Endocrine Journal
Online ISSN : 1348-4540
Print ISSN : 0918-8959
ISSN-L : 0918-8959
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REVIEW
  • Naoko Hashimoto, Hidekazu Nagano, Tomoaki Tanaka
    Type: Review
    2019 Volume 66 Issue 6 Pages 485-496
    Published: 2019
    Released: June 28, 2019
    [Advance publication] Released: May 18, 2019
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    The tumor suppressor gene p53 is mutated in approximately more than 50% of human cancers. p53 is also referred to as the “cellular gatekeeper” or “guardian of the genome” because it protects the body from spreading mutated genome induced by various stress. When the cells receives stimuli such as DNA damage, oncogene activation, oxidative stress or undernutrition, p53 gives rise to a number of cellular responses, including cell cycle arrest, apoptosis, cellular senescence and metabolic adaptation. Related to energy metabolisms, it has been reported that p53 reduces glycolysis and enhances mitochondrial respiration. p53 is also involved in the regulation of other cellular metabolism and energy production systems: amino acid metabolism, fatty acid metabolism, nucleic acid metabolism, anti-oxidation, mitochondrial quality control, and autophagy. Moreover, recent studies have shown that p53 gene polymorphisms affect life expectancy and lifestyle-related disease such as type 2 diabetes, suggesting that there is a certain relationship between p53 function and metabolic disorders. In addition, mutant p53 protein does not only lose the tumor suppressor function, but it also gains novel oncogenic function and contributes to tumor development, involving cellular metabolism modification. Therefore, the importance of multifunctionality of p53, particularly with regard to intracellular metabolisms, arouses therapeutic interest and calls attention as the key molecule among cancer, lifestyle-related diseases and life expectancy.

ORIGINAL
  • Ann-Rong Yan, Xiaojuan Zhang, Hong Shen, Xia Zhou, Rui Li, Zhexing Yua ...
    Type: Original
    2019 Volume 66 Issue 6 Pages 497-514
    Published: 2019
    Released: June 28, 2019
    [Advance publication] Released: March 19, 2019
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    Excessive iodine intake has been associated with increased risk of thyroid cancer (TC) in many studies, but the results have not been consistent. Since it was common knowledge that urinary iodine (UI) is considered a sensitive marker of current iodine intake, we conducted a meta-analysis to clarify the association between high UI and TC. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, and the Cochrane Collaboration. Between-group meta-analyses were performed to compare UI between TC patients and the healthy/euthyroid subjects in local residents and benign thyroid nodules (BTN) patients. Then, between-group meta-analyses to compare the incidence rate of iodine excess were also conducted. The 22 case-control studies included in the meta-analyses represented 15,476 participants. It is the first time to clarify that UI was increased in PTC patients, but was not altered by regional population iodine intake status. Compared with BTN patients, PTC patients exhibited both higher UIC and higher odds ratio of iodine excess only in adequate iodine intake status subgroup; UIC, not the odds ratio of iodine excess, was higher in patients with PTC than those with BTN in above requirements iodine intake subgroup. A novel insight is offered that high UI in PTC patients was less influenced by regional population iodine intake status. It is indicted that high iodine intake is not a risk factor for PTC and high urinary iodine is just a specific characteristic of the disease.

  • Yuko Asari, Kazunori Kageyama, Aya Sugiyama, Hikaru Kogawa, Kanako Nii ...
    Type: Original
    2019 Volume 66 Issue 6 Pages 515-522
    Published: 2019
    Released: June 28, 2019
    [Advance publication] Released: March 15, 2019
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    Cushing’s disease is almost always caused by hypersecretion of adrenocorticotropic hormone (ACTH) from a pituitary adenoma. A mutation in the deubiquitinase gene USP8 has been found in human ACTH-producing pituitary adenoma cells. This mutational hotspot hyperactivates USP8, rescuing epidermal growth factor receptor (EGFR) from lysosomal degradation and ensuring its sustained signaling in Cushing’s disease. An EGFR inhibitor would be an effective anti-tumor agent in EGFR-related tumors. We investigated the effect of a potent dual tyrosine kinase inhibitor, lapatinib, on ACTH production and cell proliferation in AtT-20 mouse corticotroph tumor cells. Lapatinib decreased proopiomelanocortin (Pomc) mRNA levels and ACTH levels in AtT-20 cells and also inhibited cell proliferation, induced apoptosis, and decreased pituitary tumor-transforming gene 1 (Pttg1), a hallmark of pituitary tumors, mRNA levels. KSN/Slc nude mice were subcutaneously inoculated with AtT-20 cells. After 1 week, the mice were randomized either to control or lapatinib groups. The inhibitor decreased the tumor weight of AtT-20 allografts in vivo versus control mice. Lapatinib also significantly decreased Pomc and Pttg1 mRNA levels in the tumor and plasma ACTH and corticosterone levels in vivo. Thus, lapatinib decreases the ACTH production and proliferation of corticotroph tumor cells. An EGFR-targeting therapy could be an important treatment for Cushing’s disease.

  • Lili Zhuang, Hongmei Qu, Jianxiang Cong, Huangguan Dai, Xiaoyan Liu
    Type: Original
    2019 Volume 66 Issue 6 Pages 523-533
    Published: 2019
    Released: June 28, 2019
    [Advance publication] Released: April 11, 2019
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    MicroRNAs (miRNAs), which is a type of non-coding and single-stranded small molecule RNA, bind either completely or incompletely to 3’-UTR of the target gene mRNA to inhibit mRNA translation or degradation. In our study, we aimed to explore the roles and mechanisms of miR-181c in the apoptosis of RL95-2 human endometrial carcinoma cells. Cell activity and apoptosis were detected by cell counting Kit-8 (CCK-8) assay and flow cytometry (FCM), respectively. Related mRNAs and proteins expression was determined by quantitative real-time reverse transcription PCR (qRT-PCR) and western blot assays, respectively. The binding capacity of PTEN-3’-UTR and miR-181c was assessed by luciferase reporter assay. The obtained results suggested that E2 evidently increased the cell activity of RL95-2 cells. In addition, miR-181c inhibitor suppressed the cell viability and enhanced the apoptosis capacity of E2-induced RL95-2 cells and distinctly reduced the miR-181c expression. We also found that miR-181c could bind to PTEN-3’-UTR and miR-181c inhibitor up-regulated the expression level of PTEN in E2-induced RL95-2 cells. Besides, overexpression of PTEN markedly promoted the apoptosis of E2-induced RL95-2 cells through regulating the Bax and Bcl-2 expression, and modulated the expression of AKT pathway, p53 and Cyclin D. In conclusion, our findings revealed that miR-181c affected the estrogen-dependent endometrial carcinoma cell growth by targeting PTEN. The potential effects of miR-181c on the apoptosis of E2-induced RL95-2 cells suggest that miR-181c could be an effective target for endometrial carcinoma therapies.

  • Sachiko Bandai, Ken Okamura, Megumi Fujikawa, Kaori Sato, Hiroshi Iken ...
    Type: Original
    2019 Volume 66 Issue 6 Pages 535-545
    Published: 2019
    Released: June 28, 2019
    [Advance publication] Released: March 28, 2019
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    Since there have been few reports on the long-term prognosis of Graves’ hyperthyroidism, the prognosis of 549 Graves’ hyperthyroidism patients initially treated with thionamide and followed for >8 (range: 8.6–36.4) years was studied, evaluating the change in the TSH binding inhibitor immunoglobulin activity (TBII). The distribution of the time required for the first disappearance of TBII was normal after logarithmic conversion, and the mean ± 2 SD was 1.5 (0.3–8.1) years. TBII became negative once within 5 years in 78.9% of patients. However, TBII re-elevation was observed in 47.8% of this group (fluctuating type). Remission was observed in 88.9% of the non-fluctuating type (smooth remission) and 37.2% of the fluctuating type patients. TBII remained positive for >5 years in 21.1% (smoldering type) of patients, with remission observed in only 19.8% of patients. Final remission was observed in 301 (54.8%) patients; the median time to remission was 6.8 (interquartile range: 4.0–10.9) years. A longer time until normalization of TBII and higher final thyroid weight were associated with a poor prognosis. Spontaneous hypothyroidism was observed in 6.0% of patients, independent of the TBII change. Our findings suggest that remission of Graves’ hyperthyroidism mostly occurred after 4–11 years treatment. While predicting the prognosis before therapy was difficult, the clinical course may suggest a better prognosis if TBII disappears within five years without TBII fluctuation or enlargement of the goiter. Patients may safely wait more than five years to undergo ablative therapy if they hope to avoid permanent hypothyroidism.

  • Maki Takeuchi, Junichiro Sato, Katsunori Manaka, Mariko Tanaka, Hotaka ...
    Type: Original
    2019 Volume 66 Issue 6 Pages 547-554
    Published: 2019
    Released: June 28, 2019
    [Advance publication] Released: March 28, 2019
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    Ectopic ACTH syndrome (EAS) due to a prostate small cell carcinoma (SCC) is very rare with only 26 cases reported to date and has a poor prognosis. We here describe another case of this disorder that was clinically typical based on prior reports as it showed hypercortisolemia and severe hypokalemia with multiple metastasis. However, our current case of prostate SCC causing EAS is the first to display negative immunostaining for ACTH despite detectable POMC mRNA expression in the primary lesion. ACTH immunonegativity is thought to be associated with a more aggressive disease course and a poorer prognosis although there are few studies of the underlying mechanisms. We explored two possibilities for this finding in our current patient: aberrant POMC processing prevented immunodetection with an anti-ACTH antibody; and the ACTH content per cell was below the threshold for immunodetection due to its rapid secretion or low synthesis. The aberrant processing theory was thought to be less likely because of immunonegative findings even using anti-POMC/ACTH antibodies. As the plasma ACTH levels in our patient were comparable with those reported for previous immunopositive prostate EAS cases, we speculated that the depletion of ACTH may be caused not only by rapid secretion but also by low production levels as a sign of de-differentiation. De-differentiation may therefore explain the mechanism underlying the negative correlation between immunoreactivity for ACTH in EAS and disease aggressiveness. We believe that our present findings will be of use in future prospective studies aimed at confirming the mechanism of immunonegativity.

  • Siyuan Zheng, En Liu, Ying Zhang, Tao Long, Xin Liu, Yi Gong, Tingting ...
    Type: Original
    2019 Volume 66 Issue 6 Pages 555-562
    Published: 2019
    Released: June 28, 2019
    [Advance publication] Released: March 26, 2019
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    The study was to investigate circulating zinc-α2-glycoprotein (ZAG) concentrations in women with PCOS, and changes in ZAG levels after exenatide or metformin treatment. One hundred eighty-two women with polycystic ovary syndrome (PCOS) who met the 2003 Rotterdam diagnostic criteria and 150 controls without PCOS were recruited. We partitioned women with PCOS into groups according to body mass index or blood glucose concentrations, determined serum ZAG, anthropometric parameters, metabolic and endocrine indicators, and inflammatory markers, and statistically analyzed the results. Eighty-two overweight/obese subjects of the recruited women with PCOS were then randomly assigned to groups administered either 12 weeks of exenatide injection (10 μg b.i.d.) or oral metformin (1,000 mg b.i.d.). Circulating ZAG levels were determined after 12 weeks of treatment. The results showed that circulating ZAG was significantly lower in PCOS women than in healthy women (p < 0.01). Overweight/obese women and those with higher blood glucose levels had lower circulating ZAG. After 12 weeks of exenatide or metformin treatment, there were significant increases (p < 0.01) in circulating ZAG in both treatment groups (the exenatide baseline level was 46.54 ± 2.38 ng/mL vs. 56.41 ± 2.02 ng/mL after treatment, p < 0.01; metformin baseline was 47.81 ± 2.14 ng/mL vs. 55.67 ± 2.01 ng/mL after treatment, p < 0.01), however there was no statistical difference between the 2 treatments (p > 0.05). Circulating ZAG is closely related to PCOS and could be an important adipokine involved in the occurrence and development of PCOS. ZAG might possibly be applicable as a new observational indicator in the treatment of PCOS.

  • Koji Morita, Masumi Ogawa, Michiko Kimura, Yuta Okawa, Yutaka Oki, Nao ...
    Type: Original
    2019 Volume 66 Issue 6 Pages 563-569
    Published: 2019
    Released: June 28, 2019
    [Advance publication] Released: April 03, 2019
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    A 49-year-old woman with membranous nephropathy was referred to our hospital during the tapering of oral prednisolone, because of suspicion of primary adrenal insufficiency based on a plasma ACTH level of 399.1 pg/mL in the Elecsys assay and a serum cortisol level of 3.1 μg/dL. A rapid ACTH stimulation test revealed a suboptimal response, whereas a prolonged ACTH simulation test showed a sufficient increase in her urinary free cortisol. Also, big ACTH was not detected by gel exclusion chromatography. Therefore, we speculated that ACTH levels were falsely elevated due to some interference substances. Pretreatment of her plasma with either polyethylene glycol precipitation or a heterophilic blocking tube substantially reduced her ACTH values. When either the Immulite ACTH II or the TOSOH II ACTH was tried instead of the Elecsys ACTH, her plasma ACTH values turned out to be lower and appropriate for her clinical status. These results indicated that heterophilic antibodies interfered only with the Elecsys ACTH assay presumably by bridging the capture and tracer antibodies. To our knowledge, this is the first case in which the Elecsys ACTH assay yielded falsely elevated results. Regardless of the measurement system used, if there is a discordance between assay results and clinical findings, it should be considered to adopt additional procedures and/or another assay.

  • Hiromi Konishi, Jun Shirakawa, Masanori Arai, Yasuo Terauchi
    Type: Original
    2019 Volume 66 Issue 6 Pages 571-574
    Published: 2019
    Released: June 28, 2019
    [Advance publication] Released: April 02, 2019
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    Some categories of drugs are known for causing hyperglycemia or diabetes such as steroids, antipsychotics, and immunosuppressant. However, there has been little evidence from studies about the proportion of each drug in the context of drug-induced diabetes. In this study, we used data from the Japanese Adverse Drug Event Report (JADER) database, a spontaneous reporting system database maintained at the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan, reported between April 2004 and June 2017. Among 459,250 reports of adverse drug reactions in JADER database, reported instances of the adverse event of hyperglycemia or diabetes were extracted. After the exclusion of anti-diabetes drugs, the drugs frequently implicated in the development of hyperglycemia or diabetes, including prednisolone, tacrolimus, everolimus, ribavirin, quetiapine, aripiprazole, interferon alfa-2b, risperidone, atorvastatin, dexamethasone, ciclosporin, nilotinib, methylprednisolone, or nivolumab, were identified. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, was manifested as the third most frequently associated drug with hyperglycemia or diabetes (340 cases), following prednisolone (694 cases) and tacrolimus (393 cases), and the reporting odds ratio (ROR 8.56, 95% CI 7.65–9.57) of this drug was higher than that of the two aforementioned drugs (ROR 3.96, 95% CI 3.66–4.28 and ROR 3.51, 95% CI 3.17–3.89). These results suggest that there is a potent association of evelolimus with hyperglycemia in clinical practice in Japan.

NOTE
  • Tezcan Sezgin, Muhammet İrfan Dönmez, Aylin Dirican, İsa Deniz, Bülent ...
    Type: Note
    2019 Volume 66 Issue 6 Pages 575-577
    Published: 2019
    Released: June 28, 2019
    [Advance publication] Released: March 28, 2019
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    Partial androgen insensitivity syndrome (PAIS) is a form of disorders of sexual development. Besides the issues of gender assignment, the fate of gonads in these patients poses a challenging problem. Debate still remains on the need and/or timing of gonadectomy in either complete or partial androgen insensitivity syndromes. In this case report, we present a 68-year-old patient who was raised as a woman, stayed married for 45 years and admitted to our endocrinology department with complaint of male type hair distribution after initial examination following move to a nursing home. Physical examination revealed no breast development, a phallus of 6 cm, labia majoras that include testes and a blind ending vagina. Chromosomal analysis confirmed 46,XY with intact SRY and AZF regions. Pelvic ultrasonography and magnetic resonance imaging results indicated testicular tissue in labia majoras in addition to a rudimentary prostate. Gonadectomy was not offered to the patient due to lacking evidence of benefit in this age group and considering possible hormonal side effects. Our patient might be the oldest patient to be diagnosed with PAIS. Treatment and follow-up protocols for adults with PAIS are not standardized and therefore these patients should be individually evaluated and treated. Risks and benefits of surgery should be kept in mind when suggesting gonadectomy.

ERRATUM
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