Endocrine reviews最新文献

From antiquity, Man has been fascinated by at least two processes of testicular function: virility and reproduction; their biological basis was uncovered beginning in the mid-19th century. We have divided the search into 3 epochs: the speculative and observational, the experimental, and the biochemical/physiological. The first begins with Susruta, approximately 3,000 years ago and winds its way through the Greek, Roman, the Christian Bible, Arabic, Chinese, and Indian pathways before coalescing in Europe at the dawn of the Renaissance. The second began withThomas Willis who postulated a virilizing factor from the testis. A century later de Bordeu hypothesized a neurosecretory function for the hypothalamus/pituitary. After John Hunter began to study testis implantation, it was Berthold who showed a secretory function of the testis following implantation. Charles-Éduard Brown-Séquard focused the medical and lay communities on the testis secretion with self-experimentation with animal testis extracts leading to more than four decades of uncertainty in the newly-launched science of endocrinology. Multiple series of testicular implants and vas deferens ligations for the purposes of rejuvenation of older men followed. The medical experimentation continued in the biochemical/physiological epoch where androgenic steroids were isolated, purified, identified, synthesized and used in clinical trials. The effects of castration, some known from antiquity were placed on a modern scientific basis with studies of the Skoptzy, a self-castrating sect from Russia and the castrati opera singers. Details of hypothalamic-pituitary-gonadal axis function as well as the embryology of male sexual differentiation and spermatogenesis were defined during this epoch.

Obesity is a major global concern and is generally attributed to a combination of genetic and environmental factors. Several hypotheses have been proposed to explain the evolutionary origins of obesity epidemic, including thrifty and drifty genotypes, and changes in thermogenesis. Here, we put forward the hypothesis of metaflammation, which proposes that due to intense selection pressures exerted by environmental pathogens, specific genes that help develop a robust defense mechanism against infectious diseases have had evolutionary advantages and that this may contribute to obesity in modern times due to connections between the immune and energy storage systems. Indeed, incorporating the genetic variations of gut microbiota into the complex genetic framework of obesity makes it more polygenic than previously believed. Thus, uncovering the evolutionary origins of obesity requires a multifaceted approach that considers the complexity of human history, the unique genetic makeup of different populations, and the influence of gut microbiome on host genetics.

Growth hormone (GH) is a pituitary-derived endocrine hormone required for normal postnatal growth and development. Hypo- or hypersecretion of endocrine GH results in 2 pathologic conditions, namely GH deficiency (GHD) and acromegaly. Additionally, GH is also produced in nonpituitary and tumoral tissues, where it acts rather as a cellular growth factor with an autocrine/paracrine mode of action. An increasingly persuasive and large body of evidence over the last 70 years concurs that GH action is implicit in escalating several cancer-associated events, locally and systemically. This pleiotropy of GH's effects is puzzling, but the association with cancer risk automatically raises a concern for patients with acromegaly and for individuals treated with GH. By careful assessment of the available knowledge on the fundamental concepts of cancer, suggestions from epidemiological and clinical studies, and the evidence from specific reports, in this review we aimed to help clarify the distinction of endocrine vs autocrine/paracrine GH in promoting cancer and to reconcile the discrepancies between experimental and clinical data. Along this discourse, we critically weigh the targetability of GH action in cancer-first by detailing the molecular mechanisms which posit GH as a critical node in tumor circuitry; and second, by enumerating the currently available therapeutic options targeting GH action. On the basis of our discussion, we infer that a targeted intervention on GH action in the appropriate patient population can benefit a sizable subset of current cancer prognoses.

Discovered in 1996, PCSK7 is the seventh of the 9-membered proprotein convertase subtilisin-kexin (PCSK) family. This article reviews the various aspects of the multifaceted biology of PCSK7 and what makes it an exciting new target for metabolic dysfunction-associated steatotic liver disease (MASLD), affecting ∼30% of the population globally, dyslipidemia, cardiovascular disease, and likely cancer/metastasis. We will systematically review and discuss all the available epidemiological data, and structural, cell biology, and in vivo evidence that eventually led to the discovery of PCSK7 as a novel post-translational regulator of apolipoprotein B. Interestingly, PCSK7 is the only convertase, other than PCSK9, that exhibits noncanonical/nonenzymatic functions, which will be amply described in this review. The data so far have suggested that PCSK7 is a potential safe target in MASLD treatment. This was based on human epidemiological data, as well as mouse Pcsk7 knockout and mRNA translation inhibition using hepatocyte-targeted antisense oligonucleotides following a diet-induced MASLD. Additionally, of all the 9 convertases only the gene deletion of Pcsk7 and/or Pcsk9 in mice leads to healthy and fertile animals with no apparent deleterious consequences, suggesting that their pharmacological targeting is likely safe. Accordingly, the synergistic effects of inhibiting both PCSK7 and PCSK9 in a clinical setting may represent a novel therapy for various diseases. We believe that the current surge in oligonucleotide therapy, with many Food and Drug Administration-approved oligonucleotide-based drugs now available in clinics, and the urgent need for novel MASLD therapeutics present an opportune moment for this timely review article.

Papillary craniopharyngioma (PCP) is a rare type of tumor, comprising ∼20% of all craniopharyngioma (CP) cases. It is now recognized as a separate pathological entity from the adamantinomatous type. PCPs are benign tumors, classified as World Health Organization grade 1, characterized by nonkeratinizing squamous epithelium. They typically grow as solid and round papillomatous masses or as unilocular cysts with a cauliflower-like excrescence. PCPs primarily occur in adults (95%), with increased frequency in males (60%), and predominantly affect the hypothalamus. Over 80% of these tumors are located in the third ventricle, expanding either above an anatomically intact infundibulum (strictly third ventricle tumors) or within the infundibulo-tuberal region of the third ventricle floor. Clinical manifestations commonly include visual deficits and a wide range of psychiatric disturbances (45% of patients), such as memory deficits and odd behavior. Magnetic resonance imaging can identify up to 50% of PCPs by the presence of a basal duct-like recess. Surgical management is challenging, requiring complex approaches to the third ventricle and posing significant risk of hypothalamic injury. The endoscopic endonasal approach allows radical tumor resection and yields more favorable patient outcomes. Of intriguing pathogenesis, over 90% of PCPs harbor the somatic BRAFV600E mutation, which activates the mitogen-activated protein kinase signaling pathway. A phase 2 clinical trial has demonstrated that PCPs respond well to proto-oncogene B-Raf/MAPK/ERK kinase inhibitors. This comprehensive review synthesizes information from a cohort of 560 well-described PCPs and 99 large CP series including PCP cases published from 1856 to 2023 and represents the most extensive collection of knowledge on PCPs to date.

Skin is the largest organ of the human body and undergoes both intrinsic (chronological) and extrinsic aging. While intrinsic skin aging is driven by genetic and epigenetic factors, extrinsic aging is mediated by external threats such as UV irradiation or fine particular matters, the sum of which is referred to as exposome. The clinical manifestations and biochemical changes are different between intrinsic and extrinsic skin aging, albeit overlapping features exist, eg, increased generation of reactive oxygen species, extracellular matrix degradation, telomere shortening, increased lipid peroxidation, or DNA damage. As skin is a prominent target for many hormones, the molecular and biochemical processes underlying intrinsic and extrinsic skin aging are under tight control of classical neuroendocrine axes. However, skin is also an endocrine organ itself, including the hair follicle, a fully functional neuroendocrine "miniorgan." Here we review pivotal hormones controlling human skin aging focusing on IGF-1, a key fibroblast-derived orchestrator of skin aging, of GH, estrogens, retinoids, and melatonin. The emerging roles of additional endocrine players, ie, α-melanocyte-stimulating hormone, a central player of the hypothalamic-pituitary-adrenal axis; members of the hypothalamic-pituitary-thyroid axis; oxytocin, endocannabinoids, and peroxisome proliferator-activated receptor modulators, are also reviewed. Until now, only a limited number of these hormones, mainly topical retinoids and estrogens, have found their way into clinical practice as anti-skin aging compounds. Further research into the biological properties of endocrine players or its derivatives may offer the development of novel senotherapeutics for the treatment and prevention of skin aging.

People with type 1 diabetes (T1D) are usually considered to exclusively exhibit β-cell failure, but they frequently also feature insulin resistance. This review discusses the mechanisms, clinical features, and therapeutic relevance of insulin resistance by focusing mainly on human studies using gold-standard techniques (euglycemic-hyperinsulinemic clamp). In T1D, tissue-specific insulin resistance can develop early and sustain throughout disease progression. The underlying pathophysiology is complex, involving both metabolic- and autoimmune-related factors operating synergistically. Insulin treatment may play an important pathogenic role in predisposing individuals with T1D to insulin resistance. However, the established lifestyle-related risk factors and peripheral insulin administration inducing glucolipotoxicity, hyperinsulinemia, hyperglucagonemia, inflammation, mitochondrial abnormalities, and oxidative stress cannot always fully explain insulin resistance in T1D, suggesting a phenotype distinct from type 2 diabetes. The mutual interaction between insulin resistance and impaired endothelial function further contributes to diabetes-related complications. Insulin resistance should therefore be considered a treatment target in T1D. Aside from lifestyle modifications, continuous subcutaneous insulin infusion can ameliorate insulin resistance and hyperinsulinemia, thereby improving glucose toxicity compared with multiple injection insulin treatment. Among other concepts, metformin, pioglitazone, incretin-based drugs such as GLP-1 receptor agonists, sodium-glucose cotransporter inhibitors, and pramlintide can improve insulin resistance, either directly or indirectly. However, considering the current issues of high cost, side effects, limited efficacy, and their off-label status, these agents in people with T1D are not widely used in routine clinical care at present.

Oxytocin is a hypothalamic-posterior pituitary hormone with multiple effects, ranging from regulation of energy homeostasis to bone health and psychological wellbeing, in addition to its well-known effects in labor and lactation. Patients with hypothalamic and pituitary damage have a higher risk for medical and psychiatric comorbidities despite standard-of-care hormone replacement, and a clinically relevant oxytocin deficient state has been identified in patients with arginine vasopressin deficiency (formerly known as central diabetes insipidus) in the last decade. Therefore, oxytocin deficiency in patients with hypothalamic and pituitary damage is an emerging field. While intranasal oxytocin is readily available to patients, it is not FDA-approved in the US and the quality of compounded formulations is unclear. In addition, more research is needed to establish safety and efficacy of oxytocin-based therapeutics in patients with hypothalamic and pituitary damage before recommending treatment. This Review summarizes the current knowledge of the oxytocin system, oxytocin deficiency in other clinical conditions and relevance to patients with hypothalamic and pituitary damage. We highlight emerging data supporting oxytocin deficiency in hypothalamic-pituitary disease, diagnostic challenges, development of therapeutic strategies, and future research directions to advance the field.

Primary aldosteronism (PA), the most common cause of arterial hypertension, is surgically curable if a unilateral source of the hyperaldosteronism is discovered. To identify the patients who are curable, all current guidelines recommend adrenal venous sampling (AVS), a procedure which, albeit simple in principle, remains scarcely available and markedly under-utilized, because it is still perceived as technically challenging, invasive, and difficult to interpret. The lack of uniformly accepted standards for performance and interpretation of AVS, alongside the diffuse concerns that, albeit quite rarely, it can be complicated by adrenal vein rupture, contribute to the scant utilization of AVS. In the last decade, several major studies have contributed to a greater understanding of the use of AVS in PA patients, thus paving the way to a more rational and effective application that can allow to diagnose many more PA patients with a unilateral form of the disease to be referred for curative adrenalectomy. Moreover, microcatheters and androstenedione have been introduced to increase the success rate. This review provides updated information on the subtyping of PA by means of AVS and examines key issues on the selection and preparation of patients, the optimal performance of the procedure, and the interpretation of its results for diagnostic purposes, even in the most challenging cases. Situations when AVS can be omitted before surgery and alternative functional imaging techniques that have been proposed to identify unilateral surgical curable PA to circumvent the bottle-neck represented by the limited availability of AVS world-wide, are also discussed.

Glucose-dependent insulinotropic polypeptide (GIP) is a 42-amino acid hormone that is synthesized and released from upper intestinal enteroendocrine K-cells in response to the ingestion of glucose or fat. The structure of GIP places it in the secretin/vasoactive intestinal polypeptide family of gastrointestinal regulatory peptides. Although originally named "gastric inhibitory polypeptide" on the basis of its ability to inhibit gastric acid secretion, GIP accounts for 60%-80% of the postprandial insulin response, consistent with the notion that this regulatory peptide constitutes the principal physiological incretin. Under normal conditions, GIP plays a major role in nutrient deposition and storage, both directly through its insulin mimetic properties and indirectly by enhancing insulin release. GIP is overexpressed in obese individuals, which may exacerbate insulin resistance manifested by many patients with type 2 diabetes mellitus. Enhanced postprandial secretion of GIP also initiates a vicious cycle characterized by increased nutrient uptake and storage in adipocytes, leading to insulin resistance and hyperinsulinemia, which then further increases adipocyte nutrient uptake and storage. Despite the deleterious consequences of GIP overexpression, when combined with glucagon-like peptide-1 analogues, GIP agonism has been demonstrated to provide benefit in treating obesity by mechanisms currently not fully elucidated. In contrast, consistent with the etiologic role of GIP overexpression in the pathogenesis of obesity, both genetic abrogation and immunoneutralization of GIP signaling have been shown to reduce the development of obesity in preclinical models. Whether these beneficial effects of GIP antagonism will be extended to humans needs to be determined.