Vol. 14 Supplement 1
The History of Growth Hormone Treatment for GHD in Japan
Susumu Yokoya, MD, Toshiaki Tanaka, MD
In Japan, treatment of growth hormone deficiency with pituitary-extracted human growth hormone (phGH) was covered by health insurance for the first time in 1975. However, because of the shortage of phGH, the Foundation for Growth Science (FGS) was founded in 1977 to control the use of the product by its registration system and to collect pituitary glands in Japan. In 1986, recombinant human growth hormone was first approved. Since then, the FGS has been involved in the harmonization of growth hormone measurement, assessment for treatment eligibility according to the diagnostic criteria by the research group of the Ministry of Health and Welfare, and database generation and its utilization.
Ref: Ped. Endocrinol. Rev. 2017;14(Suppl 1):201-208
Key words: Growth hormone, Growth hormone deficiency, Specified chronic diseases in childhood, Diagnostic criteria, Correction formula, Leukemia, Brain tumor
Standardization of Growth Hormone and Insulin-like Growth Factor-I Measurements
Noriyuki Katsumata, MD, PhD
Measurement of the levels of growth hormone (GH) and its related factor insulin-like growth factor I (IGF-I) is essential for the diagnosis and treatment of GH deficiency (GHD) and conditions related to excess GH such as acromegaly and pituitary gigantism. Measurement of GH levels is also used as an indicator of hypothalamic-pituitary function. Because of the marked variability in GH measurements among kits, the Study Committee for GH and Its Related Factors of The Foundation for Growth Science, Japan standardized GH values measured with various commercially available GH assay kits in Japan. The committee also established IGF-I reference values for Japanese subjects of all ages, from childhood to
adulthood. Hopefully, international harmonization of GH measurements will be achieved in the future.
Ref: Ped. Endocrinol. Rev. 2017;14(Suppl 1):209-215
Key words: Growth hormone (GH), Insulin-like growth factor I (IGF-I), Immunoassay, Radioimmunoassay (RIA), Enzyme immunoassay, Standardization
International Comparison of Adult Height in Children with Growth Hormone Deficiency and Limitations of Growth Hormone Treatment in Japan
Toshiaki Tanaka, MD
The approved therapeutic dose of growth hormone (GH) for growth hormone deficiency (GHD) varies depending on the country. Japan has the lowest therapeutic dose globally, with a single dose of 0.175 mg/kg/week. GH treatment for GHD is considered as a replacement therapy and in fact, a dose of 0.175 mg/kg/week is slightly higher than GH secretion in prepubertal healthy children but nearly the same as that of pubertal children. Although the same growth rate as that of healthy children is expected in response to replacement therapy, the catch-up growth observed for the first 1 to 2 years of GH treatment was misinterpreted as an effect of the GH replacement therapy. The real effect of the GH replacement therapy was the growth rate appeared after more than 3 years of GH therapy, when patients showed nearly the same growth rate as healthy children. Therefore, children with GHD can have a higher growth rate than healthy children only for the first 1 to 2 years of GH therapy, after which their growth rate begins to wane.
In the United States and Europe, the various therapeutic doses and high-dose treatment are accepted and the SD score of adult height after treatment is higher than that in Japan. The improvement degree of the height SD score and the adult height SD score with GH therapy are lower in Japan compared with other countries that administer a similar therapeutic dose. This suggests that the response to GH can be affected by race. Actual comparison of the response to GH between Japanese and Caucasian patients using KIGS (Pharmacia International Growth Database) data showed that both the short-term response and the effect on adult height were reduced in Japanese patients. As there is a strong positive correlation between adult height and height at the onset of puberty, treatment methods that can increase pubertal growth will be considered in the future for patients with GDH who enter puberty with short stature.
Ref: Ped. Endocrinol. Rev. 2017;14(Suppl 1):216-221
Key words: GHD, GH treatment, GH dose, Adult height, GnRH analog combination therapy
Quality of Life of SGA Children with Short Stature Receiving GH Treatment in Japan
Ryo Takahashi, RN, PhD, Madoka Ogawa, PhD, Hisao Osada, LCP, PhD
The objective of this study was to compare the quality of life (QOL) of small for gestational age (SGA) children with short stature with that of children with normal height, and examine the effects of growth hormone (GH) treatment on the QOL of the SGA children using questionnaires administered to their parents or guardians. The results showed that QOL in daily living of SGA children with short stature was lower than that of normal children based on the perceptions of their parents or guardians. In addition, GH treatment improved the physical domain of QOL of SGA children with short stature. This study suggests that GH treatment can improve QOL and reduce psychosocial problems related to short stature.
Ref: Ped. Endocrinol. Rev. 2017;14(Suppl 1):222-228
Key words: SGA children with short stature, Growth hormone treatment, Quality of life, Psychosocial problems
Growth Hormone Therapy and Brain Tumors
Akira Teramoto, MD, PhD
As one of the projects of the Adverse Events Study Group of the Foundation for Growth Science in Japan, the literatures on the recurrence and / or regrowth or new formation of brain tumors in patients treated with growth hormone (GH) were reviewed. Since the tumor volume of the sellar lesion can be accurately evaluated only by magnetic resonance imaging (MRI), the related literatures published after 1990 were retrieved by searching under keywords, such as GH, replacement therapy, brain tumor, recurrence, tumor formation, etc.
It is undeniable that GH therapy may result in tumor enlargement only in a very small percentage of cases. However, within a scientifically reliable range of confirmation with large-scale researches and case-control studies, it can be considered that there is no relation between GH therapy and the recurrence or new formation of brain tumors.
Ref: Ped. Endocrinol. Rev. 2017;14(Suppl 1):229-234
Key words: Growth hormone, Hormone replacement therapy, Brain tumor, Recurrence, Tumorigenesis
Growth Hormone Treatment and Adverse Events
Yoshikazu Nishi, MD, Toshiaki Tanaka, MD
We compiled the major adverse events included in the Annual Research Reports of the Foundation for Growth Research published in and after 2000. We conducted a review of approximately 32,000 patients treated with growth hormone (GH) who subsequently developed leukemia and who were registered with the Foundation for Growth Research (from 1975 to December 31 1997). We performed a literature review and found that GH therapy was not associated with leukemia onset in patients with no risk factors for leukemia. We also reported the onset of diabetes mellitus (DM), scoliosis, and respiratory problems in patients with Prader-Willi syndrome who were treated with GH. Osteoporosis, Hashimoto thyroiditis, and hyperlipemia were relatively frequent complications of Turner syndrome (TS).
Ref: Ped. Endocrinol. Rev. 2017;14(Suppl 1):235-239
Key words: Growth hormone treatment, Leukemia, Prader-Willi syndrome, Diabetes mellitus, Scoliosis, Respiratory problems, Turner syndrome
Revision of the Growth References for Japanese Girls with Turner Syndrome
Tsuyoshi Isojima, MD, PhD
Turner syndrome (TS) is a chromosomal disorder characterized by a short stature and the presence of primary amenorrhea. The growth patterns of girls with TS are different from those of the general population. Disease-specific growth charts are essential in clinical practice for girls with TS. TS-specific growth charts for Japanese girls were first reported in 1992 by Suwa and are widely used in clinical practice. However, the growth charts reported by Suwa may be inappropriate for girls with newly diagnosed TS because they were largely based on data obtained before the secular trend in height reached a plateau. Therefore, there is a need to revise the growth charts. We constructed new TS-specific growth charts by using the lambda-mu-sigma (LMS) method based on a database (1,867 subjects) compiled by the Foundation for Growth Science along with the semilongitudinal data before growth promotion treatment (205 subjects) obtained from the National Center for Child Health and Development and Toranomon Hospital. Herein, the development process and characteristics of the new TS-specific growth charts were reviewed.
Ref: Ped. Endocrinol. Rev. 2017;14(Suppl 1):240-251
Key words: Turner syndrome, Growth chart, LMS method, Secular trend
Adult Height in Patients with Turner Syndrome and Association with Lifestyle-related Diseases after Human Growth Hormone Treatment in Japan
Kunihiko Hanew, MD, Toshiaki Tanaka, MD
This study investigated the factors associated with adult height in Japanese women with Turner syndrome (TS) with and without human growth hormone (hGH) treatment, and the association between obesity and lifestyle-related diseases in TS based on current findings.
Adult height in women with untreated TS increased from 139.1 cm to 141.3 cm between 1992 and 2008 in a secular trend. The adult height of women with untreated TS was not significantly different between those with the 45,X and non-45,X karyotypes. The adult height after low-dose hGH treatment (0.5 IU/kg/week) was significantly lower in women with TS with spontaneous menstruation (mean, 141.9 cm) than in those women without spontaneous menstruation (mean, 145.5 cm). A recent survey reported that the mean adult height in women with TS after high-dose hGH treatment (0.35 mg/kg/week) was 149.1 cm. In addition, adult height improved with low-dose estrogen treatment started at age 12–15 years, reaching a height of 140 cm. According to the questionnaire survey administered to women with TS, conducted by the Foundation for Growth Science, the prevalence of obesity [body mass index (BMI) ≥25 kg/m2] in women with TS aged 15–39 years (24.7%) was significantly higher than that in the general female population in the same age range (9.4%). The prevalence of complications in women with TS was 5.5% for diabetes mellitus (DM), 7.7% for hypertension, 18.9% for dyslipidemia, and 11.5% for liver dysfunction, all of which were higher than the prevalence in the general female population. BMI was higher in women with TS who were diagnosed with lifestyle-related diseases than in those without lifestyle-related diseases, and the rate of each disease increased with an increase in BMI. In addition, those with multiple complications had substantially higher BMI. These findings indicate that obesity is strongly associated with the development of lifestyle-related diseases. In addition, women with TS who had any one of the complications (except for DM) had significantly lower birth weight compared with those without complications. This is consistent with the fetal programming hypothesis, which proposes that low birth weight may be associated with obese after birth and lifestyle-related diseases in adulthood. The adult height in untreated women with TS increased by 2.2 cm over 16 years. However, adult height in women with TS treated with hGH can be further increased with early high-dose hGH treatment and low-dose estrogen replacement therapy. In addition, the rate of lifestyle-related diseases among women with TS was closely associated with their weight gain. In particular, those with a BMI of ≥25 kg/m2 or higher had a higher rate of lifestyle-related diseases. These findings offer important considerations for clinical treatment of women with TS.
Ref: Ped. Endocrinol. Rev. 2017;14(Suppl 1):252-259
Key words: Turner syndrome, GH treatment, Adult height, Lifestyle - related disease, Obesity, DM, Hypertension
Iodine and Thyroid Function: A Historical Review of Goiter and the Current Iodine Status in Japan
Yozen Fuse, MD
Iodine is an essential trace element for the synthesis of thyroid hormones. Excessive, as well as deficient, iodine ingestion adversely affects thyroid function. The major sources of iodine in Japan are edible seaweeds, namely Nori, Wakame and Kombu. The iodine content of Kombu ranges from 1.5 to 5.3 mg/g. Although Japan has been regarded as a non-goitrous or iodine excess country, cases of endemic goiter in the northern island of Hokkaido could be tracked back to 1899. However, few recent data on the relationship between iodine status and thyroid dysfunction is available because there is no surveillance system to monitor iodine intake. A nationwide school-based survey throughout Japan has been conducted from 2013. As of February 2017 the survey had covered 16,193 children from 52 schools across 21 of 47 prefectures. Overall, the median urinary iodine concentration for all the sites combined was 265 μg/L suggesting iodine sufficiency not excess.
Ref: Ped. Endocrinol. Rev. 2017;14(Suppl 1):260-270
Key words: Iodine, Dietary iodine intake, Seaweed, Kombu, Goiter, Thyroid function, Japanese