Stimulation of Alpha-Adrenoceptors Facilitates the Release of Growth Hormone-Releasing Hormone from Rat Hypothalamus in vitro

While extensive evidence suggests that adrenoceptors play an important role in the control of growth hormone in the rat, there are few studies involving the direct measurement of growth hormone-releasing hormone (GHRH). We have therefore developed a radioimmunoassay for rat GHRH, and used it to investigate the modulation of GHRH release by noradrenaline from incubated rat hypothalamus in vitro. The GHRH radioimmunoassay had no significant cross-reactivity with other hypothalamic or GHRH-related peptides, and was sensitive to 4 pg/tube; intra- and interassay coefficients of variation were 6% and 12% respectively. Single incubated rat hypothalami produced a stable and readily measurable output of GHRH in successive 20 min incubations after an initial 60 min preincubation; the release of GHRH was increased in the presence of 56 mM KCI, but did not respond to KCI-depolarization when calcium was excluded from the medium. Stimulated GHRH release was identical to synthetic rat GHRH(1–43) on high-performance liquid chromatography and Sephadex G-75 chromatography.
Noradrenaline stimulated GHRH secretion in a dose-dependent manner in the concentration range 10⁻¹⁰— 10⁻⁶M, with a plateau in response at 10⁻⁷M. Stimulation with noradrenaline 10⁻⁷M was blocked by idazoxan 10⁻⁵M and attenuated by thymoxamine 10⁻⁵M, but was unaffected by timolol 10⁻⁵M. Both the α₂-adrenoceptor agonist guanfacine, and the α₁-adrenoceptor agonist methoxamine, specifically stimulated GHRH secretion.
It is concluded that noradrenaline stimulates the release of GHRH at both α₁ and α₂-adrenoceptors.     

Insular carcinomas of the thyroid exhibit poor prognosis and long-term survival in comparison to follicular and papillary T4 carcinomas

Background Insular thyroid carcinoma was described as a tumor with aggressive behavior, and patients usually present themselves with an advanced tumor stage. Whether the insular component is an independent factor for poor prognosis remains unclear. Therefore, in the present study, we compared the survival of patients with advanced insular, follicular, and papillary thyroid cancer. Materials and methods The clinical behavior of tumors in three groups of patients with T4 thyroid carcinoma—8 patients with insular, 11 patients with follicular, and 21 patients with papillary thyroid carcinomas—was compared. Disease-free survival and disease-specific death were analyzed statistically. Cox regression analysis was used to evaluate the influence of histotype and other prognostic factors. Results At 3 years, survival was 37.5% (mean 26 months) among patients with insular thyroid carcinoma, 80% (mean 59 months) among those with follicular, and 89% (mean 126 months) among those with papillary thyroid carcinomas (p = 0.007). Disease-free survival in patients without initial distant metastasis was worst in patients with insular thyroid carcinoma (20%) compared to those with follicular (75%) and those with papillary thyroid carcinomas (71%). Conclusion Patients with advanced insular thyroid carcinoma have a poorer outcome in comparison to patients with similar advanced stage who have follicular or papillary thyroid carcinoma.     

舌异位甲状腺的诊断与治疗

目的 :探讨舌异位甲状腺诊治方法。方法 :将我院从 1992年 10月～ 2 0 0 0年 2月收治的 18例舌异位甲状腺患者的临床资料进行总结分析 ,其中异位甲状腺全切除术 5例 ,部分切除术 3例 ,次全切除加部分带蒂移植10例。结果 :1例异位甲状腺癌行全切除术后出现甲状腺功能低下 ,部分切除术后 2例复发 ,其余 15例情况良好。结论 :术前常规B超检查、同位素扫描、细胞学检查和冰冻切片对异位甲状腺的诊断有指导意义 ;治疗上 ,患者无症状 ,异位甲状腺无恶变 ,可不予治疗 ,如果出现临床症状 ,对于副甲状腺 ,可作全切除术 ,若为迷走甲状腺 ,则行次全切除加部分带蒂移植是很好的方法     

Thyrotrophin-Releasing Hormone Raises Cytosolic Free Calcium Concentration in Human Adenomatous Somatotrophs and Corticotrophs; Comparison with in vivo Responsiveness to Thyrotrophin-Releasing Hormone in Patients with Acromegaly or Cushing's Disease

The effect of thyrotrophin-releasing hormone (TRH) on intracellular free Ca²⁺ concentration, [Ca²⁺)i, was investigated with the fluorescent dye fura-2 in cell suspensions obtained from 13 human growth hormone-secreting adenomas and 6 adrenocorticotrophin-secreting adenomas. Preoperatively, 9 out of 13 acromegalic patients showed a positive growth hormone response to TRH administration while none of the 6 patients with Cushing's disease had a plasma adrenocorticotrophin increase after TRH injection. In all the growth hormone-secreting adenomas the addition of TRH (100 nM) caused a significant rise in [Ca²⁺]i (from a resting level of 133±40 (±SD) to a value of 284±119 nM at 100 nM TRH, n = 42; P<0.001). The transient induced by TRH was found to have a dual origin, one due to Ca²⁺ mobilization from intracellular stores which was maintained in presence of EGTA (3mM) and verapamil (10 μM) and a plateau phase due to Ca²⁺ influx from the extracellular media. Somatostatin (0.1 μM) lowered both resting [Ca²⁺]i and TRH-induced transients. The effect of gonadotrophin-releasing hormone on [Ca²⁺]i was evaluated on cell suspensions obtained from 6 growth hormone-secreting adenomas. Gonadotrophin-releasing hormone (100 nM) caused a marked rise in [Ca²⁺]i (from 179±25 to 283±15nM) on the cell suspension obtained from the only in vivo responsive adenoma while it was ineffective in the remaining 5. Although TRH was ineffective in modifying plasma adrenocorticotrophin levels in all patients with Cushing's disease, in 5 out of 6 tumors the addition of 100 nM TRH caused a significant rise in [Ca²⁺]i (from 102.5 ± 36 to 163±66 nM, n = 22; P < 0.005). However, the effect of TRH on [Ca²⁺]i was significantly lower than that caused by arginine vasopressin, a physiological stimulator of adrenocorticotrophin release ([Ca²⁺]i values; 145±78 nM at 100 nM TRH versus 300±140 at 10 nM arginine vasopressin, n = 15; P<0.05). Moreover, the effect of arginine vasopressin on [Ca²⁺]i was detectable at concentrations as low as 0.1 nM while TRH was effective at concentrations higher than 1 nM. By contrast, gonadotrophin-releasing hormone was ineffective in increasing [Ca²]i in all the adrenocorticotrophin-secreting adenomas studied. Collectively, these data indicate that sensitivity to TRH is present in almost all the growth hormone- and adrenocorticotrophin-secreting adenomas independently of the responsiveness of the individual patients to the peptide.     

Regulation of Basal and Nursing-Induced Secretion of Growth Hormone in the Neonatal Rat: The Involvement of Serotonergic, Muscarinic Cholinergic, Alpha2-Adrenergic, Somatostatin and Growth Hormone-Releasing Hormone Systems

Various neural factors are involved in the suckling-induced increase in serum growth hormone (GH) levels in neonatal rats, and, in the present study the serotonergic, cholinergic, somatostatin and GH-releasing hormone (GHRH) systems were investigated. The serotonin (5-HT) precursor 5-hydroxy-L-tryptophan (5-HTP) and the 5-HT receptor agonist quipazine maleate stimulated serum GH levels in 2-day-old rat pups separated from their mothers for 6 h. The increase in serum GH during suckling was further elevated by 5-HTP. The 5-HT antagonist cyproheptadine decreased serum GH levels in separated 2-day-old pups, and although it reduced the amplitude of the suckling-induced increase in serum GH concentration, it did not alter the increase in serum GH on a percentage basis. The effect of the cholinergic muscarinic antagonist atropine sulfate (ATR) was similar to that of cyproheptadine. Moreover, in separated pups, ATR prevented the increase in serum GH induced by 5-HTP. In contrast with 2-day-old pups, ATR completely eliminated the suckling-induced release of GH in 10-day-old rats. However, ATR failed to prevent GH release induced by the α₂-adrenergic agonist clonidine HCI in 10-day-old male pups. While thyrotropin-releasing hormone increased serum GH levels, rat GHRH failed to alter serum GH levels either in separated or in suckled 2-day-old rat pups. Immunoneutralization for rat GHRH eliminated the increase in serum GH induced by clonidine HCI in 10-day-old pups, but (on a percentage basis) failed to prevent the GH-increasing effect of suckling in 2-day-old pups. While somatostatin failed to significantly decrease serum GH in separated 2-day-old pups, it effectively decreased serum GH levels in 2-day-old pups which were suckled. Cysteamine, which depletes hypothalamic somatostatin, increased serum GH in separated 2-day-old pups, and further increased the suckling-induced levels of serum GH. Cysteamine partially prevented the GH-decreasing effect of ATR. The present findings suggest that 1) the serotonergic and cholinergic systems are involved in the regulation of GH secretion as early as day 2 postpartum; 2) the serotonergic and cholinergic systems modulate the basal, and do not modulate the suckling-induced levels of serum GH; 3) the serotonergic system may exert its stimulatory influence on GH secretion only in the presence of a functional muscarinic cholinergic system; 4) the cholinergic system, at least in part, stimulates GH secretion via a cysteamine-sensitive system (probably by inhibiting somatostatin); 5) the cholinergic system is not functionally coupled with the α₂-adrenergic system, which stimulates GH secretion via rat GHRH; 6) since in 10-day-old pups clonidine HCI was effective only in males, while suckling was effective in both sexes, the α₂-adrenergic system is not involved in the suckling-induced increase of serum GH; and finally 7) neither somatostatin nor rat GHRH seem to be involved in the suckling-induced changes in serum GH. The findings are consistent with the hypothesis that the high circulating GH levels in the neonatal rat are due to alternative GH-releasing factors, perhaps thyrotropin-releasing hormone or γ-aminobutyric acid. The neurohumoral mediator of the suckling-induced GH release in neonatal rats remains to be identified.     

Safety, tolerability and pharmacokinetic study of recombinant human parathyroid hormone in healthy male Chinese subjects

AIM： To determine the safety, tolerability and pharmacokinetic parameters of a new drug recombinant human parathyroid hormone [ rhPTH （1-84）] in healthy male Chinese subjects. METHODS： domly divided Thirty-six healthy male volunteers were rangroups received into 3 groups. The volunteers in these single subcutaneous injection of rhPTH （ 1-84） in a dosage of 1, 2 and 4 μg/kg respectively. Blood samples were obtained before and after administration within 24 hours. The rhPTH concentrations in sennn were determined by enzyme linked immunosorbent assay （ELISA）. The pharmacokinetic parameters determined with use of standard noncompartmental analysis were the maximum serum concentration （ Cmax ）, the time to attain that concentration （ tmax ）, and the area under the serum concentration-time curve up to 24 hours（ AUC0-24 ） and up to infinity （AUC0-∞）. Dose proportionality of pharmacokinetic parameters （AUC, Cmax of every volunteer of each dosage and A UC was computed from log transformed data） and was examined by mean of analysis of variance （ANOVA） using SPSS software package. In the study, subjects＇ symptoms, objective signs, and vital signs, including blood pressure, heart rate, respiratory rate and body temperature, were checked and 12-lead electrocardiography was recorded before and after drug administration within 24 hours. Routine laboratory tests, including hematology, blood biochemistry, serum electrolyte, and urinalysis, were performed before and after drug administration within at 24 hours.[第一段]     

Parathyroid hormone decreases in vivo insulin effect on glucose utilization

Hyperparathyroidism is associated with impaired glucose tolerance, and parathyroidectomy may improve carbohydrate homeostasis. It has been suggested that parathyroid hormone (PTH) suppresses insulin secretion but it is unclear whether it also interferes with the peripheral action of insulin. To evaluate in vivo effects of PTH on insulinmediated glucose utilization, 15 male Sprague Dawley rats were continuously infused with rat PTH (1–34) using an Alzet miniosmotic pump at a rate of 0.03 nm/hour. Controls were infused with the vehicle alone. Following 5 days of PTH infusion, plasma calcium (Ca) levels were higher in the PTH-infused rats (12.3±0.2 versus 9.9±0.1 mg/dl, P<0.01). On the 5th day, glucose (700 mg/kg) and insulin (0.175 U/kg) were given as a bolus infusion through the left femoral vein, blood samples were obtained from the right femoral vein, and plasma glucose and insulin were measured at basal (0 minutes) and at 2, 5, 10, and 20 minutes postinfusion. Basal, nonfasting glucose levels were higher (166±4 versus 155±4 mg/dL, P<0.04) in the PTH-infused rats but their insulin levels were similar to those of controls (6.5±0.6 versus 5.6 ±0.5 ng/ml). Postinfusions and maximal (2 minutes) glucose and insulin levels were similar in both groups. However, although insulin levels were similar in both groups at all measured time points, glucose levels at 20 minutes were higher in the PTH-treated rats (205±13 versus 173±9; P<0.03). Also, calculated glucose disappearance rates (Kg) were decreased in the PTH-infused rats (4.05±0.3 versus 4.63±0.8; P=0.054), suggesting an impaired peripheral effect of insulin on glucose utilization. To gain insight into the potential contribution of the hypercalcemia or the PTH to these abnormalities, correlation evaluations were performed. Only in PTH-infused rats did plasma Ca correlate with plasma glucose at 0 and 20 minutes (r=0.6, P=0.02; r=0.7, P=0.01) and with the area under the glucose curve (r=0.6, P=0.03) during the glucose-insulin infusion. Also only in PTH-infused rats did PTH correlate with 0 (P=0.07) and 20-minute (P=0.02) plasma glucose levels. There was no correlation between either Ca or PTH and basal insulin levels or the area under the insulin curve in either group. Consequently, we suggest that in the rat, PTH infusion associated with hypercalcemia impairs insulin effect on glucose utilization in vivo and this defect may be induced by the Ca, PTH, or both.This study was presented in part at the 76th Annual Meeting of the Endocrine Society, Anaheim, CA, USA, June 1994.     

Effects of tumor necrosis factor alpha on parathyroid hormone-induced increases in osteoblastic cell cyclic AMP

Summary Tumor necrosis factor α (10⁻¹⁰–10⁻⁸M) had no effects on cyclic AMP production by the osteoblastic osteosarcomal cells, Saos-2 and G292, or normal rat calvarial cells. The cytokine did, however, inhibit the parathyroid hormone (PTH)-induced effect on cyclic AMP in the Saos-2 and normal rat osteoblastic cells. This inhibitory effect did not occur on prostaglandin E₂-induced cyclic AMP increases in the osteoblastic cells. Interleukin-1 (10 U/ml −100 U/ml) did not produce any effect on basal levels or PTH-induced cyclic AMP increases in these cells.     

Effects of androgen treatment in impotent men with normal and low levels of free testosterone

The relation between sexual function and serum free testosterone (fT) levels, which represent the active fraction of circulating testosterone, was evaluated. Two groups of impotent male subjects with mild hypogonadism were treated with oral testosterone undecanoate (TU); these men presented with tT/luteinizing hormone (LH) ratio and tT levels at the lower limits of normal. The first group had serum fT below 6.6 ng/ml, considered the lower normal value, according to our laboratory method, whereas the second group had normal fT limits. Administration of TU improved sexual function only in impotent men with low fT levels, but not in subjects with normal fT levels, even though the tT levels and the tT/LH ratio of the two groups were not significantly different. The results of our study suggest the presence of a minimun serum fT threshold, lying near the lower normal range, which determines the male sexual function. Moreover, serum fT levels were a more sensitive index than tT for identifying impotent men who can be successfully treated with androgens.