垂体生长激素腺瘤患者的临床特点及手术疗效初步分析

目的 研究生长激素(GH)腺瘤的临床特点及其与手术疗效的关系.方法 纳入201 1年1月至2013年10月首都医科大学附属北京天坛医院神经外科采用手术治疗的GH腺瘤患者167例.观察患者的临床特征,探讨其与手术疗效的关系;免疫组化染色观察腺瘤的激素表达情况.结果 167患者中,男、女比例为1∶1.12(79/88);30 ～ 50岁者占63.7％(106例).微腺瘤22例(13.2％),大腺瘤117例(70.1％),巨大腺瘤28例(16.8％).侵袭性腺瘤63例(37.7％),非侵袭性腺瘤104例(62.3％).非侵袭性腺瘤切除程度高于侵袭性腺瘤,差异有统计学意义(P=0.01).术前血浆GH中位水平27 ng/ml;术前催乳素＞正常值(20 ng/ml)的有43例(25.8％).术前GH水平与肿瘤体积呈正相关(r =0.285,P＜0.01).手术前后GH水平呈正相关(r=0.541,P＜0.01).免疫组化显示,腺瘤多激素表达阳性者占51.8％(85/164),单GH激素表达阳性者占48.2％(79/164),两组侵袭性及术前GH水平差异无统计学意义.随访0.6 ～4.3年,158例术前存在肢端肥大症者,150例缓解;术后糖尿病治愈21.4％(9/42),缓解21.4％(9/42);高血压治愈16.3％(7/43),缓解14.0％ (6/43).结论 GH腺瘤常见于中青年,明确诊断时多为大腺瘤.术前GH水平与肿瘤体积相关;手术对部分患者的高血压和糖尿病等合并症有效.侵袭性腺瘤手术切除程度不如非侵袭性腺瘤.     

过氧化物酶体增殖物激活受体γ在垂体腺瘤中的表达

目的 通过检测过氧化物酶体增殖物激活受体γ(PPARγ)在人垂体腺瘤组织中的表达,探讨其在垂体腺瘤中的相关机制.方法 通过免疫组化法确定经手术切除的83例垂体腺瘤组织细胞来源;采用RT-PCR、适时定量PCR检测研究83例垂体腺瘤组织及6例正常垂体组织PPARγ的mRNA表达量,采用Western blot法检测组织PPARγ蛋白质表达水平,分析不同类型垂体腺瘤组织之间核酸及蛋白水平表达量的差异.结果 GH腺瘤17例、PRL腺瘤15例、ACTH腺瘤18例、多激素腺瘤(MCPAs)17例、无功能腺瘤(NFAs)16例及正常对照组6例;mRNA水平检测显示所有垂体腺瘤组织的表达量均高于正常对照组,其中GH腺瘤的表达量最高,与其他组比较P＜0.05;蛋白水平检测显示GH腺瘤、PRL腺瘤、ACTH腺瘤及MCPAs的表达量均高于正常对照组(P＜0.05),GH腺瘤的表达量最高,NFAs的表达量与正常对照组差异无统计学意义(P＞0.05).结论 PPARγ转录及蛋白表达水平在人GH、PRL、ACTH及MCPAs垂体腺瘤组织中高表达,该基因与垂体腺瘤有一定的相关性,而无功能垂体腺瘤在核酸水平的表达量增高,蛋白水平的表达量不高,可能与激素的分泌水平有关;在GH腺瘤中的表达量最高,且与其他组相比,差异有统计学意义(P＜0.05),说明该类肿瘤与PPARγ的关系最为密切,可能与生长激素能刺激PPARγ的表达有关.     

生长激素(GH)水平在垂体GH腺瘤缓解及预后判断中的意义

目的 探讨生长激素(GH)水平的测定在垂体GH腺瘤手术缓解及预后判断中的意义.方法 回顾性分析91例经鼻蝶垂体腺瘤切除术的GH腺瘤的病例.分别测定术前、术后1d及1 w空腹垂体激素水平.结果 手术缓解率为67.0％,微腺瘤与大腺瘤缓解率(P＜0.001)、侵袭性与非侵袭性腺瘤缓解率(P＜0.001)、术前各浓度的术后缓解率(P＜0.05)、术中GH下降大于50％组与GH下降不足30％组缓解率(P＜0.01)均有明显差异.鞍内局限组与鞍外扩展组缓解率无明显差异(P＞0.05).术后1d、1 w、1个月激素缓解率无明显差异(P＞0.05).结论 术前、术后早期(术后1w、1个月)GH水平和术中GH下降程度对预后有重要预测价值;手术疗效与肿瘤大小、是否侵袭性生长和术前激素水平显著相关.     

ADAM10表达和垂体腺瘤海绵窦侵袭性的关系

目的 检测解聚素金属蛋白酶10(ADAM10)在垂体腺瘤组织中的表达,探讨其与垂体腺瘤海绵窦侵袭性的相关性.方法 收集手术切除的垂体腺瘤组织标本,应用免疫组化SP法检测90例腺瘤的ADAM10表达,应用RT-PCR方法检测42例组织的转录水平;分析其与临床资料的相关性.结果 ADAM10阳性率在侵袭性垂体瘤中高于非侵袭组(P＜0.05),ADAM10的表达与年龄、性别、腺瘤内分泌类型及肿瘤直径无相关性(P＞0.05);ADAM10 mRNA水平在侵袭性垂体瘤组中高于非侵袭组(P＜0.05),与腺瘤内分泌类型无关(P＞0.05).结论 ADAM10的表达与腺瘤海绵窦侵袭性密切相关,侵袭性腺瘤中ADAM10表达高.为寻找侵袭性的分子标志物提供了新方向,以调控ADAM10的表达为靶目标,抑制肿瘤细胞的转移和侵袭,有望成为垂体腺瘤治疗的新策略.     

垂体腺瘤中NPY的表达和细胞定位

目的探讨不同病理类型垂体腺瘤中NPY的表达水平及其在瘤细胞中的定位特点。方法收集我科2003年~2005年诊治的垂体腺瘤57例。所有病例均经手术和病理确诊。肿瘤标本进行NPY免疫组化染色。6例垂体瘤标本进行免疫电镜研究。结果本组34/57例垂体腺瘤的NPY呈阳性表达,占59.65%。NPY阳性表达率在促性腺细胞腺瘤中最高达91.7%,生长激素腺瘤和促肾上皮质激素腺瘤次之均为66.7%,零细胞腺瘤和混和性腺瘤均为50%,泌乳素腺瘤表达率最低25%。NPY在不同类型垂体腺瘤中的表达差异有统计学意义(P<0.05)。NPY在亚细胞水平的定位:4/6例(GH腺瘤2例,GH-PRL混合性腺瘤1例,PRL腺瘤2例和促性腺细胞腺瘤1例)NPY免疫电镜结果呈阳性,胶体金颗粒呈散在或小簇状分布,主要存在于胞质中分泌颗粒上,此外,粗面内质网和细胞基质中也偶见散在的胶体金颗粒,其余细胞器很少有非特异吸附的胶体金颗粒。2例PRL腺瘤偶见NPY阳性颗粒。结论①不同类型垂体瘤的NPY表达各有差异。②促性腺细胞腺瘤中的NPY表达水平较高,泌乳素腺瘤中NPY表达较低。     

侵袭性与非侵袭性泌乳素腺瘤细胞增殖活性的差异

目的　研究侵袭性与非侵袭性泌乳素 (PRL)腺瘤细胞增殖活性的差异。方法　检测 2 6例泌乳素腺瘤中细胞核增殖抗原 (PCNA)表达 ;用流式细胞仪 (FCM )检测相应腺瘤中S期细胞比例 ,比较侵袭性泌乳素腺瘤与非侵袭性泌乳素腺瘤PCNA表达与S期细胞比例的差异。结果　侵袭性PRL腺瘤中PCNA表达的阳性指数为 76 7±1 1 1 8;非侵袭性腺瘤中PCNA表达的阳性指数为 37 1± 1 0 33;两组比较 ,差别具有显著性 (P <0 0 5) ;侵袭性PRL腺瘤S期细胞比例为 1 3 57%± 2 1 6 % ;非侵袭性PRL腺瘤为 8 97%± 2 0 7% ,两组比较差别具有显著性 (P <0 0 5)。结论　PCNA表达与S期细胞比例的检测结果是一致的 ,侵袭性与非侵袭性PRL腺瘤相比 ,细胞增殖能力较强 ,复发率高     

内镜和显微手术治疗对垂体腺瘤患者术后血清MMP-9、IGF-1及激素相关指标水平的影响

目的 探讨内镜和显微手术对垂体腺瘤患者术后血清基质金属蛋白酶-9(MMP-9)、胰岛素样生长因子-1(IGF-l)及激素相关指标水平的影响.方法 以随机数值表法将2017年1月-2020年1月邯郸市中心医院神经外科收治的96例垂体腺瘤患者均分为内镜组(神经内镜下行肿瘤切除)和显微镜组(显微镜下行肿瘤切除).记录两组手术指标及术后并发症情况;于术前、术后第3天检测血清MMP-9、IGF-1、泌乳素(PRL)、生长激素(GH)及促肾上腺皮质激素(ACTH)水平.结果 与显微镜组相比,内镜组的手术时间更长,肿瘤切除程度更优,差异有统计学意义(P＜0.05).术后内镜组的血清MMP-9、IGF-1及PRL、GH及ACTH水平均低于内镜组,差异有统计学意义(P＜0.05).内镜组、显微镜组术后并发症总发生率为10.42％、27.08％,两者差异无统计学意义(P＞0.05).结论 神经内镜手术时间较显微镜更长,但在瘤体的清除、降低术后血清MMP-9、IGF-1及激素指标水平方面更具优势.     

血清GH水平与GH腺瘤侵袭性和复发的关系

目的 探讨血清生长激素(GH)水平与GH腺瘤侵袭性和复发的关系.方法 119例GH腺瘤患者手术前后测量血清GH水平,并对其病例资料进行回顾性研究.结果 术前平均GH水平为(69.0±24.8)μg/L,>50μg/L的患者侵袭性腺瘤发生率(69.2%)明显高于≤20μg/L和20～50μg/L的患者(24.1%和31.4%,P<0.05).术后早期GH≤5μg/L患者的复发率(2.8%)明显低于>5μg/L患者(50%,P<0.001).结论 术前血清GH水平与GH腺瘤的侵袭性密切相关,>50μg/L的患者侵袭性腺瘤发生率较高;术后早期GH<5μg/L可作为GH腺瘤长期缓解的预测指标之一.     

神经肽Y在人垂体腺瘤中组织学和分子生物学变化的研究

目的 探讨NPY在人垂体腺瘤细胞中的位置和表达,不同类型中的特点.方法 收集我院神经外科经手术和病理确诊的垂体腺瘤57例.免疫电镜研究NPY在垂体腺瘤细胞中的位置.免疫组化和RT-PCR检测NPY的表达.结果 (1)免疫电镜:NPY主要位于胞质的分泌颗粒中,其次位于粗面内质网和细胞基质中.(2)免疫组化:NPY在垂体腺瘤中总体表达的结果为59.6%(34/57);促性腺瘤91.7%,GH腺瘤和ACTH腺瘤均为66.7%,零细胞腺瘤和混合性腺瘤均为50%,PRL腺瘤为25%,它们间的差异有统计学意义(P=0.04).(3)RT-PCR:NPY mRNA在垂体腺瘤中均表达,其差异有统计学意义(P<0.01);促性腺瘤最高是PRL腺瘤的9.3倍、无功能腺瘤5.8倍、GH腺瘤2.7倍,其余组间的差异无统计学意义.结论 (1)人垂体腺瘤中存在NPY.(2)垂体腺瘤中的确有NPY表达,不同类型中的表达各有差异;促性腺瘤表达最高,PRL腺瘤表达最低.(3)为今后深入探讨NPY在垂体腺瘤中的作用奠定了基础.     

泌乳素腺瘤ER、PTTG、PCNA的表达与肿瘤侵袭性的关系

目的 分析泌乳素(PRL)腺瘤中雌激素受体(ER)、垂体瘤转化基因(PTTG)和增殖细胞核抗原(PCNA)表达水平与肿瘤侵袭性的关系.方法 对侵袭性PRL腺瘤24例(侵袭性组)和非侵袭性PRL腺瘤32例(非侵袭性组)采用免疫组化方法 检测腺瘤组织中ER蛋白、PTTG蛋白和PCNA蛋白表达水平;应用逆转录聚合酶链反应(RT-PCR)方法 检测腺瘤组织中ER-mRNA表达水平.结果 ER蛋白在侵袭性组中23例阳性表达,积分光密度(IOD)为(4935.12±1246.56),显著低于非侵袭性组(P＜0.01);PTTG蛋白在侵袭性组中有21例阳性表达,IOD为(9874.24±2143.56),与非侵袭性差异有统计学意义(P＜0.01);PCNA蛋白在侵袭性组中有18例阳性表达,IOD为(8456.24±1534.56),与非侵袭性差异有统计学意义(P＜0.01);RT-PCR 检测显示54例腺瘤有ER-mRNA特异扩增条带,但在侵袭性表达水平降低(P＜0.05).结论 ER表达降低及PTTG、PCNA表达增高与肿瘤的侵袭性有密切关系,可作为临床判定肿瘤侵袭性的标志分子.     

Extrahypothalamic brain prolactin: characterization and evidence for independence from pituitary prolactin

Prompted by reports of immunohistochemical localization of a prolactin-like immunoreactivity (PLI) within the rat brain, a study was undertaken to define the immunologic and biologic characteristics of this material in extrahypothalamic regions of the rat brain. Ninety-seven percent recovery of rat prolactin standard, added to homogenates of brain parts, insured that neuronal tissue did not interfere with the radioimmunoassay for rat prolactin. PLI was consistently found in the cerebellum, thalamus, brainstem (pons-medulla), hippocampus, cerebral cortex and caudate. Examination of the elution profile of each of the extrahypothalamic brain parts from Sephadex G-75 columns showed that, although a small amount of brain PLI elutes in the vicinity of the anterior pituitary prolactin marker, the bulk of brain-based PLI migrates with the void volume and as late eluting, low molecular weight material. While increasing amounts of brain extracts progressively displaced more 125I-prolactin from antibody binding, the displacement curve was not parallel to that produced by the addition of increasing amounts of anterior pituitary prolactin standards of rat origin. Extracts of various brain parts from hypophysectomized animals, analyzed for biologic activity in the Nb2 lymphoma cell assay, revealed prolactin-like bioactivity, but the bioactivity/immunoreactivity ratio for some of the brain parts was significantly lower than that for pituitary prolactin. Hypophysectomy, which led to the expected fall in serum prolactin to undetectable levels, and restraint stress, which resulted in a statistically significant 4-fold rise in serum prolactin, caused no change in prolactin concentrations in extrahypothalamic brain parts, indicating that brain PLI is regulated independently of pituitary prolactin and of circulating serum prolactin levels.     

Circulating prolactin, MPOA prolactin receptor expression and maternal aggression in lactating rats

Maternal aggression is most intense in lactating rats from the 3rd to the 12th day postpartum. The purpose of this study was to determine if plasma prolactin (PRL) and prolactin receptor (PRL-R(L)) mRNA expression in the medial preoptic area (MPOA) of lactating rats are altered in association with maternal aggression. Lactating Sprague Dawley rats were divided into five groups and exposed for 10 min to an intruder male or to an object on postpartum day 8. Trunk blood and the brain of the dams were collected 30 or 240 min after exposure and from a non-exposed group. Lower levels of prolactin were found 30 min after the aggression test. No change was detected in the number of cells expressing PRL-R(L) mRNA by in situ hybridization histochemistry (ISHH) as a function of testing. However, the correlation between plasma PRL and PRL-R(L) mRNA expression in the mothers changed from positive in control females to negative in intruder exposed animals. These data support the concept that a maternal aggressive experience, while acutely altering PRL secretion, fails to affect PRL-R(L) mRNA expression.     

Depot fluphenazine and plasma prolactin

In 14 schizophrenic patients, prolactin levels are studied in relation to dosage of depot fluphenazine and gender of patient. Prolactin levels in individual patients are similar across injection cycles. For males, the association between fluphenazine dosage and prolactin level was found to be significant (Spearman rho = .925, p less than .05).     

Serum prolactin concentrations and epilepsy

Summary In 20 healthy subjects (10 female and 10 male) and 17 patients undergoing presurgical epilepsy evaluation with intracranial EEG electrodes, circadian variations of serum prolactin (PRL) were measured. A comparison between the peak values found in normals with the postictal rises in patients, led us to consider 700 U/ml to be the threshold of diagnostic value and the observed rises above this level to be all induced by seizures. In order to asses the clinical value of this threshold, PRL was measured postictally in a further 30 patients with epilepsy and in 11 patients with psychogenic seizures. In none of the latter group did PRL rises exceed 700 U/ml, while they did so in 39% of the complex partial seizures and in 80% of the tonic-clonic seizures. There was no significant difference with respect to sex (a rise over 700 U/ml in 42% in male and in 55% in female patients). Based on the findings in 17 patients investigated by means of intracranial electrodes, we were not able to establish different criteria for different focus localisations: in 66% of both temporal as well as frontal lobe seizures the 700 U/ml level was exceeded. As a trend, in the period preceeding an epileptic seizure we found a slightly decreasing PRL level, whereas in healthy persons the PRL concentrations gradually increased in the 40 minutes before the maximum spontaneous peak was reached.     

Analysis of prolactin receptor expression in the murine brain using a novel prolactin receptor reporter mouse

Prolactin influences a wide range of physiological functions via actions within the central nervous system, as well as in peripheral tissues. A significant limitation in studies investigating these functions is the difficulty in identifying prolactin receptor (Prlr) expression, particularly in the brain. We have developed a novel mouse line using homologous recombination within mouse embryonic stem cells to produce a mouse in which an internal ribosome entry site (IRES) followed by Cre recombinase cDNA is inserted immediately after exon 10 in the Prlr gene, thereby targeting the long isoform of the Prlr. By crossing this Prlr‐IRES‐Cre mouse with a ROSA26‐CAGS‐tauGFP (τGFP) reporter mouse line, and using immunohistochemistry to detect τGFP, we were able to generate a detailed map of the distribution of individual Prlr‐expressing neurones and fibres throughout the brain of adult mice without the need for amplification of the GFP signal. Because the τGFP is targeted to neurotubules, the labelling detected not only cell bodies, but also processes of prolactin‐sensitive neurones. In both males and females, Cre‐dependent τGFP expression was localised, with varying degrees of abundance, in a number of brain regions, including the lateral septal nucleus, bed nucleus of the stria terminalis, preoptic and hypothalamic nuclei, medial habenula, posterodorsal medial amygdala, and brainstem regions such as the periaqueductal grey and parabrachial nucleus. The labelling was highly specific, occurring only in cells where we could also detect PrlrmRNA by in situ hybridisation. Apart from two brain areas, the anteroventral periventricular nucleus and the medial preoptic nucleus, the number and distribution of τGFP‐immunopositive cells was similar in males and females, suggesting that prolactin may have many equivalent functions in both sexes. These mice provide a valuable tool for investigating the neural circuits underlying the actions of prolactin.     

Studies on prolactin in major psychoses--with reference to prolactin response to stress in schizophrenia

The serum prolactin concentrations of schizophrenics with delusions or hallucinations, hypomanics, depressives, alcoholics with and without psychotic symptoms were examined. Among them, only the serum prolactin concentrations of alcoholics with psychotic symptoms were significantly higher when compared to the normal controls. In a stress experiment, the alterations of serum prolactin seen in schizophrenics were significantly greater when compared to the normal controls. The results are discussed in connection with the neurochemical mechanisms for the emotional states caused by stress.     

Serum prolactin and tardive dyskinesia

The authors correlated the serum prolactin levels of 19 men with tardive dyskinesia, 29 postmenopausal women with tardive dyskinesia, and 21 men without tardive dyskinesia with the variables age, sex, antipsychotic dosage, and severity of illness. All subjects were taking antipsychotic medication. The prolactin levels of the 14 women with severe tardive dyskinesia were significantly higher than those of the 15 women with mild symptoms. The prolactin levels of the 8 men with severe tardive dyskinesia did not differ from those of the 11 men with mild symptoms. The authors discuss the sex-related association between prolactin and severity of tardive dyskinesia in the context of recent animal studies that have examined the effect of prolactin and estrogens on the striatum.