ESSAY | TOWARD JES 100TH ANNIVERSARY
Reflections on my journey through GH–IGF research in endocrinology
2025 Volume 72 Issue 12 Pages 1263-1267
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2025 Volume 72 Issue 12 Pages 1263-1267
It is my great honor to extend heartfelt congratulations to the Japan Endocrine Society (JES) on the occasion of its 100th anniversary.
The Society, founded in 1925, was celebrating its 50th year when I joined in 1975. At that time, endocrinology was entering a new and exciting phase, and many of my contemporaries from the post-war baby boom generation became members together. Over the following half-century, I was privileged to study, grow, and engage in friendly competition with many outstanding colleagues, for which I am deeply grateful. Throughout its history, the society has fostered the discovery of new hormones, the development and adoption of new methodologies, and the integration of basic and clinical sciences. I believe that it has greatly contributed to the progress of endocrinology in Japan and around the world.
I began my own research in 1975 under the guidance of Professor Kazuo Shizume and Dr. Kazue Takano on growth hormone (GH) and its mediator, somatomedin (now known as insulin-like growth factor [IGF]). I presented my first paper at the Annual Congress of the JES in 1976, and with the exception of two years spent abroad, I continued to present my work every year until my retirement. In this essay, I would like to look back on my path over the past 50 years, along with my research on the GH–IGF axis.
My journey into GH–IGF research was shaped by two formative encounters. As a fifth-year medical student, I met Dr. Takano, who served as a clinical instructor. In the sixth year, I attended a special lecture at the Society of Tokyo Women’s Medical University by Professor Shizume entitled, “Recent Advances in Growth Hormone Research.” I first learned of the existence of somatomedin A (now IGF-I), which mediates GH action. For reasons that I could not explain at the time, I was immediately drawn to the subject.
After graduating in 1974, feeling a fresh breeze in endocrinology, I joined Professor Shizume’s Department of Medicine (then a general internal medicine department). From my first year as a resident, I had opportunities to participate in endocrine-related conferences and study groups. While training as a generalist, I also began to walk the path of an endocrinologist.
In my second year after graduation, I entered graduate school. At that time, Professor Shizume presented me with two options: (1) to go abroad for study or (2) to begin research with Dr. Takano, who was returning in 1975 from the Karolinska Institute, where she had been studying somatomedin A. Lacking confidence in my language ability and encouraged by Dr. Takano—who had told me even during my student years, “If you come to internal medicine, I will look after you”—I chose the second path and began IGF-I research under her supervision.
My research involved measuring serum somatomedin A (IGF-I) levels in various pathological states using the radioreceptor assay (RRA). I discovered the joy and excitement of pouring myself into my research from early morning until late at night. I found that serum IGF-I not only reflects GH secretory capacity but also decreases under conditions such as hepatic or renal failure, diabetes, hypothyroidism, and malnutrition. Professor Shizume was strict but invaluable in his guidance: “Always organize your results properly, and be sure to publish your original papers in English.”
I wrote my doctoral dissertation in English and, together with co-authored works, eventually produced 13 English-language papers. In March 1978, during my third year of graduate school, Dr. Takano invited me to accompany her to the International Symposium on Somatomedin in Santa Margherita, Italy. This semi-closed meeting brought together leading authorities, such as Drs. WH Daughaday, JJ Van Wyk, K Hall, and ER Froesch—names I had previously known only from journal articles. Meeting them in person was an unforgettable and stimulating experience. On our way back, Dr. Takano also arranged visits to laboratories at the Karolinska Institute in Sweden.
When my dissertation was complete, I began preparing to study abroad. At that time, four of my colleagues were already in the United States. Since my research involved measuring IGF-I levels using an RRA, I developed a strong interest in hormone receptors. After completing graduate school, I was fortunate to receive an opportunity to study at the Diabetes Branch of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the NIH, then the global center of hormone receptor research.
In September 1979, I began my fellowship at the NIH. At that time, long before the current age of instant communication, correspondence was conducted only through post and occasional telephone calls. I am most grateful to Professor Shizume, who kindly contacted Dr. Masato Kasuga, a junior colleague from the University of Tokyo, who had already been at the Diabetes Branch (DB) in June of that year, to inquire about the laboratory environment and daily life in Bethesda. Thanks to this, I was able to prepare myself, although in truth I had very little information about Bethesda or life in the suburbs of Washington, D.C., when I departed in late August. Upon my arrival at Washington National Airport, Dr. Kasuga and his wife generously met me and welcomed me into their home, where I stayed for approximately two weeks. With the help and kind support of many Japanese colleagues and their families already at the NIH, I was able to settle into life in the United States.
The DB originated as a derivative of the Clinical Endocrinology Branch (CEB), which had been headed by Dr. J. Robbins as Branch Chief and later became an independent branch under Dr. Jesse Roth as Chief. It was organized into three sections, with Dr. Jesse Roth, Drs. Ronald Kahn, and Phillip Gorden as individual Section Chiefs. I joined Dr. Gorden’s group, where research focused on not only insulin but also GH, and it was there that I began my work on GH. Among those who entered the DB in 1979 were Drs. Simeon Taylor, Derek LeRoith, and Masato Kasuga—now all recognized leaders in the field. The Branch welcomed outstanding researchers from around the world, creating a truly international environment. In addition, many distinguished investigators who had previously trained at DB or who were visiting the NIH gave seminars, affording countless opportunities for stimulating encounters.
My research focused on two main themes: the significance of GH receptor internalization and characterization of GH variants, such as placental GH. These studies culminated in four publications. Despite his responsibilities as the Clinical Director of NIDDK, and later as the Institute Director, Dr. Gorden always made time to work closely with me on manuscripts—sometimes even inviting me to his home in the evenings when his NIH schedule left no room. He and his wife extended warm personal support throughout my stay, for which I am deeply grateful. In the laboratory, I shared an office with Dr. Maxine Lesniak, who taught me experimental techniques from the very beginning and offered guidance in not only research but also many aspects of daily life.
In the DB, weekly Data Club meetings fostered lively discussions, and Journal Club sessions were held jointly with the CEB, often over lunch. Numerous joint events with DB and CEB have enriched academic and social exchanges.
I was fortunate that two of my classmates from medical school were at the NIH during that time, as their husbands had research appointments there. We often helped one another with practical matters, and through them, I came to be acquainted with seniors and colleagues, including Dr. Hajime Nawata and his wife, who welcomed me warmly at their gatherings. Friendships with many other Japanese colleagues outside my laboratory greatly enriched my life, making my years at the NIH both productive and joyful.
Research opportunities in Japan have greatly improved since those days. Nevertheless, I strongly encourage young physicians and scientists to seek training abroad. There is immense value in meeting outstanding researchers, including many Japanese colleagues, in an international setting, gaining perspectives from outside Japan and developing a global outlook.
The main themes of my research can be summarized as follows:
A) Biological actions of IGFs (IGF-I and IGF-II) in vivo
B) Pathophysiology of non-islet cell tumor hypoglycemia (NICTH)
C) Establishment of measurement methods for bioactive substances in the GH–IGF axis and their clinical applications
D) Clinical applications of GH and related substances
E) Studies on GH and IGF receptors
F) Clinical research on GH secretion disorders, including GH deficiency and acromegaly
Here, I would like to reflect on my studies on the pathophysiology of NICTH.
Although my primary research focused on IGF-I, a GH-dependent factor, I am also interested in IGF-II and its pathophysiological significance. To this end, I sought to establish a radioimmunoassay (RIA) for IGF-II. While I was able to obtain IGF-II preparations, antibodies were unavailable at the time of my research. In 1988, at the International Congress of Endocrinology in Kyoto, I presented a poster on IGF-I, and by chance, the poster next to mine reported the characterization of monoclonal antibodies to IGF-II. I asked the presenter if they were willing to provide antibodies so that I could establish an RIA, and they kindly agreed. With their generous support, I was able to establish the IGF-II RIA soon after. This was an early and vivid reminder to me of the importance of active exchange and collaboration at academic meetings, not merely passive attendance.
Using this assay, I measured IGF-II levels under various pathological conditions. Around that same time, Dr. Daughaday reported in the New England Journal of Medicine (1988) a striking case of a patient with recurrent hypoglycemia caused by a large IGF-II-producing tumor (leiomyosarcoma). The case demonstrated (1) cortisol elevation during hypoglycemia despite suppressed insulin and GH, (2) the resolution of hypoglycemia after tumor resection, (3) the expression of high levels of IGF-II mRNA and protein in the tumor, and (4) the presence of abnormal, higher-molecular-weight “big IGF-II” in both the tumor tissue and circulation.
While insulinoma is the most common cause of fasting hypoglycemia, it had long been known that the second-most frequent cause was hypoglycemia due to extra-pancreatic tumors (NICTH). Traditionally, possible mechanisms include increased glucose consumption by the tumor, secretion of insulin-like substances, or impaired counterregulatory hormone responses. To investigate this further, I began working on this matter with Dr. Izumi Fukuda (then a graduate student, now at Nippon Medical School). As few laboratories at that time were capable of measuring IGF-II, we received requests from across Japan to analyze NICTH cases. We examined serum IGF-II concentrations, the presence of high-molecular-weight IGF-II (big IGF-II; initially by gel filtration, later by Western immunoblotting), tumor IGF-II content, immunohistochemistry, and IGF binding proteins (IGFBPs).
Our study demonstrated that NICTH cases can be divided into IGF-II-producing and non-IGF-II-producing types. Big IGF-II was consistently present in the former but absent in the latter. In IGF-II-producing NICTH, serum IGF-II levels were not necessarily elevated, but IGF-I was uniformly suppressed, resulting in an inappropriately high IGF-II-to-IGF-I ratio. We also observed increased serum IGFBP-2 and decreased IGFBP-3 levels. After tumor resection, hypoglycemia resolved, big IGF-II disappeared, normal 7.5-kDa IGF-II levels increased, and IGFBP-2 and IGFBP-3 levels normalized.
Interestingly, the apparent size of big IGF-II varied among the cases (11–18 kDa). When serum samples were treated with O-glycosidase and then examined by Western blotting, all forms converged to approximately 9.5 kDa, consistent with pro-IGF-II (E1–21) containing O-linked glycans. Differences in glycosylation appear to explain the molecular weight heterogeneity. Furthermore, gel filtration under neutral conditions revealed that, in healthy subjects, IGF-II elutes predominantly in the 150-kDa ternary complex (IGF-II–IGFBP-3–acid-labile subunit [ALS]) and the 40-kDa binary complex (IGF-II–IGFBP). In contrast, IGF-II eluted as a single peak at 60–80 kDa in IGF-II-producing NICTH, representing a binary complex with IGFBPs. These complexes contained IGFBP-3 but could not bind to ALS, resulting in defective formation of the 150-kDa ternary complex.
Taken together, these findings suggest that the mechanism of hypoglycemia in IGF-II-producing NICTH is not simply due to elevated serum IGF-II levels, but rather to the increased bioavailability of IGF-II. Although ternary complexes (150 kDa) cannot cross the capillary endothelium, binary complexes (60–80 kDa) can, much like free IGF. Thus, in NICTH, the predominance of big IGF-II in binary complexes increases its bioavailability, leading to hypoglycemia. After tumor resection, ternary complex formation is restored, and hypoglycemia resolves.
Although many aspects remain to be clarified, Dr. Fukuda has continued this line of research since moving to the Nippon Medical School in 2015, and further advances are anticipated. All of these studies—A) through F)—were carried out with the invaluable collaboration of my senior mentors, colleagues, younger associates, and many co-investigators. I am deeply grateful to all of them.
In April 2009, under the leadership of then-President Professor Masatomo Mori, the JES launched a new project to address the various challenges faced by female physicians and establish strategies that would enable them to continue their professional careers as endocrinologists with pride and confidence. Thus, the Committee for Continuing Medical Education for Female Endocrinologists was established.
The Committee, chaired by Dr. Takano and composed of 22 members, including myself, held its inaugural meeting on April 23, 2009. At that meeting, we discussed the adoption of abbreviated names. Inspired by Women in Endocrinology (WE) of the Endocrine Society in the United States, I proposed the name “JES We Can”—standing for Women Endocrinologists Association, with “JES” representing the Japan Endocrine Society. The phrase was also a deliberate echo of President Obama’s campaign slogan “Yes We Can” from the 2008 U.S. presidential election, and the name was unanimously approved.
I served as the second chair of the JES We Can. During my tenure, the organization engaged in five working groups: (1) surveys on the needs of female physicians and trends among members, (2) policies for training and employment, (3) development of training programs, (4) investigations into the actual working conditions of women endocrinologists, and (5) cross-disciplinary exchanges with other societies and organizations, as well as branch-level activities. We established a number of initiatives, such as parental leave support and on-site childcare services at the JES annual and regional meetings, and launched JES We Can sessions within these conferences. After my retirement, the chairmanship was successfully passed on to Dr. Mari Suzuki, Dr. Mayumi Yamamoto, and Dr. Noriko Asahara, under whose leadership the organization has continued to grow and advance further.
Although Japan has enacted legislation to promote women’s participation in the workforce, I believe that, in addition to supporting childcare, re-education, and return-to-practice projects as safety nets, it is essential to foster and nurture female endocrinologists and researchers who will become future leaders.
My research life has been blessed by the mentorship of Professor Shizume, Dr. Takano, and Dr. Gorden and by the opportunities to work in excellent environments alongside internationally active seniors, colleagues, and enthusiastic younger scientists. Immersed in both clinical practice and research, I appreciate the fascination and joy of endocrinology.
Looking back on this half-century of research, I feel that endocrinology has made remarkable progress, but there are still many unsolved problems. I would encourage young colleagues to approach every phenomenon with the persistent questions of “why” and “how,” and to devote themselves to research with that spirit of inquiry. Furthermore, cherish every encounter, seize opportunities, and strive not only to be “No. 1” but to create something that is “Only 1.” Act with integrity in research ethics, maintaining a broad perspective and aspiring to thrive on the international stage. To mentors and leaders, I ask you to please continue to create supportive environments and provide opportunities for the younger generation.
Simultaneously, amid calls for greater gender equality, the JES has been a pioneer among medical societies in establishing organizational structures to ensure that female members can continue to shine throughout their careers, and the circle of these activities is expanding. While institutional support is vital, it is equally important for women to take the first step forward with awareness and initiative.
Finally, I extend my heartfelt wishes for the continued growth and flourishing of the JES, as it journeys into the next century.
Naomi Hizuka
Honorary Member
Professor Emeritus, Tokyo Women’s Medical University
Shizume Clinic
E-mail: hizuka.naomi@twmu.ac.jp, hizukan@gmail.com
Careers in JES
2019– Honorary Member
2015– Senior Councilor
2013–2015 Director (Education and Career Development)
2011–2015 Committee Chairperson, Committee for Continuing Medical Education for Female Endocrinologists (JES We Can)
2011–2013 Advisor
1985– Councilor
1975– Member
JES Awards
2016 Distinguished Endocrinologist Award
1989 9th JES Research Award
