight into how metabolic acidosis may contribute to secondary hyperparathyroidism in chronic kidney disease, highlighting OGR1 signaling as a potential therapeutic target.
Perinatal organophosphate flame-retardant exposure alters adult stress axis and avoidance behavior in mice.
Rojas CM, DeLucca J, Brown CA … +4 more , Yasrebi A, Chiou S, Bello NT, Roepke TA
Endocrinology · 2026 May · PMID 42089252 · Full text
Organophosphate flame retardants (OPFRs) are ubiquitous flame-retardant additives with endocrine-disrupting properties. Despite increasing evidence that OPFRs affect neurodevelopment, their effects on the neuroendocrine...
Organophosphate flame retardants (OPFRs) are ubiquitous flame-retardant additives with endocrine-disrupting properties. Despite increasing evidence that OPFRs affect neurodevelopment, their effects on the neuroendocrine stress response remain poorly understood. To examine their long-term effect on stress regulation, we treated pregnant C57Bl/6J dams to a mixture of tris(1,3-dichloro-2-propyl) phosphate (TDCPP), triphenyl phosphate (TPP), and tricresyl phosphate (TCP; 1 mg/kg each) from gestational day (GD) 7 through postnatal day (PND) 14. Adult offspring (age 8-9 weeks) were then challenged with acute stressors, including 1-hour restraint or a 6-day acute variable stress (AVS) paradigm. Perinatal OPFR exposure produced persistent, sex-specific alterations in the hypothalamic-pituitary-adrenal (HPA) axis and stress-related neurocircuitry. Following 1-hour restraint, OPFR-treated females showed heightened serum corticosterone. In addition, gene expression analysis revealed sex-dependent disruptions in key stress-regulatory pathways after OPFR treatment and 1-hour restraint in the hypothalamus (Crhr1, Crhr2, Ptpn5) and pituitary (Crhr1, Pomc, Nr3c1). Females demonstrated more differences in adrenal gene expression related to steroidogenesis (Mc2r, Cyp11b2) and catecholamine biosynthesis (Dbh, Pnmt), with OPFR-treated groups having blunted responses. OPFR AVS females displayed reduced corticosterone and Crh messenger RNA in the hypothalamus, and downregulated Pacap/Pac1r expression in the bed nucleus of the stria terminalis (BNST), accompanied by increased behavioral avoidance and immobility. In males, OPFR exposure led to increased BNST Pacap and Pac1r expression, along with hyperactivity and avoidance behaviors. Together, these findings demonstrate that early-life OPFR exposure induces lasting, sex-specific dysregulation of the HPA axis and associated stress circuits, highlighting OPFRs as developmental neuroendocrine disruptors with implications for mood- and stress-related disorders.
Generation and utility of endocrine functional testicular organoids.
Edmonds ME
Endocrinology · 2026 May · PMID 42089247 · Publisher ↗
Male infertility is increasing in prevalence due to cancer treatment, environmental exposures, and patient-specific syndromes. Traditional two-dimensional culture systems inadequately recapitulate the complex three-dimen...
Male infertility is increasing in prevalence due to cancer treatment, environmental exposures, and patient-specific syndromes. Traditional two-dimensional culture systems inadequately recapitulate the complex three-dimensional architecture, microenvironment, and endocrine milieu essential for spermatogenesis. Testicular organoid models aim to circumvent the challenges of two-dimensional culture, mimicking key aspects of the testicular microenvironment, while enabling controlled experimental manipulation and patient-specific disease modeling. Current testicular organoids demonstrate remarkable preservation of endocrine function, including sustained testosterone and inhibin B production over as great as 12-week culture periods, while maintaining gonadotropin responsiveness that mirrors the pituitary-gonadal axis regulation a testis would experience in vivo. Testicular organoids have recently been used for drug and toxicity screening, and patient-specific organoids from men with nonobstructive azoospermia and Klinefelter syndrome have been explored for disease-relevant characteristics, providing a platform for personalized medicine approaches. Despite these significant advances, achieving complete functional spermatogenesis remains challenging. Limitations include high variability in tubular morphogenesis, with significant methodologic differences across research groups, constraining reproducibility. The primary cellular actor(s) driving this phenomenon is still under investigation. Emerging opportunities at the convergence of bioengineering fabrication techniques and stem cell biology may bridge these challenges, improving microtissue vascularization, advancing scalability, and adding options for patient-personalized experiments. In this review, recent progress in testicular organoid generation, utility for endocrine investigation, remaining technical challenges, and future scientific opportunities are specifically explored. Testicular organoids provide a promising in vitro model for the study of testicular morphogenesis and spermatogenesis, testicular endocrine signaling, and male factor infertility.
Breaking the bonds: targeting protein dimerization for prostate cancer therapy.
Singh N, Heemers HV
Endocrinology · 2026 May · PMID 42087269 · Full text
Metastatic prostate cancer (PCa) remains a major cause of cancer deaths in Western men. Although androgen deprivation therapy (ADT) initially induces remissions, patients ultimately develop incurable castration resistanc...
Metastatic prostate cancer (PCa) remains a major cause of cancer deaths in Western men. Although androgen deprivation therapy (ADT) initially induces remissions, patients ultimately develop incurable castration resistance, underscoring the need for alternative or complementary therapeutic strategies. Protein-protein interactions (PPIs) play a central role in oncogenic signaling, and aberrant protein dimerization is increasingly recognized as a critical driver of PCa progression and therapeutic resistance. Both homodimeric and heterodimeric protein complexes regulate key pathways involved in androgen receptor signaling, transcriptional control, and adaptation to tumor microenvironmental stress. Here, we review current evidence for oncogenic dimerization events in PCa and discuss their relevance for PCa progression. We highlight how similar dimeric interactions have been successfully targeted for therapy in other malignancies, with several strategies advancing to late-stage clinical trials or regulatory approval, underscoring their translational potential for PCa. We summarize approaches to modulate dimerization and highlight their mechanisms of action, therapeutic advantages, and inherent limitations. By combining pre-clinical and clinical findings with conceptual therapeutic frameworks, this review outlines the opportunities and limitations of targeting protein dimerization in PCa. Collectively, we propose that rational disruption of oncogenic homo- and heterodimers represents an underexplored yet promising therapeutic strategy that could complement existing treatments and help overcome resistance in advanced PCa.
Disease-associated mutations in the STAT5B SH2 domain reprogram hepatic cholesterol and lipid metabolism.
Lee HK, Pyatkov M, Gavrilova O … +6 more , Liu N, Demby T, Ye B, Furth PA, Hennighausen L, Waxman DJ
Endocrinology · 2026 May · PMID 42084328 · Full text
Growth hormone (GH) signaling through signal transducer and activator of transcription 5 (STAT5B) is a central regulator of hepatic metabolism, yet the functional consequences of disease-associated STAT5B variants remain...
Growth hormone (GH) signaling through signal transducer and activator of transcription 5 (STAT5B) is a central regulator of hepatic metabolism, yet the functional consequences of disease-associated STAT5B variants remain poorly understood. Here, we analyzed mice carrying STAT5BY665F (gain-of-function) and STAT5BY665H (loss-of-function) variants and dissect their impact on metabolic regulation. STAT5BY665F mice developed hypercholesterolemia and enhanced insulin sensitivity, whereas STAT5BY665H mice displayed reduced body weight and impaired insulin responsiveness. Transcriptomic analyses revealed that STAT5BY665F activated lipid, cholesterol, and immune transcriptional programs, while STAT5BY665H failed to induce these pathways. Notably, STAT5BY665F substantially feminized male liver gene expression, inducing 77% of female-biased genes while repressing 51% of male-biased genes, thereby mimicking the persistent STAT5B activation characteristic of female livers. ChIP-seq demonstrated extensive STAT5BY665F enhancer occupancy at metabolic and immune loci, contrasting with the minimal chromatin engagement of STAT5BY665H. Beyond the liver, STAT5BY665F broadly reprogrammed adipose tissue gene expression, activating lipid metabolism and immune regulatory networks, whereas STAT5BY665H exerted more restricted effects. Together, these findings illustrate how alterations in STAT5B activity affect enhancer activation and can lead to changes in metabolic function and hepatic sexual dimorphism.
Mineralocorticoid and glucocorticoid receptor cooperation drives advanced phenotypes in triple-negative breast cancer.
Posani SH, Diep CH, Krutilina RI … +4 more , Playa HC, Seagroves TN, Blenis J, Lange CA
Endocrinology · 2026 May · PMID 42080517 · Publisher ↗
Oncogenic cell signaling, including the activation of cellular stress or cytokine-induced pathways, is a hallmark of cancer. In triple-negative breast cancer (TNBC), p38 MAPK phosphorylates glucocorticoid receptors (GR)...
Oncogenic cell signaling, including the activation of cellular stress or cytokine-induced pathways, is a hallmark of cancer. In triple-negative breast cancer (TNBC), p38 MAPK phosphorylates glucocorticoid receptors (GR) at Ser134 in response to cytokines such as TGFβ1. This activated Phospho-Ser134-GR (pSer134-GR) regulates genes promoting cancer cell migration, invasion, and altered metabolism. Glucocorticoids also activate the functionally and structurally-related mineralocorticoid receptors (MR) whose ligand, aldosterone, mediates hypertension, inflammation and fibrosis. We and others have previously shown the role of GR in the advanced phenotypes exhibited by TNBC, but the potential importance of GR-MR crosstalk and the specific contribution of MR remains unknown. Interestingly, our new analyses of MR expression in TNBC tumors revealed elevated MR transcript levels relative to luminal breast cancer subtypes, which are predictive of worse overall survival. Cytoplasmic MR-GR complexes that are formed upon treatment of TNBC cells with TGFβ1 required both p38 MAPK signaling and pSer134-GR. In contrast, nuclear MR-GR complexes predominated in response to dexamethasone and/or aldosterone. MR antagonists (spironolactone, finerenone) significantly reduced aldosterone- or TGFβ1-induced migratory and stemness properties and blocked MR-pGR and MR-GR interactions; MR knockdown similarly attenuated these advanced cancer phenotypes. MR expression was essential for both a functional p38 MAPK module and pSer134-GR downstream of TGFβ1 receptor activation. Crucially, MR-deficient models exhibited reduced lung metastasis following mouse tail-vein injection, phenocopying cells harboring phospho-mutant S134A-GR. As with p-Ser134-GR, we define a novel role for MR-GR cooperation downstream of TGFβ1 for regulation of TNBC cell migration, stemness, and in vivo lung colonization.
Kisspeptin made in the preoptic area is required for normal estradiol-induced LH surges and optimal fertility in females.
Puffer MS, Yang J, Esparza LA … +4 more , Rose L, Duong V, Radovick S, Kauffman AS
Endocrinology · 2026 May · PMID 42057695 · Full text
Ovulation is triggered by a surge in luteinizing hormone (LH) secretion from the pituitary. The LH surge is itself driven by a surge in gonadotropin-releasing hormone release induced by estrogen positive feedback action...
Ovulation is triggered by a surge in luteinizing hormone (LH) secretion from the pituitary. The LH surge is itself driven by a surge in gonadotropin-releasing hormone release induced by estrogen positive feedback action in the hypothalamus. While ERα-expressing kisspeptin (Kiss1) neurons in the preoptic area (in mice, the rostral periventricular region of the third ventricle [RP3V]) are proposed to mediate this estrogen positive feedback event, the functional necessity of RP3V-derived kisspeptin for the LH surge has not been directly tested. Here we leveraged Cre/lox technology and the known high co-expression of tyrosine hydroxylase (TH) with Kiss1 in only the RP3V region to generate novel transgenic mice with selective knockout (KO) of the Kiss1 gene in just RP3V neurons (Kiss1RP3V KO mice). In situ hybridization confirmed a significant 70% reduction in cells expressing Kiss1 in the RP3V region, but not in the arcuate nucleus, along with no change in RP3V Th expression. Kiss1RP3V KO females exhibited normal pubertal timing and estrous cycles. However, functional interrogation of the ability of Kiss1RP3V KO females to generate an estradiol-induced LH surge demonstrated markedly blunted LH surges and reduced occurrence of surges, in line with the partial Kiss1RP3V knockout in this group. Correspondingly, fertility assessment revealed significant subfertility, including fewer and smaller litters. This subfertility is consistent with the observed impaired LH surges, though the downstream ovarian mechanism(s) underlying the smaller litters still needs to be determined. These findings provide direct causal evidence that RP3V-derived kisspeptin is essential for normal LH surge magnitude and optimal fertility.
Estrogen receptor alpha and beta chromatin interactions govern ovarian folliculogenesis but dissipate during ovulation.
Dinh DT, McPhee TR, Foot NJ … +2 more , Robker RL, Russell DL
Endocrinology · 2026 May · PMID 42057691 · Full text
Estrogen signaling plays an important role in normal ovarian functions, including follicle development, ovulation, and ovarian cell identity maintenance. Estrogen acts through the estrogen receptors alpha (ERα) and beta...
Estrogen signaling plays an important role in normal ovarian functions, including follicle development, ovulation, and ovarian cell identity maintenance. Estrogen acts through the estrogen receptors alpha (ERα) and beta (ERβ), both of which are involved in ovarian gene regulation. However, the molecular mechanisms that lead to shared and unique receptor actions in the ovary remain poorly understood. Additionally, coregulators that contribute to ER actions in the ovary have remained unexplored. Here, we distinguished the roles of ERα and ERβ at different ovarian stages through characterizing the chromatin binding profile of each receptor in granulosa cells during pre- or peri-ovulation. We found that ERα/β genomic action was prominent during follicle development prior to ovulation. Loss of ERα/β binding after LH-stimulus was associated with the downregulation of folliculogenesis genes, while ERα/β binding contributed little to the activation of genes that are required for ovulation. ERα and ERβ showed highly similar chromatin binding patterns in granulosa cells. Through motif enrichment analysis and integration of other ovarian transcription factor cistromes, we identified potential interactors of ERα and ERβ, including a very strong overlap in chromatin binding with androgen receptor (AR) in pre-ovulatory follicles. These findings demonstrate ERα and ERβ to have highly conserved chromatin interaction functions including interaction with AR to mediate gene expression during folliculogenesis.
Digital platforms influence users and their eating habits.
Guarino G, Bracale R, Ingrosso M … +2 more , Muscogiuri G, Vaccaro C
Minerva Endocrinol (Torino) · 2026 Apr · PMID 42048064 · Publisher ↗
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Clinical obesity in Asian people: bridging the gap between adiposity and disease.
Lim S, Ji L, Tham KW … +2 more , Misra A, Kadowaki T
Nat Rev Endocrinol · 2026 Apr · PMID 42045672 · Publisher ↗
This Perspective argues for a reconceptualization of clinical obesity in Asian populations, moving beyond BMI-centric definitions towards an adiposity-based and function-based framework. Asian populations exhibit a disti...
This Perspective argues for a reconceptualization of clinical obesity in Asian populations, moving beyond BMI-centric definitions towards an adiposity-based and function-based framework. Asian populations exhibit a distinctive obesity phenotype, characterized by excess visceral and ectopic adipose tissue accumulation, reduced β-cell reserve, sarcopenic obesity and heightened cardiometabolic risk at lower BMI thresholds than for white European and North American populations, leading to systematic under-recognition of obesity-related disease when conventional criteria are applied. Building on the Lancet Commission's framework for defining and diagnosing clinical obesity, we propose an integrated approach that combines anthropometric measures, body composition assessment, metabolic and organ-specific markers and emerging biomarkers to distinguish preclinical obesity from clinical obesity on the basis of organ dysfunction and functional impairment. This approach improves risk stratification, supports earlier and more precise diagnosis and informs stage-specific management, including lifestyle intervention, pharmacotherapy and metabolic surgery, particularly in Asian populations. We discuss implications for clinical practice, prevention strategies and public health policy, emphasizing the need to align clinical guidelines, reimbursement systems and education with a function-based definition of obesity. Finally, we highlight key research priorities, including validation of biomarker-driven classifications, assessment of long-term clinical and economic outcomes and development of scalable diagnostic tools, to advance precision care and metabolic health equity across diverse Asian populations.
Highlights from SfE BES 2026.
Tysoe O
Nat Rev Endocrinol · 2026 Jul · PMID 42045671 · Publisher ↗
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Generation of a prop1 knock-in zebrafish enables single-cell transcriptomics of early pituitary development.
Martinez-Mayer J, Balakrishnan M, Cheung LY … +4 more , Günther S, Medan V, Stainier DYR, Perez-Millan MI
Endocrinology · 2026 Apr · PMID 42035243 · Publisher ↗
The adenohypophyseal placode is a developmental structure that is conserved among vertebrates and gives rise to the anterior pituitary. The earliest steps of its formation remain poorly understood. Here, we present a pow...
The adenohypophyseal placode is a developmental structure that is conserved among vertebrates and gives rise to the anterior pituitary. The earliest steps of its formation remain poorly understood. Here, we present a powerful new genetic tool: a zebrafish GAL4 knock-in reporter line for prop1. The targeted integration disrupts prop1 function, generating the first prop1-/- zebrafish, which exhibits dwarfism, impaired sexual maturation, and pigmentation defects. The generation of this new reporter line enabled the study of early pituitary development at single-cell resolution, using both scRNA-seq and live imaging. We identified epcam/Epcam as a conserved epithelial marker of the adenohypophysis in both zebrafish and mouse. We further studied transcriptional programs underlying endocrine lineage specification, discovering several previously unrecognized markers for hormone-producing lineages, including tfcp2l1, as a likely regulator of lactotrope differentiation. Cell-cell interaction analyses indicated Notch, Fgf, and Slit/Robo signaling as key regulators of progenitor maintenance and differentiation. Overall, this work provides the first single-cell atlas of early zebrafish pituitary development, a robust new genetic tool to study fundamental mechanistic insights into pituitary lineage specification and differentiation.
Leptin and cardiovascular health.
Pereira S
Endocrinology · 2026 May · PMID 42035234 · Publisher ↗
Leptin is a hormone secreted by white adipose tissue that regulates food intake. Leptin also modulates cardiovascular health. Obesity is characterized by elevated circulating leptin concentrations, which can cause leptin...
Leptin is a hormone secreted by white adipose tissue that regulates food intake. Leptin also modulates cardiovascular health. Obesity is characterized by elevated circulating leptin concentrations, which can cause leptin resistance, and increased risk of cardiovascular disease. However, the role of leptin sensitivity or leptin resistance in the pathogenesis of cardiovascular disease is unclear in humans. Overall, in vivo rodent studies indicate that factors to consider regarding the relationship between leptin and cardiovascular health are: (1) selective leptin resistance, where the effects of leptin are only impaired for certain outcomes, and (2) mosaic leptin resistance, where, within a certain outcome, leptin signaling may only be impaired in certain tissues/cells. This is further complicated by sex-specific differences. In the current mini-review, the effects of leptin on the cardiovascular system, directly and via the central nervous system, are discussed.
Prostaglandin E2 stimulates GLP-1 and GLP-2 secretion and reduces glucose absorption in the perfused rat small intestine.
Friis J, Modvig IM, Cookson TA … +5 more , Abba V, Juhl CB, Hartmann B, Holst JJ, Veedfald S
Endocrinology · 2026 Apr · PMID 42011909 · Publisher ↗
Prostaglandins are paracrine mediators derived from arachidonic acid. In the gut, they regulate mucosal integrity, epithelial function and inflammation. Glucose and possibly also prostaglandin E2 (PGE2) stimulate the rel...
Prostaglandins are paracrine mediators derived from arachidonic acid. In the gut, they regulate mucosal integrity, epithelial function and inflammation. Glucose and possibly also prostaglandin E2 (PGE2) stimulate the release of glucagon-like peptide 1 (GLP-1). As PGE2 has been reported to modulate intestinal glucose absorption, the aim of the study was to investigate the acute effect of PGE2 on GLP-1 and GLP-2 secretion as well as intestinal glucose absorption using a physiologically relevant experimental setup - the isolated perfused rat small intestine. Two protocols were employed: A) luminal glucose instillation before and during an intra-arterial infusion of PGE2 (10µmol/L). B) same as protocol A, but with the COX inhibitor indomethacin (10µmol/L) included in the perfusion buffer to block endogenous prostaglandin production. Administration of PGE2 stimulated the release of GLP-1 (2.1-fold, P=0.002) and GLP-2 (2.5-fold, P=0.002) from the perfused intestine versus vehicle. Inclusion of indomethacin in the perfusion buffer neither affected GLP-1 and GLP-2 secretion nor responses to PGE2, consistent with minimal production of prostaglandins in the non-inflamed in situ perfused intestine. We observed a decrease in glucose absorption during administration of PGE2 versus vehicle (P=0.043). In conclusion, PGE2 stimulates the secretion of GLP-1 and GLP-2, adding to its established roles in intestinal physiology. Acute administration of PGE2 significantly attenuated small intestinal glucose absorption. Our data confirms that PGE2 stimulates gut hormone release, which could be responsible for some of the effects ascribed to PGE2 and might explain the adverse effects associated with the inhibition of prostaglandin synthesis with non-steroidal anti-inflammatory drugs.
Pathophysiology, diagnosis and management of secondary osteoporosis.
Paccou J, Tsourdi E, Anastasilakis AD … +2 more , Lems WF, Compston J
Nat Rev Endocrinol · 2026 Apr · PMID 42010026 · Publisher ↗
Age-related decline in sex hormones is the most frequent cause of primary osteoporosis; however, secondary causes contribute to osteoporosis in a substantial proportion of cases. These causes are diverse and often overlo...
Age-related decline in sex hormones is the most frequent cause of primary osteoporosis; however, secondary causes contribute to osteoporosis in a substantial proportion of cases. These causes are diverse and often overlooked, ranging from endocrine diseases to chronic inflammatory conditions and medication use. The identification and exclusion of secondary causes of osteoporosis is crucial, because treatment typically begins by addressing the underlying condition. Investigation to exclude common secondary causes is recommended for everyone presenting with fractures indicative of osteoporosis. Advanced investigations are reserved for premenopausal individuals and those aged <50 years, and for older people in whom common risk factors, comorbidities or drugs predisposing to osteoporosis are absent. The risk of fracture can be underestimated by bone mineral density in some chronic diseases and overestimated in others. Specific adjustments can be made to the criteria in the online fracture risk FRAX calculator to provide a more accurate estimation of fracture risk in people with some forms of secondary osteoporosis. The response to conventional anti-osteoporosis treatments can be suboptimal if the underlying condition remains unrecognized and untreated. In most conditions, the evidence for antiresorptive or anabolic therapy is based on changes in bone mineral density rather than fracture. This Review covers the aetiology, pathogenesis, diagnosis and management of secondary osteoporosis, together with key areas for future research.
Intersection of phenotypic plasticity and anoikis enhances therapeutic vulnerability in prostate cancer.
Kouspou M, Zhu A, Martires L … +3 more , Tewari AK, Mehrazin R, Kyprianou N
Endocrinology · 2026 Apr · PMID 41992725 · Publisher ↗
During cancer metastasis, tumor cells survive in circulation by acquiring resistance to anoikis. Restoring vulnerability of cancer cells to anoikis can impair metastatic colonization, minimize treatment resistance, and t...
During cancer metastasis, tumor cells survive in circulation by acquiring resistance to anoikis. Restoring vulnerability of cancer cells to anoikis can impair metastatic colonization, minimize treatment resistance, and tumor recurrence in patients. A compelling body of evidence has identified strategies for the development of effective inhibitors that can block survival pathways such as FAK, PI3K/AKT, MAPK and integrin signaling to prevent prostate cancer cells from leaving the primary tumor/site and/or to impair their colonization at secondary sites. Transcriptomic profiling recently identified anoikis-centered genes, including CDKN1A, NEDD9, CFL1, and JAM2, that may have potential prognostic value in prostate cancer progression and may also contribute to the emergence of therapeutic resistance to antiandrogens and taxane chemotherapy. Direct cytoskeletal remodeling by cofilin, a transforming growth factor-β (TGF-β) effector is linked to phenotypic plasticity changes. NEDD9 causes cytoskeletal dynamics through signaling pathways and it is correlated with tumor aggressiveness. CDKN1A affects cell cycle regulation, and JAM2 influences cell adhesion. This review interrogates the current evidence in the literature on the cellular drivers of anoikis resistance, intersecting with phenotypic plasticity in the prostate tumor microenvironment, toward determination of the underlying molecular mechanisms that can be exploited at the translational level for therapeutic applications. The identification and subsequent validation of novel anoikis-resistance based signatures can be of potential value as predictive markers of therapy resistance and tumor recurrence in patients with advanced prostate cancer.
Hormone-dependent mitochondrial resilience in leiomyoma cells exposed to oxidative stress.
McNally R, Elkafas H, Asif H … +2 more , Wei JJ, Kim JJ
Endocrinology · 2026 Apr · PMID 41992555 · Publisher ↗
Uterine leiomyomas persist and grow within a chronically pro-oxidant environment despite reduced antioxidant capacity, suggesting the existence of adaptive stress-tolerance mechanisms. Although estrogen and progesterone...
Uterine leiomyomas persist and grow within a chronically pro-oxidant environment despite reduced antioxidant capacity, suggesting the existence of adaptive stress-tolerance mechanisms. Although estrogen and progesterone are well-established regulators of leiomyoma growth, their roles in coordinating mitochondrial function under oxidative stress remain poorly defined. Here, we investigated how estrogen and progesterone receptor signaling modulate oxidative stress-induced transcriptional programs and mitochondrial metabolic responses in uterine leiomyoma cells. Primary patient-derived leiomyoma spheroids were exposed to paraquat-induced oxidative stress in the presence of estradiol, progestins, or hormone receptor antagonists. Transcriptomic responses were assessed by RNA sequencing with differential expression and gene set enrichment analyses, while mitochondrial function was evaluated using Seahorse extracellular flux assays alongside measurements of senescence and cell viability. Estrogen and progesterone signaling reshaped oxidative stress-responsive gene expression programs linked to senescence, apoptosis, and mitochondrial regulation, which was evident with hormone receptor antagonism. Functional metabolic analyses revealed that hormonal signaling preserved mitochondrial maximal respiration and spare respiratory capacity under oxidative stress, while hormone blockade selectively impaired mitochondrial reserve capacity without compensatory glycolytic upregulation. Isoform-specific progesterone receptor effects further supported a role for differential receptor signaling in regulating mitochondrial adaptability. Together, these findings identify estrogen and progesterone receptor signaling as key regulators of mitochondrial stress tolerance in leiomyoma cells and support a model in which endocrine control of mitochondrial function enables cellular survival under sustained oxidative stress.
A protocol for physiologic LH surge induction in gonad intact female mice.
Silva MSB, Talbi R, Torres E … +6 more , Zdon S, Pereira SA, Stamatiades GA, Lopez I, Carroll RS, Navarro VM
Endocrinology · 2026 Apr · PMID 41992548 · Full text
The preovulatory luteinizing hormone (LH) surge is a defining neuroendocrine event that triggers ovulation through estradiol (E2)-dependent positive feedback on gonadotropin-releasing hormone (GnRH) secretion. Mechanisti...
The preovulatory luteinizing hormone (LH) surge is a defining neuroendocrine event that triggers ovulation through estradiol (E2)-dependent positive feedback on gonadotropin-releasing hormone (GnRH) secretion. Mechanistic studies of this process have relied predominantly on ovariectomized rodents supplemented with exogenous hormones, a paradigm that disrupts ovarian function and limits physiological and translational relevance. Here, we establish a robust and reproducible model of LH surge induction in intact female mice that preserves the hypothalamic-pituitary-gonadal axis. We show that a single low-dose injection of estradiol benzoate (EB; 0.5 µg) administered during diestrus reliably induces a temporally synchronized LH surge in most intact females, whereas EB treatment during proestrus or estrus is ineffective. EB-induced LH surges were accompanied by a significant increase in circulating progesterone, confirming the engagement of ovarian luteinizing pathways. The LH surge occurrence was independent of proestrus detection by vaginal cytology, accentuating the limited predictive value of cytology in mice. At the neuroendocrine level, EB treatment markedly increased cFOS expression in GnRH neurons across key preoptic regions and modestly activated kisspeptin neurons in the rostral periventricular area of the third ventricle, consistent with activation of E2-positive feedback circuitry. In contrast, arcuate kisspeptin neurons remained inactive, supporting their role in negative feedback. Together, these findings define a physiologically relevant, intact mouse model for studying E2-induced LH surges that maintains endogenous ovarian signaling.
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