抗苗勒氏管激素在多囊卵巢综合征中的表达及相关机制研究
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摘要
第一部分抗苗勒氏管激素在多囊卵巢综合征中的表达及与内分泌和代谢指标的相关性研究
目的探讨多囊卵巢综合征(PCOS)患者血清抗苗勒氏管激素(AMH)水平变化,及其与患者体质指数(BMI)、代谢紊乱以及激素紊乱的相关性。通过比较肥胖型和非肥胖型PCOS患者AMH的分泌特点,对比这两种亚型是否存在卵泡发育障碍机制的差异,从而为PCOS的个体化治疗提供理论依据。方法将60例PCOS患者根据BMI分为PCOS组1(BMI≥25kg/m2)30例,PCOS组2(BMI<25kg/m2)30例；30例月经周期正常的妇女为对照组,根据BMI分为对照组1(BMI≥25kg/m2)15例,对照组2(BMI<25kg/m2)15例。所有患者用化学发光法测定血清生殖激素(卵泡刺激素、黄体生成素、雌二醇、睾酮、催乳素)水平,所有患者进行糖代谢试验,化学发光法测定空腹血糖和空腹血清胰岛素水平。计算稳态模型胰岛素抵抗指数(HOMA-IR),采用ELISA测定血清AMH水平。分析比较血清AMH在各组的表达及与生殖激素和代谢指标的相关性。结果PCOS组1和PCOS组2间血清AMH水平差异无统计学意义(P>0.05),但2组均高于对照组(P<0.05)。PCOS组1与PCOS组2患者LH、LH/FSH、睾酮、空腹胰岛素及HOMA-IR均高于对照组,差异有统计学意义(P<0.05)。PCOS组1LH、LH/FSH低于PCOS组2,空腹胰岛素、HOMA-IR高于PCOS组2(均P<0.05)。PCOS组1AMH水平与睾酮、空腹血糖、空腹胰岛素、HOMA-IR呈正相关,与雌二醇、FSH呈负相关(均P<0.05),与BMI、 LH、LH/FSH无明显相关性(均P>0.05)。PCOS组2AMH水平与LH、LH/FSH、睾酮呈正相关,与BMI、FSH、雌二醇、空腹血糖、空腹胰岛素、HOMA-IR无相关性。结论PCOS患者血清AMH显著升高,其升高与体质指数无关,可能与激素紊乱和糖代谢紊乱具有一定相关性,并可能反映了疾病的严重程度。
第二部分
二甲双胍对PCOS患者AMH-雄激素-胰岛素相互作用的影响
目的通过观察二甲双胍对存在胰岛素抵抗(IR)的PCOS患者血清AMH水平的影响,探讨二甲双胍对PCOS患者的治疗作用,及在AMH-雄激素-胰岛素之间可能存在的作用机制。方法根据第一部分研究结果显示,PCOS组1(肥胖细胞转染后在胰岛素及雄激素存在的情况下,进行双荧光素酶报告基因检测。结果半定量RT-PCR结果显示：：Insulin组、Androgen组和Insulin+Androgen组的AMH, AMHRⅡ的mRNA表达较对照组增强,与对照组相比差异均有统计学意义(P<0.05)。其中Insulin+Androgen组增强更为明显,与Insulin组和Androgen组比较差异有统计学意义(P<0.05)。Western blot检测结果显示：Insulin组、Androgen组和Insulin+Androgen组的AMH. AMHRⅡ的蛋白表达较对照组增强,与对照组相比差异均有统计学意义(P<0.05)。其中Insulin+Androgen组AMH的蛋白表达增强更为明显,与Androgen组比较差异有统计学意义(P<0.05),Insulin+Androgen组AMHRⅡ的蛋白表达增强更为明显,与Insulin组和Androgen组比较差异有统计学意义(P<0.05)。免疫组化结果显示,胰岛素,雄激素的刺激作用同Western blot检测结果一致,胰岛素,雄激素分别能够对AMH,AMHRⅡ的蛋白水平表达有促进作用,胰岛素和雄激素共同作用,能够协同作用促使AMH,AMHRⅡ的蛋白水平表达更强。双荧光素酶报告基因检测结果显示：在含有AMH启动子调节序列的基因检测中Insulin组、Androgen组和Insulin+Androgen组的AMH启动子活性明显增强,与对照组相比差异均有统计学意义(P<0.05)。其中Insulin+Androgen组AMH启动子活性增强更为明显,与Insulin组和Androgen组比较差异有统计学意义(P<0.05)。结论胰岛素和雄激素可明显增强卵巢颗粒细胞AMH的mRNA和蛋白表达,并可影响AMH的基因启动子活性,且二者之间具有明显协同作用。
Part1Relationship between Plasma Concentration of Anti-Mullerian Hormone and Clinical Index in Women with Polycystic Ovary Syndrome
Objective To analyze interrelation between anti-Mullerian hormone (AMH) levels and body weight(BMI), hormone status and metabolic rate in women with polycystic ovary syndrome (PCOS). Methods Sixty women (30overweight, PCOS1group and30normal weight, PCOS2group) diagnosed as PCOS were enrolled and30women with normal period (15overweight and15normal weight non-PCOS.control1and control2respectively) were as control group. The body weight and height were measured and BMIwas calculated. The serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, testosterone, adrenal medullary hormone (AMH), androgens, fasting glucose and fasting insulin were detected, and the homeostasis model of assess ment-insulin resistance (HOMA-IR) were caculated and compared between four groups. Results The levels of AMH, LH. LH/FSHP. testosterone, fasting glucose and fasting insulin and HOMA-IR were higher in PCOS group than those of control group(P<0.05). There was no significant difference in AMH level between PCOS1and PCOS2groups (P>0.05). The levels of LH and LH/FSH were lower in PCOS1than those of PCOS2group (P<0.05). The levels of fasting insulin and HOMA-IR were higher in PCOS1group than those of PCOS2group(P<0.05). There were no correlations in AMH and BMI levels in PCOS group (P>0.05). There were positive correlations in AMH and testosterone, fasting glucose and fasting insulin and HOMA-IR in PCOS1group, but a negative correlation between estradiol and FSH. A significant positive correlation was found between LH, LH/FSH, testosterone and AMH in PCOS2group(P<0.05). Conclusion There is a significant increase in plasma AMH in patients with PCOS. The plasma AMH level is not associated with BMI, which may have correlation with hormone imbalance and metabolic disorders.
Part2The effect of metformin on AMH-androgen-insulin in women with PCOS
Objective Evaluate the levels of AMH in insulin resistance (IR) women with PCOS before and after metformin therapy. To explore the effect of metformin in patients with PCOS, and the possible mechanism on AMH-androgen-insulin. Methods According to the part one, there are26cases with insulin resistance in PCOS1group (obese) and10cases in PCOS2group (non obesity).These patients were enrolled in the second part.All patients received500mg metformin,3times/day,for4months. Serum levels of AMH, sex hormones, insulin, blood glucose, and glucose tolerance test were measured after metformin therapy. The menstrual cycle in two groups were observed. Results The levels of AMH,testosterone,insulin and HOMA-IR were decrease in PCOS1group(obese) after treatment(P<0.05). There are on change in the levels of AMH,testosterone,insulin and HOMA-IR were decrease in PCOS2group(non obesity) after treatment(P>0.05).The recovery rate of menstruation was53.85%in PCOS1and10%in PCOS2, Is similar between the two groups was statistically significant (P<0.05). Conclusion In the presence of insulin resistance, the effect of metformin treatment in patients with obese PCOS is better than the patients non obesity. There are more obvious menstrual cycle improve.the improvement of insulin resistance and hyperandrogenism in Obese PCOS patients after metformin therapy, and the lever of AMH significantly decreased at the same time.
Part3The influence of insulin and testosterone on AMH and its receptor protein expression and regulation of AMH promoter activity in ovarian granulosa cell
Objective To Explore the influence of insulin and testosterone on AMH and its receptor protein expression and regulation of AMH promoter activity in ovarian granulosa cell. Methods Cell primary culture of SD rat ovarian granulosa, the microscopic morphology identification after HE staining. Cells in processing different can be divided into the following four groups:control group (Blank):pure particle normal training.Insulin(Insulin group):100ng/ml insulin treatment for48hours. Androgen (Androgen group):105mol/L testosterone treatment for48hours. Androgen and Insulin(Insulin+Androgen group):100ng/ml insulin and105mol/L testosterone treatment for48hours together. RT-PCR detection AMH and its receptor mRNA expression and Western blot detection AMH and its receptor protein expression. IHC staining test at the same time. According to the published literature or biology database retrieval AMH promoter sequences, and cloned into the fluorescein report carrier, clone mutant AMH promoter sequences at the same time, in the presence of insulin and testosterone, change detection of fluorescein. Results RT-PCR showed that AMH.AMHR2mRNA expression was increased in Insulin group, Androge group and Androgen+Insulin group compared with the control (P<0.05).Including Insulin+Androgen group increased more obviously, compared with Insulin group and Androge group (P<0.05).Western blot showed that AMH,AMHR2protein expression was enhanced in insulin group, Androge group and Androgen+Insulin group compared with control subjects(P<0.05). AMH protein expression increased more obviously in Insulin+Androgen group,compared with Androge group(P<0.05), AMHR2protein expression increased more obviously in Insulin+Androgen group, compared with Insulin group and Androge group(P<0.05).Immunohistochemical results showed that insulin and testosterone stimulation with Western blot test results are consistent. Dual luciferase report gene detection results show that the sequence of genetic testing in containing the AMH promoter regulation of Insulin group, Androge group and Androgen+Insulin group markedly improved AMH promoter activity, compared with control subjects (P<0.05). Which the AMH promoter activity of Insulin+Androgen group is more obvious, compared with Insulin group and Androge group (P<0.05). Conculsion Insulin and testosterone enhance the mRNA and protein expression of AMH in ovarian granulosa cell obviously, and affect the AMH gene promoter activity, thereby promoting AMH transcriptional expression in ovary granulosa cells,and synergistic effect between insuliln and testosterone were observed.
目的探讨多囊卵巢综合征(PCOS)患者血清抗苗勒氏管激素(AMH)水平变化,及其与患者体质指数(BMI)、代谢紊乱以及激素紊乱的相关性。通过比较肥胖型和非肥胖型PCOS患者AMH的分泌特点,对比这两种亚型是否存在卵泡发育障碍机制的差异,从而为PCOS的个体化治疗提供理论依据。方法将60例PCOS患者根据BMI分为PCOS组1(BMI≥25kg/m2)30例,PCOS组2(BMI<25kg/m2)30例；30例月经周期正常的妇女为对照组,根据BMI分为对照组1(BMI≥25kg/m2)15例,对照组2(BMI<25kg/m2)15例。所有患者用化学发光法测定血清生殖激素(卵泡刺激素、黄体生成素、雌二醇、睾酮、催乳素)水平,所有患者进行糖代谢试验,化学发光法测定空腹血糖和空腹血清胰岛素水平。计算稳态模型胰岛素抵抗指数(HOMA-IR),采用ELISA测定血清AMH水平。分析比较血清AMH在各组的表达及与生殖激素和代谢指标的相关性。结果PCOS组1和PCOS组2间血清AMH水平差异无统计学意义(P>0.05),但2组均高于对照组(P<0.05)。PCOS组1与PCOS组2患者LH、LH/FSH、睾酮、空腹胰岛素及HOMA-IR均高于对照组,差异有统计学意义(P<0.05)。PCOS组1LH、LH/FSH低于PCOS组2,空腹胰岛素、HOMA-IR高于PCOS组2(均P<0.05)。PCOS组1AMH水平与睾酮、空腹血糖、空腹胰岛素、HOMA-IR呈正相关,与雌二醇、FSH呈负相关(均P<0.05),与BMI、 LH、LH/FSH无明显相关性(均P>0.05)。PCOS组2AMH水平与LH、LH/FSH、睾酮呈正相关,与BMI、FSH、雌二醇、空腹血糖、空腹胰岛素、HOMA-IR无相关性。结论PCOS患者血清AMH显著升高,其升高与体质指数无关,可能与激素紊乱和糖代谢紊乱具有一定相关性,并可能反映了疾病的严重程度。
第二部分
二甲双胍对PCOS患者AMH-雄激素-胰岛素相互作用的影响
目的通过观察二甲双胍对存在胰岛素抵抗(IR)的PCOS患者血清AMH水平的影响,探讨二甲双胍对PCOS患者的治疗作用,及在AMH-雄激素-胰岛素之间可能存在的作用机制。方法根据第一部分研究结果显示,PCOS组1(肥胖细胞转染后在胰岛素及雄激素存在的情况下,进行双荧光素酶报告基因检测。结果半定量RT-PCR结果显示：：Insulin组、Androgen组和Insulin+Androgen组的AMH, AMHRⅡ的mRNA表达较对照组增强,与对照组相比差异均有统计学意义(P<0.05)。其中Insulin+Androgen组增强更为明显,与Insulin组和Androgen组比较差异有统计学意义(P<0.05)。Western blot检测结果显示：Insulin组、Androgen组和Insulin+Androgen组的AMH. AMHRⅡ的蛋白表达较对照组增强,与对照组相比差异均有统计学意义(P<0.05)。其中Insulin+Androgen组AMH的蛋白表达增强更为明显,与Androgen组比较差异有统计学意义(P<0.05),Insulin+Androgen组AMHRⅡ的蛋白表达增强更为明显,与Insulin组和Androgen组比较差异有统计学意义(P<0.05)。免疫组化结果显示,胰岛素,雄激素的刺激作用同Western blot检测结果一致,胰岛素,雄激素分别能够对AMH,AMHRⅡ的蛋白水平表达有促进作用,胰岛素和雄激素共同作用,能够协同作用促使AMH,AMHRⅡ的蛋白水平表达更强。双荧光素酶报告基因检测结果显示：在含有AMH启动子调节序列的基因检测中Insulin组、Androgen组和Insulin+Androgen组的AMH启动子活性明显增强,与对照组相比差异均有统计学意义(P<0.05)。其中Insulin+Androgen组AMH启动子活性增强更为明显,与Insulin组和Androgen组比较差异有统计学意义(P<0.05)。结论胰岛素和雄激素可明显增强卵巢颗粒细胞AMH的mRNA和蛋白表达,并可影响AMH的基因启动子活性,且二者之间具有明显协同作用。
Part1Relationship between Plasma Concentration of Anti-Mullerian Hormone and Clinical Index in Women with Polycystic Ovary Syndrome
Objective To analyze interrelation between anti-Mullerian hormone (AMH) levels and body weight(BMI), hormone status and metabolic rate in women with polycystic ovary syndrome (PCOS). Methods Sixty women (30overweight, PCOS1group and30normal weight, PCOS2group) diagnosed as PCOS were enrolled and30women with normal period (15overweight and15normal weight non-PCOS.control1and control2respectively) were as control group. The body weight and height were measured and BMIwas calculated. The serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, testosterone, adrenal medullary hormone (AMH), androgens, fasting glucose and fasting insulin were detected, and the homeostasis model of assess ment-insulin resistance (HOMA-IR) were caculated and compared between four groups. Results The levels of AMH, LH. LH/FSHP. testosterone, fasting glucose and fasting insulin and HOMA-IR were higher in PCOS group than those of control group(P<0.05). There was no significant difference in AMH level between PCOS1and PCOS2groups (P>0.05). The levels of LH and LH/FSH were lower in PCOS1than those of PCOS2group (P<0.05). The levels of fasting insulin and HOMA-IR were higher in PCOS1group than those of PCOS2group(P<0.05). There were no correlations in AMH and BMI levels in PCOS group (P>0.05). There were positive correlations in AMH and testosterone, fasting glucose and fasting insulin and HOMA-IR in PCOS1group, but a negative correlation between estradiol and FSH. A significant positive correlation was found between LH, LH/FSH, testosterone and AMH in PCOS2group(P<0.05). Conclusion There is a significant increase in plasma AMH in patients with PCOS. The plasma AMH level is not associated with BMI, which may have correlation with hormone imbalance and metabolic disorders.
Part2The effect of metformin on AMH-androgen-insulin in women with PCOS
Objective Evaluate the levels of AMH in insulin resistance (IR) women with PCOS before and after metformin therapy. To explore the effect of metformin in patients with PCOS, and the possible mechanism on AMH-androgen-insulin. Methods According to the part one, there are26cases with insulin resistance in PCOS1group (obese) and10cases in PCOS2group (non obesity).These patients were enrolled in the second part.All patients received500mg metformin,3times/day,for4months. Serum levels of AMH, sex hormones, insulin, blood glucose, and glucose tolerance test were measured after metformin therapy. The menstrual cycle in two groups were observed. Results The levels of AMH,testosterone,insulin and HOMA-IR were decrease in PCOS1group(obese) after treatment(P<0.05). There are on change in the levels of AMH,testosterone,insulin and HOMA-IR were decrease in PCOS2group(non obesity) after treatment(P>0.05).The recovery rate of menstruation was53.85%in PCOS1and10%in PCOS2, Is similar between the two groups was statistically significant (P<0.05). Conclusion In the presence of insulin resistance, the effect of metformin treatment in patients with obese PCOS is better than the patients non obesity. There are more obvious menstrual cycle improve.the improvement of insulin resistance and hyperandrogenism in Obese PCOS patients after metformin therapy, and the lever of AMH significantly decreased at the same time.
Part3The influence of insulin and testosterone on AMH and its receptor protein expression and regulation of AMH promoter activity in ovarian granulosa cell
Objective To Explore the influence of insulin and testosterone on AMH and its receptor protein expression and regulation of AMH promoter activity in ovarian granulosa cell. Methods Cell primary culture of SD rat ovarian granulosa, the microscopic morphology identification after HE staining. Cells in processing different can be divided into the following four groups:control group (Blank):pure particle normal training.Insulin(Insulin group):100ng/ml insulin treatment for48hours. Androgen (Androgen group):105mol/L testosterone treatment for48hours. Androgen and Insulin(Insulin+Androgen group):100ng/ml insulin and105mol/L testosterone treatment for48hours together. RT-PCR detection AMH and its receptor mRNA expression and Western blot detection AMH and its receptor protein expression. IHC staining test at the same time. According to the published literature or biology database retrieval AMH promoter sequences, and cloned into the fluorescein report carrier, clone mutant AMH promoter sequences at the same time, in the presence of insulin and testosterone, change detection of fluorescein. Results RT-PCR showed that AMH.AMHR2mRNA expression was increased in Insulin group, Androge group and Androgen+Insulin group compared with the control (P<0.05).Including Insulin+Androgen group increased more obviously, compared with Insulin group and Androge group (P<0.05).Western blot showed that AMH,AMHR2protein expression was enhanced in insulin group, Androge group and Androgen+Insulin group compared with control subjects(P<0.05). AMH protein expression increased more obviously in Insulin+Androgen group,compared with Androge group(P<0.05), AMHR2protein expression increased more obviously in Insulin+Androgen group, compared with Insulin group and Androge group(P<0.05).Immunohistochemical results showed that insulin and testosterone stimulation with Western blot test results are consistent. Dual luciferase report gene detection results show that the sequence of genetic testing in containing the AMH promoter regulation of Insulin group, Androge group and Androgen+Insulin group markedly improved AMH promoter activity, compared with control subjects (P<0.05). Which the AMH promoter activity of Insulin+Androgen group is more obvious, compared with Insulin group and Androge group (P<0.05). Conculsion Insulin and testosterone enhance the mRNA and protein expression of AMH in ovarian granulosa cell obviously, and affect the AMH gene promoter activity, thereby promoting AMH transcriptional expression in ovary granulosa cells,and synergistic effect between insuliln and testosterone were observed.
引文
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[1]Munsterberg A, Lovell-Badge R. Expression of the mouse anti-Mullerian hormone gene suggests a role in both male and female sexual differentiation, Development,1991; 113:613-624.
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[3]growth in the mouse ovary. Endocrinology,2002; 143:1076-1084.
[4]Hirobe S, He WW, Gustafson ML, et al. Mullerian inhibiting substance gene expression in the cycling rat ovary correlates with recruited or graafian follicle selection. Biol Reprod,1994; 50:1238-1243.
[5]Salmon NA, Handyside AH, Joyce IM. Oocyte regulation of anti-Mullerian hormone expression in granulosa cells during ovarian follicle development in mice. Dev Biol,2004; 266:201-208.
[6]Themmen AP. Anti-Mullerian hormone:its role in follicular growth initiation and survival and as an ovarian reserve marker. J Natl Cancer Inst Monogr,2005; 34:18-21.
[7]Visser JA, Themmen AP. Anti-Mullerian hormone and folliculogenesis. Mol Cell Endocrinol,2005; 234:81-86.
[8]Durlinger AL, Gruijters MJ, Kramer P, et al. Anti-Mullerian hormone attenuates the effects of FSH on follicle development in the mouse ovary. Endocrinology, 2001; 142:4891-4899.
[9]Durlinger AL, Kramer P, Karels B, et al. Control of primordial follicle recruitment by anti-Miillerian hormone in the mouse ovary. Endocrinology, 1999; 140:5789-5796.
[10]McGee EA, Hsueh AJ. Initial and cyclic recruitment of ovarian follicles. Endocr Rev,2000; 21:200-214.
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[13]Kevenaar ME, Themmen AP, Laven JS, et al. Anti-Mullerian hormone and anti-Mullerian hormone type Ⅱ receptor polymorphisms are associated with follicular phase estradiol levels in normo-ovulatory women. Hum Reprod, 2007; 22:1547-1554.
[14]Wang J, Dicken C, Lustbader JW, et al. Evidence for a mullerian-inhibiting substance autocrine/paracrine system in adult human endometrium. Fertil Steri, 2009; 91(4):1195-1203.
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