本文選題：泌乳素腺瘤 + PRL　； 參考：《北京協(xié)和醫(yī)學(xué)院》2015年博士論文

【摘要】：研究背景：垂體泌乳素腺瘤是最常見的功能性垂體腺瘤,約占成人腺瘤的40%-50%。其典型的臨床表現(xiàn)為高泌乳素血癥、鞍區(qū)周圍組織壓迫癥狀、垂體前葉部分功能受損等。首選多巴胺受體激動(dòng)劑治療,可對(duì)90%的患者緩解癥狀。目前中外垂體泌乳素腺瘤相關(guān)指南認(rèn)為血清泌乳素水平高于200ng/mL的垂體腺瘤明確診斷泌乳素腺瘤,而高于100ng/mL則主要考慮泌乳素腺瘤的診斷；但是對(duì)于泌乳素水平高于正常但低于100ng/mL的患者診斷尚不明確。而10%對(duì)多巴胺受體激動(dòng)劑不敏感的患者稱之為耐藥性泌乳素腺瘤,目前對(duì)于泌乳素腺瘤耐藥機(jī)制的研究及治療是前沿領(lǐng)域,其中血管新生是否是可能的耐藥機(jī)制及潛在治療靶點(diǎn)尚待研究；而他汀類藥物作為新興的抗腫瘤藥物在垂體泌乳素腺瘤中是否存在作用仍有待研究。本文主要正對(duì)泌乳素腺瘤診斷和治療中的相關(guān)問題予以探索和分析。研究目的：1)明確垂體泌乳素腺瘤診斷的泌乳素水平臨界值的范圍。2)觀察耐藥性垂體泌乳素腺瘤與敏感性垂體泌乳素腺瘤在血管新生方面是否存在差異。3)初步探究他汀類藥物對(duì)于垂體泌乳素腺瘤MMQ和GH3細(xì)胞系的作用及潛在的作用機(jī)制。研究方法：1)采用IPP軟件半定量分析不同泌乳素水平的垂體腺瘤免疫組化PRL染色陽性程度的差異,并為確立診斷泌乳素腺瘤的血清泌乳素水平臨界值提供依據(jù)。2)采用免疫組化觀察耐藥性垂體泌乳素腺瘤及敏感性垂體泌乳素腺瘤標(biāo)本血管新生相關(guān)因子表達(dá)量的差異,如血管內(nèi)皮生長(zhǎng)因子(VEGF)和CD31；以及胞外基質(zhì)蛋白如MMP2和MMP9表達(dá)量的差異。3)使用不同濃度的辛伐他汀處理大鼠MMQ和GH3細(xì)胞系的作用,采用CCK8、流式細(xì)胞學(xué)、Western Blotting和Elisa等方法分析其對(duì)細(xì)胞增殖、凋亡、PRL表達(dá)等的作用及潛在的分子機(jī)制。結(jié)果：1)泌乳素水平高于100ng/mL的垂體腺瘤,與泌乳素水平高于正常但小于100ng/mL的垂體腺瘤相比,免疫組化PRL表達(dá)量明顯高于后者；2)耐藥性垂體泌乳素腺瘤的VEGF表達(dá)量高于敏感性垂體泌乳素腺瘤組,但二者在MMP2、MMP9和CD31方面的表達(dá)量基本沒有差異。3)耐藥性垂體泌乳素腺瘤VEGF表達(dá)量的高低與Ki67數(shù)值相關(guān),與腫瘤大小、泌乳素水平無關(guān)。4)他汀類藥物可在MMQ和GH3細(xì)胞系中抑制增殖、誘導(dǎo)凋亡、抑制PRL的分泌并抑制VEGF蛋白表達(dá)量。結(jié)論：1)血清泌乳素水平高于100ng/mL的垂體腺瘤首先考慮診斷垂體泌乳素腺瘤。2)耐藥性垂體泌乳素腺瘤VEGF的表達(dá)量與細(xì)胞增殖程度相關(guān),可能與難治性泌乳素腺瘤或侵襲性泌乳素腺瘤相關(guān)。3)他汀類藥物可能作為耐藥性垂體泌乳素腺瘤的潛在治療藥物,更多分子機(jī)制有待研究。
[Abstract]:Background: pituitary prolactin adenomas are the most common functional pituitary adenomas, accounting for 40-50 percent of adult adenomas. The typical clinical manifestations were hyperprolactinemia, compression of periSellar tissues and impaired anterior pituitary function. The first choice of dopamine receptor agonists is to relieve symptoms in 90% of patients. At present, the related guidelines of pituitary prolactin adenoma in China and abroad think that the pituitary adenoma with higher serum prolactin level than 200ng/mL has definite diagnosis of prolactin adenoma, but higher than 100ng/mL mainly considers the diagnosis of prolactin adenoma. But the diagnosis of prolactin levels higher than normal but lower than 100ng/mL remains unclear. 10% of the patients who are insensitive to dopamine receptor agonists are called drug-resistant prolactin adenomas. Whether angiogenesis is a possible drug resistance mechanism and a potential therapeutic target remains to be studied, and whether statins are a new antitumor agent in pituitary prolactin adenoma remains to be studied. This article is mainly about the diagnosis and treatment of prolactinoma. Objective: to determine the range of critical value of prolactin level in diagnosis of pituitary prolactin adenoma. (2) to observe whether there are differences in angiogenesis between drug-resistant pituitary prolactin adenoma and sensitive pituitary prolactin adenoma. Effect of statins on MMQ and GH3 cell lines of prolactinoma and its potential mechanism. Methods IPP software was used to semi-quantitatively analyze the difference of immunohistochemical PRL staining in pituitary adenomas with different prolactin levels. In order to establish the critical value of serum prolactin level in the diagnosis of prolactinoma, the expression of angiogenic factors in drug-resistant pituitary prolactin adenoma and sensitive pituitary prolactin adenoma was observed by immunohistochemistry. For example, vascular endothelial growth factor (VEGF) and CD31, and the difference in expression of extracellular matrix proteins such as MMP2 and MMP9.) the effects of simvastatin on rat MMQ and GH3 cell lines treated with different concentrations of simvastatin were observed. The effects of CCK8, flow cytometry, Western Blotting and Elisa on cell proliferation, apoptosis and expression of PRL were analyzed and their potential molecular mechanisms were analyzed. Results the prolactin level in pituitary adenomas with 100ng/mL was higher than that in pituitary adenomas with higher prolactin level than in pituitary adenomas with higher prolactin level but smaller than 100ng/mL. The expression of VEGF in prolactin adenoma was significantly higher than that in the sensitive pituitary prolactinoma group, and the expression of VEGF in the resistant pituitary prolactinoma was significantly higher than that in the sensitive pituitary prolactinoma group. However, there was no difference in the expression of MMP2, MMP9 and CD31 between them. 3) the level of VEGF expression in drug-resistant pituitary prolactin adenoma was correlated with the value of Ki67, but not with tumor size, prolactin level. 4) statins could inhibit proliferation in MMQ and GH3 cell lines. Apoptosis was induced, PRL secretion was inhibited and VEGF protein expression was inhibited. Conclusion in pituitary adenomas whose serum prolactin level is higher than that of 100ng/mL, the first consideration is to diagnose prolactin adenoma. 2) the expression of VEGF in drug-resistant pituitary prolactin adenoma is correlated with cell proliferation. May be associated with refractory prolactin adenoma or invasive prolactin adenoma. 3) statins may be a potential therapeutic drug for drug-resistant pituitary prolactin adenoma, more molecular mechanisms need to be studied.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R736.4

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相關(guān)期刊論文 前1條

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本文編號(hào)：1828666