CRH is produced in the parvocellular division of the PVN and released into the hypophysial portal circulation to stimulate ACTH synthesis and secretion, thus playing a critical role in the HPA axis regulation. The activity of CRH neurons is regulated by humoral factors such as glucocorticoid and IL-1 as well as numerous kinds of neural inputs within and from outside of the hypothalamus. Circulating glucocorticoids readily have access to the CRH neurons and thereby exert a potent inhibitory action on CRH gene transcription. The molecular mechanisms involved in the glucocorticoid negative feedback remain to be fully understood. IL-1, produced in the periphery during the inflammatory process, is a potent stimulatory factor for CRH neurons. It is not yet clear how a protein of this large molecular weight has access to brain tissues through the blood brain barrier, nor is it clear through which neural pathway the IL-1-mediated signal is conveyed to the hypothalamus. A number of neurotransmitter/modulator candidates have been implicated in the regulation of CRH neurons. Functional roles and anatomical pathways have been explored by pharmacological methods, ablation of specific neural pathway(s), and the neural tracingethod. Despite the substantial knowledge produced by these studies, physiological and/or pathophysiological roles of the respective neural circuitry are still obscure. Two major intracellular signal transduction systems, the CAMP-dependent PKA pathway and diacylglycerol-dependent PKC pathway, are implicated in transcriptional regulation of the CRH gene. The functionality of the CRE, 5'-flanking the CRH gene, has been well established in cell culture system transfected with CRH promoter-reporter constructs, thus the cAMP-dependent PKA pathway may play an essential role in CRH gene expression. The role of the PKC pathway is still controversial and requires further exploration.
We studied the expression of both fibroblast growth factor-2 (FGF-2) and FGF receptor-1 (FGFR-1) in various histological types of human thyroid neoplastic and hyperplastic tissues to clarify the biological behavior of FGF-2. A total of 37 malignant tumors (24 papillary carcinomas, 10 follicular carcinomas, 3 anaplastic carcinomas), 8 follicular adenomas, and 12 adenomatous goiters were examined by immunohistochemical methods. With immunohistochemical staining, both FGF-2 and FGFR-1 were frequently detected in human thyroid carcinoma (79.2 to 100% and 80 to 100%, respectively). In thyroid hyperplastic lesions such as adenomatous goiter, the FGF-2 immunoreactivity in follicular cells was detected in 2 of 12 adenomatous goiters (16.7%). In contrast, FGFR-1 immunoreactivity was detected in 66.7% of cases of this disease. The endothelial cells of microvessels in the stroma adjacent to the neoplasms and yperplastic lesions also showed cytoplasmic FGF-2 immunoreactivity. The difference between FGF-2 and FGFR-1 expression in adenomatous goiters was statistically significant (P<0.05). Furthermore, the difference in FGF-2 immunoreactivity between carcinoma and adenomatous goiter was statistically significant (P=0.0001). The present investigation demonstrated the possibility of an autocrine mechanism of action of FGF-2 in human thyroid carcinoma. Moreover, in thyroid hyperplastic lesions, FGF-2 derived from the stroma might be involved in the formation of nodular and/or diffuse goiters.
To reassess the clinical utility of serum pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP), a promising but controversial indicator of bone resorption, we evaluated its performance as a biochemical marker in a 6-month study of a strictly selected population of 76 Japanese postmenopausal and healthy women, 33 recipients of hormone replacement therapy and 43 non-recipients. We measured bone mineral density (BMD) of the lumbar spine (L2-L4), and serum ICTP, carboxyterminal propeptide of type I procollagen (PICP) and other conventional serum biochemical markers, e.g. bone gla protein (BGP), alkaline phosphatase, calcium and phosphate at the entry and 6 months later. We calculated the percent change between the baseline and 6-month values (Δ%) in lumbar BMD and the biochemical markers, individually, and compared the degree of correlations between Δ% in BMD and that in the biochemical markers. Δ% in ICTP and Δ% in BGP correlated with Δ% in BMD negatively and ignificantly. Especially Δ% in ICTP correlated with that in BMD to a high degree (P<0.0001). No significant correlation was observed in other biochemical markers. We concluded that serum ICTP is a sensitive and useful bone resorption marker in the postmenopausal population, which strongly correlates with the change in BMD.
The hypothalamic actions of KP102 (also called GHRP-2) on the release of GH were studied in female goats. KP102 (10-5M) was perfused into the goat hypothalamus through a microdialysis probe (CMA/10 probe with a 4mm membrane length) at a rate of 4μl/min for 90min, and plasma GH concentrations before and after perfusion were measured. The intrahypothalamic perfusion of 10-5M KP102 significantly stimulated GH release in goats (P<0.05). The GH levels began to rise after commencement of perfusion, and reached a maximum mean value at 180min. The concentrations of GH at 165, 180, 195, 210, 225 and 240min after commencement of perfusion of KP102 were significantly higher than the corresponding values for control animals (P<0.05). KP102 had no effect on GH pulse frequency, but it significantly increased the GH pulse amplitude after the perfusion (P<0.05). In contrast to KP102, intrahypothalamic perfusion of 10-5M GHRH had no effect on the stimulation of GH release in goats even if intravenous injection of 10-5M GHRH significantly stimulated GH release (P<0.05). These results suggest that KP102 may act partly on the hypothalamus to stimulate GH release in goats.
A case of 67-year-old woman with hyperthyroidism due to functioning thyroid adenoma is reported. The patient had concomitant follicular thyroid adenoma and primary hyperparathyroidism in addition to functioning adenoma. Histological examination of the excised thyroid tissue revealed occult papillary carcinoma within a functioning adenoma. Genetic analysis of such tumors indicated that functioning adenoma and papillary carcinoma may be etiologically independent. There have been a number of case reports on the coexistence of functioning thyroid adenoma and thyroid cancer or hyperparathyroidism, but none of the studies had examined the etiologic relationship of these lesions on a genetic basis. Furthermore, to our knowledge, this is the first report of the concurrence of four tumors in the neck, functioning thyroid adenoma, papillary thyroid carcinoma, follicular thyroid adenoma and parathyroid adenoma.
Saireito, a saiko agent (a Chinese herbal drug), increases the synthesis and secretion of ACTH by stimulating hypothalamic CRH release. In the present study, we examined the effect of food containing saireito (1.5%) on the recovery of the hypothalamic-pituitary-adrenal axis after treating male rats with prednisolone (PSL, 200μM) in drinking water for 14 days. Saireito was administered during and after PSL administration. The rats were decapitated at various times after PSL administration. Tail-pinch stress had been applied to some rats. The plasma ACTH response to tail-pinch stress in the PSL+saireito group recovered to the control level on day 1, but that in the group given PSL alone recovered on day 3. The ACTH level in the anterior pituitary and the CRH level in the median eminence of the PSL+saireito group returned to the control level on day 3, and that in the group given PSL alone returned to it on day 5. These results indicate that the administration of saireito reduces the negative feedback effect of PSL on the hypothalamus and pituitary dccelerates the recovery of the hypothalamic CRH and pituitary ACTH level after glucocorticoid treatment.
Atrial natriuretic peptide (ANP) has been shown to have the potential to restore renal function after ischemic injury, an underlying component of endotoxin (Et)-induced acute renal failure, and is known to counteract renal sympathetic nerve activity in renal function. We have recently found that renal denervation restores the Et-induced renal dysfunction. The purpose of this study was to examine effects of ANP infusion on the Et-induced acute renal failure in the absence of renal nerves. Ten to 14 days after bilateral renal denervation (DNX), Wistar rats (250 to 300g body wt) were used in the acute experiment. Rats with intact renal nerves (INN) served as controls. Following control clearance measurements, rats were intravenously injected with 4mg/kg Et (Escherichia coli, 055: B5). During endotoxemia, rats were infused with 10μg/kg/h ANP or saline vehicle. Et injection reduced the glomerular filtration rate (GFR) significantly in saline-infused INN and DNX rats. ANP infusion restored the greatly reduced GFR to the pre-endotoxemia level in DNX rats but not in INN rats. There was significant difference between the ANP- and saline-infused DNX rats in the percentage change relative to the basal GFR value during the ANP infusion period. ANP infusion did not improve the hyponatriuresis and oliguria after Et administration, which is independent of renal nerves. In conclusion, ANP infusion has a minor reno-protective effect in rats with Et-induced acute renal failure in the absence of the renal nerves.
We evaluated the concentration of epidermal growth factor (EGF) in platelets, serum and plasma obtained from 47 patients with Graves' disease, 7 with hypothyroidism and 20 healthy subjects. The platelets of the subjects were collected from platelet rich plasma and lysed by freezing and thawing. Subsequently the platelet debris was treated with Triton X-100. The EGF concentration was determined by homologous radioimmunoassay. The concentration of EGF in the platelets in 14 patients with untreated Graves' disease was significantly higher than that in the healthy controls. After treating these 14 patients with antithyroid agents, the EGF concentration in the platelets decreased to the level of the healthy controls. The EGF concentration in the platelets in the 7 untreated hypothyroid patients decreased after replacement therapy with thyroxine. The mean volume of the platelets in the 14 patients with untreated Graves' disease was significantly larger than in the control and decreased after treatment with antithyroid agents. The serum and plasma levels of EGF in the 7 untreated hypothyroid increased after replacement therapy. In conclusion, thyroid function affected the concentration of EGF in the platelets of patients with thyroid disorders.
Cytochrome b5, a component of the electron transfer system increases the relative activity of 17, 20-lyase to 17α-hydroxylase of P450c17 in vitro. In the present study, immunohistochemical analysis of cytochrome b5 was performed in the human adrenal gland and in adrenocortical adenomas from patients with Cushing's syndrome. In the human adrenal gland, cytocrome b5 was stained in all three adrenocortical layers but the staining was most remarkable in the zona reticularis. All of the adenomas were composed mainly of compact cells, which exhibited immunoreactive staining for cytochrome b5 as well as for P450c17 and 3β-hydroxysteroid dehydrogenase (3β-HSD). The distribution of b5 in the adenomas was correlated with that of P450c17 rather than with that of 3β-HSD. The immunoreactive staining for cytochrome b5 appeared to be more prominent in the two adenomas that produced relatively high concentrations of adrenal androgens than in adenomas that produced low concentrations of adrenal androgens. These results immunohistochemically support the functional association of b5 with androgen production through interaction with P450c17 and the previous finding that higher concentrations of cytochrome b5 are associated with greater production of adrenal androgens in adrenocortical adenomas from patients with Cushing's syndrome.
We investigated the usefulness of two biochemical markers of bone formation (PICP, the carboxy-terminal propeptide of type I procollagen, and bone ALP, bone-derived alkaline phosphatase) and a marker of bone resorption (ICTP, the carboxy-terminal telopeptide of type I collagen), to determine whether the presence of bone metastasis in prostate cancer could be evaluated and the extent of bone metastasis could be stratified by the serum levels of these markers, compared to total alkaline phosphatase (T-ALP) and prostate-specific antigen (PSA). The serum levels of PICP, bone ALP, ICTP, T-ALP and PSA were significantly higher in patients with both prostate cancer and bone metastasis (n=49) than in patients with benign prostatic hyperplasia (n=35) and patients with prostate cancer without bone metastasis (n=70). The superiority of a marker in the rate of detection of bone metastasis was evaluated with receiver operating characteristic curves. The serum marker levels were compared as a function of metastatic burden in bone (i.e., the extent of disease, EOD grade). We found that bone ALP is the most suitable marker for evaluating bone metastasis, especially for stratifying the degree of bone metastasis. Both PICP and ICTP were useful in this respect, but rather inferior to bone ALP. T-ALP had the lowest ability for detecting bone metastasis, but its correlation with the EOD grade was excellent, second to that of bone ALP. PSA showed limited reliability for stratifying the extent of bone metastasis.
Mitochondrial TrnaLeu(UUR) gene mutation is one of the candidates in the pathogenesis of NIDDM. Especially the 3243 (A→G) mutation is associated with the maternally-inherited diabetes and deafness. To evaluate the prevalence and characteristics of the 3243 point mutation in Koreans, we screened 433 Korean diabetic patients (220 men and 213 women). Genomic DNA was extracted from peripheral white blood cells and PCR was carried out with mitochondrial DNA primers (3130-3149, 3558-3539) encompassing the 3243 position. After digestion with Apa-1, five subjects showed polymorphism suggesting 3243 point mutation but when we directly sequenced the amplified DNA with an automatic sequencer, only 2 of the 5 patients were shown to have 3243 (A→G) mutation and the other 3 subjects had 3426 (A→G) mutation rather than 3243 mutation. Two diabetic patients with 3243 mutation were lean (BMI=14.4, 17.0kg/m2), had relatively lower fasting C-peptide concentrations (0.9 ng/ml each), and required insulin for management. In contrast, those with 3426 point mutation were not lean (BMI=22.6-28.0kg/m2), had relatively higher C-peptide levels (3.9-5.4ng/ml), and could be managed with oral hypoglycemic agents. None of the 5 patients had deafness. In conclusion, the prevalence of 3243 point mutation in Korean diabetic patients was approximately 0.5% and we found a new mutation mimicking 3243 mutation by PCR-RFLP (restriction fragment length polymorphism) pattern. We suggest that sequencing of the PCR product or designing smaller PCR fragment size to enhance the specificity may help to identify the exact location of the point mutation.
Some occult thyroid carcinomas are hypothesized to regress and be eventually obliterated. We report here a patient whose condition supports this hypothesis. A 51-year-old male with primary hypothyroidism due to Hashimoto's thyroiditis suffered from a rib bone tumor. He had a diffuse goiter with no nodular lesion. Serum FT4 and TSH concentrations were 0.8ng/dl and 36.4μU/ml on taking 100μg/day of T4. Anti-Tg- and -TPO-Ab were strongly positive (99 and 1380U/ml). The iodine 123 scintigraphy demonstrated clear accumulation in the rib tumor, whereas the thyroid was scarcely visible. Biopsy of the rib tumor showed papillary proliferation of large atypical cells, which were immunohistochemically positive for thyroglobulin. Metastatic bone tumor of papillary thyroid carcinoma was therefore strongly suspected. He underwent a total thyroidectomy and the thyroid was stepwise sectioned completely at 3mm intervals. The thyroid condition was diagnosed as Hashimoto's thyroiditis demonstrating diffuse and dense fibrosis, lymphocyte infiltration with lymphoid follicles and flattened atrophied follicles, but no carcinomatous foci were found. He was treated with I-131 and scintigraphy after the ingestion showed distinct accumulation in the rib tumors similar to that before thyroidectomy. No other abnormal uptake was observed. It is suggested that the primary occult thyroid papillary carcinoma regressed and was obliterated possibly by some immunologic or other hostresistance factors after it metastasized to the distant bone.
A 33-year-old woman with signs and symptoms of hypothyroidism, including increased thyroid stimulating blocking antibody (TSBAb) activity, was referred for treatment by her local physician. Her monozygote twin was treated for hyperthyroid Graves' disease 10 years earlier. This case of hyperthyroidism and hypothyroidism in identical twins suggests the involvement of environmental factors in the pathogenesis of autoimmune thyroid diseases.
Vitamin D receptor (VDR) genotype was determined in 66 Japanese patients with primary hyperparathyroidism (pHPT). In contrast to previous report showing an association between VDR genotype bb and the development of pHPT in a Swedish population, we did not find any differences in the frequencies of the VDR genotypes between pHPT and the control. The bone mineral density in the radius was significantly lower (Z score, -1.723±1.819) in bb genotype than in BB/Bb genotype (+0.255 ±2.344) in pHPT patients. Based on the fact that PTH requires vitamin D3 to take effect on calcium mobilization from bone, it is possible that VDR polymorphism may influence the PTH action on bone.
We evaluated the effect of intracerebroventricular (icy) administration of interleukin (IL) -1β on the rectal temperature and the release of noradrenaline (NA) in the hypothalamic paraventricular nucleus (PVN) of the rat. IL-1β increased rectal temperature at doses ranging from 300pg to 300ng, whereas it, at doses ranging from 3ng to 300ng, significantly stimulated the release of NA in the PVN measured by intracerebral microdialysis. The stimulatory effect of IL-1β on the release of NA was blocked by the subcutaneous injection of indomethacin. These findings suggest that IL-1β stimulates the release of NA in the PVN via prostaglandin, and that the release of NA in the PVN is not necessarily related to the increase in body temperature.
Two patients with POEMS syndrome had high basal levels of FSH in the absence of primary hypogonadism. They were fertile eugonadal men with normal serum testosterone and estradiol levels. Provocation with LH-releasing hormone revealed blunted response of FSH secretion, but normal response of LH secretion in both patients, and one had pituitary microadenoma on brain MRI. This report adds primary FSH hypersecretion in the absence of primary testicular failure to the list of endocrinopathy of POEMS syndrome.