Direct effects of catecholamines, thyrotropin-releasing hormone, and somatostatin on growth hormone and prolactin secretion from adenomatous and nonadenomatous human pituitary cells in culture.

To determine the mechanism and the site of action of catecholamines as well as hormones including thyrotropin-releasing hormone (TRH)1 and somatostatin on pituitary hormone release in patients with acromegaly and in normal subjects, the effects of these substances on growth hormone (GH) and prolactin (PRL) secretion from adenomatous and nonadenomatous human pituitary cells in culture were examined. When dopamine (0.01-0.1 microM) or bromocriptine (0.01-0.1 microM) was added to the culture media, a significant inhibition of GH and PRL secretion from adenoma cells from acromegalic patients was observed. This inhibition was blocked by D2 receptor blockade with metoclopramide or sulpiride, but not by D1 receptor blockade. Similarly, dopamine suppressed GH and PRL release by nonadenomatous pituitary cells in a dose-dependent manner, which was again blocked by D2 receptor blockade. The minimum effective concentration of dopamine required for a significant inhibition of PRL secretion (0.01 microM) was lower than that for GH release (0.1 microM). Norepinephrine, likewise, caused a suppression of PRL secretion from adenomatous and nonadenomatous pituitary cells. This effect was blocked by sulpiride, phentolamine, however, was ineffective. When TRH was added to the media, both GH and PRL secretion were enhanced in adenoma cells, while only the stimulation of PRL release was observed in nonadenomatous pituitary cells. Coincubation of TRH and dopamine resulted in variable effects on GH and PRL secretion. Somatostatin consistently lowered GH and PRL secretion in both adenomatous and nonadenomatous pituitary cells and completely blocked the TRH-induced stimulation of GH and PRL secretion from adenoma cells. Opioid peptides (1 microM) failed to affect hormone release. These results suggest that no qualitative difference in GH and PRL responses to dopaminergic agonists or to somatostatin exists between adenoma cells of acromegalic patients and normal pituitary cells, and that the direct effect of catecholamines on GH and PRL secretion from human pituitary cells is mediated mainly through dopamine receptor activation.     

高压氧治疗对亚急性期创伤性脑损伤患者腺垂体功能的影响

目的 观察高压氧（HBO）治疗对亚急性期创伤性脑损伤（TBI）患者腺垂体功能的影响。 方法 采用随机数字表法将66例亚急性期TBI腺垂体功能低下患者分为对照组及HBO组,每组33例。2组患者均给予常规治疗（包括脱水降颅压、抗感染、预防癫痫、预防褥疮、营养神经、补液及康复治疗等）,HBO组在此基础上辅以HBO干预,HBO治疗压力为0.2 MPa(2.0 ATA),每日治疗1次,每周治疗6次,共治疗20次。于治疗前、治疗20次后采用化学发光免疫分析法检测患者血清中促肾上腺皮质激素（ACTH）、生长激素（GH）、促甲状腺激素（TSH）、催乳素（PRL）、黄体生成素（LH）、卵泡刺激素（FSH）、皮质醇（COR）、胰岛素样生长因子-1（IGF-1)、游离四碘甲状腺原氨酸（FT4）、睾酮（TES）及雌二醇（E2）水平,对ACTH、GH、TSH、PRL、LH、FSH赋值并计算垂体总体激素评分。 结果 治疗20次后发现HBO组PRL、LH、TES的对数值及垂体总体激素评分［分别为（1.3±0.2）μg/L、（1.0±0.4）mU/L、（2.5±0.2）ng/dl和（22.0±2.6）分］均显著高于对照组水平［分别为（1.1±0.2）μg/L、（0.8±0.3）mU/L、（2.4±0.3）ng/dl和（20.5±2.3）分］,组间差异均具有统计学意义(P＜0.05)。 结论 在常规干预基础上辅以HBO治疗能进一步提高亚急性期TBI患者多种激素水平,促进垂体功能恢复。     

Interaction between morphine, an opioid agonist, and clonidine, an alpha-adrenergic agonist, on the regulation of anterior pituitary hormone secretion in normal male subjects

In order to investigate the possible interaction between opioid system and noradrenergic system in the regulation of pituitary hormone secretion, the effects of morphine (an opioid agonist, 10 mg i. v.), clonidine (an alpha-adrenergic agonist, infusion of 0.3 mg in 15 minutes) and clonidine + morphine (infusion of the same dose of clonidine beginning 30 minutes before morphine 10 mg i.v.) on anterior pituitary hormone secretion were studied in six normal male volunteers. Morphine alone induced both an increase in TSH and PRL serum levels and a decrease in cortisol serum levels with no changes in GH serum levels. On the contrary clonidine was able to increase GH and TSH levels and to decrease cortisol levels; PRL secretion was not affected. As regards interaction between morphine and clonidine we observed that morphine-induced increase in PRL release was potentiated by clonidine pretreatment; as regards TSH secretion its increase was greater after the administration of the two drugs with respect to the effect of the single drugs. This study, in agreement with our previous data concerning LH secretion, confirms the important link between clonidine and opioid system in neuroendocrine function, too; the possible explanations of our data are discussed.     

急性颅脑伤患者血清生长激素、催乳激素、促甲状腺激素放射免疫测定

为了进一步了解急性颅脑伤患者下丘脑-垂体功能的变化,对患者伤后最初3天血清生长激素(GH)、催乳激素(PRL)、促甲状腺激素(TSH)进行了放射免疫测定。结果表明TSH含量均在正常范围,PRL含量伤后最初2天高于正常,而第3天已降至正常,GH含量均高于正常。死亡组伤后第1天PRL含量高于生存组。并对急性颅脑伤患者血清PRL、GH升高的机理进行了探讨,认为可能与下丘脑-垂体的梗塞、坏死及PRL、GH的应激作用有关。     

Hypothalamo-pituitary dopaminergic system in patients with myotonic dystrophy

We studied the function of hypothalamo-pituitary dopaminergic system in 15 myotonic dystrophy (MyD) patients whose growth hormone (GH) responses to insulin or arginine had been normal. We obtained the following findings: (1) basal levels of plasma GH and prolactin (PRL) were normal, although the latter levels were slightly lower than controls, (2) both GH and PRL responses to L-dopa or bromocriptine were significantly blunted compared with controls, (3) PRL response to sulpiride was also significantly low compared with controls. These results indicate that hypothalamic dopaminergic neuron and its postsynaptic dopamine receptors relating to GH secretion might be impaired. It was also suggested that the dopamine receptors of pituitary PRL cells might be impaired and the PRL reserve of pituitary cells might be decreased in some case.     

Dynorphin effects on plasma concentrations of anterior pituitary hormones in the nonhuman primate

The role of dynorphin-(1-13) and dynorphin-(1-10)-amide in the neuroendocrine control of primate anterior pituitary hormones was studied in nonrestrained, ovariectomized rhesus monkeys. The effects of these opioids on plasma concentrations of prolactin (PRL), luteinizing hormone (LH), follicle stimulating hormone (FSH) and thyrotropin (TSH), and interactions with naloxone are reported here. Intravenous administration of dynorphin-(1-13), 30 to 120 micrograms/kg, significantly increased plasma PRL levels 3- to 4-fold. These PRL increases occurred within 5 min and levels remained elevated for at least 60 min. Administration of naloxone (1.0 mg/kg i.v.) antagonized the rise in PRL levels. Dynorphin-(1-13) had no significant effect on plasma LH, FSH or TSH levels. Dynorphin-(1-10)-amide (30-120 micrograms/kg) increased plasma PRL levels 2- to 4-fold at 5 to 40 min after administration. Plasma LH levels were significantly depressed 100 to 120 min postdrug. Dynorphin-(1-10)-amide produced no change in plasma FSH or TSH levels. These results indicate that dynorphin is involved in the modulation of PRL and perhaps LH secretion, although not affecting TSH or FSH release.     

Effects of exogenous melatonin on pituitary hormones in humans

The effects of melatonin on physiological function remain unclear, although the therapeutic potential of melatonin is being increasingly recognized. The aim of the present study is to investigate the effects of exogenous melatonin on the spontaneous release of pituitary hormone in humans. A double blind placebo‐controlled protocol was designed to examine 12 adult healthy volunteers and 12 sleep disorder patients who have been treating with low doses of melatonin for 1 year. Either exogenous melatonin or placebo of 1 mg was given at 09:00 hours, followed by the collection of blood samples every 20 min for 4 h. Each blood sample was examined for levels of serum melatonin, PRL, LH, FSH, GH and TSH. LH levels were higher in sleep disorder patients compared with the healthy volunteers. In other pituitary hormones, there were no significant difference between healthy adults and sleep disorder patients. In all subjects, PRL levels were stimulated by acute administration of 1 mg of exogenous melatonin, while the levels of other pituitary hormones were not affected. These results suggested that exogenous melatonin can affect the spontaneous release of LH and PRL in humans. In addition, we demonstrated that 1‐year oral melatonin treatment did not affect the responses to the acute administration of melatonin.     

Somatostatin receptor (SSTR) subtype-selective analogues differentially suppress in vitro growth hormone and prolactin in human pituitary adenomas. Novel potential therapy for functional pituitary tumors.

Previously, we have shown somatostatin receptor (SSTR) subtype-specific regulation of growth hormone (GH), thyroid-stimulating hormone, and prolactin (PRL) secretion in human fetal pituitary cultures, where GH and thyroid-stimulating hormone are mediated by both SSTR2 and SSTR5, whereas SSTR2 preferentially mediates PRL secretion. We now tested SSTR subtype-selective analogues in primary human GH- and PRL-secreting pituitary adenoma cultures. Analogue affinities determined by membrane radioligand binding in cells stably expressing human SSTR forms were either SSTR2 or SSTR5-selective. Analogues preferential either for SSTR2, including octreotide, lanreotide, and novel compounds with improved affinity for SSTR2, or new SSTR5-selective compounds suppressed GH in tumor cell cultures (up to 44% of control; P < 0.0005). However, novel analogues from both groups were 30-40% more potent than octreotide and lanreotide in suppressing GH (P < 0.05). Heterologous analogue combinations containing both SSTR2- and SSTR5-selective compounds were more potent in decreasing GH than analogues used alone (P < 0.05), or than combinations of compounds specific for the same receptor subtype (P < 0.005). In contrast, SSTR2-selective analogues did not suppress PRL release from six cultured prolactinomas studied. However, new SSTR5-selective analogues suppressed in vitro PRL secretion (30-40%; P < 0.05) in four of six prolactinomas. These results suggest that both SSTR2 and SSTR5 are involved in GH regulation in somatotroph adenoma cells, whereas SSTR5 exclusively regulates PRL secretion from prolactinoma cells. Thus, somatostatin analogues with improved selective binding affinity for these receptor subtypes may be effective in the treatment of either GH- or PRL-secreting adenomas.     

Effect of chronic methadone administration on neuroendocrine function in young adult rats

This study reports the endocrine effects of chronic methadone (METH) administration. Two treatment regimens were tested: a constant (5 mg/kg/day, CD) or increasing dose (5 mg/kg twice daily, increasing 1 mg/kg/day, ID). Basal hormone levels and endocrine responses to opiate challenge were determined on days 5, 10 and 20 and after withdrawal. METH effects on hormone secretion varied with treatment duration, dose and hormone. Tolerance to METH effects on corticosterone (CS), prolactin (PRL), growth hormone (GH), thyroid-stimulating hormone (TSH) and luteinizing hormone (LH) developed during the ID regimen and basal CS, TSH and LH levels were altered. In addition, serum testosterone, T3 and T4 decreased significantly during this regimen. In contrast, only CS secretion was affected markedly by the CD regimen. Resting levels were elevated by day 5 and the CS response to acute METH challenge was reversed. Tolerance also developed to METH-induced TSH suppression, but only with longer treatment. Similarly, basal TSH and LH levels were affected only with longer treatment. Basal PRL, GH and LH levels and LH, PRL and GH responses to acute METH challenge were not affected by the CD regimen. Changes in basal CS and TSH levels observed in these studies probably reflect abstinence, as even more pronounced changes occurred after naloxone-precipitated abstinence and suppressed rather than reversed responses were observed if animals were withdrawn for 36 hr before testing. Tolerance in some endocrine systems appears to be quite long-lasting, as CS, TSH and PRL responses to METH challenge were still decreased 3 weeks after withdrawal from the ID regimen.(ABSTRACT TRUNCATED AT 250 WORDS)     

PPAR-gamma receptor ligands: novel therapy for pituitary adenomas

Pituitary tumors cause considerable morbidity due to local invasion, hypopituitarism, or hormone hypersecretion. In many cases, no suitable drug therapies are available, and surgical excision is currently the only effective treatment. We show here abundant expression of nuclear hormone receptor PPAR-gamma in all of 39 human pituitary tumors. PPAR-gamma activating thiazolidinediones (TZDs) rosiglitazone and troglitazone induced G(0)-G(1) cell-cycle arrest and apoptosis in human, rat somatolactotroph, and murine gonadotroph pituitary tumor cells, and suppressed in vitro hormone secretion. In vivo development and growth of murine somatolactotroph and gonadotroph tumors, generated by subcutaneous injection of prolactin-secreting (PRL-secreting) and growth hormone-secreting (GH-secreting) GH3 cells, luteinizing hormone-secreting (LH-secreting) LbetaT2 cells, and alpha-T3 cells, was markedly suppressed in rosiglitazone-treated mice, and serum GH, PRL, and LH levels were attenuated in all treated animals (P < 0.009). These results demonstrate that PPAR-gamma is an important molecular target in pituitary adenoma cells and PPAR-gamma ligands inhibit tumor cell growth and GH, PRL, and LH secretion in vitro and in vivo. TZDs are proposed as novel oral medications for managing pituitary tumors.     

A case of refetoff syndrome: selective venous sampling for TSH is useful in differentiating thyroid hormone resistance from TSH secreting tumor

A 22-year old man with a goiter and clinical manifestations of mild thyrotoxicosis (finger tremor, palpitation, tachycardia) was diagnosed as a syndrome of inappropriate secretion of TSH. Serum concentrations of T4, free T4, T3 and TSH were 24.1 micrograms/100 ml, 4.07 ng/100 ml, 261 ng/100 ml and 1.72 microU/ml, respectively. Thyroidal 131I uptake at 24 hr was 80%. The BMR was within the normal range. He had a normal TSH response to TRH (500 micrograms) with a peak level of 23.8 microU/ml. The basal level of alpha-subunit of TSH was not elevated (0.35 ng/ml). Oral 1-T3 administration (75 and 150 micrograms daily) raised serum T3 concentration, reduced basal TSH and blunted TSH response to TRH. The diurnal variation of TSH was maintained. There was no evidence of abnormalities in the secretion of other pituitary hormones. These findings were compatible with thyroid hormone resistance. However, the presence of a microadenoma in the pituitary gland was suspected with CT scan. Bilateral and simultaneous venous sampling for TSH from inferior petrosal sinus showed no gradient in TSH concentration indicating that a TSH secreting pituitary tumor was unlikely. These data suggest that inappropriate TSH secretion in the present patient is resulted from resistance to thyroid hormone. In the present study selective venous sampling is useful to differentiate the thyroid hormone resistance from a TSH secreting tumor.     

Evaluation of the effects induced by four opiate drugs, with different affinities to opioid receptor subtypes, on anterior pituitary LH, TSH, PRL and GH secretion and on cortisol secretion in normal men

In order to ascertain the subtype(s) of opioid receptors involved in the control of pituitary function the effects of four different opiate drugs (morphine, pentazocine, nalorphine and buprenorphine) were studied in four groups of six normal male volunteers. Each of the drugs tested induced, with varying degrees, both a significant increase in PRL and a significant decrease in LH and cortisol. On the contrary TSH secretion was stimulated by buprenorphine and morphine only and GH by nalorphine only. FSH did not change significantly after administration of any drug. Taking into account the different affinities of the drugs used by us for the different opioid receptors, our data do not allow to demonstrate a well-defined correlation between subtypes of opioid receptors and the control of pituitary hormone secretion. The possible explanations of this fact are discussed.     

GHRH and TRH tests in patients with idiopathic and secondary GH deficiency--with special reference to GH response patterns to GHRH

To study whether patients with idiopathic GH deficiency (IGHD) show a delayed GH response pattern to GHRH, 42 patients with IGHD, 14 patients with hypothalamic tumor (2ry GHD), and 23 normal short children (NSC) were examined as to their GH response patterns to GHRH together with their TSH and PRL response patterns to TRH. After TRH injection, the mean time of the TSH peak in IGHD (67.5 +/- 6.5 min, n = 36) and 2ry GHD patients (81.7 +/- 14.8 min, n = 9) was clearly delayed comparing to that of NSC (29.1 +/- 2.9 min, n = 16; both p less than 0.01). Similarly, the mean time of the PRL peak in IGHD (38.3 +/- 3.6 min, n = 36) and 2ry GHD patients (39.5 +/- 5.8, n = 11) was significantly delayed comparing to NSC (22.0 +/- 3.5 min, both p less than 0.01). In IGHD patients, the delayed response pattern of TSH and PRL was more remarkable in patients who had breech delivery than in those with normal delivery. In contrast, the mean time of the GH peak was similar in IGHD (62.1 +/- 4.0 min, n = 41), 2ry GHD (64.1 +/- 8.1 min, n = 11) and NSC (58.0 +/- 6.1 min, n = 23). However, the decline from peak GH (120 min GH/peak GH) was significantly smaller in IGHD (54.3 +/- 4.2%) and 2ry GHD (60.7 +/- 7.3%) than in NSC (39.0 +/- 8.1%) (both p less than 0.05). Further, in IGHD patients plasma GH response was greater in patients with normal delivery than in those with breech and asphyxia delivery. These results seem to indicate: 1) the stimulus-secretion mechanism is different between somatotrophs and thyrotrophs or lactotrophs in man, 2) IGHD patients have hypothalamic lesions as well as pituitary lesions, 3) such hypothalamo-pituitary lesions in IGHD patients are greater in patients with abnormal delivery than in those with normal delivery.     

Receptor imaging with 111In-pentreotide and 123I-methoxybenzamide, and inhibition tests with octreotide and bromocriptine of mixed growth hormone/prolactin-secreting pituitary tumors.

We have performed pituitary scintigraphy with 111In-pentreotide (OCT), a somatostatin analogue, and with metoxybenzamide (IBZM) by 123I-IBZM in two patients affected by mixed growth hormone/prolactin-secreting pituitary tumors. Short-term growth hormone (GH) inhibition by a single injection of OCT (100 micrograms s.c.), and short-term prolactin (PRL) inhibition by oral administration of 2.5 mg of bromocriptine (BCR), were also performed in both patients. The first patient, a 26 year old man, showed intense tumor uptake of 123I-IBZM scintigraphy, whereas 111In-OCT scintigraphy showed moderate tumor uptake. Five hours after the BCR inhibition test, a fall of 83% in PRL plasma levels (from 8,336 micrograms/L to 1,417 micrograms/L), and of 91.6% in GH plasma levels (from 39.5 micrograms/L to 3.3 micrograms/L) were observed. OCT inhibition test suppressed GH plasma levels from 36 micrograms/L to 3.5 micrograms/L. The patient was submitted to treatment with BCR and OCT. A dramatic shrinkage of the tumor was seen after six months of therapy. The lesion disappeared one year after the start of therapy. The second patient, a 64 year old man, showed intense uptake at 111In-OCT scintigraphy, while 123I-IBZM uptake was not observed. A test dose of BCR resulted in an acute fall of PRL (from 145 micrograms/L to 118 micrograms/L), but not of GH. A test dose of OCT decreased the GH plasma level from 61 micrograms/L to 4.5 micrograms/L. The patient was submitted to treatment with BCR and OCT that resulted in a computed tomography and magnetic resonance imaging decrease of 45% of tumor volume one year after the start of therapy. Our results suggest that both suppression tests with OCT and BCR, and scintigraphic studies in vivo with 123I-IBZM and 111In-OCT can be predictive for the effectiveness of therapies with dopamine agonists and/or SS-analogs in patients with mixed PRL/GH-secreting pituitary tumors. Further studies are required to evaluate the role of suppressive tests in selecting patients for appropriate clinical treatments.     

Effects of ibopamine on serum prolactin and growth hormone levels in hyperprolactinemic and acromegalic subjects

The effects of oral doses (100, 200, and 400 mg) of a dopamine derivative, ibopamine, on serum prolactin (PRL) and growth hormone (GH) levels were evaluated in hyperprolactinemic patients, some of whom also were acromegalic. There was dose-related lowering of PRL levels. The highest dose was as effective as 500 mg L-dopa, although the duration of action was shorter, with a decrease to below 50% of basal PRL values in all patients. Serum GH did not rise in nonacromegalic subjects, but it fell after 400 mg ibopamine in the L-dopa-sensitive acromegalic patients. These data suggest, but do not prove, that ibopamine is able to directly stimulate pituitary dopamine receptors.     

ELISA联合检测方法的建立及应用

目的在微孔板平台上建立多指标联合检测的方法,为急诊、门诊及基层等多种医疗机构提供1种新的血清学检测手段。方法本研究根据酶联免疫吸附法(ELISA法)原理,以卵泡刺激素(FSH)、泌乳素(PRL)、黄体生成素(LH)、生长激素(GH)为检测靶标,在自行设计的聚苯乙烯板孔上完成反应体系的优化,包括FSH、PRL、LH、GH包被抗体浓度及酶标抗体浓度,建立1种并行分析样品中多种指标的方法。结果成功确定4种垂体激素联合检测的条件,包括4种激素抗体包被浓度、酶标抗体浓度等,并成功应用于临床样本的检测。结论本研究首次建立了1种简单、特异性高、成本低、并行分析4种垂体激素的联合检测方法,提高了常规ELISA法的检测效率。