垂体瘤的诊断、鉴别诊断与治疗——常见垂体腺瘤的临床诊断

垂体腺瘤是发生于腺垂体的良性肿瘤，占中枢神经系统肿瘤的10％～20％，是颅内最常见的肿瘤之一。根据免疫组织化学将垂体腺瘤按功能进行分类，主要有激素分泌活性腺瘤和非激素分泌活性腺瘤两大类。前者包括生长激素瘤(GH腺瘤)、催乳素瘤(PRL腺瘤)、促肾上腺皮质素瘤(ACTH腺瘸)、Nelson综合征、促甲状腺素瘤(TSH腺瘤)、促性腺素瘤(FSH和LH腺瘤)；后者包括无功能细胞腺瘤。现将临床比较     

常见垂体腺瘤的临床诊断

垂体腺瘤是发生于腺垂体的良性肿瘤 ,占中枢神经系统肿瘤的 10 %～ 2 0 % ,是颅内最常见的肿瘤之一。根据免疫组织化学将垂体腺瘤按功能进行分类 ,主要有激素分泌活性腺瘤和非激素分泌活性腺瘤两大类。前者包括生长激素瘤 ( GH腺瘤 )、催乳素瘤 ( PRL 腺瘤 )、促肾上腺皮质素瘤 ( ACTH腺瘤 )、Nelson综合征、促甲状腺素瘤 ( TSH腺瘤 )、促性腺素瘤( FSH和 L H腺瘤 ) ;后者包括无功能细胞腺瘤。现将临床比较常见的垂体腺瘤的临床表现介绍如下。1　 GH腺瘤GH腺瘤系因腺垂体生长激素分泌细胞过度分泌 GH所致。成年人若发病在骨骺联合…     

下丘脑—垂体的增龄性变化

动物实验与临床观察揭示,衰老过程中,下丘脑-垂体在结构和功能上发生了重要的改变。下丘脑生长抑素分泌增高,5～HT能神经活性增高,多巴胺和儿茶酚胺能神经活性减低。垂体后叶对ADH的调节异常。垂体前叶GH分泌减少,PRL、TSH、ACTH、LH及FSH分泌紊乱。垂体腺瘤形成。此外,下丘脑-垂体神经递质受体或激素受体减少。这些变化最终导致下丘脑-垂体功能减退及机体的老化。     

垂体前叶病变性闭经

垂体前叶即腺垂体,以垂体门脉系统与下丘脑构成下丘脑-腺垂体系统,直接接受下丘脑神经内分泌激素的调控,可以分泌FSH、LH、PRL、TSH、ACTH和GH六种激素,即性腺六项。垂体前叶病变是引起闭经的重要组成部分。由于腺垂体器质性病变或功能失调引起其分泌激素异常,尤其是促性腺激素分泌异常,进而影响下游卵巢功能,引起闭经。     

垂体腺瘤研究的若干进展

近10年来,垂体腺瘤的研究在各方面有了飞跃的进展兹分述如下: 垂体前叶细胞学 晚近在垂体正常细胞与腺瘤细胞的组织学研究方面获得了丰富的资料。由于细胞染色方法的日益完善、电子显微镜的使用、细胞免疫荧光技术的进展,对细胞的超微结构、尤其是细胞胞浆分泌性颗粒的鉴定业已达到非常精细的程度,从而得以精确判定各种不同的细胞,并按其真正的分泌功能加以命名。现已公认,垂体前叶内存在6种分泌细胞,各自产生相应的一种垂体激素,诸如GH、PRL、ACTH和β-LPH、TSH、FSH及LH。其中后两种激素是否由同一种细胞分泌,尚无定论。Bloodworth认为,还应增加两种细胞:嗜酸性干细胞和未分化细胞。此外,还可偶见瘤细胞(Oncocy-tes)。至于嫌色性细胞,在正常垂体内可能     

垂体转录活化物-1基因在人垂体腺瘤中的表达

目的　用RT PCR方法 ,定量研究垂体转录活化物 (Pit) 1mRNA在不同类型的垂体腺瘤中的表达。方法　 3 5例垂体腺瘤患者根据血清激素水平和临床表现确定腺瘤类型 ,根据影像学和术中所见对肿瘤分级和分期。用RT PCR方法检测垂体腺瘤组织中Pit 1mRNA的表达。结果　 3 5例垂体腺瘤患者有PRL腺瘤 13例 ,GH腺瘤 6例 ,GH/PRL腺瘤 2例 ,无功能瘤 11例以及ACTH腺瘤 3例。Pit 1mRNA在所有PRL瘤、GH/PRL瘤、GH瘤和 81.8% (9/ 11)无功能腺瘤中有表达。在ACTH腺瘤组中无表达。Pit 1mRNA在PRL、GH和GH/PRL 3组腺瘤中的表达量差异无显著性 ,均显著高于无功能瘤组(均P <0 .0 5)。Pit 1表达量与肿瘤分级分期无明显相关性。PRL瘤术前血清PRL值与腺瘤组织Pit 1表达量呈显著的正相关 (r=0 .92 ,P <0 .0 1) ,GH腺瘤术前血清GH值与腺瘤组织Pit 1表达量呈显著的正相关 (r =0 .98,P <0 .0 1)。结论　Pit 1mRNA在PRL、GH、GH/PRL瘤以及大部分无功能腺瘤中有表达 ,其中在PRL、GH以及GH/PRL瘤的表达量较高 ,Pit 1对垂体GH和PRL腺瘤的细胞特异分化以及分泌功能是否具有作用 ,尚待进一步研究     

124例伴血催乳素增高的生长激素分泌性垂体腺瘤临床分析

目的探讨伴血催乳素(PRL)增高的生长激素(GH)分泌性垂体腺瘤的临床特点。方法采用回顾性病例研究方法,对北京协和医院1984年至2004年收治的124例伴血PRL增高的GH分泌性垂体腺瘤患者进行临床和激素水平分析,其中87例随诊1年以上。结果124例患者中女性88例,男性36例,男性病程(8.0±7.3)年长于女性(5.5±4.3)年(P<0.01)。男性和女性患者性腺功能低减者分别占71.6%和69.4%。87例随访患者随访(5.5±4.3)年,其中垂体微腺瘤3例,非侵袭性大腺瘤28例,侵袭性大腺瘤56例。肿瘤免疫组化染色呈单纯GH( )占19.6%,其余多呈多激素染色阳性。血PRL水平与肿瘤体积呈正相关(r=0.261,P<0.05)。鞍上型肿瘤中,单纯GH腺瘤的血PRL值(58.7±1.5)μg/L,明显低于多激素染色腺瘤者的(90.3±2.4)μg/L(P<0.05)。87例随访患者的治愈率为27.6%。结论伴血PRL增高的GH分泌性垂体腺瘤好发于女性,性腺功能低减发生率高,治愈率低,血PRL的水平和肿瘤体积有关,是GH分泌性垂体腺瘤中有独特的临床特点及转归的一种特殊临床亚型。     

伴肢端肥大症垂体腺瘤患者的免疫组化研究

作者应用免疫组织化学方法测定了30例伴有肢端肥大症垂体腺瘤患者的HGH、PRL及ACTH激素抗血清染色,结果27例HGH阳性,其中HGH和PRL混合阳性8例,HGH、PRL和ACTH混合阳性2例。本文对垂俸腺癌组织病理与激素组织定位和临床症状的关系进行了探讨,阐明了免疫组化对于垂体腺瘤功能分类的意义。     

急性头部外伤的垂体前叶机能改变及其临床意义

本文综述头颅急性损伤后,垂体前叶机能的改变,重点介绍垂体前叶各种激素,包括GH、TSH、PRL.LH、ACTH等分泌的变化。此外,还对头部损伤引起的下丘脑、垂体损伤的病理、血循环障碍以及病理生理变化等作了简要阐述。     

内源性类阿片肽对下丘脑—垂体功能的调节

内源性类阿片肽有3个族系。类阿片肽通过抑制GnRH的分泌调节LH和FSH的释放这一作用只见于青春期后。类阿片肽亦抑制垂体—肾上腺轴系,然而对PRL、GH、TSH以及垂体后叶激素的调节作用尚不肯定。     

Distribution and Regulation of Proconvertases PC1 and PC2 in Human Pituitary Adenomas

Pituitary adenomas are members of the family of neuroendocrine cells and tumors which have secretory granules containing chromogranins/secretogranins and other proteins. Pituitary adenomas express the neuroendocrine specific proconvertases PC1 (also known as PC3) and PC2, which are important for the proteolytic processing of chromogranins/secretogranins molecules. We examined the distribution of PC1 and PC2 in primary cultures of 20 pituitary adenomas and analyzed the regulation of the proconvertase mRNAs and proteins by various secretagogues including hypothalamic hormones and phorbol ester to determine the role of PC1 and PC2 in CgA processing in pituitary adenomas. Although PC2 was present in all adenomas, there was a differential distribution of PC1 with PRL adenomas expressing lower levels of PC1 compared to other adenoma types by RT-PCR analysis, in situ hybridization and immunostaining. Treatment of primary cultures of pituitary adenomas with phorbol 12-myristrate 13-acetate (PMA) resulted in an increase in pancreastatin (PST) secretion in most pituitary adenomas and increased PC1 mRNA and protein expression in gonadotroph adenomas, but not in other types of adenomas. Analysis of a human pituitary adenoma cell line, immortalized by recombinant defective adenovirus (HP75), which expressed chromogranin A, FSH, PC1 and PC2 showed that PST was secreted by these immortalized cells. Treatment with TGF1 resulted in an increase in PST secretion and in PC1 mRNA and protein. These results indicate that a) there is a differential distribution of PC1 in human pituitary adenomas with PRL adenomas expressing very little PC1 mRNA and protein and b) that PC1 expression in gonadotropin hormone-producing adenomas is regulated by PMA and TGF1. These findings support the observation that chromogranin A is a substrate for the endoproteinase PC1 in human pituitary adenoma cells.     

Clonal origin of pituitary adenomas

As the pathogenesis of pituitary adenomas remains unclear, the tumor clonal composition of these common neoplasms was studied. Clonality was determined in female patients by analysis of restriction fragment length polymorphisms of the X-chromosome genes hypoxanthine phosphoribosyl transferase and phosphoglycerate kinase in conjunction with their respective methylation patterns. Peripheral lymphocyte DNA was screened from 62 female patients undergoing transsphenoidal surgery for pituitary adenoma. Eleven patients were heterozygous for the BglI site on PGK, 4 for the BamHI site on HPRT, and 1 patient for both sites. Of these 16 patients, 3 had acromegaly, 4 had Cushing's disease, 7 had hyperprolactinemia, and 2 were clinically nonfunctional. After surgery, morphological study, including immunohistochemistry and electron microscopy of the pathological specimens, allowed a direct comparison between clonality and tumor cell type. Control fresh normal pituitary tissue was found to be polyclonal. The following tumors were monoclonal: all 3 somatotroph adenomas, 4 of 4 lactotroph tumors, 3 of 4 corticotroph cell adenomas, a gonadotroph adenoma, and a nonsecretory adenoma. A mixed plurihormonal adenoma was polyclonal, as were 2 tumors consisting of adenomatous lactotrophs interspersed with nontumorous adenohypophyseal pituitary tissue and one corticotroph adenoma mixed with normal pituitary tissue. Functional pituitary adenomas derived from somatotrophs, corticotrophs, or lactotrophs and nonsecretory tumors are monoclonal in nature, suggesting that somatic cell mutations precede clonal expansion of these cells and play a major role in pituitary tumorigenesis.     

Ultrastructural Characteristics of TSH-Producing Adenomas with Special Reference to its Close Similarity to BFA-Treated Pituitary Adenoma Cells

Two of 420 patients with pituitary adenoma who underwent operation from 1989 to 1997 had thyroid stimulating hormone (TSH) producing adenoma. We investigated these TSH cell adenomas with immunohistochemical and ultrastructural methods and compared their ultrastructural features with brefeldin A (BFA, 0.5 mg/ml) treated pituitary adenoma cells. BFA-treated pituitary adenomas include a prolactin (PRL) cell adenoma, a growth hormone (GH) cell adenoma, an adrenocorticotropic hormone (ACTH) cell adenoma, a gonadotroph adenoma, and a plurihormonal adenoma. Immunohistochemical staining disclosed that one of the TSH cell adenomas produced only TSH-;bgr and that another produces both TSH-b and FSH-b. Ultrastructural analysis showed the abundance of oval-shaped dilated rough endoplasmic reticulum (rER). Within the dilated rER, the mistlike deposit or deposit along the inner margin of the rER membrane was observed. On the other hand, BFA-treated cultured pituitary adenoma cells showed the opening of the cavity of the rER cisterna and they enlarged to an oval form with time and revealed an accumulation of electron-dense deposits within the dilated rER. These ultrastructural similarities between TSH cell adenoma and BFA-treated pituitary adenoma cells indicate the functional disturbances in the secretory passage through the Golgi apparatus in TSH cell adenoma cells.     

神经生长因子对体外培养的垂体催乳素瘤细胞的抑制作用

目的 研究神经生长因子（ＮＧＦ）和溴陷亭（ＢＣ）对体外培养的垂体乳素（ＰＲＬ）分泌腺瘤细胞的激素分泌量和增殖的影响。方法 每例体外培养的垂体ＰＲＬ分泌腺瘤细胞分成４组;对照组、ＮＧＦ组、ＢＣ组和ＮＧＦ＋ＢＣ组,对不同的药物干预,观察培养液不激素分泌量和＾３Ｈ－胸腺啶脱氧核苷（ＴｄＲ）摄取率的改变。结果 在８例培养成活的垂体ＰＲＬ分泌腺瘤细胞中,与对照组相比,ＮＧＦ对ＰＲＬ分泌量的抑制作用不明显,但     

Ghrelin immunoexpression in pituitary adenomas

Ghrelin, an orexigenic hormone, is normally produced mainly in stomach. In addition, it has been demonstrated in gastric carcinoid tumors and less often in other neuroendocrine tumors. We investigated ghrelin expression by immunohistochemistry (streptavidin–biotin-peroxidase complex method) in the full spectrum of resected pituitary adenoma subtypes. Quantification of staining considered both the frequency of ghrelin-reactive tumor cells as well as their staining intensity. Cytoplasmic ghrelin immunopositivity was identified in several adenoma subtypes. Cellular staining varied considerably. In addition, the intensity of cell staining differed within the same tumor and between adenoma subtypes. The highest scores were noted in GH producing adenomas exposed to long-acting somatostatin analogs. In decreasing order, lower scores were encountered in ACTH adenomas in Cushing disease, silent subtype 3 adenomas, untreated GH adenomas, silent corticotroph adenomas of subtypes 1 and 2, dopamine agonist-treated PRL adenomas, ACTH adenomas in Nelson syndrome, and gonadotroph adenomas. No significant immunoreactivity was noted in TSH, untreated PRL, and null cell adenomas. The high immunoexpression of ghrelin in GH adenomas exposed to long-acting somatostatin analogs remains unexplained, but may be due to either increased ghrelin production or to suppression of its release. Based on our findings, it appears that ghrelin immunopositivity does not serve as a biomarker of biologic behavior, prognosis and therapeutic responsiveness in pituitary adenomas.     

Immunohistochemical detection of estrogen receptor alpha in pituitary adenomas and its correlation with cellular replication

With the aim of evaluating the relationship between pituitary tumorigenesis and the presence of estrogen receptor-alpha (ERalpha) by immunohistochemistry (IH) and their relevance to patients' clinical presentation, hormonal phenotypes of adenomas, preoperative neuroimaging findings, and the index of cellular replication MIB-1, a study was conducted with material from 91 women and 67 men with pituitary adenomas. The patients had acromegaly (29.7%), Cushing's disease (14.6%), hyperprolactinemic syndrome (20.9%), and clinically nonfunctioning tumors (34.8%). Of the patients, 14.6% had microadenomas, 52.5% had macroadenomas with or without suprasellar growth, 28.5% had invasive macroadenomas and in 4.4% the adenoma was not visualized. IH showed that 43 were positive for growth hormone (GH), 16 for corticotropin (ACTH), 18 for prolactin (PRL), 18 for PRL+GH, 6 for luteinizing hormone (LH) and follicle-stimulating hormone (FSH), 15 had a plurihormonal reaction, and 42 had nonfunctioning adenomas. The presence of ERalpha was positive in 9/158 adenomas with a median value for the percentage of labeled cells of 42.89%, and in 6/16 controls (autopsy samples) with a median value for the percentage of labeled cells of 0.024%. ERalpha was significantly more prevalent in controls than in patients with adenomas (37.5 versus 5.7%; p = 0.001); however, the mean ERalpha concentration in adenomas was significantly greater than in controls (42.89 versus 0.024%; p < 0.001). No significant difference in the concentration of ERalpha was found across the clinical presentations, hormonal phenotypes or findings of preoperative CT. Among the ERalpha-positive adenomas, ERalpha values were significantly greater in invasive macroadenomas (80%) than in microadenomas (3.33%). MIB-1 values did not differ significantly between ERalpha-positive and -negative adenomas, nor did the correlation between ERalpha values and the MIB-1 index attain significance in the total sample, even when only ERalpha-positive adenomas and positive MIB-1 indexes were considered. It was concluded that, when present in pituitary tumors, ERalpha exhibits a high concentration, and is more common in nonfunctioning and invasive adenomas, but absent in ACTH-secreting ones.     

MAP-2 Expression in the Human Adenohypophysis and in Pituitary Adenomas. An Immunohistochemical Study

MAP-2, a well characterized member of the microtubule associated protein (MAP) family, binds to and stabilizes microtubules and is involved in cell proliferation as well as neuronal differentiation. The aim of the present work was to study MAP-2 expression in human adenohypophyses and pituitary adenomas. To our knowledge, data regarding MAP-2 expression in human pituitaries has not been reported to date. For immunohistochemistry, the streptavidin-biotin-peroxidase complex method was used. Nine non-tumorous adenohypophyses and 77 adenomas (GH-, PRL-, ACTH-, TSH-, FSH/LH- and/or alpha subunit- producing or immunonegative tumors) were investigated. The results show that MAP-2 is expressed in the cytoplasm of non-tumorous adenohypophysial cells as well as of various pituitary adenoma types. No significant correlation was found between MAP-2 expression and gender, patient age, mitotic activity, MIB-1 labelling indices, hormone immunoprofile, and endocrine status, ie. hormonal activity or lack thereof. Thus MAP-2 expression cannot be used to estimate cell proliferation rate, growth potential, endocrine activity or biologic behaviour of an adenoma. Immunopositivity appeared to be stronger in the cytoplasm of adenoma cells than in that of non-tumorous adenohypophysial cells, implying that the adenoma cells contain larger quantities of MAP-2. It can be concluded that the functional activity of MAP-2 is not associated with the manufacture of any specific adenohypophysial hormone(s) and is not limited to one specific cell type.     

GLYCOPROTEIN HORMONE ALPHA-SUBUNIT AND PROLACTIN RELEASE BY CULTURED PITUITARY ADENOMA CELLS FROM ACROMEGALIC PATIENTS: CORRELATION WITH GH RELEASE

In-vitro data of pituitary adenoma cells from 28 acromegalic patients were evaluated. In addition to GH, PRL was produced by 16 adenomas (57%) and alpha-subunit by 15 adenomas (54%) while there was a significantly higher incidence of tumours producing PRL and alpha-subunit simultaneously. From 26 pituitary adenomas enough cells were obtained in order to perform secretion studies. Percentage basal hormone release (medium: (medium + intracellular hormone)) x 100% of GH and alpha-subunit by 11 adenomas showed a close correlation while such a correlation for GH and PRL was present only in a subgroup of 10 of 13 adenomas. The responses of GH and alpha-subunit release to 10nM SMS201-995, 10nM bromocriptine, 100 nM TRH and 10nM GHRH were closely related in that a response or an absent response of GH release to the four secretagogues was virtually always attended with a response or an absent response respectively of alpha-subunit release. Such a relationship was less evident with respect to the effects of SMS201-995, bromocriptine. TRH and GHRH on GH and PRL release. We conclude that basal and secretagogue-induced alpha-subunit release by cultured pituitary adenoma cells from acromegalic patients closely follows the pattern of GH release while such a relationship for GH and PRL is present only in a subgroup of the adenomas secreting GH and PRL simultaneously.