垂体催乳素瘤的病因及发病机理的实验研究
摘要
垂体催乳素瘤(Prolactin-producing tumor或prolactinoma，简称PRL瘤)是内分泌系统较常见的疾病之一，且发病人群以青壮年为主，主要表现为闭经、泌乳及巨大瘤体对周围组织(如蝶窦、视神经和下丘脑等)的压迫症状，严重威胁人们的身体健康。遗憾的是，长期以来有关PRL瘤的病因和发病机制尚不完全清楚，以至于临床上对该病的诊断和治疗还存在一些困难。本文通过证明垂体PRL瘤原发于腺垂体的可能性、检测垂体局部自分泌／旁分泌性生长因子在垂体前叶细胞中的表达与作用、及初步探讨垂体PRL瘤形成过程PRL基因高表达的分子机制等三方面的研究，旨在揭示垂体PRL瘤形成的部分机制，从而为最终阐明垂体PRL瘤的病因和发病机理，以及临床诊断与治疗垂体PRL瘤等提供一些理论与实验依据。
第一部分的工作，我们建立了移植另一异体垂体于SD大鼠肾囊内的动物模型(即每只大鼠除具有本身的原位垂体外，肾囊内另移植入一异体垂体，下称垂体异体移植大鼠)，用17-β-雌二醇(estradiol，E_2)处理60d和120d后，经整体、组织学、细胞超微结构等三个水平的形态学观察，以及采用原位杂交方法检测细胞内PRL基因表达等方面的实验研究，证明了垂体PRL瘤原发于腺垂体的可能性；随之在第二部分工作中我们采用垂体前叶细胞原代培养及激光扫描共聚焦显微镜(Laser Scanning Confocal Microscopy，LSCM)扫描、分子杂交等方法进一步探讨了垂体局部的某些自分泌／旁分泌性生长因子对垂体前叶细胞增殖活性和PRL基因表达的影响，以及在E_2体内、体外作用期间，PRL基因、转化生长因子α(transforming growth faotor α，TGFα；其功能之一可促进细胞增殖。)和转化生长因子β1(TGFβl；其功能之一可抑制细胞增殖。)基因表达水平的改变；第三部分，我们首先采用PCR-SSCP和DNA测序
The pituitary prolactin-producing tumor ( prolactinoma ) is one of the fairly common lesions in endocrine system. Most patients with pituitary prolactinoma present with amenorrhea and galactorrhea. Other clinical menifestations, such as visual disturbances, headache, cranial nerve injury, and endocrine dysfunction, may caused by oppression of macroprolactinoma on the anterior pituitary or the hypothalamus and hyperprolactinemia. However, the pathogenesis of prolactinoma is not very clear at present. In order to elucidate the mechanisms of pituitary prolactin-producing tumors formation, three parts of studies were included in this paper: 1. Demonstrating the possibility that pituitary prolactinoma induced by E_2 in SD rats may originate from the pituitary level, independently of the influences of hypothalamic factors. Male SD rats (30 days old ) were transplanted with an extra pituitary under their renal capsules and treated with s.c. implantation of an empty or E_2( 17-β-estradiol )-laden silastic capsule. After treatment with E_2 for 60 days and 120 days, the changes at the levels of the whole body, anterior pituitary tissue and cellular ultrastructure were analysized by radioimmunoassay ( RIA), light and electron microscopy, etc. 2. Testing the effects of E_2, epidermal growth factor ( EGF) and transforming growth factor β1( TGFβ1) on the proliferative activity and PRL gene expression in primary cultured anterior pituitary cells, and the effects of E_2 on the expression of TGFα, TGFβ1 in in vitro and in vivo. Northern blot assay, in situ hybridization and laser scanning confocal microscopy( LSCM ) were employed. 3. Mutation screening in the 5' flanking sequence of the PRL gene and detecting the function of the mutant, by porymerase chain reaction ( PCR )- single-strand conformation polymorphism( SSCP ), DNA sequencing techniques and PRL promoter-luciferase fusion gene transient transfection
第一部分的工作，我们建立了移植另一异体垂体于SD大鼠肾囊内的动物模型(即每只大鼠除具有本身的原位垂体外，肾囊内另移植入一异体垂体，下称垂体异体移植大鼠)，用17-β-雌二醇(estradiol，E_2)处理60d和120d后，经整体、组织学、细胞超微结构等三个水平的形态学观察，以及采用原位杂交方法检测细胞内PRL基因表达等方面的实验研究，证明了垂体PRL瘤原发于腺垂体的可能性；随之在第二部分工作中我们采用垂体前叶细胞原代培养及激光扫描共聚焦显微镜(Laser Scanning Confocal Microscopy，LSCM)扫描、分子杂交等方法进一步探讨了垂体局部的某些自分泌／旁分泌性生长因子对垂体前叶细胞增殖活性和PRL基因表达的影响，以及在E_2体内、体外作用期间，PRL基因、转化生长因子α(transforming growth faotor α，TGFα；其功能之一可促进细胞增殖。)和转化生长因子β1(TGFβl；其功能之一可抑制细胞增殖。)基因表达水平的改变；第三部分，我们首先采用PCR-SSCP和DNA测序
The pituitary prolactin-producing tumor ( prolactinoma ) is one of the fairly common lesions in endocrine system. Most patients with pituitary prolactinoma present with amenorrhea and galactorrhea. Other clinical menifestations, such as visual disturbances, headache, cranial nerve injury, and endocrine dysfunction, may caused by oppression of macroprolactinoma on the anterior pituitary or the hypothalamus and hyperprolactinemia. However, the pathogenesis of prolactinoma is not very clear at present. In order to elucidate the mechanisms of pituitary prolactin-producing tumors formation, three parts of studies were included in this paper: 1. Demonstrating the possibility that pituitary prolactinoma induced by E_2 in SD rats may originate from the pituitary level, independently of the influences of hypothalamic factors. Male SD rats (30 days old ) were transplanted with an extra pituitary under their renal capsules and treated with s.c. implantation of an empty or E_2( 17-β-estradiol )-laden silastic capsule. After treatment with E_2 for 60 days and 120 days, the changes at the levels of the whole body, anterior pituitary tissue and cellular ultrastructure were analysized by radioimmunoassay ( RIA), light and electron microscopy, etc. 2. Testing the effects of E_2, epidermal growth factor ( EGF) and transforming growth factor β1( TGFβ1) on the proliferative activity and PRL gene expression in primary cultured anterior pituitary cells, and the effects of E_2 on the expression of TGFα, TGFβ1 in in vitro and in vivo. Northern blot assay, in situ hybridization and laser scanning confocal microscopy( LSCM ) were employed. 3. Mutation screening in the 5' flanking sequence of the PRL gene and detecting the function of the mutant, by porymerase chain reaction ( PCR )- single-strand conformation polymorphism( SSCP ), DNA sequencing techniques and PRL promoter-luciferase fusion gene transient transfection
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