Endocrine reviews最新文献

From 1965 to 2015, immense strides were made into understanding the mechanisms underlying the common androgen excess disorders, premature adrenarche and polycystic ovary syndrome (PCOS). The author reviews the critical discoveries of this era from his perspective investigating these disorders, commencing with his early discoveries of the unique pattern of plasma androgens in premature adrenarche and the elevation of an index of the plasma free testosterone concentration in most hirsute women. The molecular genetic basis, though not the developmental biologic basis, for adrenarche is now known and 11-oxytestosterones shown to be major bioactive adrenal androgens. The evolution of the lines of research into the pathogenesis of PCOS is historically traced: research milestones are cited in the areas of neuroendocrinology, insulin resistance, hyperinsulinism, type 2 diabetes mellitus, folliculogenesis, androgen secretion, obesity, phenotyping, prenatal androgenization, epigenetics, and complex genetics. Large-scale genome-wide association studies led to the 2014 discovery of an unsuspected steroidogenic regulator DENND1A (differentially expressed in normal and neoplastic development). The splice variant DENND1A.V2 is constitutively overexpressed in PCOS theca cells in long-term culture and accounts for their PCOS-like phenotype. The genetics are complex, however: DENND1A intronic variant copy number is related to phenotype severity, and recent data indicate that rare variants in a DENND1A regulatory network and other genes are related to PCOS. Obesity exacerbates PCOS manifestations via insulin resistance and proinflammatory cytokine excess; excess adipose tissue also forms testosterone. Polycystic ovaries in 40 percent of apparently normal women lie on the PCOS functional spectrum. Much remains to be learned.

Preclinical models (typically ovariectomized rats and genetically altered mice) have underpinned much of what we know about skeletal biology. They have been pivotal for developing therapies for osteoporosis and monogenic skeletal conditions, including osteogenesis imperfecta, achondroplasia, hypophosphatasia, and craniodysplasias. Further therapeutic advances, particularly to improve cortical strength, require improved understanding and more rigorous use and reporting. We describe here how trabecular and cortical bone structure develop, are maintained, and degenerate with aging in mice, rats, and humans, and how cortical bone structure is changed in some preclinical models of endocrine conditions (eg, postmenopausal osteoporosis, chronic kidney disease, hyperparathyroidism, diabetes). We provide examples of preclinical models used to identify and test current therapies for osteoporosis, and discuss common concerns raised when comparing rodent preclinical models to the human skeleton. We focus especially on cortical bone, because it differs between small and larger mammals in its organizational structure. We discuss mechanisms common to mouse and human controlling cortical bone strength and structure, including recent examples revealing genetic contributors to cortical porosity and osteocyte network configurations during growth, maturity, and aging. We conclude with guidelines for clear reporting on mouse models with a goal for better consistency in the use and interpretation of these models.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors derived from neural crest cells from adrenal medullary chromaffin tissues and extra-adrenal paraganglia, respectively. Although the current treatment for PPGLs is surgery, optimal treatment options for advanced and metastatic cases have been limited. Hence, understanding the role of the immune system in PPGL tumorigenesis can provide essential knowledge for the development of better therapeutic and tumor management strategies, especially for those with advanced and metastatic PPGLs. The first part of this review outlines the fundamental principles of the immune system and tumor microenvironment, and their role in cancer immunoediting, particularly emphasizing PPGLs. We focus on how the unique pathophysiology of PPGLs, such as their high molecular, biochemical, and imaging heterogeneity and production of several oncometabolites, creates a tumor-specific microenvironment and immunologically "cold" tumors. Thereafter, we discuss recently published studies related to the reclustering of PPGLs based on their immune signature. The second part of this review discusses future perspectives in PPGL management, including immunodiagnostic and promising immunotherapeutic approaches for converting "cold" tumors into immunologically active or "hot" tumors known for their better immunotherapy response and patient outcomes. Special emphasis is placed on potent immune-related imaging strategies and immune signatures that could be used for the reclassification, prognostication, and management of these tumors to improve patient care and prognosis. Furthermore, we introduce currently available immunotherapies and their possible combinations with other available therapies as an emerging treatment for PPGLs that targets hostile tumor environments.

Glucocorticoids exert pleiotropic effects on all tissues to regulate cellular and metabolic homeostasis. Synthetic forms are used therapeutically in a wide range of conditions for their anti-inflammatory benefits, at the cost of dose and duration-dependent side effects. Significant variability occurs between tissues, disease states, and individuals with regard to both the beneficial and deleterious effects. The glucocorticoid receptor (GR) is the site of action for these hormones and a vast body of work has been conducted understanding its function. Traditionally, it was thought that the anti-inflammatory benefits of glucocorticoids were mediated by transrepression of pro-inflammatory transcription factors, while the adverse metabolic effects resulted from direct transactivation. This canonical understanding of the GR function has been brought into question over the past 2 decades with advances in the resolution of scientific techniques, and the discovery of multiple isoforms of the receptor present in most tissues. Here we review the structure and function of the GR, the nature of the receptor isoforms, and the contribution of the receptor to glucocorticoid sensitivity, or resistance in health and disease.

Since hypothalamic obesity (HyOb) was first described over 120 years ago by Joseph Babinski and Alfred Fröhlich, advances in molecular genetic laboratory techniques have allowed us to elucidate various components of the intricate neurocircuitry governing appetite and weight regulation connecting the hypothalamus, pituitary gland, brainstem, adipose tissue, pancreas, and gastrointestinal tract. On a background of an increasing prevalence of population-level common obesity, the number of survivors of congenital (eg, septo-optic dysplasia, Prader-Willi syndrome) and acquired (eg, central nervous system tumors) hypothalamic disorders is increasing, thanks to earlier diagnosis and management as well as better oncological therapies. Although to date the discovery of several appetite-regulating peptides has led to the development of a range of targeted molecular therapies for monogenic obesity syndromes, outside of these disorders these discoveries have not translated into the development of efficacious treatments for other forms of HyOb. This review aims to summarize our current understanding of the neuroendocrine physiology of appetite and weight regulation, and explore our current understanding of the pathophysiology of HyOb.

Carcinoid syndrome (CS) is a debilitating disease that affects approximately 20% of patients with neuroendocrine neoplasms (NEN). Due to the increasing incidence and improved overall survival of patients with NEN over recent decades, patients are increasingly suffering from chronic and refractory CS symptoms. At present, symptom control is hampered by an incomplete understanding of the pathophysiology of this syndrome. This systematic review is the first to critically appraise the available evidence for the various hormonal mediators considered to play a causative role in CS. Overall, evidence for the putative mediators of CS was scarce and often of poor quality. Based on the available literature, data are only sufficient to agree on the role of serotonin as a mediator of CS-associated diarrhea and fibrosis. A direct role for tachykinins and an indirect role of catecholamines in the pathogenesis of CS is suggested by several studies. Currently, there is insufficient evidence to link histamine, bradykinin, kallikrein, prostaglandins, or motilin to CS. To summarize, available literature only sufficiently appoints serotonin and suggests a role for tachykinins and catecholamines as mediators of CS, with insufficient evidence for other putative mediators. Descriptions of CS should be revised to focus on these proven hormonal associations to be more accurate, and further research is needed into other potential mediators.

Our overview covers several key areas related to recent results obtained for collagen type VI and endotrophin (ETP). (1) An introduction to the history of ETP, including how it was identified, how it is released, and its function and potential receptors. (2) An introduction to the collagen family, with a focus on what differentiates collagen type VI from an evolutionary standpoint. (3) An overview of collagen type VI, the 6 individual chains (COL6A1, A2, A3, A4, A5, and A6), their differences and similarities, as well as their expression profiles and function. (4) A detailed analysis of COL6A3, including the cleaved product endotrophin, and what separates it from the other 5 collagen 6 molecules, including its suggested function based on insights gained from knockout and gain of function mouse models. (5) The pathology of ETP. What leads to its presence and release and what are the consequences thereof? (6) Functional implications of circulating ETP. Here we review the data with the functional roles of ETP in mind. (7) We propose that ETP is a mediator for fibrotic (or fibroinflammatory) disorders. Based on what we know about ETP, we have to consider it as a target for the treatment of fibrotic (or fibroinflammatory) disorders. What segment(s) of the patient population would most dramatically respond to an ETP-targeted intervention? How can we find the population that would profit most from an intervention? We aim to present a broad overview over the ETP field at large, providing an assessment of where the future research efforts need to be placed to tap into the vast potential of ETP, both as a marker and as a target in different diseases.

Basal insulin continues to be a vital part of therapy for many people with diabetes. First attempts to prolong the duration of insulin formulations were through the development of suspensions that required homogenization prior to injection. These insulins, which required once- or twice-daily injections, introduced wide variations in insulin exposure contributing to unpredictable effects on glycemia. Advances over the last 2 decades have resulted in long-acting, soluble basal insulin analogues with prolonged and less variable pharmacokinetic exposure, improving their efficacy and safety, notably by reducing nocturnal hypoglycemia. However, adherence and persistence with once-daily basal insulin treatment remains low for many reasons including hypoglycemia concerns and treatment burden. A soluble basal insulin with a longer and flatter exposure profile could reduce pharmacodynamic variability, potentially reducing hypoglycemia, have similar efficacy to once-daily basal insulins, simplify dosing regimens, and improve treatment adherence. Insulin icodec (Novo Nordisk) and insulin efsitora alfa (basal insulin Fc [BIF], Eli Lilly and Company) are 2 such insulins designed for once-weekly administration, which have the potential to provide a further advance in basal insulin replacement. Icodec and efsitora phase 2 clinical trials, as well as data from the phase 3 icodec program indicate that once-weekly insulins provide comparable glycemic control to once-daily analogues, with a similar risk of hypoglycemia. This manuscript details the technology used in the development of once-weekly basal insulins. It highlights the clinical rationale and potential benefits of these weekly insulins while also discussing the limitations and challenges these molecules could pose in clinical practice.