Endocrine Journal
Online ISSN : 1348-4540
Print ISSN : 0918-8959
ISSN-L : 0918-8959
Volume 69, Issue 1
Displaying 1-11 of 11 articles from this issue
REVIEW
  • Masato Iwabu, Miki Okada-Iwabu, Takashi Kadowaki, Toshimasa Yamauchi
    Article type: Review
    2022 Volume 69 Issue 1 Pages 1-8
    Published: 2022
    Released on J-STAGE: January 28, 2022
    Advance online publication: September 11, 2021
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    While it is well recognized that exercise represents a radical preventive and therapeutic measure for lifestyle-related diseases, it is clear that contemporary lifestyles abound with situations where exercise may be found difficult to implement on a continuous basis. Indeed, this has led to global expectations for elucidation of the exercise-activated skeletal muscle signaling pathways as well as for development of exercise mimics that effectively activate such pathways. It is shown that exercise activates the transcriptional coactivator PGC-1α via AMPK/SIRT1 in muscle, thereby not only enhancing mitochondrial function and muscle endurance but upregulating energy metabolism. Further, adipocyte-derived adiponectin is also shown to activate AMPK/SIRT1/PGC-1α via its receptor AdipoR1 in skeletal muscles. Thus, adiponectin/AdipoR1 signaling is thought to constitute exercise-mimicking signaling. Indeed, it has become clear that AMPK, SIRT1 and AdipoR activators act as exercise mimetics. With the crystal structures of AdipoR elucidated and humanized AdipoR mice generated toward optimization of candidate AdipoR-activators for human use, expectations are mounting for the clinical application in the near future of AdipoR activators as exercise mimetics in humans. This review provides an overview of molecules activated by exercise and compounds activating these molecules, with a focus on the therapeutic potential of AdipoR activators as exercise mimetics.

ORIGINAL
  • Hiroshi Yokomichi, Mie Mochizuki, Reiji Kojima, Sayaka Horiuchi, Tadao ...
    Article type: Original
    2022 Volume 69 Issue 1 Pages 9-21
    Published: 2022
    Released on J-STAGE: January 28, 2022
    Advance online publication: August 26, 2021
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    In this study, we aimed to determine the association of neonatal/post-neonatal hypothyroidism with mother’s iodine exposure, especially povidone iodine disinfection, and hysterosalpingography. Participants were mother–child pairs in a Japanese birth cohort (n = 100,286). Risk factors of hypothyroidism were supplement intake, seaweed intake, other daily iodine intake, povidone iodine disinfection at delivery, and maternal history of hysterosalpingography, thyroid disease (Graves’ disease and Hashimoto’s thyroiditis), and medication (thiamazole and levothyroxine). Congenital hypothyroidism (CH) at age 1 year was assessed using a questionnaire. Transient hypothyroidism was defined as elevated thyroid stimulating hormone level at birth and absence of CH at age 1 year. The incidence of CH at age 1 year per 100 children was 1.1 for those born at 22–30 weeks’ gestation, 0.17 following povidone iodine disinfection, and 0.07, 0.95, 0.81, 1.17, and 1.15 with a maternal history of hysterosalpingography, Graves’ disease, Hashimoto’s thyroiditis, thiamazole use, and levothyroxine use, respectively. Odds ratios (95% confidence intervals) of CH at age 1 year for povidone iodine disinfection, hysterosalpingography history, maternal Graves’ disease, and maternal Hashimoto’s thyroiditis were 1.13 (0.71–1.79), 0.47 (0.07–3.36), 7.06 (3.70–13.5), and 5.93 (2.90–12.1), respectively. For transient hypothyroidism for povidone iodine disinfection and hysterosalpingography history, these values were 1.99 (1.51–2.62) and 0.63 (0.20–1.96), respectively. Maternal thyroid disease greatly increased neonatal/post-neonatal hypothyroidism risk. Povidone iodine disinfection may increase transient hypothyroidism risk but not the risk at 1 year of age. Hysterosalpingography does not increase hypothyroidism risk from birth to age 1 year.

  • Fang Zhao, Quan-wei Wei, Bo-jiang Li, Qian-nan Weng, Yi Jiang, Cai-bo ...
    Article type: Original
    2022 Volume 69 Issue 1 Pages 23-33
    Published: 2022
    Released on J-STAGE: January 28, 2022
    Advance online publication: August 28, 2021
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    Chronic stress affects the reproductive health of mammals; however, the impact of adrenocorticotropin hormone (ACTH) level elevation during chronic stress on the reproduction of weaned sows remains unclear. In this study, nine weaned sows with the same parturition date were randomly divided into control group (n = 4) and ACTH group (n = 5). Each group received intravenous administration of ACTH three times daily for 7 days. Blood samples were collected every 3 h after injection. A radioimmunoassay was used to measure the concentrations of cortisol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), progesterone (P4) and estradiol-17β (E2) in the blood. Estrus was determined according to changes in the vulva and the boar contact test. The mRNA expressions of glucocorticoid receptor, FSH receptor, LH receptor (LHR) in the corpus luteum (CL) were detected by qRT-PCR. The results showed that ACTH administration substantially delayed the initiation of estrus and the pre-ovulatory LH peak. The sows of control group ovulated within 10 days and the ovulation rate was 100%, while it was 60% in the ACTH group. Two sows of ACTH group showed pseudo-estrus. The E2 concentrations significantly decreased in the ACTH group at 36 h, 42 h and 66 h of the experimental period. The P4 concentrations in the ACTH group significantly decreased at 132, 138, and 147 h of the experimental period. ACTH significantly reduced the LHR mRNA expression in CLs. In conclusion, long-term repeated ACTH administration affects the endocrinology, estrus onset, and ovarian function of weaned sows.

  • Natsuko Watanabe, Jaeduk Yoshimura Noh, Takashi Akamizu, Masanobu Yama ...
    Article type: Original
    2022 Volume 69 Issue 1 Pages 35-43
    Published: 2022
    Released on J-STAGE: January 28, 2022
    Advance online publication: July 29, 2021
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    Supplementary material

    To clarify the actual administration of thiamazole (MMI), the first choice of antithyroid drugs, the actual therapy provided by the Japan Thyroid Association (JTA) members for the following conditions was surveyed. The subjects included adult patients, pregnant women, and pediatric patients with Graves’ disease who visited each medical institution from September 2019 to February 2020. Initial doses, frequency of administration, maintenance doses, maximum doses, consultation intervals for pregnant women, and dosages administrated to breastfeeding mothers were surveyed. The total number of cases collected was 11,663. Administration of 15 mg once a day was the most common initial therapy, constituted 74.4% (2,526/3,397 cases) of adults, 33.8% (44/130) of pregnant women, and 50.8% (61/120) of children. The maintenance dose before discontinuation was equivalent to 2.5 mg/day in 52.3% (3,147/6,015). The most common maximum dose for adults and children was 30 mg/day, administrated to 57.5% of adults (223/388) and 59.6% (28/47) of children; for pregnant women, it was 15 mg/day, administrated to 71.1% (27/38). The most common consultation interval for pregnant women was every four weeks (32.1%, 341/1,063). In lactating mothers, the dose was 10 mg/day or less in 366 of 465 cases (78.7%). Breastfeeding was also allowed 4–6 hours after the administration of 15–20 mg/day in 69 patients (14.8%). Breastfeeding was prohibited in 26 patients (5.6%). In conclusion, initial MMI therapy was started with 15 mg once a day in most patients, and MMI was also administrated to lactating mothers following the Graves’ disease treatment guidelines by the JTA.

  • Tetsuo Nishikawa, Fumitoshi Satoh, Yuichi Takashi, Toshihiko Yanase, H ...
    Article type: Original
    2022 Volume 69 Issue 1 Pages 45-54
    Published: 2022
    Released on J-STAGE: January 28, 2022
    Advance online publication: July 22, 2021
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    A commutability confirmation test for the blood aldosterone measurement was performed on liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) as a designated comparison method (DCM) and four chemiluminescent enzyme immunoassay (CLEIA) measurement procedures based on metrological traceability. A conventional radioimmunoassay (RIA) and two measurement procedures of CLEIA which obtains RIA equivalent values were also compared. The relationship between the DCM value and the CLEIA value with respect to 120 pg/mL of the RIA value, which is the screening criterion of primary aldosteronism (PA) was clarified. For the correlation test, 75 samples of patient serum and plasma were used. Regression analysis revealed that the standardized LC-MS/MS and four CLEIA measurement procedures were in good agreement. This is the effect of measurement specificity and calibration using by certified reference material (CRM). The median of the LC-MS/MS corresponding to 120 pg/mL of RIA was 48.5 pg/mL. In the mean of standardized four CLEIA values corresponding to the 48.5 pg/mL of LC-MS/MS value was 47.51 pg/mL and the standard deviation (SD) was 2.93 pg/mL. However, the correlation between the RIA value and the RIA equivalent of the two measurement procedures by CLEIA differed depending on the measurement procedure. This is due to the influence of RIA measurement performance. Standardized CLEIA measurements are suitable for routine measurement procedure. When converting the LC-MS/MS equivalent value by the standardized CLEIA to the conventional RIA value, it is necessary to use the conversion formula.

  • Biyan Qin, Litao Qincao, Shuying He, Yan Liao, Jie Shi, Fang Xie, Na D ...
    Article type: Original
    2022 Volume 69 Issue 1 Pages 55-65
    Published: 2022
    Released on J-STAGE: January 28, 2022
    Advance online publication: August 18, 2021
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    Supplementary material

    Obesity, closely related to systematic metabolic disorders, has become a major public health problem in recent decades. Here, we aimed to study the function of Parathyroid hormone-related protein (PTHrP) on high fat diet (HFD) induced murine obesity. Male C57BL/6J mice were transduced with adeno-associated virus vector encoding PTHrP (AAV-PTHrP) or adeno-associated virus control vector (AAV-Vehicle), following with HFD for 8 weeks. In addition, mice without transduction were fed on normal diet or HFD, respectively. Histological, metabolic and biochemical changes were detected. At the endpoint of experiment, body weight of mice treated with AAV-PTHrP did not increase as much as mice with AAV-Vehicle, but similar as mice with normal diet. Food efficiency ratio and weight of interscapular brown adipose tissue and epididymal white adipose tissue in mice overexpressed PTHrP were also lower than mice transducted with AAV-Vehicle. Besides, administration of AAV-PTHrP inhibited HFD-induced adipocyte hypertrophy. Protein level of PKA signaling pathway and thermogenic gene in adipose tissue exhibited a significant raise in HFD + AAV-PTHrP group, whereas transcription of inflammatory gene were decreased. Additionally, PTHrP overexpression ameliorated HFD-induced dyslipidemia, hepatic steatosis and insulin sensitivity. In HFD-induced murine obesity model, PTHrP is crucial to maintain metabolic homeostasis. PTHrP drives white adipose tissue browning and inhibits whitening of brown adipose tissue. Most importantly, PTHrP prevented HFD-induced obesity, hepatic steatosis and insulin resistance.

  • Jieun Kim, Jung Hee Shin, Young Lyun Oh, Soo Yeon Hahn, Ko Woon Park
    Article type: Original
    2022 Volume 69 Issue 1 Pages 67-74
    Published: 2022
    Released on J-STAGE: January 28, 2022
    Advance online publication: August 18, 2021
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    This study evaluated how to manage Bethesda category III (Bethesda III) (atypia of undetermined significance/follicular lesion of undetermined significance [AUS/FLUS]) thyroid nodules according to the Korean Thyroid Imaging Reporting and Data System (K-TIRADS) to reduce unnecessary surgeries. A total of 161 thyroid nodules diagnosed as Bethesda III underwent surgery from 2016 to 2019. Ultrasonography-guided fine-needle aspiration (US-FNA) or core needle biopsy (CNB) was used for repeat examination. K-TIRADS category was assigned to the thyroid nodules. The proportion of malignancy in Bethesda III nodules confirmed by surgery were significantly increased in proportion relative to K-TIRADS with 60.0% low suspicion, 88.2% intermediate suspicion, and 100% high suspicion nodules (p < 0.001). The proportion of malignancy in AUS and FLUS were significantly different (94.2% vs. 40.0% p = 0.003). The proportion of malignancy in AUS increased with K-TIRADS categories, but there was no difference in FLUS. All K-TIRADS high suspicion nodules were AUS as papillary carcinomas (99%), while 80% of FLUS nodules and 50% of follicular carcinomas showed K-TIRADS low suspicion. In 116 nodules with repeat FNA or CNB after initial Bethesda III results, the conclusive result rate was significantly increased in proportion to K-TIRADS with 58.3% low suspicion, 83.3% intermediate suspicion, and 88.8% high suspicion nodules (p = 0.015). K-TIRADS low suspicion nodules of Bethesda III nodules should be managed after risk-benefit consideration rather than immediate surgery or repeat examination. K-TIRADS for Bethesda III nodules can predict papillary carcinoma well, but not follicular carcinoma.

  • Kei Takasawa, Akari Nakamura-Utsunomiya, Naoko Amano, Tomohiro Ishii, ...
    Article type: Original
    2022 Volume 69 Issue 1 Pages 75-83
    Published: 2022
    Released on J-STAGE: January 28, 2022
    Advance online publication: August 07, 2021
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    To manage of 21-hydroxylase deficiency (21-OHD), transition medicine from pediatric to adult health care is an important process and requires individually optimized approaches. We sent cross-sectional questionnaire surveys on the current status of transition from pediatric to adult health care in 21-OHD patients to all councillors of the Japanese Society for Pediatric Endocrinology. Many pediatric departments (42.2%) experienced adult 21-OHD patients, and 115 patients (53 males, mean age of 26) in 46 institutions were identified. Whereas almost two-thirds of pediatric endocrinologists regarded the problems of counterparts and cooperation as hindrance of transition medicine, the major reason for continuing to be treated in pediatrics was the patient’s own request. The prevalence of long-term complications including obesity, osteoporosis, infertility, menstrual disorder, gender dysphoria, and testicular adrenal rest tumor were 27.5%, 8.8%, 11.1%, 26.3%, 7.1%, 12.5%, respectively, which is comparable to those of other cohorts previously reported. However, several items, especially infertility and osteoporosis were not checked well enough in adult 21-OHD patients treated in pediatrics. Though 44 of 62 female patients had genital reconstructive surgery, more than half of them were not followed up by gynecologists or pediatric urologists. Quite a few adult 21-OHD patients had been followed up in pediatrics even after coming of age; however, surveillance by pediatric endocrinologists of gynecological, reproductive, and mental problems may be insufficient. Therefore, multidisciplinary approaches should be required in transition medicine for 21-OHD and prerequisite for graduation of pediatrics. Pediatric endocrinologists will need to play a leading role in the development of transition systems.

  • Han-Chong Zhang, Tie Wen, Yu-Zhong Cai
    Article type: Original
    2022 Volume 69 Issue 1 Pages 85-94
    Published: 2022
    Released on J-STAGE: January 28, 2022
    Advance online publication: September 04, 2021
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    In the current study, we aimed to study the effect of miR-146a on proliferation and migration in an in vitro diabetic foot ulcer (DFU) model by targeting A-kinase-anchoring protein 12 (AKAP12). An in vitro DFU model was initially established using HaCaT cells derived from human keratinocytes and induced by advanced glycation end products (AGEs). The effects of overexpression of miR-146a on proliferation and migration ability were analysed. The expression levels of miR-146a and AKAP12 were measured by quantitative real-time polymerase chain reaction (qRT-PCR), and AKAP12, hypoxia-inducible factor-1α (HIF-1α), Wnt3a and β-catenin protein levels were measured by western blotting. The cell proliferation ability was measured by MTT, and the migration ability was analysed by a cell scratch assay. The binding between miR-146a and AKAP12 was identified using a luciferase reporter assay. The results demonstrated that AGEs significantly suppressed cell proliferation and migration, while the expression of miR-146a decreased and the expression of AKAP12 increased. A luciferase reporter assay revealed that miR-146a could directly target AKAP12. Overexpression of miR-146a promoted cell proliferation and migration in an in vitro DFU model and also promoted the expression of HIF-1α, Wnt3a and β-catenin but suppressed the expression of AKAP12. Co-overexpression of miR-146a and AKAP12 reversed the effect of miR-146a on cell proliferation and migration. Our findings revealed that miR-146a directly targeted AKAP12 and promoted cell proliferation and migration in an in vitro DFU model. This study provides a new perspective for the study of miR-146a in the treatment of DFU.

  • Lucia Sugawara, Takaaki Nakamura, Yoshitaka Ishizuka, Hiroshi Maegawa
    Article type: Original
    2022 Volume 69 Issue 1 Pages 95-100
    Published: 2022
    Released on J-STAGE: January 28, 2022
    Advance online publication: September 17, 2021
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    The etiology of central diabetes insipidus (DI) is classified into (1) idiopathic, (2) familial, and (3) secondary. Of these, familial central diabetes insipidus shows an autosomal dominant inheritance. We herein report a case in which this disease was diagnosed based on a family history of nocturnal enuresis. A 40-year-old man had had symptoms of polydipsia, polyuria and nocturia since childhood and found that his daughter had the same symptoms. Despite reaching nine years old, his daughter’s nocturnal enuresis still had not improved, resulting in her consulting a pediatrician. She was suspected of having familial neurohypophyseal diabetes insipidus (FNDI) based on her family history and was referred along with her father for a detailed examination and treatment. A hypertonic saline load test (HSLT) to evaluate the arginine vasopressin (AVP) reaction was performed in both the proband and his daughter. The results showed no increase in AVP levels in response to high plasma osmolality. The water deprivation test (WDT) revealed he was suffering from partial DI. Based on the above findings and considering the possibility of familial central diabetes insipidus, we performed a gene mutation analysis of AVP-neurophysin II (NPII). Both the father and daughter had an exon 2 abnormality in this gene (c232_234delGAG; pGlu78del), and this gene mutation is known to cause NPII protein abnormality, abolishing the function of AVP as a carrier protein. This case was considered to have provided an opportunity to understand the role of an NPII gene abnormality in familial central diabetes insipidus.

    Editor's pick

    In this issue, Sugawara L and colleague provide a line of convincing results of genetic analyses on neurophysin II (NPII) in a pedigree of neurohypophyseal diabetes insipidus.

  • Norikazu Toi, Masafumi Kurajoh, Daichi Miyaoka, Yuki Nagata, Shinsuke ...
    Article type: Original
    2022 Volume 69 Issue 1 Pages 101-105
    Published: 2022
    Released on J-STAGE: January 28, 2022
    Advance online publication: August 25, 2021
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    Bexarotene-induced central hypothyroidism (CH), for which levothyroxine (LT4) replacement is recommended, has been shown to be caused by pituitary but not hypothalamic disorder experimentally, though the underlying mechanism in humans remains unclear. Here, the pathophysiology of bexarotene-induced CH was examined using a TRH stimulation test in cutaneous T-cell lymphoma (CTCL) patients. In this retrospective longitudinal observational study, serum TSH and free T4 (F-T4) levels were measured in 10 euthyroid patients with CTCL during 24 weeks of bexarotene treatment. TRH stimulation testing was performed following CH diagnosis, with LT4 replacement dosage adjusted to maintain F-T4 at the pre-treatment level. After one week of bexarotene administration, all 10 patients developed CH, based on combined findings of low or low-normal F-T4 with low or normal TSH levels. TSH peak response after a stimulation test at one week was reached at 30 minutes. However, that was <4 μIU/mL in all patients, indicating a blunted though not exaggerated and delayed TSH response. In eight who continued bexarotene for 24 weeks, median LT4 replacement dosage was 125 (range, 75–150) μg/day. TSH level at 30 as well as 15, 60, 90, and 120 minutes after TRH stimulation was significantly correlated with LT4 replacement dosage (ρ = –0.913, p = 0.002), whereas TSH and F-T4 basal levels at one week were not. These results suggest that pituitary hypothyroidism is responsible for bexarotene-induced CH, while TSH levels after TRH stimulation precisely reflect residual pituitary-thyroid function in patients receiving bexarotene.

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