ESSAY | TOWARD JES 100TH ANNIVERSARY
Reminiscences of my life as an endocrine researcher
2023 年 70 巻 12 号 p. 1109-1111
詳細
2023 年 70 巻 12 号 p. 1109-1111
First of all, I would like to congratulate the Japan Endocrine Society (JES) on its upcoming 100th anniversary in 2026. As an old endocrinologist, I would like to leave behind a message for young clinical endocrinologists that looks back and summarizes my life as an endocrine researcher, at the request of the Editor-in-Chief of Endocrine Journal.
In my life as a researcher, I have done studies on the regulatory mechanism of the hypothalamic-pituitary-adrenal axis and on the pathophysiological mechanism of Cushing’s disease. In this essay, I look back on what I have done.
As a student I was deeply impressed by the lectures on clinical endocrinology given by Professor Tatsuo Torigai at the Second Department of Medicine, Tohoku University School of Medicine. I was most intrigued by the fact that clinical features and pathophysiological findings of endocrinological diseases were able to be explained logically and systematically. I focused on the ACTH-cortisol axis, especially ACTH as an important pituitary hormone. I started my research work under the guidance of Dr. Hiroshi Demura, my upperclassman, who was one of the most active researchers on ACTH. After completing my medical internship, I entered the Department of Medicine, Tokyo Women’s Medical College (Professor Kazuo Shizume) with Dr. Demura in 1973.
I concentrated my research efforts on the regulation of the HPA axis at the Department of Neuroendocrinology (Prof. Dorothy T. Krieger), Mount Sinai Medical Center, New York in 1976, where I could learn the basal method of ACTH and β-LPH (a precursor of β-endorphin) RIAs and other biochemical technology. In 1977, it was reported that β-endorphin, an opioid peptide, and ACTH have a common precursor, and so I had to do research in two different fields, the HPA axis and opioid peptides.
After returning to Tokyo Women’s Medical College, I continued the research on opioid peptides under the excellent guidance by Dr. Shinro Tachibana (Eizai Institute) who was first to report on the sequence of dynorphin. However, several years later, I lost interest in opioid peptides because opioid peptides were not closely related with clinical diseases and classical endocrine organs at that time. Such a situation was stressful for me. Just around that time, a sequence of ovine CRF was reported. Therefore, I decided to discontinue research on opioid peptides and focus on research on the HPA axis instead.
From these experiences, I learned that (1) the target of research should be kept in close relationship to the classical endocrine organs and clinical endocrine diseases for clinical endocrinologists, and (2) a research theme should be made in the clinical field, and then the results obtained from basic research returned to the clinical field.
On the other hand, learning the skills of ACTH RIA was the most important event for me because the results obtained by this method were accepted as reliable data in the world of research. As a result I could treat more than 100 patients with ACTH-dependent Cushing’s syndrome, among which more than 80 patients with Cushing’s disease in particular, gathered from all over Japan. Here I wish to thank Dr. Akio Kuwayama (Department of Neurosurgery, Nagoya University) for his cooperation and excellent technique in trans-sphenoidal surgery. Test data on these patients obtained before and after trans-sphenoidal surgery led to the establishment of the diagnostic criteria for Cushing’s disease in Japan. In addition, these findings led to the establishment of new disease concepts such as subclinical Cushing’s disease. From this result, I have also experienced that expertise in one thing led one to become a master in a specific field.
After that, I felt it was necessary to raise the level of research from the protein level to the gene level. I consulted Dr. Tachibana who introduced me to Dr. Masao Yamada (Laboratory of Genetics, National Children’s Medical Research Center). With his cooperation, we could use genetic technology to extend research on the analysis of gene expression of the POMC mRNA. We found that CRF stimulated synthesis and secretion of ACTH, but that vasopressin, another ACTH secretagogue, did not stimulate ACTH synthesis.
Next, I collaborated with Dr. Joseph A. Majzoub (Harvard University) and could extend my research on CRF and CRF receptor gene expression using CRF knock-out mouse. We were first to report that secretion and synthesis of hypothalamic CRF were stimulated by hypoglycemic stress.
In our clinical study, we revealed the following facts: (1) CRF in the hypothalamus and ACTH and CRF receptor in the pituitary are down-regulated by hypercortisolemia before surgery. (2) The hypothalamic CRF levels are first to recover, then the response of corticotroph to CRF recovers in the condition of low plasma cortisol levels soon after surgery. (3) ACTH receptors in the adrenal glands are up-regulated with ACTH. This means that plasma cortisol levels respond to ACTH in patients with Cushing’s disease, but do not in those with adrenal Cushing’s syndrome. (4) These results meant the recovery of the response of cortisol to ACTH starts after the recovery of ACTH secretion from the pituitary by CRF. In addition, collaboration with Dr. Keiichi Itoi (Tohoku University) helped to ramp up our study on the regulation of CRF gene in the hypothalamus by microinjection of transmitters (noradrenalin, serotonin, acetylcholine, etc.) into the paraventricular nucleus in conscious rats.
During this period, there was a time when I used to have a perfect panoramic view of the peak research-related institutes in Washington, Nashville, San Diego, London, Kyoto, and Tokyo that were breaking through the sea of clouds in the research field on the HPA axis.
I was appointed to the professorship of the Third Department of Medicine, Hirosaki University School of Medicine in 1995. Management of the department in the new environment was not easy for me. Because I could not successfully hand over my research work to my successors, I had to wait until the postgraduates grew up. So I stopped my own research work and changed my way of doing research to giving encouragement to young researchers and making summaries of my clinical studies on Cushing’s disease. I witnessed the creation of clinical guidelines of Cushing’s disease and newly established subclinical Cushing’s disease. These guidelines were made possible by the cooperation of Dr. Yutaka Oki (Hamamatsu University). I had studied the CRF-binding protein ever since I was in Tokyo. However, the leading research on human DNA and amino acid sequences was reported by groups at the Salk Institute and St. Bartholomew’s Hospital in 1991 who were ahead in this field of research at that time. This was a really unfortunate thing for me.
From these experiences, I felt that it takes more than 10 years to mentor young researchers, from giving them guidance as graduate students to having them receive training as postdoctoral fellows doing research work using various techniques learned in foreign laboratories. After that they will be provided with an opportunity to present their research results. In this regard, I wish to thank Dr. Yasumasa Iwasaki (Kochi University) for his kind cooperation during this period of my career.
In addition, I was able to convene the 81st Annual Congress of JES in Aomori, 2008. Finally, we published a textbook of clinical endocrinology and metabolism with the cooperation of the members in our department.
I also learned that the environment of academic research work has to be properly managed in accordance with researchers-network because there is a limit as to what can be done in a laboratory and it is necessary to cooperate with other laboratories.
It may become difficult to maintain the identity of endocrinology in the near future. Over the years, the number of professors of endocrinology has decreased, especially in the clinical departments of medicine. Increased numbers of patients with diabetes and obesity in lifestyle disease seem to have contributed to this phenomenon. In 2022, the first board certification examination was conducted in subspecialty areas of endocrinology, diabetes, and metabolism under the new board certification system. This is a welcome development and a necessary part of the solution to the problem. Because in most of hospitals the clinical departments of diabetes and endocrinology are combined into one, but medical treatment is performed separately. However, many patients seem to think that such doctors ought to be able to treat both of them at once. At any rate, it is imperative that the identity of endocrinology and the status of the authentic endocrinologist be preserved in the fields of education, medical treatment, and research study. In such a difficult situation, all endocrinologists should support the cultivation of a new generation of young endocrinologists through research funding, study abroad arrangements, getting posts in academic institutes and universities and so on.
We must always think about what the identity of Endocrinology and Metabolism should be in the future.
Toshihiro Suda
Honorary Member
Professor Emeritus, Hirosaki University
Honorary Director, Aomori Rosai Hospital
E-mail: sudatoshihiro@icloud.com
Careers in JES
2016– Honorary Member
2012– Senior Councilor
2005–2009 Director (Education and Career Development)
2001–2009 President for Tohoku Regional Branch
1999–2005 Director (Finance)
1983– Councilor
1973– Member
Activities in JES
2008 Chair, 81st Annual Congress of JES
2000 Chair, 1st Annual Meeting of JES Tohoku Regional Branch
JES Awards
1985 5th JES Research Award
Contributions to EJ
1999–2006 Editor
