ESSAY｜TOWARD JES 100TH ANNIVERSARY
My 50 years in adrenal endocrinology coincident with 100 years of the Japan Endocrine Society
2023 Volume 70 Issue 7 Pages 647-654
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2023 Volume 70 Issue 7 Pages 647-654
As the Japan Endocrine Society (JES) celebrates its 100th anniversary, I have had the opportunity to look back on my past 50 years of involvement with endocrinology practice and research. There were many milestones along the way, but I tried to face the challenges of the present and the future with endocrinology in my heart, supported by the JES. First of all, what impressed me the most about studying endocrinology were 1) the severity of hormonal excess experienced by a patient with Cushing’s syndrome bedridden due to multiple fractures, 2) the great potential of hormone measurement as a powerful tool for diagnosis and treatment, and 3) the dramatic therapeutic effects of non-endocrine drugs in central diabetes insipidus. Secondly, the enthusiasm and environment created by leading researchers in the field were superb support for me as a young doctor seeking to pursue the path of becoming an endocrinologist. The Second Department of Medicine, Tokyo Women’s Medical University (TWMU), led by Professor Kazuo Shizume and other prominent endocrinologists at that time, was a fantastic starting point for my subsequent career. Starting with research on renin, aldosterone, and adrenal disorders, I went on to work on cardiovascular endocrinology, before finally returning to research on adrenal disorders, which are common in my daily clinical practice. Research themes may change with time, but it is essential to return to the basics and be true to one’s origin in order to maintain lifelong integrity with one’s research theme. Multicenter studies with disease registries supported by National Hospital Organization (NHO) and the Japan Agency for Medical Research and Development (AMED) were a powerful and innovative approach to producing high-quality evidence for guidelines. Furthermore, my research experience at Dr. Tadashi Inagami’s laboratory at Vanderbilt University in Nashville, TN, USA and joint research with European Network for the Study of Adrenal Tumors (ENS@T) were of great help in promoting my research from an international perspective, where publishing scientific research papers in English is a prerequisite for presenting research outcomes. Of the various lessons learned from my years of experience, the most important were 1) starting from endocrine patients and returning the research results to clinical practice, 2) working with an international perspective and viewpoint, and 3) nurturing the next generation of endocrinologists by showing our own enthusiasm and support as a leader in the field. I believe the JES has been and will continue to be the backbone and framework for all of this.
Since becoming a member of the JES in 1977, I have engaged in medical care, research, and education in endocrinology, especially adrenal disorders, for almost 50 years. As the JES celebrates its 100th anniversary, I would like to summarize the trajectory of my career in adrenal endocrinology coincident with the progress of the JES.
I chose the path of endocrinology during my fifth year at Tohoku University for two reasons. First, I saw several Cushing’s syndrome patients with typical physical findings lying bedridden with multiple bone fractures. Second, the attending physician measured their adrenocorticotropic hormone (ACTH) and cortisol levels using self-developed assay methods to make a differential diagnosis of pituitary or adrenal disease. The seriousness of the systemic impact of excess hormones, the feasibility of measuring hormones to determine the lesion site, and the enthusiastic commentary on the endocrine diagnosis by the attending physician at the ward seminar were my primary reasons for selecting endocrinology, and they have remained firmly impressed on my memory.
Lessons learned from experience: Specific experiences in clinical medical education provide motivation to one’s research subspecialty.
I did my first clinical case study on an individual with central diabetes insipidus whom I cared for during my initial training. Since desmopressin acetate (DDAVP) was unavailable clinically, we conducted a detailed literature search on treatment. Since there was no such thing as an internet literature search on PubMed at that time, I had to ask the hospital secretary for a list of articles obtained with keywords and photocopies of relevant papers by visiting the university library. I found that treatments entirely unrelated to diabetes insipidus, including chlorpropamide (a hypoglycemia drug), clofibrate (a hyperlipidemia drug), chlorothiazide (an antihypertensive diuretic drug), and carbamazepine (an antiepileptic drug) were effective. After treatment with these medications, the patient’s urine output decreased dramatically from 15 L/day to 3 L/day (Fig. 1) [1]. I found the details of how these drugs increase arginine vasopressin (AVP) secretion and enhance its action highly intriguing. Although the treatment is a clinical case study of so-called off-label drug use by the current classification, I did not recognize it as such at the time, and I had no choice but to use those drugs to treat the patient.
Significant anti-diuretic effects of so-called ‘off-label drug use’ on polyuria in a patient with central diabetes insipidus. This figure was reproduced with permission for this manuscript by citing and modifying original Fig. 3 of Ref. 1 (Naruse et al. [1976] Hitachi Medical J 28: 8–15).
Lessons learned from experience: Hormone secretion and action are modified profoundly by unexpected agents.
I started my career as an endocrinologist at TWMU, where Professor Shizume was in charge of the Endocrinology Department. It was a time when endocrinological research and clinical practice made great strides due to the structural determination of known hormones, the discovery of new hormones, and advances in assay methods. Dr. Shizume left a significant mark on the development of endocrinology and the JES. He established the Comprehensive Medical Center of Endocrinology at TWMU, an unprecedented global center. He always recommended that the medical staff members 1) learn from patients and use clinical questions as the starting point for research and 2) publish at least one English paper every year. He inspired young endocrinologists from an international perspective through monthly reviews of the Journal of Clinical Endocrinology & Metabolism and Endocrinology on his own, encouraging presentations at international conferences, visiting world-famous medical centers such as the Mayo Clinic (Rochester, MN, USA), and inviting prominent endocrinologists from overseas. There is no doubt that the enthusiasm of this leader had a significant impact on young endocrinologists. His words are still fresh in my memory, saying, “Dr. Naruse, you look smart and ‘normal,’ so if you do your best, I will support you as much as possible. If the opportunity avails itself, I recommend you to go to the US to develop your research.” Noteworthy were the words and enthusiasm of my boss to stimulate me as a new endocrinologist.
Lessons learned from experience: The enthusiasm of leaders in the affiliation and the field and the creation of a nurturing environment for young doctors are important.
The specific topics of my endocrinology research are clear from my 333 total published papers in English (on PubMed). Most of the manuscripts are related to aldosterone, followed by those related to natriuretic peptides, endothelin/NO/CO, renin/angiotensin, PPGL, and Cushing’s/Subclinical Cushing’s syndrome (Table 1). In addition, looking at the themes over time, it is clear that they changed historically, starting with renin and aldosterone, evolving to natriuretic peptides, vasoactive factors such as endothelin, primary aldosteronism (PA), pheochromocytoma, and more comprehensive intractable adrenal diseases (Fig. 2). Although it is often unavoidable to change topics depending on the research environment and trends, I recommend maintaining consistency and context in focus for the integrity of one’s lifelong research career.
| Main topic | No. of manuscripts* |
|---|---|
| Aldosterone | 98 |
| Other | 53 |
| Natriuretic peptides | 48 |
| Endothelin/NO | 46 |
| Renin/Angiotensin | 37 |
| PPGL | 36 |
| Cushing’s syndrome/Subclinical Cushing’s syndrome | 15 |
| Total No. | 333 |
* Via PubMed search
NO: Nitric oxide, PPGL: Pheochromocytoma and paraganglioma
Historical changes in clinical and research topics: My affiliations are shown at the top of the figure. The timing of the landmark substances (renin, ANP, NO, ET, and BNP) and our clinical studies are indicated with arrows in the middle of the figure.
ANP: Atrial natriuretic peptide, NO: Nitric oxide, ET: Endothelin, BNP: Brain natriuretic peptide, NP: Natriuretic peptides including ANP, BNP, and CNP, Aldo.: Aldosterone, PPGL: Pheochromocytoma and paraganglioma, CS/SubCS: Cushing’s syndrome/Subclinical Cushing’s syndrome
Lessons learned from experience: The lifelong integrity of one’s research theme is important despite the changes in the times.
Renin research showed significant progress in the late 1970s with the isolation and purification of renin by Professor Inagami and coworkers and the discovery of extrarenal renin by Dr. Detlev Ganten and coworkers in Germany. As recommended, I went to the US and joined Professor Inagami’s laboratories at Vanderbilt University in 1980. Honestly, I was highly apprehensive about whether a clinician with no background in basic biochemical research could survive in one of the world’s top research laboratories. I still keep many letters from Dr. Inagami. Remember that there was no email at that time. What impressed me was what Dr. Inagami once said to me, “I have the same concern as you, but people are evaluated not only by experience but also by motivation and ability. I trust you.” While I was grateful for his trust and acceptance of an inexperienced researcher, I also experienced the pressure of living up to high expectations.
The laboratory consisted of a mixed group of PhDs, who mainly conducted biochemical research, and MDs, who researched the pathology of hypertension. After joining one of the world’s most advanced laboratories, I recognized that:
1. There is fierce competition with other research groups for critical research topics.
2. If a paper’s publication is delayed even by one week, its impact is significantly reduced.
3. Since the employment of researchers and assistants is highly dependent on grants, obtaining research funding is indispensable.
4. We can publish achievements with high academic value in top global journals.
Dr. Inagami came to my laboratory every day and discussed the progress and results of my research. Although studying abroad was a big challenge and placed enormous pressure on me, it enabled me to work with grit to take advantage of the opportunities given to me.
My research theme was extrarenal renin, and I studied the distribution of renin in organs other than the kidney, its biochemical characteristics, and its association with hypertension. We published several papers demonstrating that the highest amount of extrarenal renin was in the adrenal cortex, that adrenal renin concentrations increased after nephrectomy, and that adrenal renin was increased markedly in hypertensive rats [2, 3]. The increase in renin concentration in the adrenal gland as the target organ of kidney renin was an intriguing phenomenon concerning the pathogenesis of hypertension. Elucidating the pathophysiological significance of adrenal renin by excluding the effects of kidney-derived renin was technically very difficult. We had to wait for the development of gene overexpression or knockout technology, which was accomplished later by Dr. Ganten’s group (Nature, 1990).
Lessons learned from experience: Joining a cutting-edge laboratory is a chance to broaden our horizons to the world.
The secretory granules in the heart were initially assumed to contain cardiac renin, but their contents turned out to be a peptide hormone with potent natriuretic action. Atrial natriuretic peptide (ANP) attracted researchers from all over the world during the latter period of my stay in the US. It rang in a new era of endocrinology called cardiovascular endocrinology. After returning to TWMU, I did research on the pathophysiological significance of ANP using synthetic peptides, their antisera, and radioimmunoassay (RIA). We demonstrated its physiological relevance [4], significant changes in blood ANP levels in various diseases, suppression of aldosterone, renin [5], AVP, and cortisol secretion, its involvement in the so-called ‘escape phenomenon’ seen with aldosterone administration [6], its role in the antihypertensive and cardioprotective actions of β-blockers [7], and a significant increase in βANP, a dimer of ANP, in the failing human heart (in collaboration with Mayo Clinic) [8]. ANP is now clinically applied as a biomarker of heart failure and in the treatment of heart failure.
Brain natriuretic peptide (BNP) was then discovered in the cardiac ventricles, and endothelin and nitric oxide synthase were discovered in vascular endothelial cells. Clinical application of endothelin receptor antagonists is currently underway in various pathological conditions, such as pulmonary hypertension and cerebral vasospasm. Advances in cardiovascular endocrinology have brought about a paradigm shift in endocrinology, but further research is needed to establish direct involvement in the diagnosis and treatment of classic endocrine diseases.
Lessons learned from experience: Brand new cardiovascular endocrinology research inspires young researchers and fosters independence.
Since I was involved in the daily clinical care of many patients with adrenal and hypertensive diseases, it was natural to return to research on adrenal disorders. We found that an increase in the plasma aldosterone concentration (PAC) in response to metoclopramide, an anti-dopaminergic drug, helped to differentiate aldosterone-producing adenomas (APA) from idiopathic hyperaldosteronism (IHA) [9], that cardiac hypertrophy is more prominent in PA than in other forms of hypertension [10], that the basal PAC and the aldosterone to renin ratio in PA fluctuate wildly, making reproducibility a clinical issue [11], and that the angiotensin type 2 receptor mediates the so-called ‘aldosterone breakthrough phenomenon’ associated with administration of angiotensin receptor blockers [12]. Furthermore, we found the expression of various ectopic receptors, such as β1, V1, LH/hCG, and 5-HT4, in bilateral multinodular PA. Similar findings in patients with Cushing’s syndrome with bilateral adrenal hyperplasia (BMAH) were first reported by Dr. Andre Lacroix’s group in Montreal, Canada. Although we had earlier presented our findings at an International Steroid Conference in 2002, we did not publish them at the time, while Dr. Lacroix’s group later published theirs (Horm Metab Res, 2010). No matter how novel the research, the results do not obtain an international academic evaluation or profile if not published as a scholarly manuscript.
Lessons learned from experience: A return to research themes close to daily clinical practice is realistic and rational for further career.
In 2003, I moved to National Kyoto Hospital (now National Hospital Organization Kyoto Medical Center), where the government launched the Clinical Research Center of Endocrinology and Metabolism. I had the opportunity to engage in a multicenter clinical study taking advantage of a nationwide network of national hospitals. In a prospective cohort study, we investigated the frequency of PA in Japan (PHAS-J), the application rate of the JES diagnostic guidelines, the adrenal venous sampling (AVS) implementation rate, the rate of a definite diagnosis of PA subtype (PHAS-J2), and prognostic differences between the use of conventional antihypertensive drugs and MR antagonists in non-surgical cases (PHAS-J3).
Based on our experience with online disease registration, management of the administrative office, and process of ethics approval in multicenter joint research, we started the Japan PA Study (JPAS) as one of the Practical Research Projects for Rare/Intractable Diseases supported by AMED in 2015. We constructed a PA registry of about 5,000 cases, published many papers (about 50) unique to Japan and related to the diagnosis and treatment of PA, and reflected them in the PA Guidelines 2021 [14]. In addition, we have promoted industry-academia collaborative research to develop a new noninvasive PET-imaging method for subtype diagnosis of PA [15]. We expect further efforts toward the clinical application of the latest imaging method as an alternative for AVS.
Another significant adrenal disease is pheochromocytoma/paraganglioma. We started the PHEO-J Study as a research project for overcoming intractable diseases supported by the Ministry of Health, Labor, and Welfare of Japan in 2009. We conducted multifaceted efforts: a nationwide survey of malignant pheochromocytoma, the establishment of a PHEO registry, a mailing list of physicians for communication, the establishment of a patient association, the creation of clinical practice guidelines and diagnostic criteria, central pathological analysis, submission of requests for approval of unapproved and off-label drugs to the Japan Ministry of Health, Labor, and Welfare, and hosting of an international symposium (ISP2014) [15, 16]. As an initiative to inherit and comprehensively incorporate the JPAS and PHEO-J, in 2018, we started the JRAS study as one of the AMED research projects in conjunction with the ACPA-J research of the National Center for Global Health and Medicine. We established a Cushing’s syndrome, subclinical Cushing’s syndrome, and BMAH disease registry in addition to PA and PPGL. The upcoming clinical practice guidelines for these intractable adrenal diseases will reflect the study’s outcome as evidence.
Multicenter studies are not always superior to single-center studies. However, in the case of rare diseases, there are not enough cases at a single center, and selection bias dramatically affects the results. Intercenter bias can be removed by accumulating many cases through multicenter joint research. The consensus among many researchers at many institutions can be readily obtained by sharing data and results. However, there are several complications, such as effort, funding, human resources, and ethical processes. From a long-term perspective, I recommended that the JES inherit projects as a Task of the Society.
Lessons learned from experience: Multicenter studies with disease registries are a powerful and innovative approach to producing high-quality evidence, but require significant effort and funding.
The two key factors for maintaining international competitiveness and the presence of Japan are 1) the publication of papers in international journals and 2) global collaboration. As an example of the latter, we have much to learn from ENS@T in conducting multicenter studies on adrenal tumors across borders. We participated in joint research [17–22] and proposed projects ourselves as principal investigators. The first was the AVSTAT study [23], and the second was the SCOT-PA study [24]. The AVSTAT study investigated how AVS for subtype diagnosis effectively indicated adrenal surgery. Adrenal surgery was selected in 35% of patients, and medical treatment was selected in 65%. While medical treatment was indicated mainly in patients with a bilateral subtype, it was selected even in patients with a unilateral subtype. The medical treatment rate was higher in Japan than in the EU, indicating the need for a further efficient indication for AVS. In the SCOT-PA study, we investigated the details of PA screening and confirmatory tests at multiple centers. The difference in methods between centers and countries was huge, and the diagnosis of PA was not uniform, indicating the need for international standardization of diagnostic procedures. International joint research and publication of results can contribute to pertinent information exchange with other countries and promote the globalization of endocrinology research in Japan.
Our other approach to facilitating international communication is the Mayo-Japan Endocrine Seminar with Dr. William F. Young, Jr., Director of the Endocrinology Department of the Mayo Clinic as a co-organizer. We have held more than 15 seminars since 2009. We have learned much through discussion and commentary on the diagnosis and treatment of complex cases by the world’s top endocrinologist from the number one-ranked hospital by US News Best Hospitals. It also serves as an excellent opportunity to learn about new clinical research topics and questions. We must remember that Dr. Shizume emphasized the importance of learning from patients and daily clinical practice. The idea also applies to the mission of the Mayo Clinic, ‘The needs of the patient come first.’
Lessons learned from experience: Internationalization in various aspects is essential to improve the quality of adrenal gland research in Japan.
Publication of research results is critical. The abstracts presented at academic conferences do not provide research details and are insufficient as objective evidence. In addition, it is not easy to obtain information about a study unless we attend the meeting. It is difficult for overseas researchers to read and refer to non-English papers. Clinical practice guidelines usually prioritize English papers with high-impact factors through systematic reviews. Research requires a great deal of time, effort, and funding. An English-language research paper is an essential requirement that reflects its cost-effectiveness. Not being able to write a paper on the results of extensive research and losing its value over time is a negative experience. Further efforts of the researcher and the instructor’s appropriate guidance are warranted to avoid having such preventable “regrets” as a researcher.
Lessons learned from experience: Research results and efforts cannot be traced without publication in peer review English journals.
My lifelong career in endocrinology began with the following:
1. A patient immobilized in a hospital bed with Cushing’s syndrome.
2. Treatment with off-label drugs for central diabetes insipidus.
3. Measurement of the concentration of a hormone as a powerful tool for disease diagnosis.
Starting with the research on the renin-angiotensin-aldosterone system (RAAS), we went through the study of extrarenal renin, cardiovascular endocrinology represented by ANP and endothelin, implementation of nationwide multicenter joint research, such as National Hospital Organization, the establishment of an adrenal disease registry, creation of evidence and its use in clinical practice guidelines, and global collaboration. After expanding the research field, changing the methods, and applying the outcome, we finally returned to the origin of adrenal disorders (Fig. 3), which was a long way back to our starting point and original intention.
Chronological changes in various aspects of research and clinical practice: Transition with the times and feedback to adrenal disorders.
EDC: Electronic data collection
The JES was the fundamental framework and backbone that motivated us to conduct endocrinological research and apply the results to clinical practice. I express my deep gratitude to the JES for supporting 50 years of my career as an endocrinologist. With its glorious history and significant achievements, the JES will continue to support all endocrinologists in the future development of the field of endocrinology.
I wish to express my profound thanks to all who have helped me in my career, to those whose behind-the-scenes support I have not realized, and to those whom I have not been able to express my gratitude. I wish to especially thank Drs. Kazuo Shizume, Hiroshi Demura, Reiko Demura, Takao Saruta, Yukio Hirata, Fumiaki Marumo, Yukio Miura, Kazuaki Shimamoto, Kazuwa Nakao, Yoshio Yazaki, Yuichi Takakuwa, Tadashi Inagami, Zheng-pei Zeng, William F. Young, Jr. for their warm and kind support to my endocrinology career and Ms. Keiko Umegaki for her enthusiastic support as a nationwide collaborative clinical study secretary for over 15 years. Finally, I express my sincere appreciation to my family members, who have supported me over the past 50 years as an endocrinologist.
My endocrinology researches were supported in part by the JES and by grants-in-aid for the study of PA in Japan (JPAS) and the study of intractable adrenal diseases (JRAS) from the Practical Research Project for Rare/Intractable Diseases of Japan AMED (JP17ek0109122 and JP20ek0109352); for the Study on Disorders of Adrenal Hormone, Research Program on Rare and Intractable Diseases from the Ministry of Health, Labor, and Welfare, Japan; and for the Study of Advancing Care and Pathogenesis of Intractable Adrenal Diseases in Japan (ACPA-J) from the National Center for Global Health and Medicine, Japan (27–1402 and 30–1008), the Clinical Research Institute, National Hospital Organization Kyoto Medical Center, and the Clinical Research Center, Ijinkai Takeda General Hospital, Kyoto, Japan.
Mitsuhide Naruse, M.D., Ph.D.
Honorary Member
Director, Endocrine Center and Clinical Research Center, Ijinkai Takeda General Hospital
E-mail: mtsnaruse@gmail.com
Careers in JES
2019– Honorary Member
2015– Senior Councilor
2013–2015 Advisor
2009–2013 Director (Education and Career Development)
1987– Councilor
1977– Member
JES Awards
2017 Distinguished Endocrinologist Award
1993 13th JES Research Award
Contributions to EJ
2003–2010 Editor
