Eureka! The Top Endocrine Science of 2024 – Part I

For the tenth year running, Endocrine News talks to editors from Endocrine Society publications to unearth the most impressive breakthroughs in endocrine science and research for 2024. This year, we also talk to some of the “scientists behind the science” to get their insights on their cutting-edge research.

For the 10th year running, Endocrine News talks to editors from Endocrine Society publications to unearth the top endocrine discoveries of 2024 and the incredible scientists behind them.

Despite this being Eureka’s “tin anniversary,” these studies are pure gold, as selected by Endocrine Society journal editors-in-chief as well as associate editors as what they consider the top endocrinology studies published in the last 12 (or so) months.

These discoveries bridge molecular mechanisms through clinical applications and share a common thread: the increasing recognition that endocrine disorders require more personalized and nuanced approaches to treatment, whether in cancer therapy, metabolic disease, or age-related conditions.

Scientists have illuminated the complex interplay between hormones and systemic health. The discovery of brain-derived cellular communication factor 3 (CCN3) has revealed previously unknown connections between biologic systems, while new insights into the hormone LEAP2 have expanded our understanding of metabolic regulation. These findings are complemented by research showing how liver androgen receptors differently influence metabolic health in males and females, highlighting the importance of sex-specific approaches to endocrine disorders.

In the therapeutic realm, researchers have made significant strides in multiple areas: from targeted radiotherapy for metastatic pheochromocytomas to innovative approaches for preserving beta cell function in diabetes. Advances were also made in understanding the extraskeletal benefits of parathyroidectomy and the potential of combining glucagon-like peptide (GLP)-1 receptor agonists with lifestyle interventions for optimal outcomes in weight management.

Findings related to the clinical heterogeneity of polycystic ovarian syndrome (PCOS) and the varying predictive value of sex hormone–binding globulin (SHBG) levels across different populations emphasize the need for more individualized treatment approaches. This trend extends to the management of autoimmune endocrinopathies and early puberty, where both genetic and environmental factors are now better understood.

These discoveries — thanks to the scientists who made them — collectively promise to revolutionize patient care through more precise, personalized treatment strategies. By deepening our understanding of endocrine system complexity and its far-reaching effects on human health, these advances are paving the way for more effective interventions that can be tailored to individual patients’ needs, ultimately leading to better outcomes across a broad spectrum of endocrine disorders.

From the Editor of Endocrine Reviews

Endocrine Reviews Editor-in-Chief Ashley Grossman, FMedSci, emeritus professor of endocrinology, University of Oxford; senior research fellow, Green Templeton College; consultant NET endocrinologist, Royal Free London; professor of neuroendocrinology, Barts and the London School of Medicine; and consultant endocrinologist at the London Clinic Centre for Endocrinology, in the U.K., chose three JCEM publications he says will impact clinical practice.

The first is a very detailed and comprehensive review of targeted radiotherapy for metastatic pheochromocytomas/paragangliomas from September titled “Approach to the Patient: Concept and Application of Targeted Radiotherapy in the Paraganglioma Patient,” by Pacak K., Taieb D., Lin F.I., and Jha A. “In recent years, targeted radiotherapy for these tumors has become increasingly popular due to accumulating evidence of efficacy, in spite of the lack of large-scale controlled trials, with few of the adverse events associated with more conventional forms of treatment,” Grossman says. “High-activity ¹³¹I-MIBG has unfortunately been withdrawn, but the effectiveness of peptide receptor radionuclide therapy with ¹⁷⁷Lu-dotatate suggests that this will soon be the initial treatment of choice and should be actively considered by all physicians dealing with these fascinating tumors. The article is very comprehensive and well-illustrated.”

Grossman’s second pick is from July. “Also, in the area of endocrine oncology,” he says, “one not infrequently comes across patients with a MEN1 phenotype but negative genetic screening. Could these have MEN4, due to mutations of the CDKN1b gene responsible for the tumor suppressor p27?” In, “Beyond MEN1, When to Think About MEN4? Retrospective Study on 5,600 Patients in the French Population and Literature Review,” by Chevalier B., et al., among a very large French cohort investigated for MEN1, only four patients were identified as having MEN4. “These patients had milder disease, less frequently had pancreatic neuroendocrine tumors, and were diagnosed at an older age with hyperparathyroidism,” Grossman says. “This is clearly a very rare syndrome and should cause us a little less concern that we are missing the diagnosis on routine gene panel screening.”

“Returning to primary hyperparathyroidism,” he says, “it is often quite difficult to decide when surgical intervention is required, in spite of various guidelines to assist us. In particular, is there truly an improvement in bone architecture following selective parathyroidectomy?” In “Skeletal Effect of Parathyroidectomy on Patients With Primary Hyperparathyroidism: A Systematic Review and Meta-Analysis,” from July, Kongsaree N., et al. undertook a detailed review and meta-analysis, including 233,188 patients with hyperparathyroidism. “Fractures at any site were reduced, specifically hip fractures, although not in spine or radius fractures, and interestingly associated with only minimal changes in bone density,” Grossman explains. “They concluded that indeed there are improvements to be expected in bone architecture at the hip following parathyroidectomy, an argument that can be considered in some borderline patients being considered for this operation. This will certainly influence my approach to such patients with primary hyperparathyroidism, in particular those with borderline indications for operation.”

More From the Editors of Endocrine Reviews

Lauren Fishbein MD, PhD, MTR, assistant professor in medicine at the University of Colorado School of Medicine in the Division of Endocrinology, Metabolism and Diabetes and an associate editor of Endocrine Reviews chose “Outcomes of SDHB Pathogenic Variant Carriers,” by Davidoff D.H., et al. from the September issue of JCEM. “This systematic review provides data about those who carry a germline succinate dehydrogenase type B (SDHB)pathogenic variant (PV),” Fishbein says. “This is a rare/understudied condition. Those with SDHB germline PVs are at risk for developing hereditary paraganglioma-pheochromocytoma syndrome. We are finding more incidental genetic mutations or pathogenic variants through genetic testing for other reasons — part of biobanks or done for other cancers in the family, etc. The authors for this paper focus on those non-probands who have SDHB PVs and do a systematic meta-analysis for the risk of developing pheo/para, developing multifocal pheo/para and developing metastatic disease. Their work suggests there is a lower risk than previously reported for those with SDHB PVs to develop pheo/par and also a lower risk of developing metastatic disease than previously reported. These data may change our clinical management and our counseling of patients as we find more and more individuals with incidental pathogenic variants through more and more genetic testing for other reasons.”

The Scientist Behind the Science
Karel Pacak, MD, DSc, PhD of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Md. says, “this paper presents an updated approach to using targeted radiotherapy for patients with inoperable or metastatic pheochromocytoma and paraganglioma. Unlike earlier perspectives on systemic radiotherapy for these tumors, which often provided a simplified view for selecting radiopharmaceuticals, this article offers a more comprehensive and nuanced approach.

Previously, clinicians often selected a radiotherapy based on the sheer number of positive lesions for a specific radiopharmaceutical, without differentiating between lesions in critical organs (lungs/liver) versus bones/lymph nodes. This oversimplified strategy risked treatment failure, as organ lesions are known to pose greater danger than bone metastases in such cases. Additionally, certain radiotherapies induce higher bone marrow toxicity, particularly relevant in older patients and must be factored into treatment planning.

This updated approach integrates a deep understanding of both tumor and patient characteristics. For example, the selection of an appropriate radiopharmaceutical is guided by the extent of positivity in organ lesions, along with factors like tumor size (burden) and growth rate. Consider a case where radiopharmaceutical 1 shows uptake in 25 stable bone lesions and two growing liver lesions for Patient 1, while radiopharmaceutical 2 shows uptake in five stable bone lesions and five large, actively growing liver lesions for Patient 2. Prioritizing radiopharmaceutical 1 over radiopharmaceutical 2 here would represent a suboptimal choice. Similarly, a radiopharmaceutical that causes significant bone marrow suppression may not be suitable for older patients, and one that induces catecholamine release may be inappropriate for patients with elevated plasma or urinary metanephrine levels.

In summary, systemic radiotherapy for PPGL patients requires more than just identifying positive lesions. It demands careful consideration of tumor-specific: each lesion’s growth and functional characteristics, location, and the patient’s overall health status. This detailed clinical assessment often leads to improved outcomes for patients with metastatic PPGL. Furthermore, this paper identifies potential tumor/patient’s characteristics that may cause failure of systemic radiotherapy and discusses potential strategies and provide future perspectives to tackle them and make them work.”

The Scientist Behind the Science

Benjamin Chevalier, MD, MSc from the Department of Endocrinology, Diabetology and Metabolism, Lille University Hospital in Lille, France said:

“Based on 5600 NGS analyzes performed by the molecular biology laboratories of the TENgen French oncogenetic network, we identified only four pathogenic/likely pathogenic CDKN1B variants, equivalent to a prevalence of 0.07%. In comparison, the prevalence of MEN1 variants was 100 times higher (6.8%) in the same population.

We also reviewed all CDKN1B variants previously reported in the literature and matched them with the French UMD MEN1 database to evaluate commonalities and differences between the two diseases: there was no difference between incidence and age at diagnosis for pituitary adenoma (39% vs 44% for MEN1). There was also no difference regarding the incidence for primary hyperparathyroidism (84% vs 89% for MEN1) however diagnosis was made at a later age (55yo vs 42 yo for MEN1). Finally the prevalence of neuroendocrine tumor was lower in CDKN1B patients, with diagnosis also made at a later age (30% vs 62% for MEN1, mean age at diagnosis 55yo vs 42yo for MEN1).

We therefore provide for the first time an estimation of the prevalence of MEN4 as well as the most precise phenotypic characterization possible and the differences existing with MEN1.”

The Scientist Behind the Science:

“Our study, based on data from over 200,000 patients with primary hyperparathyroidism, found that parathyroidectomy can reduce the overall fracture risk by 20% and specifically lower hip fracture risk by 37%, despite an annual bone mineral density gain of only 1%-2% compared to conservative therapy,” says corresponding author Kanchana Ngaosuwan, MD, PhD, of the Princess Srisavangavadhana College of Medicine, Chulabhorn Royal Academy, in Bangkok, Thailand. “We believe the additional benefits of parathyroidectomy extend beyond mineral content enhancement, involving both skeletal and extraskeletal factors.

Regarding skeletal factors, prolonged parathyroid hormone (PTH) excess not only reduces bone density but also damages bone microarchitecture and alters skeletal geometry. By normalizing PTH levels, parathyroidectomy can enhance microarchitecture and skeletal geometry, leading to improved bone strength.

As for extraskeletal factors, PTH excess impairs balance, weakens neuromuscular function, and contributes to cognitive dysfunction, all of which increase fall risk — a key factor in hip fractures. Parathyroidectomy can improve neuromuscular and cognitive function, thereby lowering fall risk and, consequently, hip fracture risk.

In summary, our study highlights the reduced fracture risk following parathyroidectomy in patients with primary hyperparathyroidism, and this benefit likely involves more than mineral density gains alone. We speculate that parathyroidectomy may also confer protective effects by potentially improving bone microarchitecture, skeletal geometry, and neuromuscular and cognitive function.”

This post was originally published on here

Eureka! The Top Endocrine Science of 2024 – Part I

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