Microdissection testicular sperm extraction and intracytoplasmic sperm injection have made it possible for men with non-obstructive azoospermia (NOA) to conceive a child. A majority of men cannot produce sperm because spermatogenesis per se is believed to be “irreversibly” disturbed. For these men, it has been thought that any hormonal therapy will be ineffective. Further understandings of endocrinological regulation of spermatogenesis are needed and LH or FSH receptor knock out (KO) mice have revealed the roles of gonadotropin separately. Spermatogenesis has been shown to shift during evolution from FSH to LH dominance because LH receptor KO causes infertility while FSH receptor KO does not. High concentrations of intratesticular testosterone secreted from Leydig cells, ranging from 100- to 1,000-fold higher than in the systemic circulation, has pivotal roles during spermatogenesis. This is especially important during spermiogenesis, a post-meiotic step for progression from round to elongating spermatids. Sertoli cells are the target of FSH and have numerous androgen receptors, indicating that Sertoli cells are regulated by FSH and the paracrine functions of testosterone. In combination with Leydig cell-derived growth factors, particularly epidermal growth factor-like growth factors, Sertoli cells support spermatogenesis, especially at proximal levels of spermatogenesis (e.g., spermatogonial proliferation). Taken together, the current knowledge from human studies indicating that testosterone optimization by clomiphene, hCG and/or aromatase inhibitors and high dose hCG/FSH treatment can, at least in part, improve spermatogenesis in NOA. Accordingly hormonal therapy may open a therapeutic window for sperm production in selected patients.

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This study implemented a randomized crossover design to evaluate the efficacy and safety of switching from insulin glargine (IGlar) to insulin degludec (IDeg) in 18 children (11 males, 7 females; age 11.0 ± 0.5 years) with type 1 diabetes. All subjects had previously used IGlar once daily at bedtime. We compared fasting plasma glucose (FPG) and HbA1c levels, frequencies of overall and nocturnal (2200 h - 0659 h) hypoglycemia, and basal insulin dose at the baseline with those measured during a 24-week period during which IGlar or IDeg was administered in combination with pre-meal rapid acting insulin analogues. IDeg was initially given at the same dose as IGlar but was subsequently titrated to achieve FPG levels of 90-140 mg/dL. There were no significant changes in FPG and HbA1c levels from the baseline during the 24-week study period with IGlar or IDeg. The daily basal insulin dose did not significantly differ with IGlar or IDeg. Although the frequencies of overall hypoglycemia were similar, nocturnal hypoglycemia significantly decreased at 12 and 24 weeks from the baseline with IDeg use (2 ± 0.4 vs. 0 ± 0.3, 0 ± 0.5 episodes/month, both P <0.05), whereas no significant change in the frequency of nocturnal hypoglycemia was observed with IGlar. No severe hypoglycemia occurred during the study period with either basal insulin analogues. These results suggest that IDeg, injected once at bedtime, may provide similar glycemic control as IGlar while better reducing the risk of nocturnal hypoglycemia in children with type 1 diabetes.

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The intravenous methylprednisolone (iv MP) strategy for Graves’ ophthalmopathy (GO) and evaluation of its activity against the disease warrants further exploration. A prospective randomized controlled trial for 3 months was performed in a tertiary referral teaching hospital to compare the efficacy and safety of two different regimens of iv MP, and determine the value of clinical activity score (CAS) and T2 relaxation time (T2RTs) and areas of extraocular muscles (EOMs) by magnetic resonance imaging for diagnosis of active GO. Forty patients with moderate to severe GO and CAS ≥ 3 or 1 ≤ CAS < 3 with prolonged T2RTs on EOMs were randomly assigned to a monthly (MR: 1.5 g iv MP monthly for 3 months) or weekly (WR: 0.5 g iv MP weekly for 6 weeks, followed by 0.25 g weekly for 6 weeks) regimen. Overall response based on ophthalmic symptoms, T2RTs, areas of EOMs and adverse effects were recorded at each visit. The total rate of response was 71.9%. Rates of improved, unchanged, deteriorated were similar between the MR and WR groups (p>0.05). The maximum T2RTs and areas significantly decreased at the end of intervention in both groups (p<0.05). Results show that both MR and WR are effective and safe in treatment of GO. T2RTs combined with CAS can sensitively detect active GO and predict the response to iv MP.

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Parathyroid cysts (PCs) account for less than 1% of all parathyroid lesions and are most commonly located along thyroid lobes, rarely at ectopic sites. PCs are important because they can pose a differential diagnostic challenge against other cystic formations of the neck. PCs can be functional (elevated serum parathyroid hormone level) and nonfunctional. Four cases of nonfunctional PCs are presented. All four female patients underwent physical examination and ultrasonography of the neck with ultrasound-guided fine-needle aspiration biopsy (UG-FNA). The material thus obtained was stained by the standard May-Grünwald-Giemsa method. Parathyroid hormone level was determined in aspirate and serum, along with serum levels of total calcium, inorganic phosphates. In two asymptomatic patients, remission occurred after initial aspiration biopsy; one patient had compression syndrome with vocal cord paresis that required surgical treatment; and one patient had cyst recurrence that was surgically removed. Cystic neck masses can pose a major differential diagnostic problem considering different approach, treatment method, and preoperative and postoperative follow up. Surgical treatment is necessary in case of functional and large nonfunctional PCs (due to compression syndrome), whereas individualized therapeutic approach is used in case of small nonfunctional PCs. Ultrasonography with UG-FNA, cytologic analysis of the material obtained, and determination of parathyroid hormone level in aspirate and serum are crucial for making an accurate diagnosis.

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A 37-year-old female patient was hospitalized because of general fatigue and loss of axillary and pubic hair after massive bleeding at delivery of her third child. The basal levels of both plasma adrenocorticotropin hormone (ACTH) and serum cortisol were very low, 5.2 pg/mL and 1.9 μg/dL, respectively. Based on the fact that ACTH showed a low response to insulin tolerance test and a normal response to corticotropin-releasing hormone (CRH), she was diagnosed with hypothalamic adrenal insufficiency. No organic lesions were found in the hypothalamic-pituitary region by pituitary MRI and hydrocortisone therapy was instituted. Basedow’s disease was also discovered and treated with methimazole, and thyroid function returned to normal. Surprisingly, adrenal insufficiency gradually resolved, making it possible to stop hydrocortisone therapy 2 years from the onset of disease. To our knowledge, there are no previous case reports discussing the remission of hypothalamic adrenal insufficiency. The etiology of the unusual clinical course of this case remains unclear and we discussed several possibilities of the pathogenesis.

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Slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM), believed to be caused by β-cell destruction through islet-cell autoimmunity, gradually progresses to an insulin-dependent state over time. Although the presence of anti-glutamic acid decarboxylase antibody (GADA) is required for the diagnosis of SPIDDM, a recent change in the GADA assay kit from radioimmunoassay (RIA) to enzyme-linked immunosorbent assay (ELISA) yields mismatched GADA test results between the two kits, leading to confusion in understanding the pathological conditions of SPIDDM in Japan. Thus, this study aimed to clarify the difference in the clinical characteristics of GADA-ELISA-positive and GADA-ELISA-negative patients originally diagnosed as SPIDDM by GADA-RIA test. As a result, 42 of 63 original GADA-RIA-positive SPIDDM patients (66.7%) were found to be GADA-ELISA-positive, whereas the remaining 21 patients (33.3%) were found to be GADA-ELISA-negative. In patients with shorter disease duration, GADA-ELISA-positive patients showed significantly lower serum C-peptide levels than GADA-ELISA-negative patients. Meanwhile, in patients with longer disease duration, serum C-peptide levels were comparably decreased in GADA-ELISA-positive and GADA-ELISA-negative patients. A significant inverse correlation between serum C-peptide level and disease duration was observed in GADA-ELISA-negative patients, but not in GADA-ELISA-positive patients, suggesting that insulin secretory capacity may be gradually impaired over time also in GADA-ELISA-negative SPIDDM patients. In conclusion, physicians should be aware that GADA-ELISA-positive SPIDDM may be strongly associated with a future insulin-dependent state. Meanwhile, physicians should be careful in treating GADA-ELISA-negative SPIDDM patients diagnosed as type 2 DM, and cautiously follow the clinical course, in accordance with SPIDDM.

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A number of detected neuroendocrine neoplasms (NENs) has been on the increase due to our awareness of the NENs risk and the development of different imaging techniques. Therapy of NENs involves surgery, chemotherapy, “cold” somatostatin analogs (SSA), peptide receptor radionuclide therapy (PRRT) and kinase inhibitors in pancreatic NENs. The aim of this study is to assess the efficacy of SSA in combination with “hot” somatostatin analogs, and the survival rate of our patients with advanced NENs. Seventy nine patients with metastatic NEN and positive somatostatin receptor scintigraphy (SRS) were enrolled in the study. Every patient was supposed to receive a dose of 7.4 GBq/m² PRRT in 4-5 cycles every 4-9 weeks. Response to the therapy was assessed according to Response Evaluation Criteria In Solid Tumors (RECIST). SSA were administered one month after the last cycle of PRRT and have been continued during the whole follow up period. Median observation time was 33 months (IQR 13.6-55.6), median time to progression was 28 months (IQR 12.1-39.2) and median time to event was 28 months (IQR 12.1-39.2). Overall survival for this group of patients was 60 months. PFS was 39 months and EFS was equal to 33 months. In our group of patients not many serious adverse events were observed. PRRT using radiolabelled somatostatin analogs followed by therapy with “cold” somatostatin analogs is a promising treatment option for patients with metastatic or inoperable somatostatin receptor-positive NENs with the possibility of survival prolongation.

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The aim of this 24-week, prospective randomized open-label study was to compare the effects of alogliptin and vildagliptin on glucose control, renal function, and lipid metabolism. In Study 1, DPP-4 inhibitor-naive type 2 diabetes (T2DM) were randomly assigned to alogliptin 25 mg/day or vildagliptin 50 mg twice daily. In Study 2, T2DM on treatment with 50 mg/day sitagliptin were switched to either 25 mg/day alogliptin or 50 mg twice daily vildagliptin. The primary endpoint was change in glycosylated hemoglobin (HbA1c) level at 24 weeks, while the secondary endpoints were changes in urinary albumin excretion and low-density lipoprotein cholesterol (LDL-C) levels at 24 weeks. In Study 1, HbA1c levels changed at 24-week by -0.5±0.7% in the alogliptin group (p=0.002, relative to baseline) and -0.7±0.9% in the vildagliptin group (p=0.001, relative to baseline), and the extent of these changes were comparable between the two groups (p=0.219). The decrease in log urinary albumin excretion was more significant in the vildagliptin group (p=0.008). In Study 2, HbA1c levels at 24-week changed by 0.2±0.7% in the switch-to-alogliptin group (p=0.007) and 0.0±0.6% in the switch-to-vildagliptin group (p=0.188), indicating a significant difference between the groups (p=0.003). In both studies, the changes in LDL-C levels were comparable between the two groups. The two drugs had comparable glucose-lowering effects in DPP-4 inhibitor-naive patients but the effect was more pronounced for vildagliptin in patients switched from sitagliptin. The results may point to subtle yet important differences between the two DPP-4 inhibitors. This trial was registered with UMIN (no. #000019022).

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The effects of incretin therapies on pancreatic safety are currently being evaluated. In 3 phase 3 clinical studies of once weekly dulaglutide 0.75 mg (dulaglutide) in Japanese patients with type 2 diabetes (T2D), symptoms suggestive of acute pancreatitis as well as pancreatic enzymes were assessed and the risk of acute pancreatitis was evaluated. Patients who met any of the predefined criteria (clinical signs/symptoms of acute pancreatitis, confirmed amylase or lipase level ≥3 times the upper limit of normal [ULN], abdominal imaging of the pancreas) were adjudicated for acute pancreatitis by a blinded external committee. A total of 43 events in 40 patients (dulaglutide, 35/917 patients; liraglutide, 2/137 patients; insulin glargine, 2/180 patients; and placebo, 2/70 patients) were adjudicated (1 patient had events adjudicated during both placebo and dulaglutide treatment); 2 patients treated with dulaglutide had acute pancreatitis confirmed (2/917 [0.2%]; 2.651 patients/1,000 patient-years). One of these patients was diagnosed by the investigator with acute pancreatitis related to dulaglutide, but there was no typical abdominal pain. The event in the other patient occurred following an endoscopic ultrasound-guided fine needle aspiration. Transient increases in lipase ≥3×ULN were observed in 2% of patients in both the dulaglutide and liraglutide groups; the incidence in dulaglutide-treated patients was not significantly different from the incidences in liraglutide, placebo-, or insulin glargine-treated patients. Results of systematic assessments of pancreatic safety in 3 phase 3 studies for up to 52 weeks do not suggest an increased risk of acute pancreatitis in Japanese patients treated with dulaglutide.

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Familial dysalbuminemic hyperthyroxinemia (FDH) is an autosomal dominant condition and is the most commonly inherited euthyroid hyperthyroxinemia in Caucasians. However, it is extremely rare in Asian populations. A 30-year-old Japanese woman, who was incidentally found to have apparent thyroid dysfunction, was admitted to our hospital in 2004. She had extremely elevated serum free thyroxine (FT₄), moderately elevated free triiodothyronine (FT₃), and normal thyroid-stimulating hormone (TSH). Clinical thyroid examination revealed no abnormalities other than small goiter. Anti-thyroglobulin antibody titer was positive, but titers of other anti-thyroid antibodies, including antithyroid peroxidase antibody, TSH receptor antibodies, and thyroid-stimulating antibody, were negative. Levels of FT₃, FT₄, and TSH were similar when measured by three different laboratory kits, and FT₄ was still high when measured by equilibrium dialysis. By affinity chromatography, FT₄, TT₄, and albumin were extracted to the same fraction, and the levels of FT₄ and TT₄ were extremely high. By combination of reversed phase liquid chromatography and mass spectrometry techniques, the amino acid sequence of human serum albumin was determined. The patient was found to be a heterozygote for p.R218P mutation in the gene for human serum albumin and was diagnosed as FDH. This patient, who harbored the p.R218P mutation in the albumin gene, is the fifth case report of FDH in Japan. This condition is characterized by extremely high serum FT₄ and moderately high serum FT₃ levels. Although rare, FDH should be considered in the differential diagnosis for syndrome of inappropriate secretion of TSH (SITSH) in Japan.

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No serological cut-off exists to separate low T3 syndrome (LT) and central hypothyroidism (CH). The objective of this retrospective study was to propose such a cut-off. The first participant group comprised 52 patients from the age of six to twenty years. This group consisted of patients of 36 anorexia nervosa with LT and 16 CH. The second participant groups comprised 229 patients of all the same range of ages at the same hospital and included LT (n = 58) and CH (n = 4) patients, respectively. The third group of participants comprised 125 LT and 27 CH patients at the same hospital at all ages less than eighteen years. The last group of participants comprised 10 CH patients from the other two hospitals. The main outcome measure was fT3/fT4 ratio (pg/mL, ng/dL respectively). This ratio in the first group was significantly different (p < 0.05) between LT and CH. When the cut off value of fT3/fT4 was set as 2.0, the sensitivity of the LT and CH patients in the second group was 62% and 100%, respectively. This cut-off value of 2.0 was useful for distinguishing LT from CH only above the age of two years, as shown in the third group. The fT3/fT4 in 10 subjects with CH in the last group, aged 2 to 7 years, ranged from 2.55 to 7.71. In conclusion, fT3/fT4 less than 2.0 suggests LT rather than CH for patients from the age of two to eighteen years.

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Estrogen replacement therapy in Turner syndrome should theoretically mimic the physiology of healthy girls. The objective of this study was to describe final height and bone mineral density (BMD) in a group of 17 Turner syndrome patients (group E) who started their ethinyl estradiol therapy with an ultra-low dosage (1-5 ng/kg/day) from 9.8-13.7 years. The subjects in group E had been treated with GH 0.35 mg/kg/week since the average age of 7.4 years. The 30 subjects in group L, one of the historical groups, were given comparable doses of GH, and conjugated estrogen 0.3125 mg/week ∼0.3125 mg/day was initiated at 12.2-18.7 years. The subjects in group S, the other historical group, were 21 patients who experienced breast development and menarche spontaneously. Final height (height gain < 2 cm/year) in group E was 152.4 ± 3.4 cm and the standard deviation (SD) was 2.02 ± 0.62 for Turner syndrome. The final height in group L was 148.5 ± 3.0 cm with a SD of 1.30 ± 0.55, which was significantly different from the values for group E. The volumetric BMD of group S (0.290 ± 0.026 g/cm³) was significantly different from that of group L or E (0.262 or 0.262 g/cm³ as a mean, respectively). This is the first study of patients with Turner syndrome where estrogen was administered initially in an ultra-low dose and then increased gradually. Our estrogen therapy in group E produced good final height but not ideal BMD.

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POU class 1 homeobox 1 (POU1F1) regulates pituitary cell-specific gene expression of somatotropes, lactotropes, and thyrotropes. In humans, two POU1F1 isoforms (long and short isoform), which are generated by the alternative use of the splice acceptor site for exon 2, have been identified. To date, more than 30 POU1F1 mutations in patients with combined pituitary hormone deficiency (CPHD) have been described. All POU1F1 variants reported to date affect both the short and long isoforms of the POU1F1 protein; therefore, it is unclear at present whether a decrease in the function of only one of these two isoforms is sufficient for disease onset in humans. Here, we described a sibling case of CPHD carrying a heterozygous mutation in intron 1 of POU1F1. In vitro experiments showed that this mutation resulted in exon 2-skipping of only in the short isoform of POU1F1, while the long isoform remained intact. This result strongly suggests the possibility, for the first time, that isolated mutations in the short isoform of POU1F1 could be sufficient for induction of POU1F1-related CPHD. This finding improves our understanding of the molecular mechanisms, and developmental course associated with mutations in POU1F1.

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