Ectopic ACTH syndrome (EAS) is a potentially fatal endocrine disease that results from a variety of neuroendocrine tumors (NETs), such as small cell lung cancer (SCLC) and bronchial typical carcinoid. Typical carcinoid is usually slow growing, not associated with plasma progastrin releasing peptide (ProGRP) elevation. Here, we report a 47-year-old female smoker with progressive typical carcinoid and plasma ProGRP elevation. Several types of Cushingoid features were found on physical examination. In addition, laboratory examination showed elevated plasma ACTH and serum cortisol levels. These findings indicated ACTH-dependent Cushing’s syndrome. Moreover, the serum cortisol level was not suppressed by overnight high-dose dexamethasone treatment, suggesting the presence of an extra-pituitary tumor. Contrast-enhanced brain MRI revealed no pituitary adenoma, which also supported the idea that EAS occurred in the present case. Strikingly, chest computed tomographic (CT) scan showed a single 18-mm peripheral nodule in the right middle lobe of the lung. Tumor marker analysis revealed an elevation in plasma ProGRP. These data suggested a possibility that SCLC secreted ACTH and caused EAS in this patient. Of note, the plasma ACTH level was increased (1.7 fold) in l-desamino-8-D-arginine vasopressin (DDAVP) test, also suggesting the specific clinical feature in this case. After additional imaging examinations, we performed surgical resection with the suspicion of limited SCLC. As a result, pathological examination revealed a vasopressin receptor Ib (V1b) receptor-negative bronchial typical carcinoid with ACTH production and mediastinal lymphatic metastasis. In summary, we present a case of EAS caused by progressive bronchial typical carcinoid with plasma ProGRP elevation. We propose a novel subtype of lung typical carcinoid.
The present study examined the effects of progesterone (P) and 17β-estradiol (E2) on fetal damage and intrauterine pressure in ovariectomized pregnant mice. The mice were ovariectomized on gestational day (GD) 9 (copulation plug = GD 0), and daily subcutaneous injection of various doses of P (2, 3 or 4 mg) or 4 mg P plus E2 (0.05 or 0.1 μg) was given thereafter. Although P alone increased percentage of normal fetuses on GD 17 dose-dependently, fetal injury with edematous hematomata on their extremities was frequently observed. In the group treated with 4 mg P, the injured fetus was found at the highest percentage (18%) and intrauterine pressure was significantly higher than that in intact pregnant mice (controls). No injured fetus on GD 17 was found by the treatment with 4 mg P plus 0.05 or 0.1 μg E2, and the treatments decreased the intrauterine pressure to the level of controls. Percentage of normal fetuses in the ovariectomized mice treated with 4 mg P plus 0.05 μg E2 was similar to that of controls, while that in the ovariectomized mice treated with 4 mg P plus 0.1 μg E2 markedly decreased. The results suggest that estrogen decreases intrauterine pressure to defend fetal damage in ovariectomized P-treated mice, and a high estrogen level interrupted pregnancy while keeping this estrogen action.
A heterozygous NR5A1 mutation is one of the most frequent causes of 46,XY DSD (disorders of sex development). We here reported a NR5A1-related 46,XY DSD patient, who first received endocrinological attention at 10 years of age for clitoromegaly. The patient had been reared as a girl, and no signs of virilization had been detected before. On examination, her clitoris was 35 mm long and 10 mm wide, with Tanner 3° pubic hair. Urogenital sinus and labial fusion was absent, while her uterus was found to be severely hypoplastic. Her basal testosterone level was 94.8 ng/dL, suggesting the presence of functioning Leydig cells. Gonadal histology revealed bilateral dysplastic testes consisting of mostly Sertoli cell-only tubules and Leydig cell hyperplasia. Novel heterozygous Arg313Leu substitution in NR5A1 was identified in the patient. Literature search confirmed twelve other cases of this scenario, namely, severe under-virilization in utero followed by spontaneous virilization around puberty in NR5A1-related 46,XY DSD. Of interest, Leydig cell hyperplasia was documented in 6 out of 9 patients for whom testicular histology was available. To keep in mind about the possible restoration of Leydig cell function around puberty, even in patients without discernible in utero androgen effect, may be of clinical significance, because it will give a great impact on the judgement about sex assignment.
Early onset puberty and irregular estrous cycles occur more frequently in rats which are fed a high-fat diet. Kisspeptin is an essential factor for the regulation of sexual maturation and is co-expressed with neurokinin B in neurons in the hypothalamic arcuate nucleus. However, the effects of a diet change on kisspeptin neuronal signaling are not well-understood. Therefore, in this study, we examined the immunoreactivity pattern of the kisspeptin/kiss1-receptor (KISS1R) and neurokinin B/neurokinin3-receptor (R). Pups born to high-fat diet rats were exposed to a high-fat diet until the onset of puberty. From puberty, the offspring originally exposed to a high–fat diet were fed a normal diet up to 85 postnatal days (PND 85). We examined kisspeptin/Kiss1-receptor and neurokinin B/neurokinin3-receptor immunoreactivity (IR) in the arcuate nucleus of the pups. The onset of puberty in the high-fat group was significantly earlier than the control group. At the onset of puberty, the densities of kisspeptin and neurokinin B IR cells were significantly higher in the high-fat diet group than in the control group; however, the densities of KISS1 and neurokinin 3-receptor IR cells did not differ between the two groups. At PND 85, the density of kisspeptin and neurokinin B IR cells did not differ between control and high fat group. The density of densities of KISS1 and neurokinin 3-receptor IR cells also did not differ between groups at this stage. These data suggest that a high-fat diet can influence puberty onset and the immunoreactivity of kisspeptin and neurokinin B. These effects can be modified by dietary control.
Follicular cell-derived thyroid carcinomas, including thyroid squamous cell carcinomas (SCCs) and anaplastic carcinomas, are immunoreactive for paired-box gene 8 (PAX8), while non-follicular cell-derived thyroid carcinomas stain negative for the PAX8 antibody. Intrathyroid thymic carcinoma (ITTC) arising from the intrathyroidal ectopic thymus exhibits moderate-to-strong nuclear reactivity for polyclonal PAX8. This is difficult to understand given that PAX8 is not associated with embryonic thymic development. We aimed to determine the diagnostic significance of monoclonal PAX8 antibody in distinguishing ITTCs from follicular cell-derived thyroid carcinomas. Ten ITTCs, 14 poorly differentiated thyroid carcinomas (PDTCs), 14 thyroid SCCs, 7 thymic tissue specimens, 7 thymomas, and 1 thymic carcinoma were analyzed using antibodies against polyclonal and monoclonal PAX8, thyroid transcription factor-1, p63, and CD5. Four ITTCs (40.0%) stained positive for polyclonal PAX8; none stained positive for monoclonal PAX8. All PDTCs and 92.9% of SCCs were immunoreactive for both polyclonal and monoclonal PAX8. All PDTCs, 46.2% of SCCs, and none of the ITTCs were immunoreactive for thyroid transcription factor-1. Eight ITTCs (80.0%), but none of the PDTCs and SCCs, were immunoreactive for CD5. We are the first to show that ITTCs stain negative for monoclonal PAX8. Monoclonal PAX8 is a more reliable marker than polyclonal PAX8 for determining follicular cell origin. We conclude that monoclonal PAX8 is a useful marker for distinguishing ITTCs from PDTCs and SCCs. Monoclonal PAX8 negativity is additional evidence in support of ITTCs not being follicular cell-derived thyroid carcinomas, but having a thymic origin.
A 45-year-old male suddenly experienced left-flank abdominal pain. Echocardiography revealed akinesis of the ‘takotsubo cardiomyopathy’ type. He experienced a sudden haemodynamic collapse (blood pressure, 324/154 mmHg; pulse rate, 180 beats/min) during emergency cardiac catheterisation. An abdominal computed tomography (CT) revealed expansion of a soft tissue mass 64 × 33 mm in dimension in the left adrenal region, with accumulation of fluid surrounding the left pararenal space. Three days after the attack, his urinary catecholamine concentrations were slightly elevated. We suspected the patient as having a pheochromocytoma followed by acute haemorrhagic rupture, based on signatures of adrenal mass, ‘takotsubo cardiomyopathy’, and the hypertensive crisis. Over the next few weeks, he recovered well as an outpatient, and his blood pressure remained around 110/60 mmHg without medication. Three weeks after the attack, an abdominal CT showed shrinkage of the ruptured adrenal mass (to a diameter of 30 mm) and absorption of the retroperitoneal hematoma. On day 190 after the attack, abdominal CT did not detect any left adrenal mass. This is the first report of the case showing a complete vanishing of ruptured adrenal mass with takotsubo cardiomyopathy. Although surgical approaches for ruptured adrenal mass involve either emergency or elective surgery, the patients did not need even the elective surgery. Accumulation of the similar cases may unravel clinical factors predicting self-limiting of the ruptured adrenal mass to avoid unnecessary risky surgery.
GH therapy in pediatric patients with Prader-Willi syndrome (PWS) improves body composition, but discontinuation of GH after achieving adult height has been implicated in its deterioration. Although there is evidence for the deleterious effects of visceral adipose tissue (VAT) rather than subcutaneous adipose tissue (SAT) on the development of obesity-related complications, the effects of GH discontinuation on fat distribution in adults with PWS has not been fully investigated. Therefore, we utilized dual-energy X-ray absorptiometry (DEXA) and abdominal computed tomography (CT) to compare the fat distribution between before and 6 months or 12 months after the cessation of GH therapy in 7 adult PWS patients. GH therapy was initiated at a mean age of 4.1 ± 1.4 years and discontinued at a mean age of 18.9 ± 1.8 years. Serum IGF-1 levels were decreased by discontinuation of GH therapy. Fat mass was significantly increased 6 and 12 months after GH cessation, whereas muscle mass and bone mineral density were unchanged during both study periods. Abdominal CT analysis revealed that elevations in fat mass were due to increases in VAT rather than SAT. Circulating low-density lipoprotein (LDL) cholesterol levels were significantly elevated 6 months after GH cessation. In conclusion, discontinuation of GH therapy caused rapid increases in visceral adipose tissue and LDL cholesterol levels. These findings indicate that continuation of GH therapy may be a therapeutic option to maintain body composition; however, further studies regarding the long-term benefits and adverse effects of GH therapy in adults with PWS are required.
Long-term glucose supplementation is required to prevent hypoglycemia after massive insulin overdosing. We fitted the blood insulin concentration-time profile to the model: I = A·exp(–a·t) + B·exp(–b·t), where I (μU/mL) is the serum/plasma insulin concentration, A (μU/mL) and B (μU/mL) are the peak insulin concentrations of each component, a (time–1) and b (time–1) are the time constants of each component, and t (h) is the time elapsed from the peak of blood insulin level. Additional components were considered as needed. Patient 1 had auto-injected 600 U NovoRapid® 30Mix, and Patient 2 had auto-injected 300 U Novolet®R (regular) and 1,800 U NovoLet®N (NPH). We used the disappearance of therapeutic doses of the respective insulin in healthy individuals as controls, and we obtained parameters by Excel solver. In Patient 1, the parameter values were A = 1490.04 and a = 0.15 for insulin aspart and B = 60.66 and b = 0.04 for protaminated aspart. In Patient 2, the values were A = 784.45 and a = 0.38 for regular insulin and B = 395.84 and b = 0.03 for NPH. Compared with controls, the half-lives (t1/2) for insulin aspart and protaminated aspart were 4 and 2 times longer, respectively, in Patient 1. In Patient 2, the t1/2 for regular and NPH insulin were 2 and 7 times longer than those in the controls, respectively. In conclusion, the t1/2 for insulin was elongated 2 to 7 times after massive overdosing, explaining why glucose supplementation is needed for long periods in these cases.
Musk is a secreted external hormone or information compound that is stored in musk scent glands of the males of species within the family Moschidae, such as Moschus berezovskii. The secretion of musk changes periodically during the courtship and reproduction periods, with the early stage of secretion occurring from May to July, and the maturation stage occurring from August to April of the following year. In this study, we analyzed the dynamic changes in musk components from June to April of the following year. The result showed that musk morphological character, water content, total ion chromatographic pattern, and composition undergo seasonal change. Luminescence immunoassay and radioimmunoassay analyses were performed to determine corresponding fecal hormone levels. The results showed that testosterone, estrogen, and cortisol levels in feces change on a seasonal basis, and are significantly higher in June than in other months (p < 0.01). Correlation analysis showed that the contents of four examined musk components (muscone, cyclopentadecanone, cholesterol, and cholestenol) from June to August were significantly highly negatively correlated with fecal testosterone and estradiol levels (p < 0.01). In contrast, the correlation coefficients were low or not significant from August to April of the following year. These results indicate that testosterone and estradiol may play a major role in determining musk composition during the early stage of musk secretion but not during the course of musk maturation, which suggests that musk secretion may be promoted by increases in sex hormones in June.
The efficacy of thyroxine suppressive therapy in reducing nodular growth and its effect to bone mineral density (BMD) in postmenopausal women is still debated. This study aimed to evaluate the therapeutic effect of thyroxine and its influence on BMD. Postmenopausal women with nodular or multinodular goiter during 2013–2015 at Chang Gung Memorial Hospital were enrolled and retrospectively traced back to the first date of visit or treatment. Ninety-four eligible patients were enrolled, of whom 45 were thyroxine-treated (LT-4 group) and 49 were treatment-naïve (control group). Data, including volume of nodules, were analyzed retrospectively. BMD was measured in each LT-4 group patient since the year of enrollment. Nodular volumes were reduced in both LT-4 (from 4.89 ± 4.46 to 4.10 ± 4.57 mL, p = 0.033) and control group (3.48 ± 4.36 to 3.09 ± 2.88 mL, p = 0.239) at initial 2-year follow-up. Nodular volume in LT-4 group increased insignificantly (from 4.89 ± 4.46 to 4.91 ± 5.40 mL, p = 0.711) at the end of 7-year follow-up. The best cut-off predictive nodular volume that may have responded to thyroxine is 2.6 mL (AUC, 0.740; sensitivity, 0.750; specificity, 0.733) during first 2 year. Lumbar spine, total hip and femoral neck BMD were not significantly changed during 2 year’s thyroxine suppression therapy. In conclusion, thyroxine suppressive therapy in postmenopausal women had significant reduction in nodule volume at initial 2 years of treatment, especially in volume larger than 2.6 mL. Prolonged thyroxine treatment did not benefit nodular size reduction and may affect BMD minimally in postmenopausal women.
Glucocorticoid resistance syndrome (GRS) is a rare genetic disorder caused by inactivating mutations of the NR3C1 gene which encodes the glucocorticoid receptor. The phenotypic spectrum is broad but typically include symptoms of adrenal insufficiency, mineralocorticoid excess and hyperandrogenism. We report a new case associated with a novel NR3C1 mutation. A 55-year-old woman with lifelong history of low body weight, hyperandrogenism and anxiety was seen at the endocrine clinic after left adrenalectomy and salpingoophorectomy for lesions suspicious of ovarian cancer and adrenal metastasis. The tumors turned out to be a 3.5 cm benign ovarian serous adenofibroma and a 3.5 cm multinodular adrenal mass. She complained of worsened fatigue and inability to recover weight lost with surgery. Pre-operative serum and urinary cortisol were elevated, but she had no stigma of Cushing’s syndrome. Plasma ACTH was elevated and a 1-mcg cosyntropin stimulation test was normal. Her fatigue persisted over ensuing years and ACTH-dependent hypercortisolemia remained stable. Low dose oral dexamethasone failed to suppress endogenous cortisol. A pituitary MRI was normal but revealed incidental brain aneurysms. Bone densitometry showed profound osteoporosis. On the bases of this contradictory clinical picture, glucocorticoid resistance syndrome (GRS) was suspected. Using next generation sequencing technology, a novel heterozygous pathogenic variant in the NR3C1 gene was detected. We speculate that vascular malformations and profound osteoporosis, findings associated to cortisol excess, reflect in our patient a variable tissue sensitivity to glucocorticoids. In conclusion, in patients with clinically unexpected ACTH-dependent hypercortisolemia, primary glucocorticoid resistance (GRS) should be considered.
The aim of this study was to investigate for first time the thyroid function in patients with inflammatory bowel disease (IBD) and the potential effect of anti-TNF (tumor necrosis factor) therapy. We evaluated 41 patients with IBD (25M/16F, 36.5 ± 11.3 y, 27 with Crohn’s disease and 14 with ulcerative colitis), without any known thyroid disorder. Eighteen patients (9M/9F, 33.6 ± 8.8 y) were on anti-TNF therapy, while 23 patients (16M/7F, 38.7 ± 12.5 y) were treated with Azathioprine and Mesalazine (Aza/Mes) for more than 1 year. Twelve patients from the second group were then treated with anti-TNF and studied 6 months later. We assessed thyroid function by measuring thyroid stimulating hormone (TSH), free thyroxine (FT4), triiodothyronine (T3), thyroid peroxidase autoantibodies (TPOAb) and thyroglobulin autoantibodies (TgAb) levels. One patient presented with overt and one with subclinical hyperthyroidism. Thyroid auto-antibodies were positive in 12.2%. Patients from the anti-TNF group had lower levels of FT4 (1.09 ± 0.15 vs. 1.38 ± 0.9 ng/dL, p = 0.042), while TSH and T3 were comparable. The percentage of patients with positive thyroid auto-antibodies was lower in the anti-TNF group (5.6% vs. 17.4%). In the subgroup of patients who changed to anti-TNF, we found statistically significant reduction in FT4 after 6 months (1.26 ± 0.24 vs. 1.08 ± 0.15 ng/dL, p = 0.044), without changes in TSH and T3 levels. There was no change regarding thyroid auto-antibodies. In conclusion, patients with IBD showed a quite high percentage of thyroid autoimmunity. After treatment with anti-TNF, FT4 levels were found to be reduced, while no changes in TSH, T3 levels and thyroid auto-antibodies were noted.
A 43-year-old woman with an 8-year history of diabetes, hypertension, and dyslipidemia presented with amenorrhea and convulsion. Her MRI scan revealed a 3.5-cm T2-hyperintense pituitary macroadenoma with suprasellar extension to the frontal lobe and bilateral cavernous sinus invasion. Her serum levels of GH and insulin-like growth factor-I (IGF-I) were elevated to 9.08 ng/mL (normal range: <2.1 ng/mL) and 1,000 ng/mL (normal range: 90–233 ng/mL, SD score +10.6), respectively. Bromocriptine insufficiently suppressed her GH levels, while octreotide paradoxically increased her GH levels. Together with her characteristic features, she was diagnosed with acromegaly caused by an invasive GH-producing pituitary macroadenoma. As performing a one-stage operation would have been extremely difficult, she was first treated with pasireotide long-acting release (40 mg monthly) for 5 months followed by a successful transsphenoidal surgery. One month after the first injection, biochemical control was achieved (IGF-I, 220 ng/mL; GH, 1.26 ng/mL), and tumor shrinkage of approximately 50% was observed. The resected tumor was histologically diagnosed as a sparsely granulated somatotroph adenoma, with higher expression of somatostatin receptor subtype 5 (SSTR5) than that of SSTR2A. The germline aryl hydrocarbon receptor interacting protein (AIP) mutation was negative, and several tumor cells were weakly immunoreactive for AIP. Despite the presence of a residual tumor postoperatively, biochemical control was achieved 6 months after the final injection of pasireotide. In conclusion, this case suggests that pasireotide may be an option for preoperative first-line therapy in invasive and octreotide-resistant sparsely granulated somatotroph adenomas.
Changes in imaging findings and hormone levels before and after pheochromocytoma rupture, as well as detailed histopathology of resected tumors, have rarely been reported. A 52-year-old woman developed hypertension and diabetes mellitus in 2014, but despite treatment with antihypertensive and hypoglycemic drugs, good control was not achieved. On April 2, 2016, the patient started to have headaches and palpitations, and on April 6, she visited our hospital. Plain computed tomography (CT) of the abdomen showed a 4-cm, isodense mass in the left adrenal gland, and the patient was hospitalized for further examination. Because the patient had hypertension, tachycardia, and hyperglycemia on admission, therapies for those were started. Catecholamine levels were markedly elevated. However, after the patient developed left flank pain on Day 4, antihypertensive and insulin therapies were no longer required. Plain CT then showed heterogeneous high density areas in the left adrenal mass. On Day 7, 3 meta-iodobenzylguanidine scintigraphy showed no abnormal uptake. On Day 8, contrast CT showed low density areas within the left adrenal tumor and contrast enhancement of the tumor margins, and catecholamine levels were markedly decreased. Elective left adrenal tumor resection was performed on Day 49. The capsule of the resected tumor was ruptured. Histopathology showed widespread hemorrhagic necrosis and viable cell components in the tumor margins. Positive chromogranin A staining of the tumor cells confirmed a diagnosis of pheochromocytoma. This patient displayed remarkable changes in imaging findings and hormone levels before and after pheochromocytoma rupture. Pheochromocytoma rupture and hemorrhagic necrosis were confirmed histopathologically.
Hypouricemia is a high-risk factor of exercise-induced acute kidney injury (EIAKI) probably through a lack of an antioxidant effect of uric acid. Xanthine oxidoreductase (XOR) is an enzyme that catalyzes the formation of uric acid from hypoxanthine and xanthine, leading to an increase in superoxide and reactive oxygen species. Activation of XOR has been proposed to promote oxidative stress-related tissue injury. We measured plasma XOR activity by a sensitive and accurate assay using a combination of liquid chromatography and triple quadrupole mass spectrometry in subjects with relatively low levels of uric acid (≤4.0 mg/dL) who were recruited from 627 subjects (male/female: 292/335) in the Tanno-Sobetsu Study, a population-based cohort. The numbers of subjects with uric acid ≤4.0 mg/dL, ≤3.0 mg/dL and ≤2.0 mg/dL were 72 (11.5%, male/female: 5/67), 13 (2.1%, all females) and 2 (0.3%, both females), respectively. Plasma XOR activities in 5 male subjects were below the median value of the 292 male subjects. In 12 (17.9%) of the 67 female subjects with uric acid ≤4.0 mg/dL, plasma XOR activities were above the upper quartile value of the 335 female subjects. Eleven of the 12 female subjects with high plasma XOR activity and a low uric acid level had liver dysfunction and/or insulin resistance. In conclusion, unexpected high plasma XOR activities were found in some female subjects with relatively low levels of uric acid. Measurement of plasma XOR activity may help to identify hypouricemic patients with a high risk for EIAKI.
Gain-of-function ATP-binding cassette subfamily C member 8 (ABCC8) mutations are known to cause neonatal diabetes mellitus and maturity-onset diabetes in the young. However, the intrafamilial heterogeneous nature of diabetes caused by the ABCC8 mutation is not fully understood to date. To clarify the intrafamilial heterogeneous nature of monogenetic diabetes, we conducted a case study on a family with ABCC8 mutations. We investigated eight family members, including a neonatal diabetes patient, based on metabolic features and genetic analysis. All coding exons and exon–intron boundaries of the KCNJ11, ABCC8, GCK, HNF1A, and HNF4A genes were amplified from genomic DNA and directly sequenced. Five gene mutation carriers with ABCC8 (c.1819G>A/p.V607M) were identified in this family, and the onset and severity of diabetes progressively worsened across the three generations. Each of the ABCC8 gene mutation carrier family members were diagnosed with diabetes as follows: the grandfather with type 2 diabetes at 35 years of age, the aunt with slowly-progressive insulin-dependent diabetes at 18 years of age, the mother with ketosis-onset insulin-dependent diabetes at 14 years of age, the sister with impaired glucose tolerance at 9 years of age, and the proband with transient neonatal diabetes at birth. The present study shows the heterogeneous nature of diabetes in a family with a gain-of-function mutation in the ABCC8 gene.
This cross-sectional study aimed to examine changes in thyroid-stimulating hormone (TSH) concentration over age in China and investigate relationship between TSH and risk factors for cardiovascular disease (CVD) among euthyroid subjects. TSH, free triiodothyronine (FT3), free thyroxine (FT4), blood lipid, and glucose were measured. 7,693 individuals were subdivided into different age groups. Associations between TSH and CVD risk factors [age, body mass index (BMI), systolic and diastolic blood pressure, total cholesterol (TC), triglycerides, low density lipoprotein-cholesterol (LDL-C) and high density lipoprotein-cholesterol (HDL-C) and fasting plasma glucose (FPG)] were evaluated with Pearson correlation analysis. Results showed that 2.5th percentile for TSH was consistent across age groups, whereas 97.5th percentile increased in subjects older than 40 years with upper limit being 6.83 mIU/L in subjects aged 60–69 years and 8.07 mIU/L in those older than 70 years. The age-speciﬁc upper limits reclassiﬁcation rate was higher in all age bands as compared to the common cut-off value. TSH was positively associated with age, SBP, DBP, TC and LDL-C and negatively with FT3 and FT4. Serum TSH within new reference range had a linear correlation with SBP, TC and LDL-C in subjects aged <60 years. There were no significant differences in BMI, blood pressure, lipid profile or FPG among subjects 60–69 and older than or equal to 70 years. Elevated TSH within new reference range is associated with risk factors for CVD in subjects aged <60 years. Thus, there might be age-related difference in the relationship between CVD risk factors and elevated serum TSH.
The aim of this study was to determine the relationships between free testosterone (FT) level and parameters including laboratory data and data from questionnaires and to determine symptoms leading to the detection of late onset hypogonadism (LOH). We retrospectively reviewed medical records of patients in whom serum FT was measured in our hospital. Aging Male Symptoms (AMS) score, self-rating depression scale (SDS) and frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) score were used for questionnaires. A total of 205 patients were included in the analysis (55.2 ± 15.6 years of age, mean ± SD). Among them, 119 patients (58.0%) had an FT level of less than 8.5 pg/mL, which fulfills the diagnostic criterion of LOH syndrome according to the clinical practice manual for LOH in Japan. It was revealed that FSSG score was inversely correlated to serum FT levels (r = –0.3395, p < 0.001), although SDS and AMS scales did not show significant correlations to FT levels. Our study revealed a high prevalence of LOH syndrome among patients in whom the majority complained of general symptoms. Although GERD symptoms are generally not considered to be typical symptoms of LOH, our study indicates that those symptoms might be clues for the detection of LOH.
Several studies have shown the correlation between vitamin D [25(OH)D] deficiency and thyroid autoimmunity and reducing of thyroid autoantibodies in patients with normal levels of vitamin D combining with thyroid hormone replacement. However, other authors not agree with this association. It is still unclear whether the low 25(OH)D levels are the result of HT disease or a part of its cause. We studied 88 patients with HT regarding vitamin D status and thyroid autoimmunity markers as well as the relationship with cytokines produced by Th1, Th2, and Th17 cells compared with a control group of 71 euthyroid healthy subjects. The present study demonstrated that vitamin D concentrations were similar in patients HT and the control group. The reduction of free T4 levels was a predictor of vitamin D insufficiency for Hashimoto’s thyroiditis, but not for the control group. Lower concentrations of TNF-α was a predictor of lower levels of vitamin D. Differences in the association between HT and vitamin D insufficiency remain unresolved in the literature. The thyroid hormone status would play a role in the maintenance of vitamin D sufficiency, and its immunomodulatory role would influence the presence of autoimmune thyroid disease. The positive correlation between free T4 and vitamin D concentrations suggests that adequate levothyroxine replacement in HT would be an essential factor in maintaining vitamin D at sufficient levels.
Weight reduction is important in patients with sleep-disordered breathing (SDB). In Japanese patients, slight weight reduction is effective for improving the severity of SDB. However, the effect of weight reduction after administration of sodium glucose co-transporter 2 (SGLT2) inhibitor for SDB remains unclear. The aim of this study was to evaluate the improvement of SDB from baseline after administration of dapagliflozin (5 mg) once daily for 24 weeks among Japanese patients with obesity and type 2 diabetes mellitus. Thirty Japanese patients with type 2 diabetes mellitus and SDB were enrolled in a 24-week, prospective, open-label, single-arm, multicentre trial. SDB was defined as at least five 3% oxygen desaturation index (ODI) events per hour, and moderate to severe SDB was defined as at least 15 ODI events per hour. The primary endpoint was the change in 3% ODI between before dapagliflozin administration and at 24 weeks. The prevalence of moderate to severe SDB was 20% in the present study. After administration of dapagliflozin, fasting glucose, HbA1c, aspartate aminotransferase, total cholesterol, low-density lipoprotein cholesterol, and estimated globular filtration rate decreased significantly. The improvement of 3% ODI was observed in patients with moderate to severe SDB but not mild SDB (from 25.0 ± 3.8 at baseline to 18.5 ± 6.1 at 24 weeks, p = 0.017). In conclusion, dapagliflozin might improve moderate to severe SDB but not mild SDB in Japanese patients with obesity and type 2 diabetes mellitus.
Various oral glucose-lowering agents are available in Japan. Although the objective characteristics of these drugs are well described, little is known about treatment satisfaction by patients using these agents. The aim of this study was to assess treatment satisfaction of diabetic patients visiting diabetes clinics using the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and to determine the association of the DTSQ scores with various factors including oral glucose-lowering agents. The study subjects were 754 outpatients who had been treated with one or more oral glucose-lowering agents, but not insulin or glucagon-like peptide-1 receptor agonist. The collected data included the response to DTSQ as completed by the patients, various parameters pertaining diabetes treatment including adherence, motivation, life style, social support, complications and cost burden from the patients and attending physicians. The associations among satisfaction scores and various parameters were analyzed by multiple linear regression analysis. In all subjects, use of sodium-glucose cotransporter 2 inhibitor (SGLT2i) were positively, and irregular diet time were negatively associated with satisfaction scores significantly as well as some factors which had been previously reported to be associated. Subgroup analysis showed that adherence to diet and use of SGLT2i were positively in obese (body mass index ≥25 kg/m2), and HbA1c and irregular work time were negatively in non-obese (<25 kg/m2) patients associated with satisfaction scores. These results suggest that SGLT2i is really used with high satisfaction, especially by obese patients and that factors associated with treatment satisfaction might differ between obese and non-obese patients using oral glucose-lowering agents.
To identify the spectrum and prevalence of thirteen causative genes mutations in congenital hypothyroidism (CH) patients, we collected blood samples and extracted genomic DNA of 106 CH patients, and designed a customized targeted next-generation sequencing panel containing 13 CH-causing genes to detect mutations. A total of 132 mutations were identified in 65.09% of patients (69/106) on the following nine genes: DUOX2, TG, TPO, TSHR, TTF1, TTF2, NKX2-5, PAX8 and GNAS. 69.70% (92/132) mutations related to thyroid dyshormonogenesis genes, including DUOX2 (n = 49), TG (n = 35), and TPO (n = 8). 21.21% (28/132) mutations related to thyroid dysgenesis genes, including TSHR (n = 19), TTF1 (n = 5), TTF2 (n = 1), PAX8 (n = 2), and NKX2-5 (n = 1). 9.09% (12/132) mutations related to GNAS, which was associated with thyrotropin resistance. No mutation of THRA, TSHB, IYD or SLC5A5 was detected. Among 69 mutations detected patients, 41 (59.42%) patients were two or more mutations detected, and mutations of 30 (43.48%) patients related to two or three genes. According to the pathomechanism of the mutant genes, 57.97% CH patients were classified as thyroid dyshormonogenesis. Overall, DUOX2, TG and TSHR mutations were the most common genetic defects in Chinese CH patients, and thyroid dyshormonogenesis could be the first genetic etiology of CH in Chinese. Besides, multiple mutations accounts for a part of genetic pathogenesis.
Limited joint mobility (LJM) of hand, which is one of the complications of diabetic hand, is associated with diabetic micro- and macroangiopathy although the precise pathogenesis is not completely understood. Neutrophil-lymphocyte ratio (NLR), a simple and novel inflammatory marker, has been reported to have a predictive effect to some diabetic complications in recent years. However, it is not elucidated about the relationship between LJM of hand and NLR in patients with type 2 diabetes. We evaluated the relationships between LJM of hand and NLR in 335 consecutive patients with type 2 diabetes in this cross-sectional study. LJM of hand was diagnosed by a ‘prayer sign’ or ‘table test’. LJM of hand was present in 80 patients. The patients with LJM of hand had significantly older age, longer duration of diabetes, worse renal function, and higher proportion of diabetic neuropathy, retinopathy and nephropathy. NLR in patients with LJM of hand was higher than that in patients without LJM of hand (2.54 ± 1.46 vs. 2.11 ± 1.04, p = 0.004). Multivariate logistic regression analysis revealed that LJM of hand was positively correlated with NLR (odds ratio, 1.31; 95% confidence interval 1.03–1.69, p = 0.027) after adjustment for age, sex, duration of diabetes, body mass index, hemoglobin A1c, hypertension and dyslipidemia. Our results demonstrate a positive relation between LJM of hand and NLR in patients with type 2 diabetes.
11-oxygenated C19 steroids (11oxC19s) are newly specified human androgens. Although median serum levels of 11oxC19 were reported to be higher in patients with polycystic ovary syndrome (PCOS) than in unaffected women, inter-individual variations in androgen levels among PCOS patients have poorly been investigated. Here, we quantified four 11oxC19s, i.e., 11-ketotestosterone (11KT), 11β-hydroxytestosterone (11OHT), 11β-hydroxyandrostenedione (11OHΔ4A), and 11-ketoandrostenedione (11KΔ4A), in blood samples of 28 PCOS patients and 31 eumenorrheic women using liquid chromatography-tandem mass spectrometry. We referred to our previous data of classic androgens in these individuals. We found that 11OHT levels were higher in the PCOS group than in the eumenorrheic group. Moreover, although the median values of 11KT, 11KΔ4A, and 11OHΔ4A were comparable between the two groups, these steroids were markedly increased in some patients. Of the 28 patients, 8 had high levels of both 11oxC19s and classic androgens, whereas 4 had an increase only in 11oxC19 levels, and 12 had an increase only in classic androgen levels. Intragroup variations in androgen levels were relatively large in the PCOS group. Levels of 11OHT and 11KT were significantly higher in overweight/obese patients than in normal weight patients and correlated with body mass indexes. These results highlight the clinical significance of 11oxC19s as circulating androgens in PCOS patients and indicate that the accumulation of 11oxC19s and/or classic androgens is an essential feature of PCOS. The profiles of circulating androgens appear to vary among patients. In particular, overweight/obesity likely enhances the 11oxC19s accumulation in PCOS, although this notion awaits further validation.
Acromegalic arthropathy is a common complication of acromegaly and harms the quality of life of the patients even after acromegaly is in long-term remission. A recent study demonstrated by knee MRI the characteristic structural features of acromegalic arthropathy. However, the effects of treatment for acromegaly on such structural features are almost unknown. This study was undertaken to analyze the effects of transsphenoidal surgery (TSS) on acromegalic arthropathy and elucidate whether knee MRI findings are reversible or irreversible. We analyzed 22 patients with acromegaly (63.7% females, median age 58 years) by knee MRI at diagnosis. Out of these 22 patients, 16 who underwent TSS (68.9% female, median age 58 years) were also subjected to knee MRI 2 months after TSS. As for X-ray undetectable findings, MRI detected synovial thickening, bone marrow lesion, ligament injury and meniscus injury in 22.7%, 22.7%, 4.7% and 59.1% of the patients, respectively. With respect to the 16 patients who underwent TSS, clinical and structural improvements were observed respectively in 100%, 66.7% and 66.7% of the patients who showed knee joint pain, synovial thickening and bone marrow lesion before TSS. However, no patient showed structural improvement of meniscus injury after TSS. In acromegalic arthropathy, synovial thickening and bone marrow lesions are reversible while meniscus injury is irreversible. Because all those findings are associated with the exacerbation of arthropathy, they may be therapeutic targets for preventing the progression of arthropathy by endocrinological and orthopedic intervention.
Type 1 diabetes mellitus (T1DM) is a syndrome of loss of glucose homeostasis caused by the loss of β cell chronic autoimmunity against islet cells. Islet-specific epitopes coupled antigen presenting cells by Ethylenecarbodiimide (ECDI) is a promising strategy to induce antigen-specific tolerance. However, single epitope induced tolerance is insufficient to prevent the onset of T1DM. The aim of this study is to evaluate the efficacy of whole islet antigens in preventing the onset and progression of T1DM and identify the underlying immune mechanism in NOD mice. In this study, the whole islet antigens, derived from islet lysate isolated from BALB/c mice, were coupled to splenocytes of BALB/c mice by ECDI fixation (SP-Islet lysate), and then intravenously administrated to NOD mice. The results showed that, compared with control group, SP-Islet lysate group significantly decreased T1DM incidence and improved the survival of NOD mice. SP-Islet lysate treated mice had reduced insulitis score and autoantibody levels, and improved glucose tolerance and insulin/glucagon production. Furthermore, the effector memory T cells (TEMs) were downregulated and regulatory T cells (Tregs) were upregulated by the SP-Islet lysate treatment, with reduced populations of Th1&Th17 cells. In conclusion, ECDI-fixed splenocytes carrying whole islet antigens effectively prevented the onset of T1DM in NOD mice, via suppressing the production of autoantibodies and inducing anergy of autoreactive T cells.
Thyrotropin (TSH)-producing adenomas are a rare cause of hyperthyroidism and are a type of functional pituitary adenoma. The diagnosis of TSH-producing adenoma is a challenging problem in clinical endocrinology. Since growth hormone-releasing peptide-2 (GHRP-2) fails to induce TSH secretion in normal subjects, the effect of GHRP-2 on TSH levels was therefore examined in patients with TSH-producing adenomas. A total of 5 patients (4 women and 1 man) referred to our departments for further evaluation of pituitary hormones were followed-up using the GHRP-2, TSH-releasing hormone (TRH), octreotide, and bromocriptine tests to examine and evaluate TSH secretory dynamics in TSH-producing adenomas. Of 5 patients, 2 (40%) showed such a significant response, defined as a >50% increase in serum TSH level above baseline in the GHRP-2 test. Additionally, 1 patient showed a 48% increase in serum TSH level. In 1 patient whose adenoma was completely removed, basal serum concentrations of TSH were sufficiently suppressed after the operation, and serum TSH levels failed to increase in response to GHRP-2 administration. In 4 patients (80%), a poor response of serum TSH levels was observed in the TRH test. In 2 out of 5 patients (40%), serum TSH levels were significantly decreased following octreotide administration. No patient demonstrated a significant response to the bromocriptine test. In addition to TRH test, the GHRP-2 test as a potential diagnostic tool for TSH-producing pituitary adenomas.
Previous studies have shown a relationship between type 2 diabetes mellitus and birth weight. We performed this meta-analysis to resolve the problem of inconsistent results. We conducted a literature search of PubMed, Embase and the Cochrane Library using “Diabetes Mellitus, Type 2,” “Birth Weight,” and some related free words. Twenty-one studies were included in accordance with inclusion and exclusion criteria, involving a total of 313,165 participants and 22,341 type 2 diabetes mellitus cases. A modified version of the Newcastle-Ottawa Scale was used to evaluate the methodological quality of studies included. We used Review Manager 5.3 for data merging and statistical analysis. Results were expressed as odds ratio (OR) and 95% confidence interval (95% CI). The risk of diabetes with low birth weight (<2,500 g) was higher than that with birth weight ≥2,500 g, (OR = 1.51, 95% CI: 1.43, 1.58). Compared with normal birth weight (2,500–4,000 g), low birth weight, but not high birth weight, increased the risk of diabetes (OR = 1.41, 95% CI: 1.26, 1.58). There is a negative association between birth weight and the future risk of type 2 diabetes mellitus.
Diagnosis of adrenal insufficiency requires evaluation by dynamic stimulation tests. The insulin tolerance test (ITT) is accepted as the gold-standard test for the evaluation of hypothalamo-pituitary-adrenal (HPA) axis but the test is unpleasant and dangerous. Although it takes more time, glucagon stimulation test (GST) is a good alternative to ITT. The primary aim of this study was to compare the ITT and GSTs in the evaluation of HPA axe in patients with pituitary disorders. We conducted a prospective study in which ITT and GST were performed within 7 days in 81 patients. Serum cortisol was measured. We divided our population in Group 1 (G1): Adrenal Insufficiency (Peak cortisol under ITT <200 ng/mL) and Group 2 (G2): normal response (Peak cortisol under ITT >200 ng/mL). Receiver-operating characteristic (ROC) analysis was performed to identify the thresholds for GST. The mean peak of cortisol under GST was not significantly different from that obtained after ITT in the whole cohort (182.67 ± 89.07 ng/mL vs. 179.75 ± 79.01 ng/mL), and it was significantly reduced in patients of G1 (p < 10–3). ROC curve analysis showed that the best diagnostic accuracy was obtained with a peak cortisol cut-off to GST of 167 ng/mL (sensitivity, 89%; specificity, 79%). Using this cut-off, 86.4% of the patients were correctly classified. In our prospective series, GST is a potential accurate and safe alternative test for the assessment HPA. Test-specific cut-offs should be applied to avoid misinterpretation.
Intravenous (i.v.) glucocorticosteroids (GCs) constitute the first-line treatment for active and moderate-to-severe Graves’ orbitopathy (GO). In cases of persistent disease, rituximab, a monoclonal anti-CD20 antibody, may be used, although studies have yielded conflicting results. In case 1, a 50-year-old female heavy smoker presented with severe bilateral disfiguring eyelid edema of four months, bilateral exophthalmos and a clinical activity score (CAS) of 5/7. Laboratory investigation showed thyrotoxicosis and high thyroid-stimulating immunoglobulin (TSI) levels [32 IU/L (normal <1.75]. After minor improvement by i.v. methylprednisolone and standard retrobulbar radiotherapy (20 Gy), her visual acuity progressively declined to “hand motion”. Rituximab was administered (two pulses of 500 mg, two weeks apart), with significant response. At 3 1/2 years of follow-up, CAS is 0/7 and CD20+ lymphocytes remain at the lower normal range. In case 2, a 78-year-old non-smoker male was referred for management of severe active GO, one month after total thyroidectomy for Graves’ thyrotoxicosis (TSI: 6.74 IU/L). Over the preceding two-three months, severe GO manifested with chemosis, constant diplopia, loss of color vision and acuity of 1/10 bilaterally (CAS: 7/7). Following partial response to i.v. methylprednisolone and concomitant radiotherapy, rituximab (two pulses of 500 mg each, two weeks apart), was administered. Vision partially recovered and GO remains in remission one year later, even after 131I (100 mCi) administration for papillary thyroid carcinoma (TSI: 0.9 IU/L and CD20+ count at the lower normal range). In conclusion, rituximab may be an effective second-line therapy in GO patients, providing long-lasting remission.
Vitamin D deficiency affects >60% of the Korean population. Recent reports in Caucasian, African American, and Chinese populations indicate an association between vitamin D status and related single nucleotide polymorphisms (SNPs), but specific associations differ among study populations. We investigated the relationship between five SNPs involved in the vitamin D metabolic pathway (DHCR7 rs12785878, GC rs2282679, CYP2R1 rs12794714, CYP2R1 rs10741657, and CYP24A1 rs6013897) and serum 25-hydroxyvitamin D [25(OH)D] status in Koreans using the Korea National Health and Nutrition Examination Survey, a nationwide database. Whether the association was modified by demographic and lifestyle factors, including sex, body mass index (BMI), smoking status, drinking status, physical activity, and sun exposure, were also investigated. The results showed the serum level of 25(OH)D was associated with rs12785878, rs2282679, and rs12794714 genotypes, but not with rs10741657 or rs6013897. The genetic risk score (GRS) calculated by summing the number of alleles of these 5 SNPs was associated with low circulating levels of 25(OH)D. However, the negative association between 25(OH)D and GRS was modified by obesity and sun exposure. Specifically, negative associations between 25(OH)D and GRS were present in adults with lower BMI (<25 kg/m2) and longer sun exposure time (≥2 h/day). In conclusion, common variants of vitamin D-related SNPs are associated with vitamin D status in Koreans, and this genetic effect was masked when BMI ≥25 kg/m2 or sun exposure <2 h/day. Additionally, seasonal variation must be considered in future studies among Koreans.
This paper aims to investigate the influence of lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor, darapladib, on insulin resistance (IR) in streptozotocin (STZ)-induced diabetic pregnant rats. The rat models were divided into Control (normal pregnancy), STZ + saline (STZ-induced diabetic pregnant rats), STZ + Low-dose and STZ + High-dose darapladib (STZ-induced diabetic pregnant rats treated with low-/high-dose darapladib) groups. Pathological changes were observed by Hematoxylin-eosin (HE) and Immunohistochemistry staining. Lp-PLA2 levels were determined by enzyme-linked immunosorbent assay (ELISA). An automatic biochemical analyzer was used to measure the serum levels of biochemical indicators, and homeostatic model assessment for insulin resistance (HOMA-IR) and insulin sensitivity index (ISI) were calculated. Western blot was applied to determine levels of inflammatory cytokines. Compared with Control group, rats in the STZ + saline group were significantly decreased in body weight, the number of embryo implantation, the number of insulin positive cells and pancreatic islet size as well as the islet endocrine cells, and high-density lipoprotein (HDL-C) level, but substantially increased in Lp-PLA2, low-density lipoprotein (LDL-C), fatty acids (FFA), serum total cholesterol (TC), triglyceride (TG) levels. Moreover, the increased fasting plasma glucose (FPG) and HOMA-IR and inflammatory cytokines but decreased fasting insulin (FINS) and ISI were also found in diabetic pregnant rats. On the contrary, rats in the darapladib-treated groups were just opposite to the STZ + saline group, and STZ + High-dose group improved better than STZ + Low-dose group. Thus, darapladib can improve lipid metabolism, and enhance insulin sensitivity of diabetic pregnant rats by regulating inflammatory cytokines.
Several articles have shown the inverse association between total testosterone (TT) or sex hormone–binding globulin (SHBG) and hepatic steatosis. No articles report associations of TT, SHBG, free testosterone (FT), and bioavailable testosterone (BioT) with aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratios. Therefore, we investigated the associations of TT, FT, BioT and SHBG with hepatic steatosis and AST/ALT ratios. A total of 218 men were enrolled. We diagnosed hepatic steatosis by ultrasound. TT and SHBG showed a reduced risk for hepatic steatosis when analyzed with or without adjusting for age, smoking, alcohol consumption and physical activity. Compared with the lowest quartile, the ORs for hepatic steatosis in the third and fourth quartiles (0.32 [95% CI: 0.14–0.75] and 0.27 [95% CI: 0.10–0.73], respectively) of SHBG were significantly lower after adjustments. The OR for hepatic steatosis in the fourth quartile of TT (0.41 [95% CI: 0.17–0.95]) was significantly lower than in the lowest quartile after adjustments. The mean AST/ALT ratios in men with hepatic steatosis were lower than those without hepatic steatosis (0.83 and 1.04, respectively), due to the elevated ALT levels in hepatic steatosis groups. Furthermore, TT and SHBG were positively associated with AST/ALT ratios with and without adjustments. In conclusion, higher TT and SHBG levels in men are associated with the reduced risk of hepatic steatosis and elevated AST/ALT ratios, independent of age, smoking, alcohol consumption and physical activity.
Hashimoto’s thyroiditis (HT) is considered a T helper-type 1 (Th1) cytokine-dominant autoimmune thyroid disease. Caveolin-1 (Cav-1), a part of the thyroxisome multiprotein complex, is localized at the apical pole of thyrocytes and is indispensable for synthesis of thyroid hormones and modulation of oxidative stress in order to avoid cell damage and apoptosis. Reduced autophagy induces thyroid follicular cells (TFC) apoptosis by activating reactive oxygen species (ROS) in HT patients. Nevertheless, whether Cav-1 has roles in the regulation of autophagy remains largely unclear. In this study, we examined Th1 cytokines and Cav-1 expression in HT thyroid tissues, determined the effects of interleukin-1beta (IL-1β) and interferon-gamma (IFN-γ) on Cav-1 and autophagy activity in TFC, and investigated the association between Cav-1 and autophagy activity in vitro. Our results indicate that higher levels of IL-1β and IFN-γ and lower levels of Cav-1 were expressed in thyroid tissues of HT patients than in those of normal controls. Cav-1 mRNA and protein levels were significantly decreased in TFC exposed to IL-1β and IFN-γ, accompanied by decreased expression of autophagy-related protein LC3B-II. Interestingly, small interfering RNA (siRNA)-mediated Cav-1 knockdown in TFC reduced LC3B-II protein expression. Taken together, these results suggest that lack of Cav-1 expression inhibited autophagy activity in TFC exposed to Th1 cytokines (IL-1β and IFN-γ), which might be a novel pathogenetic mechanism of HT.