The soliloquy of a clinical endocrinologist who spent half a century as an academic member

I. Encounter with endocrinology

The development of endocrinology always brings us to new eras in the clinical field, where I have been able to apply new knowledge fruitfully during my work as a clinician as well as a researcher for half a century. The expansion of understanding of the endocrine system aroused my interests in its relationships to the nervous and immune systems, which are now known to work closely together. Looking back, I ask what progress has been made in the last half century. The development of radioimmunoassay in the 1960s and early 1970s provided new diagnostic and research tools enabling a much easier understanding of the pathophysiology of endocrine disorders than when we could only measure hormone concentrations using biological or chemical assays. The sensitivity and specificity of hormone assays was further improved by the development of enzyme immunoassays and the introduction of monoclonal antibodies. Such improvements allowed the demonstration that the incidences of subclinical or preclinical endocrinopathies were higher than previously thought. For example, we could distinguish suppressed TSH from the normal range of this pituitary hormone in each subject and demonstrate diurnal and seasonal variations in TSH secretion, as had previously been shown for ACTH or GH. Some patients with hypothyroidism required an increased dose of L-thyroxine during cold weather, necessitating the fine tuning of replacement therapy. The syndrome of inappropriate secretion of thyrotropin (SITSH) can be discriminated from mild hyperthyroidism due to Graves’ disease or painless thyroiditis, and occasionally a minimal TSH-producing tumor is found in a patient who visited for annual health checkup (Fig. 1). In other hands, the discovery of anti-TSH receptor antibodies and improvements in their measurement greatly facilitated the diagnosis of Graves’ disease compared to previous methods involving the measurement of thyroidal uptake of radioactive iodine. These techniques have enabled the translation of tedious laboratory work to routine clinical diagnostic tasks.

Fig. 1

A case with TSH producing tumor

The measurement of blood concentrations of hormones with relatively high molecular weight was established in the 1960s, but it remained difficult to measure the small molecular weight peptides such as neuropeptides. Difficulties here included rapid degradation of peptides in the blood, as well as the fact that these peptides originated not only in the hypothalamus but also in other regions of brain, pancreatic islets, and the gastrointestinal tracts [1]. The widespread distribution of neuropeptides has revealed relationships among the endocrine, nervous, and immune systems and the importance of these relationships for homeostasis. For example, TRH is not only a TSH releasing hormone but is also a central nervous system neurotransmitter which was found to be decreased in spinocerebellar degeneration and in a mouse model of the condition [2]. Those findings were followed by the clinical application of TRH in treating this intractable disease.

The techniques which we used in the laboratory may sometimes help us to investigate new research. The isolation of pancreatic islets of Langerhans to observe effect of various agents on hormone secretion could be applied to measure anti-islet cell surface antibodies by islet cells and immunochemistry when type-1 diabetes has been disclosed to be one of autoimmune diseases [3].

II. Toward the future

Autoimmune thyroid disease, along with diabetes, are the most common conditions encountered in clinical endocrinology. Some patients respond poorly to treatment. We need to be able to predict from the start of treatment which patients will prove difficult to manage. In autoimmune thyroid disease, the titers of anti-TSH receptor antibodies may be useful but are insufficiently predictive alone; similarly, measurement of several cytokines [4] or microRNAs [5] will also not be sufficient.

The laboratory measurement of blood glucose was tedious and time-consuming, but now real-time continuous glucose monitoring (CGM) tells us the fluctuations of blood glucose, allowing the fine tuning of insulin administration to keep glucose concentrations within the normal range.

Well, where do we stand and where do we go in front of the 100^th anniversary of the Japan Endocrine Society (JES)? In the century of clinical endocrinology, the discovery of insulin and glucocorticoids gave us incredible abilities to treat patients with previously intractable diseases. However, progress in the treatment of endocrine diseases seems to be at a standstill. No conclusive treatment has been found for Graves’ disease, and the administration of insulin for diabetes still requires injection, although oral administration is now available or under development for analogs of other peptides such as TRH, arginine vasopressin or GLP-1.

I spent a fruitful academic life, and would like to entrust the future to young scientists. There are still so many problems to be solved by clinical scientists in endocrinology. I expected that the new generation could solve those questions when I hosted the meeting, the 23^rd JES Clinical Update on Endocrinology & Metabolism in Nagoya (Fig. 2). Yes, I think it’s important for clinical endocrinologists who have a wide range of knowledge to treat patients who are troubled with complicated problems.

Fig. 2

23^rd JES Clinical Update on Endocrinology & Metabolism in Nagoya

Finally, I would like to say congratulation and pay my honorable respects for the 100^th anniversary of the JES.

Acknowledgements

The author is grateful to Emeritus Professor Brian L. Furman (Strathclyde Institute of Pharmacy & Biomedical Sciences) for his advice and criticism on this manuscript.

References

• 1   Mackes  K,  Itoh  M,  Green  K,  Gerich  J (1981) Radioimmunoassay of human plasma somatostatin. Diabetes 30: 728–734.
• 2   Endo  S,  Itoh  M,  Serizawa  O (1993) Serotonergic regulation of the spinal cord content of thyrotropin releasing hormone in the cerebellar ataxia mutant mouse. J Neurol Sci 118: 194–201.
• 3   Itoh  M (1989) Immunological aspects of diabetes mellitus: Prospects for pharmacological modification. Pharmacol Ther 44: 351–406.
• 4   Itoh  M,  Uchimura  K,  Makino  M, et al. (2000) Production of IL-10 and IL-12 in CD40 and interleukin 4-activated mononuclear cells from patients with Graves’ disease. Cytokine 12: 688–693.
• 5   Yamada  H,  Itoh  M,  Hiratsuka  I, et al. (2014) Circulating microRNAs in autoimmune thyroid diseases. Clin Endocrinol (Oxf) 81: 276–281.

Biographies

Mitsuyasu Itoh

Honorary Member

Professor Emeritus, Fujita Health University

Director, Nagoya Comprehensive Medical Center

Email: [e-mail]

Careers in JES

2019– Honorary Member

2015– Senior Councilor

2011–2014 President for Tokai Regional Branch

1987– Councilor

1974– Member

Activities in JES

2014 Chair, 23^rd JES Clinical Update on Endocrinology & Metabolism

2008 Chair, 7^th Annual Meeting of JES Tokai Regional Branch

Contributions to EJ

2007–2014 Editor