Endocrine Reviews

Baxter, Robert C

2023 Endocrine Reviews

doi: 10.1210/endrev/bnad008pmid: 36974712

The 6 high-affinity insulin-like growth factor binding proteins (IGFBPs) are multifunctional proteins that modulate cell signaling through multiple pathways. Their canonical function at the cellular level is to impede access of insulin-like growth factor (IGF)-1 and IGF-2 to their principal receptor IGF1R, but IGFBPs can also inhibit, or sometimes enhance, IGF1R signaling either through their own post-translational modifications, such as phosphorylation or limited proteolysis, or by their interactions with other regulatory proteins. Beyond the regulation of IGF1R activity, IGFBPs have been shown to modulate cell survival, migration, metabolism, and other functions through mechanisms that do not appear to involve the IGF-IGF1R system. This is achieved by interacting directly or functionally with integrins, transforming growth factor β family receptors, and other cell-surface proteins as well as intracellular ligands that are intermediates in a wide range of pathways. Within the nucleus, IGFBPs can regulate the diverse range of functions of class II nuclear hormone receptors and have roles in both cell senescence and DNA damage repair by the nonhomologous end-joining pathway, thus potentially modifying the efficacy of certain cancer therapeutics. They also modulate some immune functions and may have a role in autoimmune conditions such as rheumatoid arthritis. IGFBPs have been proposed as attractive therapeutic targets, but their ubiquity in the circulation and at the cellular level raises many challenges. By understanding the diversity of regulatory pathways with which IGFBPs interact, there may still be therapeutic opportunities based on modulation of IGFBP-dependent signaling.

Jha, Smita; Simonds, William F

2023 Endocrine Reviews

doi: 10.1210/endrev/bnad009pmid: 36961765

Recent data suggest an increase in the overall incidence of parathyroid disorders, with primary hyperparathyroidism (PHPT) being the most prevalent parathyroid disorder. PHPT is associated with morbidities (fractures, kidney stones, chronic kidney disease) and increased risk of death. The symptoms of PHPT can be nonspecific, potentially delaying the diagnosis. Approximately 15% of patients with PHPT have an underlying heritable form of PHPT that may be associated with extraparathyroidal manifestations, requiring active surveillance for these manifestations as seen in multiple endocrine neoplasia type 1 and 2A. Genetic testing for heritable forms should be offered to patients with multiglandular disease, recurrent PHPT, young onset PHPT (age ≤40 years), and those with a family history of parathyroid tumors. However, the underlying genetic cause for the majority of patients with heritable forms of PHPT remains unknown. Distinction between sporadic and heritable forms of PHPT is useful in surgical planning for parathyroidectomy and has implications for the family. The genes currently known to be associated with heritable forms of PHPT account for approximately half of sporadic parathyroid tumors. But the genetic cause in approximately half of the sporadic parathyroid tumors remains unknown. Furthermore, there is no systemic therapy for parathyroid carcinoma, a rare but potentially fatal cause of PHPT. Improved understanding of the molecular characteristics of parathyroid tumors will allow us to identify biomarkers for diagnosis and novel targets for therapy.

Warren, Annabelle M; Grossmann, Mathis; Christ-Crain, Mirjam; Russell, Nicholas

2023 Endocrine Reviews

doi: 10.1210/endrev/bnad010pmid: 36974717

Hyponatremia is the most common electrolyte disorder, affecting more than 15% of patients in the hospital. Syndrome of inappropriate antidiuresis (SIAD) is the most frequent cause of hypotonic hyponatremia, mediated by nonosmotic release of arginine vasopressin (AVP, previously known as antidiuretic hormone), which acts on the renal V2 receptors to promote water retention. There are a variety of underlying causes of SIAD, including malignancy, pulmonary pathology, and central nervous system pathology. In clinical practice, the etiology of hyponatremia is frequently multifactorial and the management approach may need to evolve during treatment of a single episode. It is therefore important to regularly reassess clinical status and biochemistry, while remaining alert to potential underlying etiological factors that may become more apparent during the course of treatment. In the absence of severe symptoms requiring urgent intervention, fluid restriction (FR) is widely endorsed as the first-line treatment for SIAD in current guidelines, but there is considerable controversy regarding second-line therapy in instances where FR is unsuccessful, which occurs in around half of cases. We review the epidemiology, pathophysiology, and differential diagnosis of SIAD, and summarize recent evidence for therapeutic options beyond FR, with a focus on tolvaptan, urea, and sodium-glucose cotransporter 2 inhibitors.

Eisenhofer, Graeme; Pamporaki, Christina; Lenders, Jacques W M

2023 Endocrine Reviews

doi: 10.1210/endrev/bnad011pmid: 36996131

Pheochromocytoma and paraganglioma (PPGL) require prompt consideration and efficient diagnosis and treatment to minimize associated morbidity and mortality. Once considered, appropriate biochemical testing is key to diagnosis. Advances in understanding catecholamine metabolism have clarified why measurements of the O-methylated catecholamine metabolites rather than the catecholamines themselves are important for effective diagnosis. These metabolites, normetanephrine and metanephrine, produced respectively from norepinephrine and epinephrine, can be measured in plasma or urine, with choice according to available methods or presentation of patients. For patients with signs and symptoms of catecholamine excess, either test will invariably establish the diagnosis, whereas the plasma test provides higher sensitivity than urinary metanephrines for patients screened due to an incidentaloma or genetic predisposition, particularly for small tumors or in patients with an asymptomatic presentation. Additional measurements of plasma methoxytyramine can be important for some tumors, such as paragangliomas, and for surveillance of patients at risk of metastatic disease. Avoidance of false-positive test results is best achieved by plasma measurements with appropriate reference intervals and preanalytical precautions, including sampling blood in the fully supine position. Follow-up of positive results, including optimization of preanalytics for repeat tests or whether to proceed directly to anatomic imaging or confirmatory clonidine tests, depends on the test results, which can also suggest likely size, adrenal vs extra-adrenal location, underlying biology, or even metastatic involvement of a suspected tumor. Modern biochemical testing now makes diagnosis of PPGL relatively simple. Integration of artificial intelligence into the process should make it possible to fine-tune these advances.

Townsend, Logan K; Steinberg, Gregory R

2023 Endocrine Reviews

doi: 10.1210/endrev/bnad012pmid: 37115289

Complex multicellular organisms require a coordinated response from multiple tissues to maintain whole-body homeostasis in the face of energetic stressors such as fasting, cold, and exercise. It is also essential that energy is stored efficiently with feeding and the chronic nutrient surplus that occurs with obesity. Mammals have adapted several endocrine signals that regulate metabolism in response to changes in nutrient availability and energy demand. These include hormones altered by fasting and refeeding including insulin, glucagon, glucagon-like peptide-1, catecholamines, ghrelin, and fibroblast growth factor 21; adipokines such as leptin and adiponectin; cell stress–induced cytokines like tumor necrosis factor alpha and growth differentiating factor 15, and lastly exerkines such as interleukin-6 and irisin. Over the last 2 decades, it has become apparent that many of these endocrine factors control metabolism by regulating the activity of the AMPK (adenosine monophosphate–activated protein kinase). AMPK is a master regulator of nutrient homeostasis, phosphorylating over 100 distinct substrates that are critical for controlling autophagy, carbohydrate, fatty acid, cholesterol, and protein metabolism. In this review, we discuss how AMPK integrates endocrine signals to maintain energy balance in response to diverse homeostatic challenges. We also present some considerations with respect to experimental design which should enhance reproducibility and the fidelity of the conclusions.

Gild, Matti L; Clifton-Bligh, Roderick J; Wirth, Lori J; Robinson, Bruce G

2023 Endocrine Reviews

doi: 10.1210/endrev/bnad013pmid: 37204852

A personalized approach to the management of medullary thyroid cancer (MTC) presents several challenges; however, in the past decade significant progress has been made in both diagnostic and treatment modalities. Germline rearranged in transfection (RET) testing in multiple endocrine neoplasia 2 and 3, and somatic RET testing in sporadic MTC have revolutionized the treatment options available to patients. Positron emission tomography imaging with novel radioligands has improved characterization of disease and a new international grading system can predict prognosis. Systemic therapy for persistent and metastatic disease has evolved significantly with targeted kinase therapy especially for those harboring germline or somatic RET variants. Selpercatinib and pralsetinib are highly selective RET kinase inhibitors that have shown improved progression-free survival with better tolerability than outcomes seen in earlier multikinase inhibitor studies. Here we discuss changes in paradigms for MTC patients: from determining RET alteration status upfront to novel techniques for the evaluation of this heterogenous disease. Successes and challenges with kinase inhibitor use will illustrate how managing this rare malignancy continues to evolve.

Khan, Danyal Z; Hanrahan, John G; Baldeweg, Stephanie E; Dorward, Neil L; Stoyanov, Danail; Marcus, Hani J

2023 Endocrine Reviews

doi: 10.1210/endrev/bnad014pmid: 37207359

The vital physiological role of the pituitary gland, alongside its proximity to critical neurovascular structures, means that pituitary adenomas can cause significant morbidity or mortality. While enormous advancements have been made in the surgical care of pituitary adenomas, numerous challenges remain, such as treatment failure and recurrence. To meet these clinical challenges, there has been an enormous expansion of novel medical technologies (eg, endoscopy, advanced imaging, artificial intelligence). These innovations have the potential to benefit each step of the patient’s journey, and ultimately, drive improved outcomes.Earlier and more accurate diagnosis addresses this in part. Analysis of novel patient data sets, such as automated facial analysis or natural language processing of medical records holds potential in achieving an earlier diagnosis. After diagnosis, treatment decision-making and planning will benefit from radiomics and multimodal machine learning models. Surgical safety and effectiveness will be transformed by smart simulation methods for trainees. Next-generation imaging techniques and augmented reality will enhance surgical planning and intraoperative navigation. Similarly, surgical abilities will be augmented by the future operative armamentarium, including advanced optical devices, smart instruments, and surgical robotics. Intraoperative support to surgical team members will benefit from a data science approach, utilizing machine learning analysis of operative videos to improve patient safety and orientate team members to a common workflow. Postoperatively, neural networks leveraging multimodal datasets will allow early detection of individuals at risk of complications and assist in the prediction of treatment failure, thus supporting patient-specific discharge and monitoring protocols.While these advancements in pituitary surgery hold promise to enhance the quality of care, clinicians must be the gatekeepers of the translation of such technologies, ensuring systematic assessment of risk and benefit prior to clinical implementation. In doing so, the synergy between these innovations can be leveraged to drive improved outcomes for patients of the future.