孕三烯酮对大鼠血清雌孕激素及在位和异位子宫内膜雌孕激素受体的影响

目的:探讨孕三烯酮(gestrinone)治疗子宫内膜异位症的作用机理。方法:用自体移植术建立大鼠子宫内膜异位症动物模型,随机分组给药,3周后剖腹,取血测定雌二醇(E2)、孕酮(P)浓度,取出子宫及移植物,固定、切片,免疫组化SP法测定各组动物子宫及移植物的雌激素受体(ER)和孕激素受体(PR)的表达。结果:孕三烯酮高剂量使大鼠血清E2、P水平降低,而中低剂量对E2、P水平影响不大。免疫组化结果则显示移植物的ER、PR含量较子宫内膜低,孕三烯酮高、中剂量可下调在位和异位子宫内膜ER、PR表达,而低剂量孕三烯酮则不能明显改变ER、PR的表达量。结论:孕三烯酮可通过降低体内雌孕激素水平以及下调在位及异位子宫内膜ER、PR的表达,发挥对子宫内膜异位症的治疗作用。     

育龄期功能失调性子宫出血患者子宫内膜组织中雌、孕激素及其受体的变化与意义

目的:研究育龄期功能失调性子宫出血患者子宫内膜组织中雌、孕激素及其受体的变化。方法:随机采集2005年8月至2006年11月北方学院附属第一医院妇产科门诊育龄期功血35例患者的静脉血及子宫内膜功能层组织为研究组,以20例月经正常健康女性排卵后期标本为对照组。(1)采用放免法测定研究组及对照组血清及子宫内膜组织中雌二醇(E2)、孕激素(P)的含量;(2)HE染色后对子宫内膜进行组织学诊断;(3)用TUNEL原位标记技术精确测定子宫内膜功能层细胞凋亡指数;(4)用免疫组化法检测子宫内膜中雌、孕激素受体(ER、PR)的表达。结果:育龄期功血患者以排卵型为主(30/35),其子宫内膜组织中E2含量高于对照组(P<0.05),而P含量低于对照组(排卵后期的子宫内膜),二者差异有统计学意义(P<0.05);两组血清中E2、P差异无统计学意义(P>0.05),但血清、子宫内膜中E2和P呈正相关(rE2=0.74,PE2<0.01;rP=0.65PP<0.01);育龄期功血患者子宫内膜中ER、PR表达及凋亡指数较对照组显著增高,差异有统计学意义(P<0.01)。结论:育龄期功血绝大多数可能系体内作用于子宫内膜的雌、孕激素产生的时间、数量及其受体比例失衡所致,细胞凋亡也参与了功血的发生。     

Effect of mifepristone on estrogen and progesterone receptors in human endometrial and endometriotic cells in vitro

OBJECTIVE: To investigate the expressions of estrogen (E) receptor and progesterone (P) receptor in human eutopic and ectopic endometrium and the effect of mifepristone (RU486) on them. DESIGN: Prospective study. SETTING: University hospital. PATIENT(S): Twenty-two patients with ovarian endometriosis and 13 patients with uterine leiomyoma were recruited. INTERVENTION(S): Samples of ovarian endometrioma cyst tissue and endometrium were obtained from the 22 patients. A sample of endometrium was obtained from the 13 patients. MAIN OUTCOME MEASURE(S): Expressions of E and P receptors were determined using immunocytochemical method. RESULT(S): P receptor expression in endometrial epithelial cells with endometriosis was significantly higher than that without endometriosis in the early secretory phase. Estrogen receptor and epithelial P receptor expressions in endometriotic cells were significantly lower than those of endometrial cells during the proliferative phase, similar with the latter during the early secretory phase and significantly higher during the late secretory phase. RU486 down-regulated the expressions of E and P receptors in both the eutopic and the ectopic endometrial cells, and in some cases this down-regulating effect was more apparent when the concentration of RU486 was higher. CONCLUSION(S): Different steroid receptor expressions indicate different hormonal regulation between endometriotic and endometrial cells. The down-regulating effect on E and P receptors may be one of the therapeutic mechanisms of RU486 on endometriosis.     

Progesterone stimulates cardiac muscle protein synthesis via receptor-dependent pathway

OBJECTIVE: To examine the effect of ovarian hormones on the regulation of cardiac growth. DESIGN: Ovariectomized rat model with replacement of 17beta-estradiol (E(2)) and progesterone (P). SETTING: University research laboratory. PATIENT(S): Female Sprague-Dawley rats (7-8 weeks old). INTERVENTION(S): Rats were separated into five groups: [1] sham-operated (S; n = 6), [2] ovariectomized plus placebo (OVX; n = 8), [3] OVX plus 17beta-E(2) (OVX+E(2); n = 8), [4] OVX plus P (OVX+P; n = 8), and [5] OVX+E(2)+P (n = 7). MAIN OUTCOME MEASURE(S): Cardiac muscle protein synthesis rates, steroid hormone receptor protein expression, and plasma volume. RESULT(S): Cardiac protein synthesis was greater in OVX+P (mean +/- SE; 11.4 +/- 1.5% per day) rats compared with S (5.9 +/- 0.6%/day), OVX (6.9 +/- 0.5%/day), OVX+E(2) (5.2 +/- 0.4%/day), and OVX+E(2)+P (6.8 +/- 0.3%/day) groups. Treatment of OVX+P rats with the P receptor antagonist RU 486 (n = 9) reduced protein synthesis rates to control levels (7.5 +/- 0.5% per day), indicating that P regulates cardiac protein metabolism through a receptor-dependent pathway. Both P and estrogen receptors were found in cardiac tissue homogenates, suggesting the possibility of direct effects of ovarian hormones on the heart. Progesterone replacement had an additional effect of increasing plasma volume. Rats in the OVX+P group had a 20% greater plasma volume compared with animals in the S group (5.24 +/- 0.22 vs. 4.19 +/- 0.26 mL/100 g). This effect of P replacement to increase plasma volume was not blocked by RU 486 (5.01 +/- 0.24 mL/100 g), suggesting that volume expansion was not solely responsible for the effects of P on cardiac protein synthesis. CONCLUSION(S): Our findings indicate a role for ovarian hormones in the regulation of cardiac growth in female rats.     

Metabolism of estrone sulfate in endometriotic tissue and in uterine endometrium in proliferative and secretory cycle phase

The metabolism of [3H]estrone sulfate (E1S) into [3H]estrone (E1) and [3H]estradiol-17 beta (E2) was studied in samples of endometriotic tissue and uterine endometrium obtained simultaneously from 13 patients, 7 in the proliferative and 5 in the secretory cycle phase, and 1 menstruating. E1S was efficiently converted into E1 and E2 by both types of tissue. Total hydrolysis (formation of E1 + E2), as well as the specific formation of E2, was higher in uterine endometrium than in endometriotic tissue, especially in the proliferative phase. Cycle phase associated variations in E2 formation occurred in both tissues, but were statistically significant only for uterine endometrium. E2 formation and total hydrolysis were correlated in endometriotic tissue, but not in uterine endometrium, indicating certain differences in the regulation of estrogen metabolism.     

射频消融技术对子宫肌瘤组织中ER、PR表达影响的临床试验研究

目的 :开腹直视下射频消融子宫肌瘤后 ,观察射频消融对子宫肌瘤组织中ER、PR表达的影响 ,初探射频治疗子宫肌瘤的机制。方法 :30例需开腹行子宫切除术的多发性子宫肌瘤患者 ,分别用 0 .5cm、1.2cm长的射频自凝刀行肌瘤部位射频消融 ,治疗后立即切除子宫 ,作为试验组 ,并于消融灶中心 (A组 )、边缘 (B组 )、边缘外 1cm(C组 )、边缘外 2cm(D组 )处取材 ,HE染色观察病理变化 ,免疫组化检测ER、PR水平 ;选同一子宫上未做射频治疗的肌瘤组织作为对照组。结果 :射频治疗后 ,消融灶中心肌瘤组织呈凝固性坏死 ,ER、PR无表达 ;消融灶边缘肌瘤细胞变性 ,ER、PR表达减少 (P <0 .0 5 ) ;消融灶边缘外1cm ,肌瘤细胞无变性、坏死 ,但ER、PR表达低于对照组 (P <0 .0 5 ) ;消融灶边缘外 2cm ,ER、PR与对照组差异无显著性 (P >0 .0 5 )。结论 :射频消融技术使肌瘤组织凝固性坏死 ,ER、PR的表达丧失及低表达是射频消融技术能够治疗子宫肌瘤的循证依据     

Effect of Decapeptyl, an agonistic analog of gonadotropin-releasing hormone on estrogens, estrogen sulfates, and progesterone receptors in leiomyoma and myometrium

Estrogens (estrone [E1] and estradiol [E2]), their sulfates and progesterone receptor (PR) were evaluated in patients with uterine leiomyomata nontreated and treated with Decapeptyl (D-Trp6-gonadotropin-releasing hormone [GnRH]; Ipsen Biotech, Paris, France). Estrogen concentrations are very high in the leiomyoma (secretory phase, pg/g tissue [mean +/- SEM]: n = 10; E1: 147 +/- 24; E2: 850 +/- 116; E1-sulfate: 1,668 +/- 808; E2-sulfate: 718 +/- 126). Decapeptyl treatment provokes a significant decrease in E2 and particularly in E1 and E2 sulfates. Progesterone receptors were higher in the leiomyoma than in the myometrium; after a long treatment (3 to 4 months) a significant decrease in both tissues is observed. The decrease provoked by D-Trp6-GnRH on estrogens (unconjugated and sulfates) and in PR in the leiomyoma after long treatment, supports the hypothesis that estrogens are implicated in the cause of these tumors.     

米非司酮对子宫肌瘤及子宫肌层组织雌、孕激素受体的影响

目的 了解米非司酮对子宫肌瘤及子宫肌层组织中雌激素受体（ＥＲ）,孕激素受体（ＰＲ）的影响。方法 对２０例临床诊断为子宫肌瘤并有手术指征。无内科合并症患者（服药组）,从月经第１天起予米非司酮每日２５ｍｇ口服,连续９０ｄ,应用彩色超声检查服药前,后子宫肌瘤的变化,以及血清激素水平,血脂,肝肾功能,电解质,血常规的变化,停药后立即手术,并配对选２０例临床情况相似的子宫肌瘤患者作为对照组,用ＥＲ,ＰＲ单克     

米非司酮对子宫肌瘤组织中孕激素受体基因表达的影响

目的研究子宫肌瘤组织中孕激素受体（ＰＲ）基因的表达情况,从ＰＲ基因的转录及翻译水平探讨米非司酮治疗子宫肌瘤的作用机理。方法采用Ｎｏｒｔｈｅｒｎ印迹法和羟基磷灰石（ＨＡＰ）单点饱和分析法,分别测定２７例单纯手术治疗（单纯手术组）及６例术前口服米非司酮每天２５ｍｇ共３个月（米非司酮组）的子宫肌瘤患者的肌瘤瘤心、瘤边缘及子宫体正常肌组织中ＰＲｍＲＮＡ和ＰＲ蛋白。结果单纯手术组瘤心和瘤边缘中ＰＲｍＲＮＡ及ＰＲ蛋白水平在卵泡期和黄体期均显著高于子宫体肌组织（Ｐ＜０．０１）,呈持续高表达,而瘤心和瘤边缘间差异无显著性（Ｐ＞０．０５）;米非司酮组４例术前未停药者,肌瘤及子宫体肌组织中ＰＲｍＲＮＡ和ＰＲ蛋白水平均明显降低,２例术前停药１月者,上述组织中ＰＲｍＲＮＡ与单纯手术者相似,但ＰＲ蛋白仍处于低水平。结论子宫肌瘤中ＰＲ基因呈持续高表达。米非司酮能抑制ＰＲ基因的表达,在ｍＲＮＡ水平上的影响是可逆的,在蛋白水平上的影响持续时间较长。     

Norplant皮下埋植后子宫内膜形态和雌、孕激素受体含量的变化

目的探讨Ｎｏｒｐｌａｎｔ皮下埋植后子宫内膜形态和雌、孕激素受体（ＥＲ、ＰＲ）含量的变化与子宫异常出血的关系。方法应用免疫组化、ＷｅｓｔｅｒｎＢｌｏｔ和原位杂交技术结合计算机图像分析,观察１６例Ｎｏｒｐｌａｎｔ皮下埋植后和２３例正常周期的内膜的形态学改变、细胞增殖状态及ＥＲ、ＰＲ蛋白及其ｍＲＮＡ的表达。结果埋植Ｎｏｒｐｌａｎｔ后,内膜ＤＮＡ含量降低;螺旋动脉数量减少,腺体的构成比例降低;腺体构成比例与雌二醇（Ｅ２）水平呈正相关,与子宫异常出血呈负相关,与年龄和体重无相关性,随使用期延长,腺体构成比增加。埋植后,内膜ＥＲ含量低于月经周期各期水平,但ＰＲ含量相当于或高于月经周期最高水平。ＥＲ、ＰＲｍＲＮＡ表达减弱,以ＥＲｍＲＮＡ表达降低更明显。结论内膜腺体和螺旋动脉再生修复不良和ＥＲ、ＰＲ表达异常,可能是Ｎｏｒｐｌａｎｔ致子宫异常出血的病理学基础     

米非司酮对离体异位与在位子宫内膜雌、孕激素受体含量的影响

目的　探讨子宫内膜异位症(内异症)的异位与在位内膜雌、孕激素受体(ER、PR)含量,及米非司酮对其影响。方法　采用免疫细胞化学法,分析22例内异症患者的在位内膜细胞和其中12例患者的异位内膜细胞体外培养后的ER、PR含量,观察不同浓度米非司酮(1×10-6mol/L和1×10-4mol/L)作用后的变化,并以13例正常子宫内膜作对照。结果　内异症的在位内膜ER、PR含量呈明显周期性变化,分泌早期腺体PR含量显著高于正常子宫内膜［组织化学评分(下同)为2.77±0.32与2.20±0.26,P<0.05］。内异症的异位内膜,增殖期ER(腺体0.65～2.17,间质0.45～1.03)、PR含量(腺体0.55～1.77,间质0.40～1.27)显著低于在位内膜(ER腺体1.50～3.23,间质0.80～1.96;PR腺体1.55～3.34,间质0.98～2.50,P<0.05～0.01);分泌早期无差异;分泌晚期腺体ER含量(3.27±0.31)、PR含量(3.33±0.23)与间质ER含量(1.87±0.31)显著高于在位内膜(分别为0.28±0.11、0.36±0.23和0.26±0.15,P<0.01),而间质PR含量无差异。米非司酮可明显降低内异症的异位和在位内膜ER、PR含量(P<0.01),且米非司酮浓度越高,ER、PR含量降低越明显。结论　内异症的异位和在位内膜ER、PR含量明显不同,米非司酮可下调异位和在位内膜ER、PR的含量。     

Differential expression of endometrial integrins and progesterone receptor during the window of implantation in normo-ovulatory women treated with clomiphene citrate

OBJECTIVE: To assess the effect of clomiphene citrate (CC) on endometrial epithelial integrins and P receptors (PR) during the window of implantation. DESIGN: Controlled, prospective, clinical study. SETTING: Teaching hospital and university research laboratory. PATIENT(S): Thirty-one fertile, normo-ovulatory women participated in this trial. Thirteen women exhibited a CC-stimulated cycle with 50 mg on days 5-9, and 18 women with spontaneous menstrual cycles served as controls. INTERVENTION(S): Endometrial biopsies in the midluteal phase. MAIN OUTCOME MEASURE(S): Immunohistochemical determination and endometrial cellular localization of alpha1, alpha v, beta3, and alpha4 epithelial integrins and PR during the window of implantation. The staining intensity was assessed by a semiquantitative index (HSCORE) and compared by nonparametric Mann-Whitney test. RESULT(S): Higher plasma levels of P and E2 and delayed histologic dating of the endometrium (38%) were features of CC-treated women. In addition, a low epithelial beta3 integrin expression and persistent PR were observed in glandular epithelial cells of "out-of-phase" endometrial biopsies from CC-treated women. In contrast, in "in-phase" biopsies, neither epithelial PR nor beta3 integrin were different from spontaneous control cycles. There was no difference in the expression of alpha1, alpha v, and alpha4 between the groups studied. CONCLUSION(S): The administration of clomiphene produces aberrant endometrial beta3 integrin expression in conjunction with a failure in the down-regulation of PR during the window of implantation in a significant number of normo-ovulatory women, notwithstanding the higher plasma P levels. Therefore, CC might affect the expression of endometrial receptivity markers.     

IGF-I和IGF-I受体在早孕期大鼠子宫中的表达及意义

目的 :探讨类胰岛素样生长因子 - I(IGF- 1 )和 IGF- I受体 (IGF- IR)在围着床期大鼠子宫内膜和胚胎滋养层细胞中的表达、意义及其与孕激素 (P)的关系。方法 :收集自然交配的孕 3～ 1 0 d大鼠的血清及子宫组织 ,以动情期雌鼠为对照。采用放射免疫法测定大鼠血清 P水平 ;免疫组化Ls AB法检测 IGF- I、IGF- IR及孕激素受体 (PR)在孕早期大鼠子宫内膜及胚胎滋养层细胞中的表达 ,计算机图像分析法进行定量。结果 :IGF- I及其受体在大鼠内膜腺、腔上皮 ,蜕膜细胞及滋养层细胞中均有表达。IGF- I在大鼠子宫内膜中的表达强度随孕天逐渐升高 ,孕 5～ 7d达到最强 ,此后降到动情期水平 ,与 P及 PR无显著性相关。IGF- IR的表达强度随孕天降低 ,孕 5～ 6 d达到最小值 ,孕 8～ 1 0 d又上升到动情期水平 ,与 P及 PR均呈显著性负相关 (P<0 .0 5 )。IGF- I和 IGF-IR在孕 8～ 1 0 d大鼠滋养层细胞中的表达强度随孕天逐渐升高 ,与血 P及 PR均无显著性相关。结论 :IGF- I与 IGF- IR在围着床期大鼠子宫内膜中的表达出现分离 ,既抑制了 IGF- I对子宫内膜过强的促生长作用 ,使之蜕膜化 ;同时又满足了孕早期胚胎生长发育所需的较高 IGF- I水平 ,此效应主要受 P调节。 P和 IGF- I对胚胎滋养层细胞功能的调节可能是独立进行的。     

过期妊娠胎盘等部位雌,孕激素受体水平的测定

采用荧光激素结合法，分别对３０例过期妊娠（过期妊娠组）和２７例足月妊娠妇女（对照组）有关的靶组织（胎盘、胎膜、子宫胎盘床和子宫下段肌层）的雌激素受体（ＥＲ）和孕激素受体（ＰＲ）进行了定性和定量分析。结果：过期妊娠组子宫胎盘床及胎膜ＥＲ水平较对照组明显减少，而ＰＲ却无明显差异；过期妊娠组各靶组织内ＥＲ与ＰＲ的比值（ＥＲ／ＰＲ）都明显低于对照组；各靶组织ＥＲ与ＰＲ水平呈明显的正相关；有宫缩者子这吕下段     

Widespread increases of cortical serotonin type 2A receptor availability after hormone therapy in euthymic postmenopausal women

OBJECTIVE: To use statistical parametric mapping to determine the extent of previously reported serotonin type 2A (5HT(2A)) receptor binding potential (BP) increases in postmenopausal women following hormone therapy. DESIGN: Repeated measures positron emission tomography (PET) study. SETTING: Academic research environment. PATIENT(S): Five healthy, postmenopausal women. INTERVENTION(S): Serial PET images of [(18)F]altanserin uptake were acquired to measure 5HT(2A) receptor BP at menopausal baseline, following estradiol (E(2)), and following combined E(2) + micronized progesterone (P(4)). MAIN OUTCOME MEASURE(S): 5HT(2A) receptor BP. RESULT(S): Combined E(2) + P(4) treatment was associated with significant increases in the 5HT(2A) receptor BP increases in widespread areas of cerebral cortex. Treatment with E(2) alone was also associated with widespread cortical BP increases, although these changes reached statistical significance in fewer regions. The rate of [(18)F]altanserin metabolism was significantly decreased in the E(2) + P(4) condition relative to menopausal baseline, but this difference did not appear to correlate with changes in 5HT(2A) receptor BP. CONCLUSION(S): Estradiol priming followed by combined E(2) + P(4) is associated with widespread increases in 5HT(2A) receptor BP in the cerebral cortex, consistent with the E(2)-associated increases in 5HT(2A) receptor density previously observed in experimental animals.     

来曲唑治疗大鼠子宫内膜异位症模型作用及机制的研究

目的:探讨第3代芳香化酶抑制剂(aromatase inhibitors,AIs)来曲唑治疗大鼠子宫内膜异位症模型的效果及作用机制。方法:用自体子宫内膜移植方法建立大鼠内异症模型,随机将20只建模成功大鼠分为来曲唑组和盐水对照组,比较治疗前后EM大鼠异位病灶体积的变化;免疫组化法检测异位内膜病灶中细胞色素P450芳香化酶(P450arom)、环氧合酶-2(COX-2)、血管内皮生长因子(VEGF)、增殖细胞核抗原(PCNA)蛋白的表达;末端转移酶介导的缺口末端标记法(TUNEL)检测细胞凋亡情况;放射免疫分析法测定大鼠血清FSH、LH、E2水平。结果:来曲唑组异位病灶体积缩小(P<0.01);异位内膜中P450arom、COX-2、VEGF、PCNA蛋白表达与对照组相比均明显降低(P<0.05);来曲唑组异位内膜细胞凋亡率较对照组明显增加(P<0.01);两组大鼠血清FSH、LH、E2水平无明显差异(P>0.05)。结论:来曲唑治疗大鼠子宫内膜异位症模型有效。来曲唑通过降低异位内膜局部P450arom、COX-2、VEGF蛋白表达及抑制异位内膜增殖并促进凋亡发挥治疗子宫内膜异位症的作用。来曲唑对大鼠血清FSH、LH、E2水平无明显影响。     

Conversion of circulating estrone sulfate to 17beta-estradiol by ovarian tumor tissue: a possible mechanism behind elevated circulating concentrations of 17beta-estradiol in postmenopausal women with ovarian tumors.

AIM: Elevated serum levels of 17beta-estradiol (E2) are frequently found in postmenopausal women with ovarian tumors not classified as estrogen-producing. Conversion of circulating estrone sulfate (E1S) to E2 is one alternative way of E2 formation in target tissues in postmenopausal women. Our aim was to find out if conversion of circulating E1S to E2 by the tumor tissue could be a reason for elevated serum E2 levels in postmenopausal women with 'non-estrogen-producing' ovarian tumors. METHOD: Serum E2 was measured in 12 postmenopausal women with 'non-estrogen-producing' ovarian tumors (nine benign, three malignant). Total hydrolysis of and [3H]E2 formation from [3H]E1S by the tumor tissue homogenates was studied in vitro. RESULTS: Serum E2 showed significant positive correlations with total hydrolysis of and [3H]E2 formation from [3H]E1S in the total material as well as in the benign tumor subgroup. [3H]E2 formation was the most important independent variable. CONCLUSION: Conversion of circulating E1S to E2 by the tumor tissue could be one important reason for elevated S-E2 levels in postmenopausal women with 'non-estrogen-producing' ovarian tumors.     

Reduction of apoptosis and proliferation in endometriosis

OBJECTIVE: To evaluate whether endometriosis could be related to an impaired balance between apoptosis and proliferation, two processes which could be modulated by hormonal status. DESIGN: Immunohistochemical study. SETTING: Academic research laboratory. INTERVENTION(S): Endometriotic samples obtained from peritoneum of women aged 26-40 years who were undergoing laparoscopy for pain or infertility. MAIN OUTCOME MEASURE(S): Apoptotic cells were detected with the use of the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. The production of p53 and bcl-2, estrogen and Progesterone (P) receptors, and cellular proliferation were assessed by immunohistochemistry in eutopic and ectopic endometria from 30 patients with endometriosis throughout the menstrual cycle. Results were compared with those from normal endometria from 15 fertile patients. RESULT(S): Endometriotic lesions were characterized by reduced TUNEL and p53 stainings and by enhanced bcl-2 staining. No correlation between apoptosis and estrogen receptor or P receptor levels was found. A lower amount of steroid receptor was found in endometriotic tissues, without cyclic modulation, compared with the eutopic endometrium. CONCLUSION(S): Our results suggest that when endometrial tissue is located at ectopic locations, it differs from eutopic endometrium by its proliferation rate, steroid hormone levels, and markers of apoptosis. A reduced sensitivity of endometriotic cells to apoptosis could promote the dissemination and implantation of these cells to ectopic sites.