【作者】 王民；

【导师】 曲元明；

【作者基本信息】 山东大学 ， 外科学， 2012， 博士

【摘要】 目的肢端肥大症是一种发病率比较低的疾病,它的特点是血清中生长激素(GH)和胰岛素样生长因子1(IGF-1)的含量增高。尽管肢端肥大症的病程进展比较缓慢,但它可导致全身各个系统的改变,尤其是面容和肢体末梢的变化。由于肢端肥大症可引起心、脑血管及肺部并发症,因而,患者的发病率和死亡率要高于正常人群。一般来说,大多数肢端肥大症患者都是由生长激素腺瘤引起的,他们所表现出的症状体征也都是由血液中过高的生长激素引起的；而且,在肢端肥大症患者中,大约有16-27%的病人最终发展为肢端肥大症合并高泌乳素血症,即患者血清中生长激素和泌乳素(PRL)同时升高。由于生长激素合并高泌乳素血症患者的发病率相对较低,所以,到目前为止,此类患者还没有比较完整的临床研究资料。本研究的主要目的在于通过比较单纯生长激素增高的肢端肥大症患者与肢端肥大症合并高泌乳素血症患者的临床资料,来揭示生长激素合并高泌乳素血症患者的临床特点。方法第一部分患者术前临床特点回顾性分析2002.01至2010.06期间在山东省立医院神经外科就诊的生长激素及泌乳素腺瘤的患者。其中,279例患者具有完整的术前及术后一年的临床资料。所有患者均在我院接受经鼻蝶入路垂体瘤切除术治疗,并且保留比较完整的临床资料。所有患者都接受了术前MRI检查。根据患者术前血清生长激素和泌乳素的水平,患者分为GH组(单纯GH升高的患者)和GH+PRL组(GH与PRL均升高的患者)。为了研究GH+PRL患者的PRL水平,选取部分泌乳素腺瘤患者作为PRL组。所有患者均在术前、术后3天、3月和术后12月进行GH和PRL测定。在治疗和随访期间,我们主要观察了患者的临床表现、激素水平、免疫组化结果以及MRI表现方面的改变,借此来研究生长激素腺瘤合并高泌乳素血症患者的临床特点和影响手术效果的因素。第二部分：标本处理所有组织标本均先用10%福尔马林溶液进行固定,然后用石蜡包埋,最后用苏木精进行染色处理。所有标本均用GH和PRL抗体进行检测。结果第一部分：临床特点在GH组,男性占50.5%,患者的平均发病年龄为45.6±13.9岁(11.4-75.2岁),从开始发病到就诊的平均间隔时间为66.0±65.3月(0.5-324月),肿瘤平均最大直径为2.2±0.9cm(0.6-4.2cm)。在GH+PRL组,男性占42.3%,患者的平均发病年龄为40.4±11.4岁(20.1-72.6岁),平均间隔时间为52.8±49.4月(1.0-240月),肿瘤平均最大直径为2.6±1.1cm(0.5-5.8cm)。两组患者在平均发病年龄(P=0.001)和肿瘤平均最大直径(P=0.004)方面有明显的差异,但在性别比例(P=0.209)和发病间隔(P=0.067)上两者无明显差异。患者最常见的临床表现为面容改变、手脚增大、头痛、头晕、恶心呕吐、易疲劳及手脚麻木,常见的并发症为高血压和糖尿病。由垂体内分泌功能紊乱引起的常见临床表现为多饮多尿、性欲减退,在女性还表现为月经紊乱和溢乳。在这些临床表现中,头痛、头晕、恶心呕吐、肢端麻木、性欲减退以及易疲劳的发病率在两组患者中没有明显的差异,但在面容改变、多饮多尿、手脚增大、月经紊乱和溢乳上,两者差异明显。在并发症方面,糖尿病的发病率差异明显。数据表明,GH组患者的面容改变、多饮多尿、手脚增大和糖尿病的发病比例较高,但在女性患者中,月经紊乱和溢乳的发病率明显要低。第二部分：激素水平的比较GH组患者术前GH和PRL水平分别为42.35±30.48ng/ml和15.21±12.26ng/ml.GH+PRL组患者的GH和PRL水平分别为23.43±15.78ng/ml和131.29±76.62ng/ml.与GH+PRL组相比,GH组患者的GH水平明显偏高(P<0.001),但PRL水平明显偏低(P<0.001)。术后,除了GH组患者的PRL水平无明显变化外,两组患者的激素水平均明显下降。GH组患者术后3天的GH水平为20.37±18.31ng/ml,术后1年的水平为23.87±20.01ng/ml,两者之间无明显差别。在GH+PRL组,患者术后3天、术后1年的GH水平分别为13.61±10.86ng/ml和14.84±11.62ng/ml；在相同时间点上,PRL的水平分别为32.96±15.91ng/ml和33.44±15.38ng/ml。而且,术后各时间点的GH和PRL之间没有明显差异。但是,不论是GH还是PRL,两种激素的术前、术后水平均存在明显的差异。PRL组患者术前PRL水平为169.2±92.0ng/ml,术后3天、1年的PRL水平分别为45.4±30.5ng/ml和42.9±34.8ng/ml。第三部分：免疫组化结果GH组患者GH和PRL免疫组化的阳性率分别为91.2%和30.7%。GH+PRL组患者GH和PRL免疫组化的阳性率分别为84.5%和86.6%。所以,两组患者的PRL阳性率差别明显。而且,进一步的分析后发现,GH和PRL免疫组化的阳性率与术前激素水平没有明显的相关性(r=+0.348,P>0.05和r=+0.457,P>0.05)。第四部分：MRI结果分析在GH和GH+PRL组,术前大中腺瘤患者的比例分别为60.4%和45.1%,两组患者差异明显(P=0.041)。根据术后三个月的MRI检查结果分析,GH组患者肿瘤切除率(全切及次全切)为80.7%,GH+PRL组的切除率为69.1%,两者差异明显(P=0.037)。第五部分：复发率通过分析术后1年的激素和MRI检查结果,我们发现,GH和GH+PRL组的肿瘤复发率分别为7.1%和11.3%,两者之间没有明显的差别(P=0.185)。结论1.与单纯GH升高的生长激素腺瘤患者相比,GH+PRL患者具有发病年龄早、典型外貌特征少,但肿瘤直径较大的特点。特别是在女性患者,生长激素合并高泌乳素血症患者的月经紊乱和溢乳的发病率明显增高。2. GH+PRL患者的生长激素水平相对较低,但泌乳素水平明显偏高。GH+PRL患者的PRL免疫组化阳性率高,但GH阳性率与单纯GH患者相比无明显差别。而且,免疫组化阳性率与术前激素水平没有明显的相关性。3. GH+PRL患者肿瘤的全切及次全切率比单纯GH患者低,但二者复发率无明显差别。更多还原

【Abstract】 ObjectiveAcromegaly is a rare disease characterized by excess secretion of growth hormone (GH) and increased circulating concentrations of insulin-like growth factor-1(IGF-1). It is characterized by slowly progressive acquired somatic disfigurement (mainly involving face and extremities) and systemic manifestations. The disease is associated with increased morbidity and premature mortality, due to cardiovascular, cerebrovascular, or respiratory causes. In general, the underlying abnormality in most cases is hypersecretion of GH by the pituitary GH-producing tumors. Nonetheless, about16-27%of these patients have increased GH and prolactin (PRL) levels. Therefore, the characteristics of acromegaly with increased growth hormone (GH) and hyperprolactinemia in patients were not clearly established, probably due to the relatively low annual incidence. The aim of this study is to evaluate clinical data from a large cohort of acromegalic patients with and without hyperprolactinemia.Design and methodsPart1. patients and their characteristics before surgeryA retrospective chart review was performed on all patients with GH producing adenomas treated between January2002and June2010at the Department of Neurosurgery, Provincial Hospital Affiliated to Shandong University, Jinan. A total of279patients had a complete set of data before and one year after surgery. Magnetic resonance imaging (MRI) examinations were done in all patients. Based on the preoperative GH and PRL levels, patients were classified as follows:GH group (acromegalic patients with elevated GH levels), GH+PRL group (acromegalic patients with both elevated GH and prolactin levels) and PRL group (patients with prolactinoma). GH and PRL levels were assessed before surgery and3days and12months after surgery respectively. A stabilization or a further improvement of postoperative changes in clinical, hormonal, immunohistochemical and magnetic resonance imaging (MRI) parameters was observed in all patients throughout the follow-up period.Part2. immunohistochemistry examinationAll specimens were fixed in10%formalin, embedded in paraffin and stained by the haematoxylin-eosin method. All the resected tissues were examined by immunohistochemistry with antibodies against GH and PRL.ResultsPart1. Clinical features before surgeryIn GH group,50.5%of the patients were male; the mean age at diagnosis was45.6±13.9years (range,11.4-75.2years). The mean time interval from the onset of acromegaly-specific symptoms and signs to the date of diagnosis was66.0±65.3months (range,0.5-324months). The mean maximal diameter of adenomas was2.2±0.9cm (range,0.6-4.2cm). In GH+PRL group,42.3%of the patients were male; the mean age at diagnosis, the mean time interval and the mean maximal diameter of adenomas were40.4±11.4years (range,20.1-72.6years),52.8±49.4months (range,1.0-240months) and2.6±1.1cm (range,0.5-5.8cm) respectively. The mean age at diagnosis and mean maximal diameter of adenomas were significantly different between the two groups (P=0.001and P=0.004, respectively), but gender and the mean time interval had no significant differences. The most common presenting clinical manifestations and complications encountered in the two groups (GH group vs. GH+PRL group) were coarse facial features (75.4%vs.54.3%), large hands and feet (73.8%vs.58.6%), headache (38.5%vs.41.9%), dizziness (10.0%vs.10.1%), nausea and vomiting (4.6%vs.3.9%), fatigue (3.8%vs.3.9%), distension and numbness (3.8%vs.1.6%), hypertension (10.0%vs.3.9%), diabetes mellitus (17.7%vs.6.9%) and those of pituitary endocrinological disturbances:polyuria and polydipsia (16.2%vs.5.4%), hyposexuality (4.6%vs.10.9%), and in females, menstrual disorder (13.8%vs.54.3%) and galactorrhea (3.1%vs.22.4%). No significant differences were observed in headache (P=0.613), dizziness (P=1.0), nausea and vomiting (P=1.0), hyposexuality (P=0.066), distension and numbness (P=0.447), fatigue (P=1.0) and hypertension (P=0.085). But there were significant differences between the two groups:coarse facial features (P=0.013), polyuria and polydipsia (P=0.008), large hands and feet (P<0.001), menstrual disorder (P<0.001), galactorrhea (P<0.001) and diabetes mellitus (P=0.013). So, data indicated that there were higher incidences of coarse facial features, polyuria and polydipsia, large hands and feet and diabetes mellitus in GH group patients, but the incidences of menstrual disorder and galactorrhea in female patients were especially lower than that of GH+PRL group.Part2. Comparison of hormone levelsThe levels of GH and PRL in GH group before surgery were42.35±30.48ng/ml and15.21±12.26ng/ml, while those in GH+PRL group were23.43±15.78ng/ml and131.29±76.62ng/ml respectively. Therefore, the GH level of GH group was significantly higher than that of GH+PRL group (P<0.001), whereas the PRL was extremely lower (P<0.001). The GH and PRL levels of the two groups decreased obviously after surgery, except the PRL of GH group. The GH levels of GH group were20.37±18.31ng/ml at3days,19.26±18.22ng/ml at3months and23.87±20.01ng/ml at12months after the operation, and there were no significant differences with each other (P=0.526). In GH+PRL group, the postoperative levels of GH at the three time points were13.61±10.86ng/ml,13.22±11.52ng/ml and14.84±11.62ng/ml respectively, while those of PRL were32.96±15.91ng/ml, 31.82±17.63ng/ml and33.44±15.38ng/ml respectively. Also, both the postoperative GH and PRL levels in GH+PRL group had no significant differences with each other (P=0.584and P=0.778, respectively). However, there were significant differences when the postoperative levels of GH or PRL were compared between two groups. Moreover, except the PRL of GH group, there were also significant differences when pre-and postoperative levels of GH or PRL were compared (P<0.01,P<0.01and P<0.01,respectively). The preoperative PRL level was169.2±92.0ng/ml, and the postoperative PRL levels were45.4±30.5ng/ml at3days and42.9±34.8ng/ml at12months.Part3. Immunohistochemistry evaluationIt showed that the positive rates of GH and PRL in GH group were91.2%and30.7%, and those results of GH+PRL group were84.5%and86.6%respectively. So, significant difference was observed between the PRL positive rates of the two groups (P<0.05), whereas GH, as expected, did not (P=0.11). Moreover, there is no significant correlation between the preoperative mean GH or PRL concentrations and the immunostaining positive rates (r=+0.348, P>0.05and r=+0.457, P>0.05, respectively).Part4. MRI findingsThe proportion of preoperative meso-and macro-adenoma of GH+PRL group was significantly higher than that of GH group (60.4%vs.45.1%, P=0.041). According to the MRI findings at3-month after surgery, the overall resection rate of GH+PRL group was distinctly lower than that of GH group (69.1%vs.80.7%, P=0.037).Part5. recurrence rateHormone and MRI examinations were performed on all patients12-month after surgery. By analyzing these data, we found the recurrence rates of GH and GH+PRL group were7.1%and11.3%, and no significant difference was observed between the two groups (P=0.185).Conclusions 1. Compared to patients with merely GH-secreting adenomas, acromegalic patients with hyperprolactinemia are characterized by an earlier onset of disease, lesser acromegalic features, lower GH levels, but larger tumor sizes, whereas in female patients, GH-prolactin secreting adenomas are associated with higher incidences of menstrual disorders and galactorrhea.2. Compared to patients with merely GH-secreting adenomas, acromegalic patients with hyperprolactinemia have lower GH but higher PRL levels and higher PRL but normal GH positive rates. Moreover, no significant correlations between the preoperative mean GH or PRL concentrations and the immunostaining positive rates were observed.3. Compared to patients with merely GH-secreting adenomas, the resection rate is lower in acromegalic patients with hyperprolactinemia, but there is no significant differences in recurrence rate between these patients.更多还原