Adrenal All Stars: Catching Up with a Handful of the Endocrine Society’s Leaders in Adrenal Research and Treatment

Research and clinical care of adrenal diseases have improved significantly even in the past few years. Endocrine News speaks with a few notable experts in this space about these developments, gaps that are currently barriers to further ones, and how research informs the clinic and back again. When Gary D. Hammer, MD, PhD , professor of Internal Medicine, Cell and Developmental Biology, and Molecular and Integrative Physiology at the University of Michigan in Ann Arbor, and past president of the Endocrine Society, was interviewing for his job at Michigan, he was taken to a famous restaurant in Ann Arbor to meet with the head of the cancer center, and the legendary Wolverines football coach Bo Schembechler. (Schembechler’s wife passed away from adrenal cancer.) Schembechler told Hammer he only had one question for him: “Did you or did you not negotiate football tickets?” The room of 500 people erupted in laughter, but Schembechler stood silent and crossed his arms. “I stood up, looked him in the eye and said, ‘Bo, I think that’s why I’m here with you tonight,’” Hammer says. “We were best friends until the day he died.” For patients with adrenal disease – congenital adrenal hyperplasia, Cushing syndrome , adrenakl insufficiency, primary aldosteronism, pheochromocytoma and adrenal cancer– endocrinologists and other adrenal experts have been joining forces – locally, nationally and internationally – to collaborate and leverage expertise in both the clinical care of patients and research into disease mechanisms as they search for novel therapies for these rare diseases,. There have been some incredible developments even in the past five years: new and still-experimental medications, gene therapies, new surgery techniques, even coalitions of international researchers cooperating. Endocrine News caught up with Hammer; Deborah Merke, MD, MS , senior investigator and chief of the Department of Pediatrics at the National Institutes of Health; Nancy Dugal Perrier , MD, Walter and Ruth Sterling Endowed Professor of Surgery, Department of Surgical Oncology; chief, Section of Surgical Endocrinology; associate director, Multidisciplinary Endocrine Center, M.D. Anderson Cancer Center, Houston, Texas; Emilia Modolo Pinto, PhD , a researcher in the Department of Pathology at St. Jude’s Children’s Research Hospital in Memphis, Tenn.; and William Rainey, PhD , Jerome W. Conn Professor of medicine in the Departments of Molecular & Integrative Physiology and Internal Medicine at the University of Michigan, to discuss the recent breakthroughs, things still on the horizon, and the gaps that still need to addressed before reaching it. Endocrine News : How do you view the current state of adrenal research and clinical care? Are there any gaps that need to be addressed? Are there areas in adrenal that need more attention? Emilia Pinto : Adrenal research has advanced significantly over the past two decades, particularly in uncovering the molecular mechanisms behind adrenal tumors and congenital adrenal disorders. Still, important gaps remain. Rare adrenal diseases are still underrepresented in large-scale studies, and clinical care often relies on limited evidence or extrapolation from other patient populations. One critical point is that pediatric and adult adrenocortical tumors are biologically distinct diseases, with different genetic drivers, developmental contexts, and clinical behaviors, yet they are often treated and studied under the same framework. Recognizing and operationalizing this distinction is crucial for both research and patient care. There’s also a gap between genomic discoveries and their integration into everyday care, especially for risk assessment, surveillance, and counseling of individuals with predisposing variants. While preclinical models, such as patient-derived cell lines, organoids, and animal models, are increasingly available, current treatments remain only loosely connected to the underlying biology, which limits the translation of molecular insights into targeted therapies. At St. Jude, and through collaborative efforts such as the International Pediatric Adrenocortical Tumor Registry (IPACTR), we have a unique opportunity to study these questions in the context of rare pediatric tumors, where deeply annotated clinical cohorts can be directly integrated with genomic and developmental data. Thanks to these efforts, we can now turn insights from rare pediatric adrenal tumors into real strategies to improve patient care. William Rainey : This is an amazing time to be an adrenal researcher with recently developed technologies having a significant impact on our abilities to take a deeper dive into adrenal biology and disease. On the basic and translational science side, I would highlight four areas where the field is moving ahead but where additional work is needed. First, we need a stronger foundational understanding of adrenal stem cell biology and its role in normal adrenal homeostasis, so that our research can be translated into tissue engineering and adrenal cell–based therapies. Second, we need deeper insight into the genetic, epigenetic, and hormonal mechanisms that drive the sexual dimorphism observed in adrenal disorders such as primary aldosteronism, Cushing syndrome, and adrenocortical carcinoma. Third, we need to clarify the physiologic and pathologic regulators of adrenal androgen production. This area remains one of the least understood of human adrenal biology, in part because mice are unable to model human adrenal androgen synthesis. Finally, as in all areas of biomedical research, the adrenal field needs to adopt appropriate artificial intelligence tools in ways that can strengthen our basic research and accelerate translation. On the clinical side of adrenal research, two areas are likely to remain especially active in the coming years. First, we still lack therapies that reliably reproduce physiologic cortisol circadian rhythms in adrenal insufficiency as well as restoring these patterns after patients are treated for Cushing syndrome. The clinical benefits of re-establishing normal cortisol rhythmicity could have a significant impact on patient quality of life. Second, there is growing momentum to expand screening for adrenal steroid–excess disorders, particularly primary aldosteronism and Cushing syndrome. Hopefully these efforts will be accelerated by the increasing use of artificial intelligence in primary care, which could improve recognition of adrenal (and other endocrine) diseases and lead to earlier diagnostic evaluation. Deborah Merke : Now is a very exciting time to be doing adrenal research as we are making major advances in the clinical care of adrenal disorders, especially congenital adrenal hyperplasia (CAH). I have spent my entire career studying CAH, the most common cause of adrenal insufficiency in children and a complex and challenging disorder to manage due to the many hormonal imbalances. We are now entering a new era with the availability of novel drugs to treat CAH. The treatment of CAH with glucocorticoids that began in the 1950’s was lifesaving, and since that time we have used glucocorticoids to not only treat the adrenal insufficiency, but also to suppress the ACTH-driven adrenal androgen production characteristic of CAH. Excess glucocorticoids have been needed to adequately suppress adrenal androgens. Many years of studying the pathophysiology of CAH and the adverse outcomes due to both disease-related and treatment-related factors has finally resulted in the availability of new drugs. In the EU, a modified-release form of hydrocortisone that approximates physiological cortisol circadian secretion has improved outcomes and was approved in 2021. In the US, a CRF-1 antagonist is FDA approved for patients four years of age and older with classic CAH since December 2024. This drug is an adjunctive treatment to glucocorticoid replacement and for the first time allows clinicians to control adrenal androgens using a non-glucocorticoid medication and therefore reduce glucocorticoid dose. Several gaps exist. Importantly, the use of alternative strategies is in its infancy and there is a lack of worldwide access to newly developed drugs. An oral modified-release form of hydrocortisone that was designed to mimic physiological circadian cortisol secretion (marketed as Efmody) is available in the EU; while the CRF-1 antagonist (marketed as Crenessity) is available in the US. Long-term follow-up is lacking. Although we have learned that circadian physiological glucocorticoid dosing is ideal, much needs to be learned about how best to replace glucocorticoid to optimize quality-of-life and disease control. Nancy Dugal Perrier : As a committed surgical endocrine oncology oncologist for 25 years now, it has been fascinating watching the progression over these last 25 years of what has happened with technology and new information. In particular, I think where we stand with the ability to do two things in the perioperative space: First is to be able to identify the mutation of adrenal tumors, particularly for fetal pheochromocytomas and the surrounding paragangliomas. I think knowing the more than two dozen mutations that are affiliated and using that as a predictor of how to personalize treatment for that patient has just been explosive in the last decade. And now we see it as being a part of all of our operative decision making, not only our postoperative, but also our preoperative decision making. I think the complexity of thinking through disease at presentation and then being able to really predict and prevent downstream disabilities from that, predicting who’s at high risk for bilateral disease, that’s asynchronous, who, at what age are they presenting with the aggressiveness of the disease and what we can expect. I think we can anticipate that much better now, and our surgical deployments are certainly more specific. Thi…