Nuclear steroid/thyroid vitamin A/D receptor genes form a gene superfamily and encode DNA-binding transcription factors that control the transcription of target genes in a ligand-dependent manner. It has become clear that chromatin remodeling and the modification of histones, the main components of chromatin, play crucial roles in gene transcription, and many distinct classes of NR-interacting co-regulators have been identified that perform significant roles in gene transcription. Since NR dysfunction can lead to the onset or progression of endocrine disease, elucidation of the mechanisms of gene regulation mediated by NRs, as well as the identification and characterization of co-regulator complexes (especially chromatin remodeling and histone-modifying complexes), is essential not only for better understanding of NR ligand function, but also for pathophysiological studies and the development of therapeutic interventions in humans.
A new cookie test was developed for the simultaneous evaluation of multiple risk factors such as glucose intolerance, hyperinsulinemia, insulin resistance and postprandial dyslipidemia. The cookie consisting of 75 g carbohydrate and 25 g fat is ingested and the blood samples are obtained at 0, 1 and 2 hours later. When the two carbohydrate sources, liquid glucose and test cookie, were compared as a glucose load within 3 months, the 2 hr plasma glucose levels were not statistically different, proposing the use of the same criteria at 2 hour glucose level for the diagnosis of diabetes and impaired glucose tolerance (IGT) in subjects without exocrine pancreatic dysfunction. In addition, hyperinsulinemia, insulin resistance (AUC insulin, and/or AUC insulin X AUC glucose), and postprandial hyperlipidemia (ΔTG, Triglyceride; ΔRLP, remnant like particles) have been simultaneously uncovered. Reactive hypoglycemia with adverse epigastric discomfort was observed in 26.3% of the control subjects with liquid glucose, while it was observed in only 1 case (5.3%) without any symptom with cookie tests. In fact, one reactive hypoglycemia out of 5 with liquid glucose turned out to be IGT with cookie test. In 64 subjects with lifestyle-related diseases, cookie test revealed hyperinsulinemia and insulin resistance in 56% respectively, postprandial hyperlipidemia in 39%, diabetes and IGT in 22–23% of each of the subjects and all showed at least one abnormal value. In contrast, in university students with exercise habit, all showed normal results with cookie test. In addition, improved insulin sensitivity over non-exercise group was obverved. In summary, the cookie test provided more informations compared with OGTT using liquid glucose and with fewer side effects. Simultaneous evaluation of glucose intolerance, hyperinsulinemia, insulin resistance, and postprandial hyperlipidemia was also possible.
The role of thyroid hormone (T3) in the regulation of growth and development of the central nervous system including the cerebellum has been well established. However, the effects of thyroid hormone on malignant tumors derived from the cerebellum remain poorly understood. Our analysis mainly focused on expression levels of TR isoforms and the effects of thyroid hormone in human medulloblastoma HTB-185 cells. Northern blot analysis revealed TRα2 mRNA but not TRα1, β1 or β2 mRNA in the cell. The TRα1 and TRβ1 mRNAs were detected only by RT-PCR method and TRβ2 was not expressed. Incubation of T3 for 24 h decreased TRα1, TRα2 and TRβ1 mRNA. Addition of actinomycin D caused an acute increase in the basal TR mRNA levels and the rate of decrease of all kinds of TR isoform mRNA was accelerated in the T3-treated groups compared to controls, indicating that the stability of TR mRNA was affected by T3. Incubation with cycloheximide also blocked a decrease in TR mRNA levels in the T3-treated HTB-185 cells suggesting that down-regulation of TR mRNA required the synthesis of new protein. Our data provide novel evidence for the expression of TRs down-regulated by T3 in HTB-185 cells, suggesting that TR expression is post-transcriptionally regulated by T3 at the level of RNA stability.
We studied the effect of exercise on circulating adipokine, high sensitivity C-reactive protein (hs-CRP), and metabolic parameters in obese young women. Ninety-six healthy Japanese young female students aged 18–23 years were studied. The longitudinal intervention study of a 7-month exercise training program (30–60 min/day, 60–70% HR-reserve, 200–400 kcal, 4–5 days/week) was performed in eight obese female students (BMI ≥25 kg/m2). Eight control female students (mean BMI = 22 kg/m2) were included in the follow-up study. Body weight, body mass index (BMI), percentage of body fat (%Fat), body fat mass, lean body mass, health-promoting lifestyle profile-scale (L-scale), Vo2max (maximal oxygen uptake), hs-CRP, lipids, insulin homeostasis model assessment (HOMA-R), fasting levels for circulating adiponectin, leptin, and TNF-α, were measured before and after the exercise program. In obese subjects, body weight, BMI, %Fat, body fat mass, lean body mass, hs-CRP, leptin, and TNF-α were significantly higher, and L-scale and adiponectin were lower than those in control subjects. In obese subjects, exercise decreased body weight, BMI, %Fat, body fat mass, lean body mass, hs-CRP, leptin, and TNF-α, and increased L-scale, Vo2max, HDL-cho, and adiponectin. It was concluded that changes in circulating adipokine levels are involved in the improvement of the metabolic state by exercise and may be useful markers for evaluation and prescription of exercise.
Possible interference of fibroblasts is suggested in aspiration biopsy nucleic acid diagnosis (ABND). However, detection of fibroblasts in the aspirates is difficult, because the gene expression profiles of thyroid malignancies and fibroblasts are much alike in many aspects. To identify a specific marker for thyroid-derived fibroblasts, the data of the serial analysis of gene expression (SAGE) were compared to screen differentially expressed genes between fibroblasts and thyroid normal and tumor tissues. In the SAGE data, 5 genes were identified to be differentially expressed. Among these, thrombospondin 1 (TSP-1, THBS1) mRNA was the most differentially expressed. Further, the overexpression of TSP-1 mRNA in fibroblasts was confirmed by real-time RT-PCR analysis using 73 thyroid normal and tumor tissues and 7 cultures of thyroid-derived fibroblasts. These results suggest that TSP-1 mRNA is a possible marker for contamination of thyroid-derived fibroblasts.
Endocrinologic tests sometimes fail to distinguish adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma from ectopic ACTH-secreting tumor. The authors experienced a case of Cushing's disease associated with a pancreatic tumor. Venous sampling contributed to the final diagnosis of Cushing's disease in this complex case, while endocrinologic tests showed paradoxical results. A 54-year-old woman presented with Cushing's syndrome and pancreatic tumor. Magnetic resonance imaging (MRI) failed to reveal a pituitary tumor, but a gadolinium-enhanced tumor with cystic components was seen in the pancreatic tail. Results of conventional endocrinologic tests suggested ectopic ACTH syndrome, but venous sampling including cavernous sinus sampling indicated an ACTH-secreting pituitary adenoma. Transsphenoidal surgery revealed a pituitary microadenoma, and total removal of the tumor was achieved. Postoperative abdominal MRI revealed that the pancreatic tumor diminished gradually without treatment. Selective cavernous sinus sampling was useful for distinguishing ACTH-secreting pituitary adenoma from ectopic ACTH syndrome in this complex case. This was a rare case in which the pancreatic tumor diminished after total removal of the ACTH-secreting pituitary adenoma.
We report a 35-year-old woman with active acromegaly despite pituitary surgery and irradiation who received continuous octreotide LAR treatment for the control of GH excess until discovery of her pregnancy. The patient delivered a healthy boy following an uneventful pregnancy after discontinuing octreotide LAR as soon as possible at the early phase of pregnancy. Despite a substantial maternal-fetal transfer of octreotide, postnatal development was normal at 3 years of age. In almost all previously described cases, octreotide was discontinued after pregnancy was confirmed. No side-effects of mother or fetus have been reported. Octreotide treatment in pregnancy seems to be feasible and safe. Due to the still-limited number of reported cases treated with octreotide LAR, the potential benefits of octreotide LAR treatment should be weighed carefully against its possible risks.
An open-label prospective cross-over trial was performed to compare the efficacy and adverse effects of nateglinide with those of voglibose on Japanese early type 2 diabetes (who were oral hypoglycemic agent naïve and whose HbA1C levels were between 7.0 and 7.9% before treatment). Fourteen patients received 270 mg/day of nateglinide and 15 patients received 0.6 mg/day of voglibose. After 12 weeks of either therapy, the drugs were switched and treatment was continued for another 12 weeks. After 3-month treatment with each drug, HbA1C value decreased significantly (baseline HbA1C 7.24 ± 0.42%, 6.70 ± 0.47% with nateglinide: p<0.01, 6.93 ± 0.62% with voglibose: p<0.05) but the difference in the effect between nateglinide and voglibose was not significant (p = 0.121). Symptoms related to hypoglycemia (e.g., increased appetite, palpitation, sweating, tremor) were scarcely observed with either voglibose or nateglinide treatments. Abdominal fullness/borborygmi was frequently reported, with variable severity, by patients on voglibose but this was absent or mild in those on nateglinide. After completion of both arms of the study, more patients favored nateglinide than voglibose. Our results suggest that nateglinide is an effective and safe drug in the treatment of early type 2 diabetes, similar to voglibose.
Cushing's disease is a disorder of hypercortisolism caused by a pituitary micro- or macro-adenoma. Most patients with Cushing's disease have a bilateral adrenal enlargement, which depends on the duration of the disease, as a result of the long standing ACTH stimulation of both adrenal glands. However, in macronodular adrenocortical hyperplasia (MNH) that is caused by Cushing's disease, if the MNH gains autonomy, a bilateral adrenalectomy, as well as the removal of pituitary adenoma, is often essential. We encountered a patient diagnosed with Cushing's disease with bilateral adrenal tuberculosis simulating MNH. She had taken anti-tuberculosis medications one year prior to admission due to spinal tuberculosis. Sellar MRI revealed a pituitary macroadenoma, but adrenal CT showed enlargement in both adrenal glands that appeared to be MNH. A hormonal study and bilateral inferior petrosal sinus sampling revealed Cushing's disease. Therefore, she underwent trans-sphenoidal surgery of the pituitary mass. The pituitary surgery was successful and the serum cortisol returned to normal range. However, the adrenal mass rapidly enlarged after removing the pituitary tumor without showing evidence of a recurrence or adrenal autonomy of hypercortisolism. Accordingly, a laparoscopic left adrenalectomy was performed to examine the nature of the mass. The resected left adrenal gland was pathologically determined to have a lesion of tuberculosis with some part of the intact cortex. So we assumed that the cause of rapid adrenal enlargement might be due to adrenal tuberculosis. In summary, to the best of our knowledge, this is the first case of Cushing's disease coexisting with both adrenal tuberculosis simulating a bilateral MNH.
Follistatin (FS) is produced and secreted from gonadotroph cells in pituitary gland as well as granulosa cells in the ovary. In the present study, we found that the FS promoter is activated by GnRH in the gonadotroph cell line, LβT2. Therefore, we examined the signal transduction pathways involved in the mechanism. The activation of the FS promoter by GnRH was inhibited by calphostin C, a protein kinase C inhibitor, and U0126, a MAP kinase kinase (MEK) inhibitor. Phosphorylation by protein kinase C of myristoylated alanine-rich C kinase substrate (MARCKS) in LβT2 cells was observed after 3-min treatment with GnRH and declined after 30 min. The subsequent activation of MAP kinase was also transient, and down-regulation of protein kinase C completely inhibited the MAP kinase activation by GnRH, suggesting that the transient activation of protein kinase C led to the transient activation of MAP kinase. Although phorbol 12-myristate 13-acetate treatment increased phosphorylation of MARCKS and activated MAP kinase, it did not activate the FS promoter. Genistein, a tyrosine kinase inhibitor, completely inhibited the GnRH-induced activation of the FS promoter, while no inhibition of the MAP kinase pathway was observed. These results suggest that the activations of both the protein kinase C and tyrosine kinase pathways are necessary for the activation of the FS promoter in gonadotroph cells.
A 25-year-old man was found to have a large right adrenal mass detected by abdominal echography and computed tomography, and presented with a mild gynecomastia. Endocrine study showed increased serum concentrations and urinary excretion of estrogens and dehydroepiandorosterone sulfate (DHEA-S). The patient had no Cushingoid features but autonomous cortisol secretion, compatible with the diagnosis of subclinical Cushing's syndrome. Surgical removal of the adrenal tumor led to normalization of serum and urinary excretion of estrogens and DHEA-S. Histopathological examination revealed a high-grade adrenocortical carcinoma (ACC). The disorganized expression of all the steroidogenic enzymes in individual tumor cells was demonstrated by immunohistochemical analysis, and the abundant expression of both aromatase mRNA and insulin-like growth factor (IGF)-II mRNA was shown by RT-PCR. These data suggest the excessive secretion of estrogen as well as the ineffective steroidogenesis by the adrenal tumor. This is a very rare case of estrogen-secreting ACC associated with subclinical Cushing's syndrome.
We investigated the relationship between plasma adiponectin levels and the parameters of the metabolic syndrome among Koreans. In 67 male and 115 female subjects, aged from 30 to 70 years, plasma adiponectin levels were positively correlated with HDL-cholesterol levels (r = 0.295, P<0.001), but negatively correlated with waist circumference (r = –0.140, P = 0.020), triglycerides (r = –0.174, P = 0.021), fasting plasma glucose (r = –0.159, P = 0.036), fasting plasma insulin (r = –0.172, P = 0.023) and HOMA-IR (r = –0.182, P<0.001), after adjustment for age, sex, and BMI. Stepwise multiple regression analyses revealed that HDL-cholesterol, sex, and HOMA-IR were the independent associated factors for plasma adiponectin levels. Multiple logistic analyses demonstrated that HOMA-IR, BMI, and age were the predominant independent factors associated with the metabolic syndrome, while plasma adiponectin levels exhibited a protective effect against the presence of the metabolic syndrome according to both NCEP ATP III criteria and IDF definition. Hypoadiponectinemia is associated with the phenotype of the metabolic syndrome as well as components of the metabolic syndrome.
Corticosteroid treatment is frequently associated with psychiatric disturbances. These adverse effects are unusual with low dose of corticosteroid. We describe a patient who rapidly developed a steroid-induced psychosis with very low dose of prednisolone. A 48-year-old woman of Sheehan's syndrome was admitted to hospital with insomnia, euphoric moods and visual hallucinations. She had taken prednisolone (10 mg in the morning and 5 mg at night) for 6 days before admission. These symptoms appeared after first dose of prednisolone. A diagnosis of acute psychosis was made. After improvement of acute psychosis with discontinuation, re-administration of prednisolone at a dose of 2.5 mg per day gave rise to agitation and insomnia. She recovered completely by gradual dosage increase of short-acting corticosteroid after the discontinuation of prednisolone.
In this study, we sent questionnaires to doctors treating severe short stature with severe GH deficiency (GHD) (height SDS (HtSDS) below –4 and all peak GH to provocative stimuli below 2 μ/L) (abbreviated as Severe Case), and obtained effective replies of 51 cases. The clinical characteristics, etiologies, and pathophysiology of these patients were examined. Among the 51 Severe Cases no consanguinity was observed, 44 were IGHD (24 males and 20 females), 3 were GH-1 gene deletion, 2 were Pit-1 gene mutation, and 2 were achondroplasia. HtSDS in these Severe Cases was already remarkably low at 12 (–3.0) and 24 months old (–3.9), while their birth weight and birth length were within normal ranges. Among 44 patients with IGHD, 12 were isolated GHD, and the remaining 32 were combined pituitary hormone deficiency (CPHD). Pituitary MRI was undergone in 25 idiopathic GHD, and abnormal findings (pituitary atrophy, interruption of stalk, and ectopic posterior lobe) were observed in 21 patients with CPHD. More than half of these patients had the history of breech delivery. Three patients with GH-1 gene mutation showed normal pituitary MRI, whereas one of two patients with Pit-1 mutation showed pituitary atrophy and narrowing of pituitary stalk. In conclusion, Severe Cases tended to have CPHD, and the incidence of Severe Case was only 0.6% of total IGHD. Although GHD due to genetic disorders is considered to be extremely rare (0.06% of total IGHD), the incidence reaches high levels (9.8%) among Severe Cases. Growth disorders in these Severe Cases seem to occur soon after delivery. Much earlier diagnosis and hGH treatment are desirable to attain better final height in the Severe Cases. GH-1 and Pit-1 gene analyses are crucial, when genetic abnormalities other than achondroplasia are suspected.