Growth hormone (GH) and insulin-like growth factor-I (IGF-I) play essential roles in growth in childhood, and continue to have important metabolic actions in adults. Adult growth hormone deficiency (AGHD) is characterized by increased visceral adiposity, abnormal lipid profiles, premature atherosclerosis, decreased quality of life, and increased mortality. Recently, case reports and several clinical studies suggest that GHD state in adults is associated with an increased prevalence of nonalcoholic fatty liver disease (NAFLD) and progression to nonalcoholic steatohepatitis (NASH) or liver cirrhosis. As a mechanistic insight, growing evidence has revealed that GH as well as IGF-I play essential roles in the liver. Further investigation is necessary to clarify the precise mechanisms by which GH and IGF-I exert their effects in the liver; however, it should be noted that NAFLD/NASH has emerged as an important comorbidity in AGHD.

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Perinatal undernutrition is known to disturb reproductive development, in particular by delaying the onset of puberty in certain species. Using a rat model, we studied whether hypernutrition after birth can rescue the delayed onset of puberty in intrauterine undernourished female rats. Pregnant rats were divided into two groups: the maternal normal nutrition (mNN, n = 8) and maternal undernutrition (mUN, n = 9) groups. In the mUN group, dams received 50% of the daily food intake of the mNN group from day 15 of pregnancy until delivery. Pups from both the mNN and mUN dams were then separated into two groups, based on their postnatal feeding conditions: control-normal nutrition (control-NN), control-hypernutrition (control-HN), Intrauterine growth retardation (IUGR)-normal nutrition (IUGR-NN), and IUGR-hypernutrition (IUGR-HN). Litter sizes of the hypernutrition groups were controlled to five pups per dam, and normal nutrition groups to 12-13 pups per dam. From postnatal day 30, pups were inspected daily for vaginal opening (VO). The age of VO in the IUGR-NN group was 35.7 ± 2.4 days (mean ± SD), which was significantly delayed compared to that of the control-NN group (33.8 ± 0.8 days). The age of VO in the IUGR-HN group was 35.5 ± 2.3 days, which was significantly delayed compared to that of the control-HN group (33.5 ± 0.8 days). Interestingly, the age of VO did not differ between the IUGR-NN and IUGR-HN groups. In conclusion, maternal undernutrition delays puberty in female offspring, and this delay in puberty cannot be rescued with hypernutrition after birth.

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The objectives of this study were to investigate whether preoperative serum thyrotropin (TSH) concentrations can be used for risk prediction of differentiated thyroid cancers (DTC), in particular, microcarcinomas (DTMC), which may be in an early stage of development of DTC. The cohort of this retrospective study consisted of 1,870 patients who underwent surgery on thyroid nodules at a single hospital in an iodine-sufficient region in China. Serum TSH and anti-thyroid antibodies were measured and diagnoses were based on surgical pathology reports. Of 1,870 patients, 14.4% (n=269) had DTC. Eighty-nine DTCs were DTMC. As TSH increased, the prevalence of DTC rose clearly. The odds ratio in favor of having DTC with a serum TSH 1.9-4.8 mIU/L and > 4.8 mIU/L, compared with having a serum TSH 1.0-1.9 mIU/L were 1.57 (95% CI 1.03-2.40, P=0.038) and 5.71 (95% CI 2.31-14.14, P=0.0002), respectively. A similar pattern was yielded when excluding subjects with high thyroid autoantibodies. Higher TSH was also associated with lymph node metastasis and advanced disease (stage III and IV). However, preoperative TSH was 1.17 mIU/L in patients with DTMC vs. 1.08 mIU/L in patients with benign pathology (P = 0.80). The pattern of escalating prevalence with higher TSH did not apply to DTMC. In conclusion, serum TSH is not a good risk predictor of DTMCs. Elevated TSH level may be related to advanced stage, that is, progression of thyroid cancer, but not with the development of thyroid cancer, since microcarcinomas do not have any relation with TSH level.

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Obstructive sleep apnea (OSA) has long been suggested to increase the risk of development of autoimmune diseases. We investigated the prevalence of Hashimoto’s thyroiditis (HT) in 245 euthyroid individuals, who were suspected of having OSA. After polysomnography, subjects were grouped according to apnea-hypopnea index (AHI) consecutively as controls (n=27F/32M, AHI<5), mild-OSA (n=22F/37M, 5≤AHI<15), moderate-OSA (n=23F/38M, 15≤AHI<30) and severe-OSA (n=30F/36M, AHI≥30). Diagnosis of HT based on thyroid ultrasound and positivity of serum anti-thyroglobulin (anti-TG) and anti-thyroid peroxidase (anti-TPO) antibodies. Hashimoto’s thyroiditis was diagnosed in 32.2% of controls and in 46.8% of all OSA patients (p=0.03). Severe-OSA patients had the highest HT frequency (51.5%) compared to controls (p=0.02), mild-OSA (42.3%, p=0.03) and moderate-OSA (45.9%, p=0.05) groups. Forty-two of control subjects (71.2%) were negative for both of the anti-TPO and anti-TG, whereas 99 (53.2%) of OSA subjects were positive at least for one of them (p=0.01). HT was detected in 62% of females, 29% of males (p<0.001). Severe female OSA patients had the highest HT prevalence (73.3%), while male control subjects had the lowest (18.7%) among all groups (p<0.001). There was no significant correlation between thyroid volume and severity of OSA but isthmus thickness was significantly correlated to AHI (p<0.01, r=0.22). In conclusion, OSA patients presented higher HT prevalence parallel to severity of OSA, especially among women. These results may lead to further investigations about relation between OSA and auto-immune thyroiditis and to development of screening schemas for severe-OSA patients for early diagnosis of HT before development of hypothyroidism.

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Human augmenter of liver regeneration (hALR) is a sulfhydryl oxidase that is highly expressed in spermatogonia and early spermatocytes. To investigate the physiological effects of hALR in spermatogenesis, we generated a hALR transgenic mouse model driven by the human TSPY (testis-specific protein, Y-encoded) promoter that allows the transgene to be specifically activated in the testes. hALR content was found to be increased in both germ cells. The histological and TUNEL analysis of transgenic testes revealed a number of spermatogenetic defects including primary spermatocyte overpopulation followed by depletion through apoptosis, degenerating and detached nucleated germ cells, haploid cell loss and intraepithelial vacuoles of varying sizes. In line with these features, adult transgenic male mice also displayed a reduction in fertility. Our data suggest that regulated spatial and temporal expression of hALR is required for normal testicular development and spermatogenesis, and overexpression of hALR results in influencing the sperm morphology and quantity and the eventual reduction in male fertility. Present findings in the mouse may be of interest to human male fertility.

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An initial high-dose treatment of glucocorticoid has been proposed to prevent chronic androgen excess, improving the final height prognosis of 21-hydroxylase deficiency (21-OHD) patients. In Japan, it is recommended to use an extremely high-dose of hydrocortisone (HDC) (100-200 mg/m²/day) for initial treatment by the Japanese Society for Pediatric Endocrinology. However, a precise evaluation of the treatment has not been carried out. In this study, we retrospectively analysed the effects of initial high-dose HDC therapy on the linear growth of classical 21-OHD patients discovered by newborn screening. Thirty patients (14 females) were eligible for this study, all of whom were initiated with high dose HDC therapy. The height standard deviation score (Ht-SDS) was 0.76 ± 0.65 at birth, and decreased to -1SD or less until the age of 12 months, subsequently catching up by 3 years of age (-0.56 ± 0.76). The growth pattern and the height at the age of two years were very similar to those previously observed in patients without initial high dose HDC therapy. We did not find any significant difference in growth retrospectively between the high- or low-dose HDC group (initial treatments of ≥150 mg/m²/day and 100 mg/m²/day, respectively). Bone ages did not exceed chronological ages at the ages of three and six years. Our data suggest that an initial high-dose HDC treatment does not profoundly affect linear growth during first three years of life and that the treatment could be a valuable option for 21-OHD patients without having an obvious adverse effect on linear growth.

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The prevalence of vitamin D deficiency, presenting as hypocalcemic seizures or rickets in children, is increasing worldwide due to insufficient vitamin D intake and lack of exposure to sunshine. However, considering that relatively few children with low 25-hydroxyvitamin D [25(OH)D] levels manifest symptoms, it is possible that genetic factors may predispose individuals to vitamin D deficiency. Recent twin studies have reported that the level of serum of 25(OH)D is influenced by genetic factors. In addition, genome-wide association studies and candidate gene studies have revealed that several vitamin D-related genes, including VDR, GC, NADSYN1, CYP2R1, CYP24A1, CYP27B1, and C10orf88 contribute to variations in serum 25(OH)D levels. To investigate whether genetic predisposition contributes to vitamin D deficiency, we analyzed polymorphisms in vitamin D-related genes in 30 Japanese patients with vitamin D deficiency presenting at less than 4 years of age, along with 66 controls. A χ² test showed that the genotype frequencies of BsmI polymorphism in VDR and rs10898191 in NADSYN1 were significantly different between the two groups. The allele frequencies of BsmI, ApaI, TaqI in VDR, rs10898191 in NADSYN1, and rs705117 in GC were also significantly different. In particular, the frequency of the BAtS haplotype in VDR was significantly increased in the patient group relative to controls (p = 0.0014; odds ratio, 5.61; 95% confidence interval 1.92 - 16.40). Although this is a small study, our findings suggest that VDR, NADSYN1, and GC polymorphisms may be linked to the manifestation of vitamin D deficiency in Japanese children.

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The present study was undertaken to determine clinical features of hypopituitarism in elderly subjects. Thirty-one elderly patients with hypopituitarism were enrolled. They were 19 males and 12 females, with the ages of 70.7±5.4 years ranging from 62 to 80 years. High prevalence of hyponatremia (80.6%) and hypoglycemia (29.0%) was found, and it was totally different from that in hypopituitarism from general population. There were two groups of hyponatremia derived from their clinical courses, namely, acute deterioration of hyponatremia and chronically persistent hyponatremia. Analysis for deficient hormones clearly showed that ACTH deficiency was highly found in 30 of 31 patients. There was no difference in serum cortisol levels between the hyponatremic and normonatremic patients. Despite hypoosmolality, plasma arginine vasopressin (AVP) was apparently high in the hyponatremic patients compared with in the normonatremic ones. The present study indicates that hyponatremia is the valuable finding for initiating diagnosis of hypopituitarism, and that augmented release of AVP may be involved in developing hyponatremia in elderly patients with hypopituitarism.

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The best treatment option for recurrent papillary thyroid carcinoma (PTC) is reoperation when the recurrent lesion is locoregional. The prognostic significance of serum thyroglobulin (Tg) levels before reoperation and the association between the outcome of reoperation and Tg level remain unclear. Our study aimed to determine the outcomes of patients who underwent reoperation and their association with serum Tg levels. We retrospectively studied 79 patients with PTC with locoregional recurrence whose whole-body scan results were negative for any recurrence but whose serum Tg levels were detectable after first-line treatment. All the patients underwent reoperation and follow-up examinations, which involved serial serum Tg measurements after thyroxine withdrawal (T4-off Tg), neck ultrasonography, chest computed tomography, and/or fluorodeoxyglucose-positron emission tomography, to detect further recurrence. During the median follow-up duration of 89 months (range, 38-332 months), 30 patients (38.0%) experienced a second recurrence even after the reoperation. Among all patients, only 12 whose Tg levels decreased postoperatively to undetectable levels showed no recurrence. Most recurrences were detected in the patients with high T4-off Tg levels after the reoperation (T4-off Tg level (ng/mL), number of patients with recurrence, %: <1, 0/12, 0%; 1-10, 9/31, 33.3%; >10, 16/22, 72.7%; P < 0.001). In conclusion, recurrence occurred in 38.0% of the patients even after the reoperation. The postoperative T4-off Tg level was a good indicator of recurrence after the reoperation. Therefore, patients who experience recurrence should undergo follow-up examinations that involve routine measurements of T4-off Tg levels, especially when postreoperative values exceed 10 ng/mL.

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Previous studies have shown that several types of stem cells can differentiate into insulin-secreting islet beta-cells and that these cells can reduce blood glucose in some trials, but there has been no report of a long-term follow-up. We assessed the long-term effects of the use of autologous bone marrow mononuclear cells in the treatment of type 2 diabetes mellitus (T2DM). Based on the willingness to receive implantation of bone marrow mononuclear cells, One hundred and eighteen patients with T2DM were divided into two groups; the patients in group I were treated with autologous bone marrow mononuclear cells and patients in group II were treated with insulin intensification therapy. Mononuclear cells from bone marrow were injected back into the patient’s pancreas via a catheter. Patients were followed-up after the operation at monthly intervals for the first 3 months and thereafter every 3 months for the next 33 months, the occurrence of any side effects and the results of laboratory examinations were evaluated. There were no reported acute or chronic side effects in group I and both the HbA1c and C-peptide in group I patients were significantly better than either pretherapy values or group II patients during the follow-up period. These data suggested that the implantation of autologous bone marrow mononuclear cells for the treatment of T2DM is safe and effective. This therapy can partially restore the function of islet beta-cells and maintain blood glucose homeostasis in a longer time.

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