肝郁型高泌乳素血症患者人格特征及大鼠模型神经内分泌改变的研究
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摘要
目的
本研究在临床调查方面通过对临床肝郁型HPRL病例人格和心理调查,试图从社会-心理模式来探讨肝郁型高泌乳素血症的性格取向,为HPRL的心理治疗和预防提供理论依据；在情志致病和心理应激理论的基础上,探索合理的肝郁型高泌乳素血症(Hyperprolactinemia, HPRL)动物模型的制备,为今后中医药对HPRL辨证施治的动物学研究奠定基础；从行为学和神经-内分泌系统两方面与传统HPRL模型进行比较,来探讨肝郁型高泌乳素血症的发病机制。
方法
1.临床研究方法
A组：肝郁型高泌乳素血症组(HPRL)共28例,B组：肝郁型非高泌乳素血症组30例,C组：正常对照组25例。以连续两次PRL≥30ng/ml为HPRL诊断标准。
以月经病、不孕、溢乳就诊的肝郁型病人于月经周期第1-3天上午9：30-10：30(静坐15min)空腹抽取外周静脉血,化学发光法测定血清泌乳素(Prolactine, PRL)、促卵泡生成素(FSH)、促黄体生成素(LH)、雌二醇(Estradiol, E2)和睾酮(Testosterone, T),无明显月经周期的患者不拘时检测,泌乳素增高患者需复查血清泌乳素水平,符合纳入和排除标准的分为一组(A组),泌乳素正常的符合肝郁型非高泌乳素血症纳入标准及排除标准3-8项的归为肝郁型非高泌乳素血症组(B组)。正常对照组为同期医院体检中心的健康人群(C组)。A、B两组进行肝郁症状的量化评分。
A、B、C三组人在30分钟内填写艾森克心理问卷和STAI(State—Trait Anxiety Inventory, STAI-Form)焦虑评定表。艾森克问卷以“是”或“否”作答。把答案输入到艾森克成人测试软件5.0,得到P(精神质)、E(内外向)、N(神经质)、L(撒谎)四个维度的T分。STAI焦虑评定表分为状态焦虑评定表(S-AI)和特质焦虑评定表(T-AI)各有20题按1-4级填写,正向题目根据答案按4-1反相记分,负向题目则按1-4正相记分。
2.实验研究方法
SPF级SD雌性大鼠37只,体重200g±20g。饲养1W后,按体重分层后再随机分为四组,分别为：
A组：肝郁组11只
B组：肝郁+甲氧氯普胺(灭吐灵)组10只
C组：甲氧氯普胺组8只
D组：正常组8只
模型制备：从造模第1天开始,B、C两组大鼠于皮下注射甲氧氯普胺注射液,62.5mg/kg体重,每天1次,连续8天；B组在皮下注射甲氧氯普胺的同时,从造模第1天开始和A组一起给予5种不可预知的心理应激刺激。刺激方法随机安排21d内连续进行。D组不接受任何刺激。
观察动物的排便、精神状况、活动度及体重变化；在最后一次造模后,12h内禁食,自由饮水,于造模开始第22天上午称重后于8：00-11：00在10%水合氯醛麻醉后,断头取血,保存血清于-80℃保存待测性激素。冰块上分离出下丘脑组织,称重后保存于-80℃的冰箱中,待检测单胺类神经递质去甲肾上腺素(Norepinephrine Bitartrate, NE)和5-羟色胺(5-hydroxytryptamine Hydrochloride,5-HT)。
结果
1.临床调查结果
(1)性激素比较：肝郁型HPRL患者血清LH、E2明显低于肝郁型非高泌乳素血症组(p<0.05)。两组FSH经统计,差异不显著(p>0.05),在T值上肝郁型HPRL有上升趋势,但差异不显著(p>0.05)。
(2)肝郁积分和年龄比较：结果提示：肝郁型HPRL组的肝郁积分与肝郁型非高泌乳素血症组相比无明显差异(p>0.05)。三组妇女年龄分布无统计学意义,具有可比性(p>0.05)。
(3)艾森克人格问卷分析：L(测谎量表)值在三组中无明显差别(p>0.05)；肝郁型高泌乳素血症组在P(精神质)、N(神经质)积分上均显著高于肝郁型非高泌乳素血症组和正常组,差异均有统计学意义(p<0.01),在E(内外倾)积分上与肝郁型非高泌乳素血症组无明显差别(p>0.05),但明显低于正常组(p<0.01)；肝郁型非高泌乳素血症组和正常组相比,E分值明显低于正常组(p<0.01),N分明显高于正常组(p<0.01),而P分值与正常组无明显差别(p>0.05)。
(4)焦虑评分比较：肝郁型高泌乳素血症组、肝郁型非高泌乳素血症组和正常组相比状态焦虑值和特质焦虑值均明显升高,有统计学意义(p<0.05),肝郁型高泌乳素血症组和肝郁型非高泌乳素血症组相比,状态焦虑值明显升高,有统计学意义(p<0.01),特质焦虑积分也明显升高(p<0.01)。
2.动物实验结果
(1)行为学观察：随着造模时间的推移,肝郁模型组(A组)和肝郁+甲氧氯普胺模型组(B组)大鼠均表现为毛色失去光泽,易于脱落,活动减少,喜欢贴笼壁,大便稍稀,甲氧氯普胺组(C组)大鼠则表现为镇静、思睡、乏力,在受外界刺激时A、B组大鼠紧张度和对应激的反应程度高于C组。
(2)体重比较：造模前,各组体重组间比较,无统计学意义(p>0.05),具有可比性;造模后,A、B组体重增加缓慢,与D组比较,有明显统计学意义(p<0.05),C组与D组比较无统计学意义(p>0.05),A组与B组比较,体重增加较B组缓慢,差异有统计学意义(p<0.05)。
(3)性激素比较：造模后,A、B组大鼠血清PRL值与D组比较显著升高,结果具有统计学意义(p<0.01),C组PRL值与D组比较显著升高,有统计学意义(p<0.05),A、B组的血清PRL值与C组相比无显著差异(p>0.05),A组与B组血清PRL比较无显著差异(p>0.05)。A、B、C三组大鼠血清E2与D组比较,结果降低,均有统计学意义(p<0.01)；A、B组的血清E2值与C组相比无显著差异(p>0.05),A组与B组血清E2比较无显著差异(p>0.05)。FSH的比较：A、B、C三组大鼠与D组相比,显著降低(p<0.01),A、B组的FSH值与C组相比,差异无统计学意义(p>0.05),A、B两组FSH值相比无统计学差异(p>0.05)。
(4)下丘脑神经递质含量比较：结果提示：造模后,A、B、C三组大鼠下丘脑NE含量与D组比较,结果降低,有统计学意义(p<0.01),A、B、C三组大鼠下丘脑NE含量两两比较差异均无统计学意义(p>0.05)；A、B两组大鼠下丘脑5-HT含量与C、D组比较,结果显著升高(p<0.01),而A与B相比较,C与D相比较5-HT含量均无统计学差异。
结论
1.肝郁型HPRL存在高焦虑特质和焦虑状态,和肝郁型非HPRL人群相比在人格方面更倾向于内向、神经质(情绪不稳定,焦虑、担心、常常郁郁不乐、忧心忡忡,有强烈的情绪反应,以至于出现不够理智的行为)、精神质(孤独、不关心他人,不近人情,感觉迟钝,与别人不友好等),其中高精神质的性格特征可能为肝郁型HPRL的人群所特有。
2.根据中医的七情学说和现代医学的生理-心理-社会模式而复制的心理应激型肝郁模型在研究肝郁型高泌乳素血症上是可行的,与传统的甲氧氯普胺所致高泌乳素血症组以及二者的复合组相比,其大鼠的泌乳素水平均升高,其他内分泌改变也是一致的；其行为学、体重和神经递质改变更符合肝郁的表现,与现代情志致病的发病机理一致；这也从一个侧面反映了心理应激型肝郁可能是导致特发性HPRL的重要原因之一。
3.肝郁型HPRL大鼠存在神经和内分泌两方面的改变。神经递质方面,肝郁型HPRL组表现为NE的降低和5-HT的升高,而甲氧氯普胺HPRL组只表现为NE的降低；内分泌方面,升高的PRL可通过扰乱中枢神经递质的分泌平衡来间接使FSH和LH降低,并通过中枢和外周两种途径达到对卵巢功能的抑制,使甾体激素失衡而导致不孕、月经不调甚至闭经。由此可见,肝郁型高泌乳素血症的发生与精神刺激密切相关,其可能的机理是应激对中枢系统的刺激使中枢神经递质失衡,而失衡的神经递质又可通过下丘脑-垂体-性腺轴使内分泌出现紊乱,由此而致神经-内分泌平衡的破坏。
Objective
To prevent HPRL in advance and introduce psychotherapy to HPRL patients with liver qi stagnation, this study analysed the mental status and character traits of HPRL patients with liver qi stagnation through the Eysenck Personality Questionnaire and the State—Trait Anxiety Inventory;Based on Seven Emotions and psychological stress theory, this study attempted to explore animal model of HPRL caused by liver qi stagnation to provide theoretical evidence to regulate the syndrome differentiation of Traditional Chinese Medicine(TCM). It also attempted to discover the etiology and pathogenesis of HPRL caused by liver qi stagnation, by comparing the traditional HPRL model with liver qi stagnation in an animal model triggered by psychological stress on both behavior study and the neuroendocrine system.
Method
1.Method of clinical study
Group A:28 HPRL(PRL≥30ng/ml) patients with liver qi stagnation; Group B:30 liver qi stagnation patients with menstrual disorders and/or infertility; Group C:25 normal people.
The sex hormones of patients diagnosed with liver qi stagnation who also have menstrual disorders, infertility, or galactorrhea, were tested with chemiluminescence immunoassay during the first three days of the menstrual cycle at 9:30-10:30am. According to PRL value, inclusive and exclusive criterions, these patients were divided into A and B groups. Subjects in Group C are from the Physical Examination Center during the same period. Both Group A and Group B would be estimated on the degree of liver qi stagnation. Groups A, B and C filled in the Eysenck Personality Questionnaire(EPQ) and State—Trait Anxiety Inventory(STAI-Form) within 30min. The EPQ was filled in with "Yes" or "No" answers and transformed into T scores with Psychoticism(P),Neuroticism(N), Extroversion(E) and Lie(L) dimensions by EPQ adult test software 5.0. The STAI-Form included a State Anxiety and Trait Anxiety form, and each of them included 20 questions.
2. Method of experimental study
37 specific pathogen free (SPF) SD female rats, weighing 200g±20g, were divided into four groups randomly at different weight levels after raising for one week Group A:Liver qi stagnation group with 11 rats
Group B:Liver qi stagnation+metoclopramide group with 10 rats
Group C:Metoclopramide group with 8 rats
Group D:Control group with 8 rats
Model preparation:From the 8th day, Groups B and C received a metoclopramide subcutaneous injection in the amount of 62.5mg per kilogram of body weight daily for 8 days. In the mean while, Group B also received 5 kinds of unpredictable psychological stress for 21 days with Group A.
The general condition of each group was observed, such as defecation, mental condtion, activity and weight. After the last stimulation, all the rats were deprived of food, but received their normal water supply for 12 hours. The rats were weighed, and between 9:30-10:30 am the rats'heads were removed under 10% chloral hydrate anaesthesia on the 29th day. Blood serum was kept at -80℃to test the sex hormones. The hypothalamus was seperated on ice, and after being weighed, was kept at -80℃to test monoamine neurotransmitters such as noroepinephrine(NE) and 5-hydroxytryptamine(5-HT). Result
1. Results of clinical research
(1) Sex hormone comparison:The serum value of both E2 and FSH in HPRL patients with liver qi stagnation (Group A) was lower than in liver qi stagnation patients with menstrual disorders and/or infertility (Group B) (p <0.05), while that of PRL in Group A was significantly higher than in Group B (p<0.01).Both serum values of FSH and T showed no statistical difference (p>0.05).
(2) Comparison of liver qi stagnation scoring and age:It showed that the liver qi stagnation scoring in both Group A and Group B showed no difference (p>0.05). And among Groups A、B and C, it showed no age difference (p> 0.05)
(3) EPQ analysis:It showed no difference in Lie(L) among these three groups (p>0.05). Compared with Group B, Group A had significantly higher scores in Psychoticism(P) and Neuroticism(N) (p<0.01), and no statistical difference in Extroversion(E) (p>0.05). Compared with Group C, Group A had ssignificantly higher scores in P and N (p<0.01), and lower scores in E (p <0.05). Compared with Group C, Group B had higher scores in N (p<0.01) and lower scores in E (p<0.01), while there was no difference in P (p>0.05)
(4) Anxiety comparison:Both State Anxiety and Trait Anxiety scoring were higher in Groups A and B than in Group C (p<0.05). Both State Anxiety and Trait Anxiety scoring was higher in Group A than in Group B (p<0.01)
2. Results of animal experimental study
(1)Behavioral observation:As time passed by, dodge, slackness, looser stools, and matte fur were observed among rats in Groups A and B, while only calm, somnolence and lacking in strength were observed in Group C. Anxiety and overreaction to the stimulator appeared in both A and B groups, but not the C group.
(2)Weight comparison:Before any stimulation, the weight of the rats in all four groups showed no statistical significance (p>0.05).In the total 21 days the weight of the rats in Groups A and B grew more slowly than in Groups C and D, while in Groups C and D there was no change in weight (p>0.05). It also showed that the rats in Group A grew more slowly than those in Group B (p<0.05)
(3)Sex hormone comparison:After the experiment the serum value of PRL in Groups A、B and C was higher than in Group D (p<0.05), while it showed no difference among Groups A、B and C (p>0.05).The serum value of both E2 and FSH in Groups A、B and C was significantly lower than in Group D (p< 0.01), while that of both sex hormones showed no difference among Groups A、B and C (p>0.05)
(4)The comparison of the concentration of hypothalamic monoamine neurotransmitters:NE concentration in Groups A、B and C was significantly lower than in Group D (p<0.01),while that of 5-HT was higher in Groups A and B than in Groups C and D (p<0.01). NE concentrations among Groups A、B and C showed no significant difference (p>0.05).5-HT concentrations in Groups A and B showed no significant difference (p>0.05) and in Groups C and D showed no significant difference either (p>0.05) Conclusion
1. Clinical research suggested that HPRL patients with liver qi stagnation tend to have high levels of both state anxiety and trait anxiety. In the disposition aspects, HPRL patients tend more toward introversion, neuroticism (which includes mood swings, anxiety, worry, depression, and unreasonable behavior caused by overreaction), and psychoticism (loneliness, lack of sympathy, lack of empathy, slow reaction time, hostility, etc.). And high scores on psychoticism may be the unique characteristic of HPRL patients.
2. The liver qi stagnation model triggered by psychological stress has the same PRL, FSH and E2 levels compared with the traditional metoclopramide model and the two combined HPRL animal model. And according to the Seven Emotions Theory of Chinese medicine and physiological-psychological-social mode of modern medicine, the former model is a more feasible way in the study of HPRL which exibites liver qi stagnation. And its behavior, weight change and changes in neurotransmitters also conformed the clinical manifestation of liver qi stagnation patients. It also indicated that the liver qi stagnation model triggered by psychological stress could be one of the substantial causes of HPRL.
3. The changes in neuroendocrine network can be seen in HPRL models caused by liver qi stagnation. The changes of hypothalamic monoamine neurotransmitters can be seen in both HPRL models caused by liver qi stagnation and by metoclopramide injection, which were NE reduction and 5-HT increase in HPRL models caused by liver qi stagnation and only NE reduction in HPRL models caused by metoclopramide injection. Thus it can be seen that the onset of HPRL has a close relationship with emotional stimulation and its possible mechanism is the stress that causes the disorder of the central neurotransmitters by stimulating the central nervous system. The neurotransmitters cause the disorder of the sex hormones by influencing the hypothalamic-hypophysical-sex gland axis.
本研究在临床调查方面通过对临床肝郁型HPRL病例人格和心理调查,试图从社会-心理模式来探讨肝郁型高泌乳素血症的性格取向,为HPRL的心理治疗和预防提供理论依据；在情志致病和心理应激理论的基础上,探索合理的肝郁型高泌乳素血症(Hyperprolactinemia, HPRL)动物模型的制备,为今后中医药对HPRL辨证施治的动物学研究奠定基础；从行为学和神经-内分泌系统两方面与传统HPRL模型进行比较,来探讨肝郁型高泌乳素血症的发病机制。
方法
1.临床研究方法
A组：肝郁型高泌乳素血症组(HPRL)共28例,B组：肝郁型非高泌乳素血症组30例,C组：正常对照组25例。以连续两次PRL≥30ng/ml为HPRL诊断标准。
以月经病、不孕、溢乳就诊的肝郁型病人于月经周期第1-3天上午9：30-10：30(静坐15min)空腹抽取外周静脉血,化学发光法测定血清泌乳素(Prolactine, PRL)、促卵泡生成素(FSH)、促黄体生成素(LH)、雌二醇(Estradiol, E2)和睾酮(Testosterone, T),无明显月经周期的患者不拘时检测,泌乳素增高患者需复查血清泌乳素水平,符合纳入和排除标准的分为一组(A组),泌乳素正常的符合肝郁型非高泌乳素血症纳入标准及排除标准3-8项的归为肝郁型非高泌乳素血症组(B组)。正常对照组为同期医院体检中心的健康人群(C组)。A、B两组进行肝郁症状的量化评分。
A、B、C三组人在30分钟内填写艾森克心理问卷和STAI(State—Trait Anxiety Inventory, STAI-Form)焦虑评定表。艾森克问卷以“是”或“否”作答。把答案输入到艾森克成人测试软件5.0,得到P(精神质)、E(内外向)、N(神经质)、L(撒谎)四个维度的T分。STAI焦虑评定表分为状态焦虑评定表(S-AI)和特质焦虑评定表(T-AI)各有20题按1-4级填写,正向题目根据答案按4-1反相记分,负向题目则按1-4正相记分。
2.实验研究方法
SPF级SD雌性大鼠37只,体重200g±20g。饲养1W后,按体重分层后再随机分为四组,分别为：
A组：肝郁组11只
B组：肝郁+甲氧氯普胺(灭吐灵)组10只
C组：甲氧氯普胺组8只
D组：正常组8只
模型制备：从造模第1天开始,B、C两组大鼠于皮下注射甲氧氯普胺注射液,62.5mg/kg体重,每天1次,连续8天；B组在皮下注射甲氧氯普胺的同时,从造模第1天开始和A组一起给予5种不可预知的心理应激刺激。刺激方法随机安排21d内连续进行。D组不接受任何刺激。
观察动物的排便、精神状况、活动度及体重变化；在最后一次造模后,12h内禁食,自由饮水,于造模开始第22天上午称重后于8：00-11：00在10%水合氯醛麻醉后,断头取血,保存血清于-80℃保存待测性激素。冰块上分离出下丘脑组织,称重后保存于-80℃的冰箱中,待检测单胺类神经递质去甲肾上腺素(Norepinephrine Bitartrate, NE)和5-羟色胺(5-hydroxytryptamine Hydrochloride,5-HT)。
结果
1.临床调查结果
(1)性激素比较：肝郁型HPRL患者血清LH、E2明显低于肝郁型非高泌乳素血症组(p<0.05)。两组FSH经统计,差异不显著(p>0.05),在T值上肝郁型HPRL有上升趋势,但差异不显著(p>0.05)。
(2)肝郁积分和年龄比较：结果提示：肝郁型HPRL组的肝郁积分与肝郁型非高泌乳素血症组相比无明显差异(p>0.05)。三组妇女年龄分布无统计学意义,具有可比性(p>0.05)。
(3)艾森克人格问卷分析：L(测谎量表)值在三组中无明显差别(p>0.05)；肝郁型高泌乳素血症组在P(精神质)、N(神经质)积分上均显著高于肝郁型非高泌乳素血症组和正常组,差异均有统计学意义(p<0.01),在E(内外倾)积分上与肝郁型非高泌乳素血症组无明显差别(p>0.05),但明显低于正常组(p<0.01)；肝郁型非高泌乳素血症组和正常组相比,E分值明显低于正常组(p<0.01),N分明显高于正常组(p<0.01),而P分值与正常组无明显差别(p>0.05)。
(4)焦虑评分比较：肝郁型高泌乳素血症组、肝郁型非高泌乳素血症组和正常组相比状态焦虑值和特质焦虑值均明显升高,有统计学意义(p<0.05),肝郁型高泌乳素血症组和肝郁型非高泌乳素血症组相比,状态焦虑值明显升高,有统计学意义(p<0.01),特质焦虑积分也明显升高(p<0.01)。
2.动物实验结果
(1)行为学观察：随着造模时间的推移,肝郁模型组(A组)和肝郁+甲氧氯普胺模型组(B组)大鼠均表现为毛色失去光泽,易于脱落,活动减少,喜欢贴笼壁,大便稍稀,甲氧氯普胺组(C组)大鼠则表现为镇静、思睡、乏力,在受外界刺激时A、B组大鼠紧张度和对应激的反应程度高于C组。
(2)体重比较：造模前,各组体重组间比较,无统计学意义(p>0.05),具有可比性;造模后,A、B组体重增加缓慢,与D组比较,有明显统计学意义(p<0.05),C组与D组比较无统计学意义(p>0.05),A组与B组比较,体重增加较B组缓慢,差异有统计学意义(p<0.05)。
(3)性激素比较：造模后,A、B组大鼠血清PRL值与D组比较显著升高,结果具有统计学意义(p<0.01),C组PRL值与D组比较显著升高,有统计学意义(p<0.05),A、B组的血清PRL值与C组相比无显著差异(p>0.05),A组与B组血清PRL比较无显著差异(p>0.05)。A、B、C三组大鼠血清E2与D组比较,结果降低,均有统计学意义(p<0.01)；A、B组的血清E2值与C组相比无显著差异(p>0.05),A组与B组血清E2比较无显著差异(p>0.05)。FSH的比较：A、B、C三组大鼠与D组相比,显著降低(p<0.01),A、B组的FSH值与C组相比,差异无统计学意义(p>0.05),A、B两组FSH值相比无统计学差异(p>0.05)。
(4)下丘脑神经递质含量比较：结果提示：造模后,A、B、C三组大鼠下丘脑NE含量与D组比较,结果降低,有统计学意义(p<0.01),A、B、C三组大鼠下丘脑NE含量两两比较差异均无统计学意义(p>0.05)；A、B两组大鼠下丘脑5-HT含量与C、D组比较,结果显著升高(p<0.01),而A与B相比较,C与D相比较5-HT含量均无统计学差异。
结论
1.肝郁型HPRL存在高焦虑特质和焦虑状态,和肝郁型非HPRL人群相比在人格方面更倾向于内向、神经质(情绪不稳定,焦虑、担心、常常郁郁不乐、忧心忡忡,有强烈的情绪反应,以至于出现不够理智的行为)、精神质(孤独、不关心他人,不近人情,感觉迟钝,与别人不友好等),其中高精神质的性格特征可能为肝郁型HPRL的人群所特有。
2.根据中医的七情学说和现代医学的生理-心理-社会模式而复制的心理应激型肝郁模型在研究肝郁型高泌乳素血症上是可行的,与传统的甲氧氯普胺所致高泌乳素血症组以及二者的复合组相比,其大鼠的泌乳素水平均升高,其他内分泌改变也是一致的；其行为学、体重和神经递质改变更符合肝郁的表现,与现代情志致病的发病机理一致；这也从一个侧面反映了心理应激型肝郁可能是导致特发性HPRL的重要原因之一。
3.肝郁型HPRL大鼠存在神经和内分泌两方面的改变。神经递质方面,肝郁型HPRL组表现为NE的降低和5-HT的升高,而甲氧氯普胺HPRL组只表现为NE的降低；内分泌方面,升高的PRL可通过扰乱中枢神经递质的分泌平衡来间接使FSH和LH降低,并通过中枢和外周两种途径达到对卵巢功能的抑制,使甾体激素失衡而导致不孕、月经不调甚至闭经。由此可见,肝郁型高泌乳素血症的发生与精神刺激密切相关,其可能的机理是应激对中枢系统的刺激使中枢神经递质失衡,而失衡的神经递质又可通过下丘脑-垂体-性腺轴使内分泌出现紊乱,由此而致神经-内分泌平衡的破坏。
Objective
To prevent HPRL in advance and introduce psychotherapy to HPRL patients with liver qi stagnation, this study analysed the mental status and character traits of HPRL patients with liver qi stagnation through the Eysenck Personality Questionnaire and the State—Trait Anxiety Inventory;Based on Seven Emotions and psychological stress theory, this study attempted to explore animal model of HPRL caused by liver qi stagnation to provide theoretical evidence to regulate the syndrome differentiation of Traditional Chinese Medicine(TCM). It also attempted to discover the etiology and pathogenesis of HPRL caused by liver qi stagnation, by comparing the traditional HPRL model with liver qi stagnation in an animal model triggered by psychological stress on both behavior study and the neuroendocrine system.
Method
1.Method of clinical study
Group A:28 HPRL(PRL≥30ng/ml) patients with liver qi stagnation; Group B:30 liver qi stagnation patients with menstrual disorders and/or infertility; Group C:25 normal people.
The sex hormones of patients diagnosed with liver qi stagnation who also have menstrual disorders, infertility, or galactorrhea, were tested with chemiluminescence immunoassay during the first three days of the menstrual cycle at 9:30-10:30am. According to PRL value, inclusive and exclusive criterions, these patients were divided into A and B groups. Subjects in Group C are from the Physical Examination Center during the same period. Both Group A and Group B would be estimated on the degree of liver qi stagnation. Groups A, B and C filled in the Eysenck Personality Questionnaire(EPQ) and State—Trait Anxiety Inventory(STAI-Form) within 30min. The EPQ was filled in with "Yes" or "No" answers and transformed into T scores with Psychoticism(P),Neuroticism(N), Extroversion(E) and Lie(L) dimensions by EPQ adult test software 5.0. The STAI-Form included a State Anxiety and Trait Anxiety form, and each of them included 20 questions.
2. Method of experimental study
37 specific pathogen free (SPF) SD female rats, weighing 200g±20g, were divided into four groups randomly at different weight levels after raising for one week Group A:Liver qi stagnation group with 11 rats
Group B:Liver qi stagnation+metoclopramide group with 10 rats
Group C:Metoclopramide group with 8 rats
Group D:Control group with 8 rats
Model preparation:From the 8th day, Groups B and C received a metoclopramide subcutaneous injection in the amount of 62.5mg per kilogram of body weight daily for 8 days. In the mean while, Group B also received 5 kinds of unpredictable psychological stress for 21 days with Group A.
The general condition of each group was observed, such as defecation, mental condtion, activity and weight. After the last stimulation, all the rats were deprived of food, but received their normal water supply for 12 hours. The rats were weighed, and between 9:30-10:30 am the rats'heads were removed under 10% chloral hydrate anaesthesia on the 29th day. Blood serum was kept at -80℃to test the sex hormones. The hypothalamus was seperated on ice, and after being weighed, was kept at -80℃to test monoamine neurotransmitters such as noroepinephrine(NE) and 5-hydroxytryptamine(5-HT). Result
1. Results of clinical research
(1) Sex hormone comparison:The serum value of both E2 and FSH in HPRL patients with liver qi stagnation (Group A) was lower than in liver qi stagnation patients with menstrual disorders and/or infertility (Group B) (p <0.05), while that of PRL in Group A was significantly higher than in Group B (p<0.01).Both serum values of FSH and T showed no statistical difference (p>0.05).
(2) Comparison of liver qi stagnation scoring and age:It showed that the liver qi stagnation scoring in both Group A and Group B showed no difference (p>0.05). And among Groups A、B and C, it showed no age difference (p> 0.05)
(3) EPQ analysis:It showed no difference in Lie(L) among these three groups (p>0.05). Compared with Group B, Group A had significantly higher scores in Psychoticism(P) and Neuroticism(N) (p<0.01), and no statistical difference in Extroversion(E) (p>0.05). Compared with Group C, Group A had ssignificantly higher scores in P and N (p<0.01), and lower scores in E (p <0.05). Compared with Group C, Group B had higher scores in N (p<0.01) and lower scores in E (p<0.01), while there was no difference in P (p>0.05)
(4) Anxiety comparison:Both State Anxiety and Trait Anxiety scoring were higher in Groups A and B than in Group C (p<0.05). Both State Anxiety and Trait Anxiety scoring was higher in Group A than in Group B (p<0.01)
2. Results of animal experimental study
(1)Behavioral observation:As time passed by, dodge, slackness, looser stools, and matte fur were observed among rats in Groups A and B, while only calm, somnolence and lacking in strength were observed in Group C. Anxiety and overreaction to the stimulator appeared in both A and B groups, but not the C group.
(2)Weight comparison:Before any stimulation, the weight of the rats in all four groups showed no statistical significance (p>0.05).In the total 21 days the weight of the rats in Groups A and B grew more slowly than in Groups C and D, while in Groups C and D there was no change in weight (p>0.05). It also showed that the rats in Group A grew more slowly than those in Group B (p<0.05)
(3)Sex hormone comparison:After the experiment the serum value of PRL in Groups A、B and C was higher than in Group D (p<0.05), while it showed no difference among Groups A、B and C (p>0.05).The serum value of both E2 and FSH in Groups A、B and C was significantly lower than in Group D (p< 0.01), while that of both sex hormones showed no difference among Groups A、B and C (p>0.05)
(4)The comparison of the concentration of hypothalamic monoamine neurotransmitters:NE concentration in Groups A、B and C was significantly lower than in Group D (p<0.01),while that of 5-HT was higher in Groups A and B than in Groups C and D (p<0.01). NE concentrations among Groups A、B and C showed no significant difference (p>0.05).5-HT concentrations in Groups A and B showed no significant difference (p>0.05) and in Groups C and D showed no significant difference either (p>0.05) Conclusion
1. Clinical research suggested that HPRL patients with liver qi stagnation tend to have high levels of both state anxiety and trait anxiety. In the disposition aspects, HPRL patients tend more toward introversion, neuroticism (which includes mood swings, anxiety, worry, depression, and unreasonable behavior caused by overreaction), and psychoticism (loneliness, lack of sympathy, lack of empathy, slow reaction time, hostility, etc.). And high scores on psychoticism may be the unique characteristic of HPRL patients.
2. The liver qi stagnation model triggered by psychological stress has the same PRL, FSH and E2 levels compared with the traditional metoclopramide model and the two combined HPRL animal model. And according to the Seven Emotions Theory of Chinese medicine and physiological-psychological-social mode of modern medicine, the former model is a more feasible way in the study of HPRL which exibites liver qi stagnation. And its behavior, weight change and changes in neurotransmitters also conformed the clinical manifestation of liver qi stagnation patients. It also indicated that the liver qi stagnation model triggered by psychological stress could be one of the substantial causes of HPRL.
3. The changes in neuroendocrine network can be seen in HPRL models caused by liver qi stagnation. The changes of hypothalamic monoamine neurotransmitters can be seen in both HPRL models caused by liver qi stagnation and by metoclopramide injection, which were NE reduction and 5-HT increase in HPRL models caused by liver qi stagnation and only NE reduction in HPRL models caused by metoclopramide injection. Thus it can be seen that the onset of HPRL has a close relationship with emotional stimulation and its possible mechanism is the stress that causes the disorder of the central neurotransmitters by stimulating the central nervous system. The neurotransmitters cause the disorder of the sex hormones by influencing the hypothalamic-hypophysical-sex gland axis.
引文
[1]钱卫平,邱耀芳,张碧娟,等.功能性高泌乳素血症发病特征及治疗[J].深圳医学,1999,12(2)：28-29.
[2]Machida T, Taga M, Minaguchi H. Prolactin secretion in endometriotic patients[J]. Eur Jobstet Gynecol Reprod Biol,1997,72(1):89.
[3]Freeman ME, Kanyicska B, Lerant A, et al. Prolactin:structure, function, and regulation of secretion. Physiol Rev,2000,80(4):1523-1631.
[4]Ain R, Tash JS, Soares MJ. Prolactin-like protein-A is a functional modulator of natural killer cells at the maternal-fetal interface. Mol Cell Endocrinol,2003,204(1-2):65-74.
[5]Garzia E, Borgato S, Cozzi V, et al. Lack of expression of endometrial prolactin in early implantation failure:a pilot study [J].Hum Reprod,2004,19(8):1911-1916.
[6]Luciano AA. Clinical presentation of hyperprolactinemia[J]. J Reprod Med. 1999,44(12 Suppl):1085.
[7]郝志强,田小平,何浩明,等.吗丁啉对血清泌乳素影响的实验观察[J].放射免疫学杂志,2000,13(2)：120.
[8]Biller B M, Luciano A, Crosignani P G, et al. Guidelines for the diagnosis and treatment of hyperprolactinemia[J]. J Reprod Med.1999,44(12 Suppl): 1075-1084.
[9]魏桂林,徐小薇,李大魁.药物与高催乳素血症[J].药物不良反应杂志,2000,2(2)：73-76.
[10]邢福祺,刘芸.高催乳素血症的诊断与治疗[J].中国实用妇科与产科杂志,2001,17(4)：217-218.
[11]陈景海.溴隐亭治疗高泌乳素血症的临床观察[J].中国医院药学杂志,2006,26(5)：601-603.
[12]李明.高催乳素症治疗药卡麦角林[J].国外医药·合成药、生化药、制剂分册,1999,20(4)：221-222.
[13]杨卉.高催乳素血症的研究进展[J].国外医学计划生育分册,2004,23(3)：147-150.
[14]傅佳峰.垂体泌乳素腺瘤的治展.Journal of International Neurology and Neurosurgery,2005,32(6):558-561.
[15]Webster J, Piscitell G, Polli A, et al. N Engl J Med,1994,331:904-909.
[16]Biller BM. Hyperprolactinemia. Int J Fertil Womens Med,2001,44(2):74-77.
[17]Molitch ME Pathologic hyperprolactinemia Endocrinol Metab Clin North Am, 1992,21:877.
[18]高丽君.邹德琛教授治疗闭经—溢乳综合征经验[J].中医药学报,1999,6：29-30.
[19]孙跃农,阎继兰,李春华,等.中医辨证治疗高泌乳素血症36例临床分析[J].云南中医中药杂志,2000,21(2)：6-8.
[20]王臻.柴芍二仙汤治疗女性高泌乳素血症30例疗效观察[J].新中医,2005,37(7)：41-42.
[21]徐吉祥.芍药甘草汤治疗高泌乳素血症型女性不孕症临床观察[J].中国中西医结合杂志.2003,23(8)：602.
[22]周京晶.杨鉴冰教授辨治高泌乳素血证的经验[J].陕西中医学院学报,2008,31(2)：10-11.
[23]何贵翔.高催乳素血症证治心得[J].南京中医药大学学报(自然科学版),2000,16(6)：376-377.
[24]奚嘉.柴胡疏肝散加减治疗高泌乳素血症临床观察[J].辽宁中医杂志,1999,26(12)：550-551.
[25]许筱梅.重用白芍治疗高泌乳素血症[J].新中医,2006,38(5)：84.
[26]白素霞,周永慧.中西医结合治疗高泌乳素血症32例[J].江西中医药,2006,37(5)：37.
[27]王芙蓉.丹栀逍遥散加味合芍药甘草汤治疗高泌乳素血症30例[J].山西中医.2002,18(2)：23.
[28]王俊玲,刘菊芳.调肝补肾方治疗高泌乳素血症的临床研究[J].中国中医药科技,2002,9(5)：265-266.
[29]杨桂芹,郑学芳.高泌乳素血症从肝肾论治临床观察30例[J].河南中医药学刊,2001,17(1)：29-30.
[30]赵福玉,何晓颖,韩力.中药治疗高泌乳素血症的临床研究[J].中国妇幼保健,2001,16(11)：690-691.
[31]张挺.自拟清肝散治疗高泌乳素血症50例[J].现代中医药,2003,1(1)：39-40.
[32]翁雪松,金毓莉,冯杜熊.化痰泄浊法治疗高催乳素血症的临床研究[J].上海中医药杂志,2004,38(1)：24-25.
[33]李涌弦,于传鑫.实用妇科内分泌学[M].上海：上海医科大学出版社,2006：76.
[34]张丽珠.临床生殖内分泌与不育症[M].北京：科学出版社,2006：403.
[35]吴素玲.针灸三阴交穴治疗产后型高泌乳素血症32例.四川中医.2002,20(11)：25.
[36]刘莉莉,孙伟.电针配合中药治疗高泌乳素血症42例临床观察.中国现代医生.2007,45(20)：1-2.
[37]侯雁.针药并行治疗高泌乳素血症30例[J].中国中医急症,2004,3(10)：696.
[38]夏雷,张海蓉.抑乳颗粒对高泌乳素血症大鼠子宫卵巢bcl-2/bax的影响[J].中成药,2008,30(5)：657.
[39]李松滨,李宝龙.调肝汤对肝郁动物模型大鼠泌乳素影响的研究[J].中医药学报,2008,36(1)：32.
[40]赵祯,曹宇,袁淑德.人参茎叶皂甙对实验性高催乳素血症大鼠催乳素和动情周期的影响[J].中国应用生理学杂志,2005,21(2)：144-5.
[41]张志玲,刘菊芳,李惠林,等.坤安冲服剂对高泌乳素血症大鼠血清激素水平的影响[J].广州中医药大学学报,2004,21(4)：302-303.
[42]Kahn D, Gavaler J S, Makowka L. Dose hyperprolactinemia affect hepatic regeneration independent of sex steroids [J]?Lab Clinic Medicine,1988, 12(5):644.
[43]魏安华,蔡亚玲,吴金虎,等.麦芽提取物对高泌乳素血症小鼠泌乳素水平的影响[J].医药导报,2009,28(11)：1441-1443.
[44]Link C N, Kawamura H, Okamur A, et al. Inhibition of ovulation, steroidogenesis and collagenolytic activity in rabbits by sulpiride-induced hyperprolactinemia[J]. J Reprod Fert,1988,83:611.
[45]张思佳,何春娜,乔乐士,等.仙甲冲剂对实验性高泌乳素血症的药理作用[J].中国优生与遗传杂志,2000,8(4)：52-5319.
[46]辛浩琳.抑乳灵口服液对大鼠高泌乳素血症状态下生殖激素影响的实验研究[D]. 吉林大学硕士学位论文.2005.
[47]Sung-keum Park, Michael Selmanoff. Neuroendocrinology[M].1991, 53:404-410.
[48]夏雷.抑乳颗粒治疗高泌乳素血症的实验研究[D].山东中医药大学硕士论文,2007.
[49]刘菊芳,陈新,桂耀庭,等.补肾调肝敛乳方治疗高泌乳素血症的实验研究[J].中药新药与临床药理.2006：7(2)22-24.
[50]周威.大麦芽提取物治疗实验性高泌乳素血症的研究[D].湖北中医学院硕士学位论文.2009.
[51]徐春,梁立武,刘晓军.中药降乳散对乙烯雌酚诱发的大鼠泌乳素瘤的抑制作用[J].中华中医药杂志.2007,22(7)：37-40.
[1]曹泽毅,翁梨驹,郎景和,等.中华妇产科学.北京：人民卫生出版社.2010.2169.
[2]王霞灵,周大桥.肝郁患者血清泌乳素测定临床意义探讨.湖北中志,1995,(5)：53.
[3]陈国林,等.通过肝阳上亢证的辩证探讨证的研究方法.中国医报,1988,(5)：671.
[4]龚耀先.修订艾森克个性问卷手册.长沙：湖南地图出版社,1992,1245.
[5]王向东,王希林,马弘.心理卫生评定量表手册中国心理卫生杂志增订版,1999.
[6]姚泰主编.生理学,第6版.北京：人民卫生出版.2001,401-402.
[7]Most SB, Chun MM,Widders DM, eta.1 Attentional rubbernecking:cognitive control and personality in emotion-induced blindness. Psychon BullRev,2005,12(4):654.
[8]邵小珍,官锐园,徐国英.急诊护士焦虑与人格特征的相关性研究.中国实用护理杂志,2007,23(4)：68-69.
[9]高鹏程,黄敏儿.高焦虑特质的注意偏向特点.心理学报,2005,40(3)：307-3.
[10]Sung-keum Park, Michael Selmanoff. Neuroendocrinology.1991,53:404-410.
[11]敖海清,徐志伟,严灿,等.柴胡疏肝散及逍遥散对慢性心理应激大鼠血清皮质酮及胃肠激素的影响.中药新药与临床药理,2007,18(4)：288-291.
[12]Carter WR, Hemmn J, Stokes K. Promotion of diabetes onset by stress in BB rat. Diabetologia,1987,30:674.
[13]辛浩琳.抑乳灵口服液对大鼠高泌乳素血症状态下生殖激素影响的实验研究.吉林大学硕士学位论文.2005.
[14]李松滨,李宝龙.调肝汤对肝郁动物模型大鼠泌乳素影响的研究.中医药学报.2008,36(1)：32-33.
[15]郝世凤.女性肝郁状态下神经递质、激素的实验研究.成都中医药大学硕士论文.2004.
[16]Ko SM, Kua EH, Ng TP, et al. Life events and minor psychiatric morbidity in a community survey. Stress and Health,2001,17:41-46.
[17]王淑贞,主编.妇产科理论与实践.上海：上海科技出版社,1993,82.
[18]乔明琦,王文燕,张惠云,等.肝气逆肝气郁两证病因流行病学调查及情志致病方式研究.中西医结合杂志,2007,27(2)：117-119.
[19]乔明琦,于霞,张惠云,等.“多情交织共同致病首先伤肝”假说及其论证.山东中医药大学学报.2006,30(1)：8-10.
[20]Katz R J, Rot h K A, Carroll B J. Acute and chronic stress effects on open field activity in the rat:implications for a model of depression. Neurosci Biobehav Rev,1981,5(2):247-251.
[21]金光亮,王胜兰.关于建立肝郁证动物模型的思考.山东中医药大学学报.2004,28(6)：408-409.33
[22]于琦,金光亮.三种复方对慢性应激肝郁模型大鼠海马5-HT1A受体基因表达的影响.北京中医药.2008,27(1)：57.59
[23]严灿,徐志伟,吴丽丽,等.建立中医情志致病动物模型的思考.中国临床康复.2006,10(3)：155-157.
[24]张志玲,刘菊芳,李惠林,等.坤安冲服剂对高泌乳素血症大鼠血清激素水平的影响.广州中医药大学学报.2004,21(4)：302-303.
[25]Yelle CA, Corenbium B. Idiopathic hyperprolactinemia evolving into macro-prolactinemia. Endocrinoligist 2002,12(3):6.
[26]陈泽奇,陈国林,金益强,等.肝气郁结证病理生理学基础研究.中国现代医学杂志,2000,10(10)：21.
[27]姚传芳.情感性精神障碍.长沙：湖南科学技术出版社.1999：59-69.
[28]孙朋波,丛亚莉.使用甲氧氯普胺应注意的问题.中国误诊学杂志.2008,8(24)：6044.
[29]罗颂平,梁国珍.中西医结合生殖免疫与内分泌学.北京：人民军医出版社,2004,86.
[30]丁寿根.应激过程中下丘脑-垂体-肾上腺轴的调控机理.国外医学.军事医学分册,1994,11(1)：9.
[2]Machida T, Taga M, Minaguchi H. Prolactin secretion in endometriotic patients[J]. Eur Jobstet Gynecol Reprod Biol,1997,72(1):89.
[3]Freeman ME, Kanyicska B, Lerant A, et al. Prolactin:structure, function, and regulation of secretion. Physiol Rev,2000,80(4):1523-1631.
[4]Ain R, Tash JS, Soares MJ. Prolactin-like protein-A is a functional modulator of natural killer cells at the maternal-fetal interface. Mol Cell Endocrinol,2003,204(1-2):65-74.
[5]Garzia E, Borgato S, Cozzi V, et al. Lack of expression of endometrial prolactin in early implantation failure:a pilot study [J].Hum Reprod,2004,19(8):1911-1916.
[6]Luciano AA. Clinical presentation of hyperprolactinemia[J]. J Reprod Med. 1999,44(12 Suppl):1085.
[7]郝志强,田小平,何浩明,等.吗丁啉对血清泌乳素影响的实验观察[J].放射免疫学杂志,2000,13(2)：120.
[8]Biller B M, Luciano A, Crosignani P G, et al. Guidelines for the diagnosis and treatment of hyperprolactinemia[J]. J Reprod Med.1999,44(12 Suppl): 1075-1084.
[9]魏桂林,徐小薇,李大魁.药物与高催乳素血症[J].药物不良反应杂志,2000,2(2)：73-76.
[10]邢福祺,刘芸.高催乳素血症的诊断与治疗[J].中国实用妇科与产科杂志,2001,17(4)：217-218.
[11]陈景海.溴隐亭治疗高泌乳素血症的临床观察[J].中国医院药学杂志,2006,26(5)：601-603.
[12]李明.高催乳素症治疗药卡麦角林[J].国外医药·合成药、生化药、制剂分册,1999,20(4)：221-222.
[13]杨卉.高催乳素血症的研究进展[J].国外医学计划生育分册,2004,23(3)：147-150.
[14]傅佳峰.垂体泌乳素腺瘤的治展.Journal of International Neurology and Neurosurgery,2005,32(6):558-561.
[15]Webster J, Piscitell G, Polli A, et al. N Engl J Med,1994,331:904-909.
[16]Biller BM. Hyperprolactinemia. Int J Fertil Womens Med,2001,44(2):74-77.
[17]Molitch ME Pathologic hyperprolactinemia Endocrinol Metab Clin North Am, 1992,21:877.
[18]高丽君.邹德琛教授治疗闭经—溢乳综合征经验[J].中医药学报,1999,6：29-30.
[19]孙跃农,阎继兰,李春华,等.中医辨证治疗高泌乳素血症36例临床分析[J].云南中医中药杂志,2000,21(2)：6-8.
[20]王臻.柴芍二仙汤治疗女性高泌乳素血症30例疗效观察[J].新中医,2005,37(7)：41-42.
[21]徐吉祥.芍药甘草汤治疗高泌乳素血症型女性不孕症临床观察[J].中国中西医结合杂志.2003,23(8)：602.
[22]周京晶.杨鉴冰教授辨治高泌乳素血证的经验[J].陕西中医学院学报,2008,31(2)：10-11.
[23]何贵翔.高催乳素血症证治心得[J].南京中医药大学学报(自然科学版),2000,16(6)：376-377.
[24]奚嘉.柴胡疏肝散加减治疗高泌乳素血症临床观察[J].辽宁中医杂志,1999,26(12)：550-551.
[25]许筱梅.重用白芍治疗高泌乳素血症[J].新中医,2006,38(5)：84.
[26]白素霞,周永慧.中西医结合治疗高泌乳素血症32例[J].江西中医药,2006,37(5)：37.
[27]王芙蓉.丹栀逍遥散加味合芍药甘草汤治疗高泌乳素血症30例[J].山西中医.2002,18(2)：23.
[28]王俊玲,刘菊芳.调肝补肾方治疗高泌乳素血症的临床研究[J].中国中医药科技,2002,9(5)：265-266.
[29]杨桂芹,郑学芳.高泌乳素血症从肝肾论治临床观察30例[J].河南中医药学刊,2001,17(1)：29-30.
[30]赵福玉,何晓颖,韩力.中药治疗高泌乳素血症的临床研究[J].中国妇幼保健,2001,16(11)：690-691.
[31]张挺.自拟清肝散治疗高泌乳素血症50例[J].现代中医药,2003,1(1)：39-40.
[32]翁雪松,金毓莉,冯杜熊.化痰泄浊法治疗高催乳素血症的临床研究[J].上海中医药杂志,2004,38(1)：24-25.
[33]李涌弦,于传鑫.实用妇科内分泌学[M].上海：上海医科大学出版社,2006：76.
[34]张丽珠.临床生殖内分泌与不育症[M].北京：科学出版社,2006：403.
[35]吴素玲.针灸三阴交穴治疗产后型高泌乳素血症32例.四川中医.2002,20(11)：25.
[36]刘莉莉,孙伟.电针配合中药治疗高泌乳素血症42例临床观察.中国现代医生.2007,45(20)：1-2.
[37]侯雁.针药并行治疗高泌乳素血症30例[J].中国中医急症,2004,3(10)：696.
[38]夏雷,张海蓉.抑乳颗粒对高泌乳素血症大鼠子宫卵巢bcl-2/bax的影响[J].中成药,2008,30(5)：657.
[39]李松滨,李宝龙.调肝汤对肝郁动物模型大鼠泌乳素影响的研究[J].中医药学报,2008,36(1)：32.
[40]赵祯,曹宇,袁淑德.人参茎叶皂甙对实验性高催乳素血症大鼠催乳素和动情周期的影响[J].中国应用生理学杂志,2005,21(2)：144-5.
[41]张志玲,刘菊芳,李惠林,等.坤安冲服剂对高泌乳素血症大鼠血清激素水平的影响[J].广州中医药大学学报,2004,21(4)：302-303.
[42]Kahn D, Gavaler J S, Makowka L. Dose hyperprolactinemia affect hepatic regeneration independent of sex steroids [J]?Lab Clinic Medicine,1988, 12(5):644.
[43]魏安华,蔡亚玲,吴金虎,等.麦芽提取物对高泌乳素血症小鼠泌乳素水平的影响[J].医药导报,2009,28(11)：1441-1443.
[44]Link C N, Kawamura H, Okamur A, et al. Inhibition of ovulation, steroidogenesis and collagenolytic activity in rabbits by sulpiride-induced hyperprolactinemia[J]. J Reprod Fert,1988,83:611.
[45]张思佳,何春娜,乔乐士,等.仙甲冲剂对实验性高泌乳素血症的药理作用[J].中国优生与遗传杂志,2000,8(4)：52-5319.
[46]辛浩琳.抑乳灵口服液对大鼠高泌乳素血症状态下生殖激素影响的实验研究[D]. 吉林大学硕士学位论文.2005.
[47]Sung-keum Park, Michael Selmanoff. Neuroendocrinology[M].1991, 53:404-410.
[48]夏雷.抑乳颗粒治疗高泌乳素血症的实验研究[D].山东中医药大学硕士论文,2007.
[49]刘菊芳,陈新,桂耀庭,等.补肾调肝敛乳方治疗高泌乳素血症的实验研究[J].中药新药与临床药理.2006：7(2)22-24.
[50]周威.大麦芽提取物治疗实验性高泌乳素血症的研究[D].湖北中医学院硕士学位论文.2009.
[51]徐春,梁立武,刘晓军.中药降乳散对乙烯雌酚诱发的大鼠泌乳素瘤的抑制作用[J].中华中医药杂志.2007,22(7)：37-40.
[1]曹泽毅,翁梨驹,郎景和,等.中华妇产科学.北京：人民卫生出版社.2010.2169.
[2]王霞灵,周大桥.肝郁患者血清泌乳素测定临床意义探讨.湖北中志,1995,(5)：53.
[3]陈国林,等.通过肝阳上亢证的辩证探讨证的研究方法.中国医报,1988,(5)：671.
[4]龚耀先.修订艾森克个性问卷手册.长沙：湖南地图出版社,1992,1245.
[5]王向东,王希林,马弘.心理卫生评定量表手册中国心理卫生杂志增订版,1999.
[6]姚泰主编.生理学,第6版.北京：人民卫生出版.2001,401-402.
[7]Most SB, Chun MM,Widders DM, eta.1 Attentional rubbernecking:cognitive control and personality in emotion-induced blindness. Psychon BullRev,2005,12(4):654.
[8]邵小珍,官锐园,徐国英.急诊护士焦虑与人格特征的相关性研究.中国实用护理杂志,2007,23(4)：68-69.
[9]高鹏程,黄敏儿.高焦虑特质的注意偏向特点.心理学报,2005,40(3)：307-3.
[10]Sung-keum Park, Michael Selmanoff. Neuroendocrinology.1991,53:404-410.
[11]敖海清,徐志伟,严灿,等.柴胡疏肝散及逍遥散对慢性心理应激大鼠血清皮质酮及胃肠激素的影响.中药新药与临床药理,2007,18(4)：288-291.
[12]Carter WR, Hemmn J, Stokes K. Promotion of diabetes onset by stress in BB rat. Diabetologia,1987,30:674.
[13]辛浩琳.抑乳灵口服液对大鼠高泌乳素血症状态下生殖激素影响的实验研究.吉林大学硕士学位论文.2005.
[14]李松滨,李宝龙.调肝汤对肝郁动物模型大鼠泌乳素影响的研究.中医药学报.2008,36(1)：32-33.
[15]郝世凤.女性肝郁状态下神经递质、激素的实验研究.成都中医药大学硕士论文.2004.
[16]Ko SM, Kua EH, Ng TP, et al. Life events and minor psychiatric morbidity in a community survey. Stress and Health,2001,17:41-46.
[17]王淑贞,主编.妇产科理论与实践.上海：上海科技出版社,1993,82.
[18]乔明琦,王文燕,张惠云,等.肝气逆肝气郁两证病因流行病学调查及情志致病方式研究.中西医结合杂志,2007,27(2)：117-119.
[19]乔明琦,于霞,张惠云,等.“多情交织共同致病首先伤肝”假说及其论证.山东中医药大学学报.2006,30(1)：8-10.
[20]Katz R J, Rot h K A, Carroll B J. Acute and chronic stress effects on open field activity in the rat:implications for a model of depression. Neurosci Biobehav Rev,1981,5(2):247-251.
[21]金光亮,王胜兰.关于建立肝郁证动物模型的思考.山东中医药大学学报.2004,28(6)：408-409.33
[22]于琦,金光亮.三种复方对慢性应激肝郁模型大鼠海马5-HT1A受体基因表达的影响.北京中医药.2008,27(1)：57.59
[23]严灿,徐志伟,吴丽丽,等.建立中医情志致病动物模型的思考.中国临床康复.2006,10(3)：155-157.
[24]张志玲,刘菊芳,李惠林,等.坤安冲服剂对高泌乳素血症大鼠血清激素水平的影响.广州中医药大学学报.2004,21(4)：302-303.
[25]Yelle CA, Corenbium B. Idiopathic hyperprolactinemia evolving into macro-prolactinemia. Endocrinoligist 2002,12(3):6.
[26]陈泽奇,陈国林,金益强,等.肝气郁结证病理生理学基础研究.中国现代医学杂志,2000,10(10)：21.
[27]姚传芳.情感性精神障碍.长沙：湖南科学技术出版社.1999：59-69.
[28]孙朋波,丛亚莉.使用甲氧氯普胺应注意的问题.中国误诊学杂志.2008,8(24)：6044.
[29]罗颂平,梁国珍.中西医结合生殖免疫与内分泌学.北京：人民军医出版社,2004,86.
[30]丁寿根.应激过程中下丘脑-垂体-肾上腺轴的调控机理.国外医学.军事医学分册,1994,11(1)：9.