2024 Volume 71 Issue 5 Pages 429-435
Hormones are produced by multiple organs in the body, circulate via the blood, and play essential roles in maintaining homeostasis throughout the body. The failure of the endocrine system to function appropriately not only causes classical endocrine diseases and diabetes, but also dysfunction of various organs including the brain, autonomic nervous system, immune system, cardiovascular system, liver, kidney, bone, and muscle.
I have had a satisfying career pursuing clinical work and research in endocrinology, metabolism, and diabetology, attracted to these areas of internal medicine where patients can make dramatic improvements, or even be cured, by proper diagnosis and treatment. Early in my career, I spent several years learning about endocrinological diseases at Kyushu University Hospital; by conducting various hormone stimulation or suppression tests and measuring hormone levels myself, which is how I learned the foundations of clinical endocrinology. I then spent a year working with diabetic patients at the Diabetes Center of the Kitakyushu Municipal Medical Center, learning the importance of patient care. I was taught that dietary therapy should be given to patients not only by registered dietitians, but also by doctors themselves, using a food exchange list. These experiences gave me the opportunity at a young age to master both fields, becoming a genuine endocrinologist and diabetologist.
I started my research career in 1982 and membership of the Japan Endocrine Society (JES) in 1983 at the Third Department of Internal Medicine in Kyushu University, which was presided over by the late Professor Hiroshi Ibayashi. My research mentor was Dr. Hajime Nawata (Fig. 1), who later became a professor in the same department and the 16th president of the JES. I conducted research on both the functional relationship between the adrenal cortex and the adrenal medulla, and the physiological significance of opioids in the adrenal medulla and pheochromocytoma, obtaining a degree on the latter theme. During this time my understanding of hormones developed as I measured and analyzed various hormones using radioimmunoassays (RIAs).
IOC and LOC members of 11th International Congress on Hormonal Steroids/7th International Congress on Hormones and Cancer, October 21–25, 2002, Fukuoka, Japan (Chairman: Prof. Hajime Nawata)
Back row from left: author, the late Prof. Yukitaka Miyachi, Prof. Hajime Nawata, the late Prof. Hisahiko Sekihara, Prof. Hironobu Sasano
Front row from left: Professors the late Marcella Motta (Italy), Jos H. Thijssen (Netherlands), the late Fernand Labrie (Canada), Evan R. Simpson (Australia), Jesus A. Tresguerres (Spain) and Kathryn B. Horwitz (USA)
In 1987, I had the opportunity to study at Prof. Michael R. Waterman’s lab at Southwestern Medical School in Dallas. At that time, Prof. Waterman was a world leader in the field of steroidogenic P450 (Fig. 2). There, I conducted studies clarifying the molecular basis of an unsolved disease called 17α-hydroxylase deficiency, a form of congenital adrenal hyperplasia (CAH) that causes hypertension and hypogonadism. At that time, since there was no PCR, cloning of the patient’s DNA was required. Although the process took a lot of time, in a sense, I felt lucky to learn the principles that form the basis of molecular biology. I was amazed by the mysteries of life, in which a single DNA base substitution prevented a patient from synthesizing androgens, dramatically changing their social gender from male to female. Ultimately, genetic and enzymatic analysis of many cases of 17α-hydroxylase deficiency revealed that the underlying molecular mechanism was a combined deficiency of 17α-hydroxylase/17,20-lyase activities [1, 2]. Through my research on CAH, I had opportunities to communicate with many pediatricians who treated patients with congenital adrenal diseases, including CAH. These personal relationships later helped me organize the team for establishing the clinical practice guidelines for adrenal insufficiency in both childhood and adults, published by the JES [3].
Prof. Waterman’s laboratory members, Dallas, 1989
First row center: the late Prof. Michael R. Waterman. Second from right in last row: Dr. Tsuneo Imai, endocrine surgeon and the former professor of Aichi Medical University.
After returning to Japan, I was involved in research on an important transcriptional factor for steroidogenesis, Ad4BP/SF-1 (adrenal 4 binding protein/steroidogenic factor-1/steroidogenic factor-1) [4, 5], discovered by Prof. Ken-ichirou Morohashi (Fig. 3) and Prof. Keith L. Parker. Surprisingly, transfection of this gene into mesenchymal stem cells produced steroidogenic cells, and the in vivo cell transplantation of these cells saved the lives of bilaterally adrenalectomized mice [6, 7]. I was also involved in basic research on androgen action, especially in lifestyle-related diseases. In contrast to estrogen, testosterone was not well researched at that point, although pioneering basic work was being conducted by Prof. Shigeaki Kato. Now, investigations by ourselves and others have revealed that endogenous testosterone has many beneficial effects on men’s health, including protection against obesity, diabetes mellitus, and atherosclerosis [8-13]. We extended this research into the development of selective androgen receptor modulators (SARMs), which beneficially affect bone, muscle, and metabolism, but have little effect on the prostate: we found a candidate SARM in the compound S42 [14, 15]. Although no SARMs have yet appeared on the market, they are a promising drug for older people suffering from sarcopenia and frailty. During this time, I was also involved in the publication of late-onset hypogonadism (LOH) clinical practice guidelines, first in 2008 (under Chairman Prof. Michio Namiki), and then for the revision in 2022 (under Chairman Prof. Shigeo Horie), an experience that gave me the opportunity to work in an interdisciplinary environment with many urologists.
Chairs and speakers at Satellite Symposium 13 (New aspects of steroids) of 14th International Congress of Endocrinology, Kyoto, Japan 2010
From left: Doctors and Professors Liu Min, Tomoko Tanaka, author (Chair), Gary Hammer (President of American Endocrine Society 2020–2021), the late Marion B Sewer, Amanda Swain, Ken-ichirou Morohashi (Chair), Masahiro Akishita and Hiroaki Masuzaki (current Editor-in-Chief of Endocrine Journal).
Another important development during my research career was the establishment of a steroidogenic, human ovarian granulosa-like tumor cell line, KGN, from a patient with invasive ovarian granulosa cell carcinoma. This cell line was established in 2001 by my colleague, Dr. Yoshihiro Nishi, at Kyushu University [16] (Fig. 4). The KGN cell line is quite unique in that it possesses relatively high aromatase activity and shows a steroidogenesis pattern similar to that of human granulosa cells. KGN cells have been used as in vitro models for research on endocrine disruptors [17, 18], and the use of KGN cells promoted collaboration with many gynecologists and basic scientists. KGN cells are now donated to the RIKEN Cell Bank and are very popular among researchers around the world.
Aromatase Conference 2000, Port Douglas, Australia, November 4–7, 2000
A: Front row right end: Prof. Yi-Ming Mu (Chinese PLA General Hospital, China).
Back row left end: Prof. Makio Shouzu and third, Prof. Nobuhiro Harada. (Both famous aromatase researchers.)
B: Dr. Yoshihiro Nishi (right) who established KGN cell line.
Owing to my involvement in a wide range of research fields, I have had opportunities to interact with clinical doctors in various fields, including internal medicine, pediatrics, urology, neurosurgery, and gynecology, as well as outstanding researchers of basic sciences in Japan and abroad. This interdisciplinary aspect of endocrinology is a benefit that is not always present in other academic fields.
During my early career, I was fortunate to find myself in the era of the discovery and measurement of new hormones, the increasing understanding of signal transduction mechanisms, and the rise of molecular biology. However, these developments meant the basic understanding of classical endocrinology seemed to have reached a plateau in the 20th century. Research on genetically modified mice led to the observation of various unexpected physiological changes in organs other than the main gene-expressing organ. Such observations triggered interest in inter-organ network research.
In recent years, connections between various organs via hormones, cytokines, and neural networks have been elucidated. For example, adipose tissue is now known to be the largest hormone-secreting organ, and unhealthy obesity and metabolic syndrome, which cause cardiovascular disease, are now associated with adipocytokine-induced chronic inflammation and ectopic fat accumulation in the abdominal cavity and around the heart. The effect of endocrine disruption on the liver is evidenced by metabolic dysfunction-associated fatty liver disease (MAFLD), which largely results from obesity, insulin resistance, and diabetes; it is considered the main target of liver disease now that viral hepatitis has almost been eradicated. Meanwhile, hormones secreted by some organs can positively impact classical endocrine disorders, for example, osteocalcin secreted from osteoblasts and myokines secreted from muscle protect against diabetes. In fact, the suppression of osteocalcin secretion by glucocorticoids partly explains the link between osteoporosis and diabetes, which are well-known side effects of glucocorticoids. Finally, since metabolic abnormalities and sex steroids are now known to have important roles in osteoporosis and sarcopenia, endocrinologists and metabolic specialists are expected to play active roles in treating these diseases in the future.
More recently, research has revealed that the gut microbiome and clock genes are also closely related to obesity and diabetes; therefore, it is now clear that lifestyle habits, including the amount, content, speed and timing of food consumption; daily physical activities; and quality and quantity of sleep are also important factors in disease progression. Almost all organs in the body construct functional networks, such as the cardiorenal, gut–brain, and bone–muscle axes, and contribute to the maintenance of homeostasis. In addition, although incretins (glucagon-like peptide [GLP]-1 and glucose-dependent insulinotropic polypeptide [GIP]) were a relatively minor research area in the past, GLP-1 agonists, and dual GLP-1 and GIP agonists, are now emerging as drugs that may fundamentally change the treatment of obesity and diabetes. Sodium-glucose co-transporter-2 (SGLT2) inhibitors are also gaining attention as drugs with protective effects on the cardiorenal system. In addition, since diabetic patients are more prone to cancer, anti-diabetic drugs may also lead to cancer prevention. Although further investigations are needed, we found that metformin, GLP-1 agonists and SGLT2 inhibitors had potent anti-cancer effects, at least in experimental studies [19, 20].
Given the complex relationship between multiple organs, diseases and treatments, we now seem to have entered an era in which the progress of research in one area has the potential to affect various other fields. As the understanding of these relationships deepens, an integrated knowledge of multiple organs will become essential to clinicians and researchers.
As already mentioned, endocrinology is an interdisciplinary field. For diagnosis and treatment of endocrinological disorders, a cooperative approach between various fields is essential. For example, smooth transitioning of patient care from pediatrician to internist is needed in congenital or child-onset endocrinological disorder cases, while close collaboration between internists and neurosurgeons, gynecologists and urologists is indispensable for patients with endocrine tumors. In cases of amenorrhea, menopause, and polycystic ovary syndrome in women, and late-onset hypogonadism in men, close communication between internists and gynecologists or urologists, respectively, is essential. In line with this, the JES board-certified specialist system started in 1990, covering the fields of internal medicine, pediatrics, and gynecology and obstetrics. In 2018, this specialist system was reformed to further include urology and neurosurgery as specialist fields (Fig. 5). Apart from having knowledge of their own field, specialists are now required to gain knowledge of other fields by attending educational lectures designated by the JES. I firmly believe that this reform will significantly contribute to the development and evolution of clinical endocrinology and endocrinological research in Japan.
Board certified specialist system by the JES and the JDS
MAFLD, metabolic dysfunction-associated fatty liver disease; MetS, metabolic syndrome; LOH, Late-onset hypogonadism; PCOS, polycystic ovary syndrome
The JES and the Japan Diabetes Society (JDS) have made a timely agreement to unite their board certification systems. This new, board-certified system implemented by the JES and the JDS is called the Endocrinology, Diabetes and Metabolism specialist system (Fig. 5). This reform is extremely welcome and I would like to acknowledge the pioneering approach of both the JES and the JDS. It is also good news for patients, in that the number of specialists who are familiar with both fields will increase.
The need for close collaboration between endocrinologists and diabetologists has been further supported by the impact of immune checkpoint inhibitors as a treatment for advanced malignancies. These drugs can induce immune-related adverse events (irAEs) in several organs, including endocrine organs, since the immune and endocrine systems are interconnected. Endocrine irAEs comprise hypopituitarism, primary adrenal insufficiency, thyroid dysfunction, hypoparathyroidism, and type 1 diabetes mellitus. Therefore, close coordination between many departments, including endocrinologists and diabetologists, is essential for the management of irAEs. In addition, the management of diabetes, hypertension, and osteoporosis induced by glucocorticoids used in many diseases, including orthopedic, autoimmune, and blood diseases, requires collaboration between the relevant therapeutic department and an endocrinologist or diabetologist. Therefore, there is a greater need than ever for physicians to have a wide knowledge base about endocrine and metabolic systems and diseases.
Another instance in which combined knowledge of both endocrinology and diabetology is essential is in the treatment of patients with diabetes and hypertension. Since there is such a large number of patients with diabetes, it is not always possible to consider the etiology of hyperglycemia and/or coexistent hypertension. However, if blood sugar is managed without consideration of the fact that hyperglycemia and/or hypertension can be caused by etiologies other than diabetes, treatment resistance can occur. This may be prevented by a wide-ranging clinical view that considers the possibility of endocrine diabetes and/or hypertension caused by Cushing’s syndrome, subclinical Cushing’s syndrome [21], primary aldosteronism [22], pheochromocytoma, and acromegaly. Since almost 50% of diabetic patients have hypertension, there can be a preconception that high blood pressure is caused by diabetes. However, primary aldosteronism accounts for 5%–10% of all hypertension, and 2–4 million hypertensive patients may have this disease. Therefore, without knowledge of endocrine hypertension, many hypertensive patients may be treated in the category of essential hypertension.
Endocrinology and diabetology can also benefit from the crossover of certain strengths of one specialty to the other. For example, one strength in diabetic medicine is the careful care and education of patients; by contrast, this could be considered a weakness in endocrine medicine. Therefore, a specialist doctor certified by the JES and the JDS could bring their understanding of patient care from diabetic medicine and improve this aspect of endocrine medicine. As a result, I strongly believe that expertise in both diabetology and endocrinology will facilitate the acquisition of complementary knowledge and skills by physicians and dramatically increase the trust of patients. Wouldn’t it be great if patients thought of us as “kind and capable doctors who know everything”?
Finally, although endocrine diseases are thought to be relatively rare, this is not necessarily the case; including undiagnosed patients, thyroid disorders are estimated to affect 10 to 20 million people. Pituitary tumors, adrenal gland tumors, and calcium metabolism disorders are often discovered incidentally during examinations and are relatively common among endocrine diseases. Therefore, endocrinology is an important therapeutic area and I hope that many current and future young doctors will aim to become specialists in both endocrinology and diabetes mellitus, rather than one or the other. Based on my experience, it is great fun to pursue both fields, both from clinical and research perspectives. I sincerely hope that as a result of the collaboration between the JES and the JDS, many board-certified endocrinology, metabolism and diabetology specialists with multifaceted and flexible thinking, as well as fulfilling careers, will be nurtured from now on.
Enjoy the interdisciplinary aspects of endocrinology; this leads to interactions with clinicians and researchers from various fields, which broadens your horizons, enriches your life as a doctor and leads to the success of the JES. In addition, physicians who are well educated in all fields of endocrinology, metabolism, and diabetology can be confident as genuine endocrinologists and greatly contribute to the patients’ wellness. The development of such specialists will increase the impact of the JES more than ever.
Toshihiko Yanase
Honorary Member
Former Professor, Fukuoka University
Director, Seiwakai Muta Hospital
Email: t-yanase@seiwakai-hp.jp
Careers in JES
2023– Honorary Member
2019– Senior Councilor
2015–2019 Director (Education and Career Development)
1994– Councilor
1983– Member
Activities in JES
2018 Chair, 28th JES Clinical Update on Endocrinology & Metabolism
2011 Chair, 11th Annual Meeting of JES Kyushu Regional Branch
JES Awards
2016 15th JES Award
Contributions to EJ
2011–2018 Editor
2002–2005 Editor
