Adult-onset testosterone deficiency (TD) in men is diagnosed by the finding of low serum testosterone levels and recognised, associated symptoms. The condition has high prevalence in men over 50 years of age, particularly those with type 2 diabetes (T2DM). Accumulating data show adult-onset TD is associated with increased mortality risk. We review the literature and consider the evidence suggesting testosterone therapy (TTh) reduces mortality, especially in men with T2DM. We previously reported that in the Burntwood Lichfield Atherstone Sutton Coldfield Tamworth (BLAST) study screened cohort of men with adult-onset TD and T2DM adult-onset TD was associated with increased mortality with TTh decreasing this higher mortality. The data hinted that the effect was greater in older men. We confirmed this observation with statistical analyses to study the effect of age on the association between adult-onset TD and mortality; Cox regression analysis demonstrated that the reduced risk (hazard ratio: 0.61, 95% CI: 0.38–0.96) following TTh was restricted to men above the median age of 65.89 years. Finally, we speculate on putative mechanisms that may mediate these associations. Heterogeneity in men with adult-onset TD is expected in view of its definition of low testosterone levels together with associated clinical phenotypes that are not always directly related. Many of these classifying phenotypes are associated with increased mortality. Thus, it is perhaps possible that mechanism(s) of all-cause mortality reduction following TTh is via the impact on these associated phenotypes such as the metabolic syndrome (MetS), hyperglycaemia, hypertension, dyslipidaemia, low haematocrit, sex hormone binding levels, erectile dysfunction, etc. We propose that further research studying the effect of TTh takes heterogeneity into account.

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Congenital adrenal hyperplasia due to 21-hydroxylase deficiency leads to high morbidity and mortality, despite the availability of life-saving corticosteroid replacement therapy. Gene therapy represents a promising potential treatment for monogenic disorders such as congenital adrenal hyperplasia, overcoming the limitations of corticosteroid replacement approaches. Adeno-associated viral vectors are currently the leading vector for direct in vivo gene delivery. However, physiological properties of the adrenal gland limit the application of adeno-associated viral vector-based gene addition strategies. To achieve durable correction in the adrenal gland, gene editing must be employed to stably introduce a genetic modification into the CYP21A2 locus. The safety of this and other gene editing approaches could be greatly improved by using lipid nanoparticles for the delivery of editing machinery mRNA. While little data exists regarding adrenocortical lipid nanoparticle targeting, physiological features of this organ (such as high relative blood flow, fenestrated endothelium, and cholesterol uptake) indicate the promise of these delivery vectors for the treatment of monogenic diseases of the adrenal cortex. This review discusses the complexities of developing gene therapy for congenital adrenal hyperplasia and explores the viability of novel gene therapy strategies in this application.

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Stress is a state of threatened or perceived as threatened homeostasis that can be induced by various external and internal stimuli such as psychosocial factors, inflammatory or injurious conditions, and infections. In order to restore body homeostasis, adrenal glands produce and secrete glucocorticoids (GCs) and catecholamines (CAs), which are the main stress hormones that support the survival and adaptation of the organisms to the new environment. In contrast to the rather beneficial impact of acute and short-lasting stress, chronic stress and related dysregulation of the stress system is implicated in the development of many non-communicable diseases, including cancer. Particularly, ever-increasing experimental and clinical evidence implicates the involvement of CAs and GCs as well as the overexpression of their receptors in the activation of the major pathways involved in tumour development, metastasis, and resistance to various therapies. More importantly, results of experimental and epidemiological studies revealed that overexposure to stress hormones during pre- and early postnatal life might induce life-long or even transgenerational dysregulation of the stress system and predispose it to the development of various tumours. Although the exact mechanisms involved in the latter process are not yet fully known, it has been demonstrated that GC-induced epigenetic modifications can change the expression of several key genes involved in the regulation of the stress system, tumour initiation, and epigenetic imprinting. When such alterations occur in stem/progenitor cells (SPCs), this might not only lead to long-term dysfunction of the stress system but might promote the generation of cancer stem cells (CSCs). This review article discusses a hypothesis that stress hormones-mediated epigenetic reprograming of various SPCs during sensitive developmental periods, might contribute to their dysfunction and increased sensitivity to malignant transformation, thereby promoting tumorigenesis.

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The escalating prevalence of diabetes poses a significant health concern. Uncontrolled diabetes leads to a multitude of complications. A comprehensive management plan and continual adaptation of guidelines is needed. The American Diabetes Association (ADA) is a guiding force in this domain, providing diabetes care recommendations for clinicians, laboratorians, researchers, and policymakers since 1989. The latest ADA guidelines present both challenges and opportunities for laboratories. The increased emphasis on glycated hemoglobin (HbA1c) testing for early diagnosis and personalized monitoring is expected to increase testing volumes, potentially leading to a rise in point-of-care testing. Ensuring standardized testing procedures becomes paramount to maintaining consistent and reliable results across laboratories. Moreover, laboratories may need to expand their test menus to accommodate the growing demand for personalized medicine approaches and collaborate closely with healthcare providers to support informed decision-making. This commentary provides a focused analysis of the 2024 ADA guidelines for the laboratory assessment of diabetes.

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Stress hormones, namely glucocorticoids, have diverse actions throughout the body in regulating development, tissue metabolism, inflammation, circadian rhythms, and skeletal homeostasis. While endogenous glucocorticoid levels are important to support bodily homeostasis, chronically elevated levels can cause damage to tissues and drive diseases including bone loss (i.e., osteoporosis), myopathy (i.e., sarcopenia) and metabolic disturbances (i.e., glucose intolerance, diabetes, and abnormal fat accrual). There is substantial evidence that basal glucocorticoid levels increase during ageing while at the same time the amplitude of the diurnal variation in glucocorticoid secretion decreases. However, the significance of these changes for skeletal health is not well understood and has only recently been studied in more detail. Evidence from genetically modified mouse models indicates that changes in glucocorticoid signaling associated with ageing induce bone loss, sarcopenia and drive osteoarthritic joint disease. These studies provide important insights into the role of glucocorticoids in age-related skeletal diseases which will aid in the development of novel treatments especially needed for osteoarthritis which disproportionally affects the elderly.

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For the past 100 years, insulin supplementation has been the mainstay of treatment for type 1 diabetes (T1D), which is characterized by progressive autoimmune-mediated loss of insulin-producing β cells in the islets of Langerhans over the last decades, technological advances in glucose monitoring and therapeutics have greatly improved the care and management of these patients. However, morbidity, mortality, and quality of life remain challenges for patients with T1D. Islet transplantation has been successfully performed, but there are several limiting factors, such as the lack of cadaveric donors and the need for lifelong immunosuppressive therapy. Therefore, there is a great medical need for alternative therapeutic approaches. In the current review, the current knowledge on novel approaches for the treatment of T1D with a focus on the potential of using chimeric antigen receptor (CAR)-T cells and natural killer (NK) cells is summarized.

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Artificial intelligence (AI) has gained attention for various reasons in recent years, surrounded by speculation, concerns, and expectations. Despite being developed since 1960, its widespread application took several decades due to limited computing power. Today, engineers continually improve system capabilities, enabling AI to handle more complex tasks. Fields like diagnostics and biology benefit from AI’s expansion, as the data they deal with requires sophisticated analysis beyond human capacity. This review showcases AI’s integration in endocrinology, covering molecular to phenotypic patient data. These examples demonstrate AI’s potential and power in research and medicine.

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Diabetes and cancer are two chronic metabolic diseases with ever-increasing incidence rates worldwide. These disorders can often occur together, as diabetes presents an important risk factor for cancer and some cancers could in turn lead to diabetes. In this perspective article, many more commonalities between diabetes and cancer are highlighted, including the role of lifestyle and environmental factors in the pathogenesis, the presence of a rather long latency period before clinical diagnosis of invasive disease, as well as the ultimate progression to diabetic complications or malignant metastases. Moreover, both of these devastating disorders still lack curative treatment options, whereas several currently approved antidiabetic and anticancer drugs have been originally derived from different natural sources. However, while in the case of diabetes, the main therapeutic goal is to maintain the pancreatic islet mass by preserving β-cells survival, the major purpose of cancer therapy is to kill malignant cells and reduce the neoplastic mass of solid tumors. It is expected that both diabetes and cancer, two systemic diseases with epidemic proportions, would be managed more effectively through an integral approach, considering many different aspects related to their pathogenesis, including also lifestyle changes and dietary modifications.

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Hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome is a rare genetic disorder caused by haploinsufficiency of the GATA3 gene. A very limited number of cases have been reported in the literature to date. Diagnosis is challenging as the phenotypic expression has wide heterogeneity due to variable penetrance of the underlying genetic mutation. Although the condition is inherited in an autosomal dominant pattern, sporadic cases do occur. This report presents a case of a 22-year-old female diagnosed with HDR syndrome, featuring bilateral cataract and bicornuate uterus. The GATA3 mutation detected in the patient was not identified in the family, suggesting it to be arising de novo. The present case report describes the rare phenotypic findings of bilateral cataract and bicornuate uterus associated with HDR, thus expanding the clinical spectrum of the syndrome.

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The accumulation of adipose tissue is associated with metabolic disorders, including insulin resistance, type 2 diabetes (T2D), dyslipidemia, metabolic syndrome, and cardiovascular diseases (CVD). Menopause might predispose women to increase body weight and adipose tissue, and decrease lean muscle mass. Furthermore, postmenopausal women display fat mass redistribution with greater accumulation in the visceral area mainly due to hormonal shifts that result in a higher testosterone/estradiol ratio. These effects are associated with a less favorable adipokine profile, dyslipidemia, insulin resistance, and cardiac dysfunction after menopause. Fat mass is determined by the balance between the storage of triacylglycerol (TAG) (lipogenesis) and the removal of stored TAG (lipolysis) in combination with the differentiation of new adipocytes (adipogenesis). Disturbances in adipose tissue dynamics lead to an increase in lipogenesis (hypertrophy) and/or in adipogenesis (hyperplasia) to accommodate excess energy intake. While large adipocytes are dysfunctional and have greater secretion of inflammatory adipocytokines, small adipocytes are healthier and associated with metabolic improvements. Different strategies can be used to prevent or reduce body weight gain and fat mass, as well as to maintain healthy adipose tissue; however, due to robust evidence, lifestyle interventions should be pillars in this process. This review provides a comprehensive summary of findings on the role of a balanced diet and physical exercise in improving body composition and promoting healthy adipose tissue in postmenopausal women.

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Metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly emerging as a global health crisis, affecting over 30% of the population and demanding urgent attention. This redefined condition, previously known as non-alcoholic fatty liver disease (NAFLD), reflects a deeper understanding of the intricate interplay between metabolic dysfunction and liver health. At the heart of MASLD lies the troubling accumulation of triglycerides (TGs) in hepatocytes, which precipitates insulin resistance and oxidative stress, ultimately leading to more severe forms like metabolic dysfunction-associated steatohepatitis (MASH). Excitingly, recent research has spotlighted the farnesoid X receptor (FXR) as a groundbreaking therapeutic target. FXR not only regulates lipid metabolism but also combats inflammation and insulin resistance, making it a potential game-changer in the fight against MASLD. With only one FDA-approved drug, resmetirom, currently available, the exploration of FXR agonists opens new avenues for innovative treatments that could revolutionize patient care. By harnessing the power of FXR to restore metabolic balance and integrating advanced strategies like lipidomics and fatty acid profiling, we stand on the brink of transforming how we approach MASLD and its associated complications, paving the way for a healthier future. This review delves into the promising role of FXR in combating MASLD and its implications for related metabolic disorders, emphasizing the urgency for advanced strategies to detect and manage this burgeoning epidemic.

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The glucocorticoid receptor alpha (GRα), a vital component of the ancient glucocorticoid (GC) signaling system, is essential for vertebrate survival. It regulates fertility, fetal development, organ function, vascular and neural integrity, metabolism, immune responses, and stress adaptation. While GRα’s anti-inflammatory properties have been acknowledged since the mid-20th century, its crucial role as the master regulator of homeostatic corrections in both health and critical illness has only recently come to light. In critical illness, GRα facilitates a seamless transition through three essential phases of homeostatic correction. Initially, in the Priming Phase, it activates immune responses and mobilizes energy reserves to defend against stressors like infection and injury, enhancing glucose metabolism, supporting mitochondrial function, and strategically deploying immune cells to areas of damage. Next, during the Modulatory Phase, GRα fine-tunes inflammatory responses, manages oxidative stress, regulates vascular tone, and maintains cellular integrity. Finally, in the Restorative Phase, GRα plays a crucial role in resolving inflammation, initiating tissue repair, supporting cellular regeneration, facilitating debris clearance, and reestablishing anatomical and physiological balance for long-term recovery. GRα coordinates complex molecular interactions, including co-regulation with pro-inflammatory transcription factors, ensures mitochondrial stability, and metabolic balance under stress. However, depleted bioenergetic and micronutrient reserves in critically ill patients can impair GRα’s capacity, increasing morbidity and mortality risks. This review highlights the need to reassess current GC treatment strategies and integrate micronutrient support to optimize GRα function. Such an approach could strengthen immediate immune defenses, enhance long-term recovery, reduce GC dose and duration, and minimize adverse effects.

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Obesity is a multifactorial disease linked to many comorbidities and has an impact on brain health. It is also known that obesity disrupts the endocannabinoid (eCB) system in the central nervous system and in the periphery, which complicates the underlying mechanisms behind obesity. However, weight loss through lifestyle interventions or bariatric surgery may alleviate obesity-related comorbidities, as well as restore eCB tone. Several studies have reported a decrease in circulating eCBs following weight loss, likely due to the positive association of these mediators with fat mass. However, further research is needed to clarify whether this reduction is a consequence of weight loss or plays a role in facilitating it. This review explores changes in circulating eCBs following weight loss and their potential roles in cerebral homeostasis and the reward system. It examines how lifestyle modifications and bariatric surgery may influence central eCB signalling and contribute to long-term weight loss success. Understanding the mechanisms behind improved brain function after weight loss could provide insights into optimizing obesity treatments.

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