Endocrinology最新文献

Glucocorticoids are an important signal for the differentiation of many types of cells. Consistent with this, several studies have demonstrated that glucocorticoids promote the somatotrope differentiation program and functionality. Interestingly, we previously found that loss of the forkhead factor, FOXO1, results in delayed emergence of somatotropes and prevents glucocorticoid-induced premature differentiation of somatotropes. In the present study, we find that pituitary-specific deletion of Nr3c1, the gene encoding the glucocorticoid receptor, impairs somatotrope differentiation and increases lactotrope numbers embryonically and at 5 days after birth. The number of somatotropes remains reduced at age 7 weeks in females and males, but lactotrope cell numbers are increased only in females at this age. FOXO1 is nearly undetectable in pituitary glands from mouse embryos lacking NR3C1 and continues to be reduced in adults. These findings suggest that glucocorticoids are an important signal for determining the balance between somatotropes and lactotropes and that FOXO1 may mediate NR3C1 induction of somatotrope differentiation.

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.

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.

The transcription of the Hairless gene (Hr), which encodes a histone demethylase, is strongly induced by thyroid hormone (T3) in many cell types. This is mediated by heterodimers formed between T3 nuclear receptors and retinoid X receptors. These heterodimers are bound to specific DNA response elements present in regulatory sequences and activate transcription upon T3 binding. To address the significance of this regulation, we identified a single DNA response element upstream of the Hr transcription start site, which plays a key role in this regulation. A single nucleotide mutation in this DNA response element, which prevents the binding of heterodimers, was shown to prevent the activation of Hr by T3 signaling in mice. Analysis of gene expression in the heart and striatum of mice homozygous for this mutation highlights the influence of the Hairless cofactor on thyroid hormone signaling.

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.

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.

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.

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.

Metabolic syndrome (MetS), including obesity, dyslipidemia, hypertension, insulin resistance, and often testosterone (T) deficiency, is increasingly linked to impaired lung function, worsened by systemic inflammation. COVID-19 highlighted the vulnerability of metabolically impaired patients to respiratory complications. Preclinical mechanistic studies remain limited. This study examined MetS effects on lung function and morphology, and the impact of T therapy in a high-fat diet (HFD)-induced MetS rabbit model. Male New Zealand White rabbits were assigned to: regular diet, HFD 6 weeks, HFD 12 weeks (HFD12W), HFD + T 12 weeks (HFD + T12W), and HFD + T last 6 weeks (HFD12W + T6W). Lung function was measured via airway opening pressure (PAO), and tissues analyzed for macrophages (RAM11), collagen (picrosirius red), and inflammatory/fibrotic gene expression. HFD induced MetS features, hypogonadism, increased PAO, reduced compliance, elevated fatty acids, and early macrophage remodeling. At 12 weeks, inflammation and fibrosis were prominent, with upregulation of IL1β, LOX1, RORγt, TLR2, COL1A1, COL3A1, and TGFβ1. T therapy increased plasma T, improved metabolic parameters, reduced PAO, and reversed inflammatory/fibrotic gene expression. Histology confirmed decreased macrophage clustering and fibrosis. PAO inversely correlated with T, with levels <3.76 nM predicting abnormal PAO with >80% sensitivity and specificity. MetS causes progressive lung injury via macrophage dysregulation, inflammation, and peribronchiolar fibrosis. T deficiency is central, as hormone administration improved lung function and histology. Immune-driven mechanisms, including Th2/Th17 cytokines and epithelial-mesenchymal transition markers, likely contribute. T's anti-inflammatory and antifibrotic effects may involve cAMP signaling. Clinically, assessing T and metabolic status is crucial, and T therapy may help mitigate lung consequences of MetS.