雌激素受体对子宫腺肌病和子宫内膜异位症发病影响的研究
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摘要
目的:通过应用选择性雌激素β受体激动剂WAY-200070对子宫内膜异位症及子宫腺肌病异位病灶生长的影响,研究雌激素受体在这两种疾病中的作用,并为从抗雌激素途径治疗这两种疾病提供依据。
方法:将子宫腺肌病异位病灶、子宫内膜异位症在位内膜、卵巢巧克力囊肿囊壁以及正常子宫内膜四种不同组织分别种植于SCID小鼠颈背部皮下,建立其相应的鼠模型。移植后第2天给予药物,实验组颈背部皮下注射WAY-200070 5mg/kg/d,对照组颈背部皮下注射等体积生理盐水(NS),连用14天,后将小鼠处死,移植物取出后称重,采用HE染色观察子宫内膜腺体和间质的成活率,免疫组化法半定量腺体和间质,逆转录聚合酶连反应(RT-PCR)测定ERβ以及ERα表达。
结果:子宫腺肌病异位病灶、子宫内膜异位症在位内膜、卵巢巧克力囊肿囊壁以及正常子宫内膜四种不同组织移植到SCID小鼠后均可成活,正常子宫内膜、在位内膜及卵巢异位囊肿壁模型组异位病灶重量在种植后有明显缩小(P＜0.05),但与对照组比较无显著差异(P＞0.05);而子宫腺肌病异位病灶用药组重量缩小的差值与对照组比较有差异(P＜0.05)。四组移植物取出后RT-PCR测定ERβmRNA含量,同时除腺肌病组以外的其他三组分别测定实验组与对照组的ERαmRNA含量,差异均也无统计学意义(P＞0.05)。腺肌病组免疫组化半定量后实验组和对照组腺体和间质的差异有统计学意义(P＜0.05),随后,又测定了腺肌病组异位病灶内巨噬细胞和自然杀伤细胞的含量,结果实验组和对照组差异无统计学意义。
结论:选择性雌激素β受体激动剂WAY-200070对子宫内膜异位症动物模型无明显治疗作用,而对子宫腺肌病的动物模型产生了一定影响,但作用途径与巨噬细胞和自然杀伤细胞没有关系,可能通过其他途径发生作用,具体作用机制有待进一步研究。
Objective:To investigate the effects of selective estrogen receptor-βagonist (WAY-200070) on focus development of endometriosis(EM) and adenomyosis (AM),provide the data of treating endometriosis(EM) and adenomyosis(AM).
Methods:Eutopic endometrium of endometriosis,ovarian endometriotic cysts,adenomyotic focus and normal endometrium were subcutaneously transplanted into SCID mice,and the SCID mice models were established.Then the next day the mices were randomized into treatment group received WAY-200070(5mg/kg·d) by subcutaneous injection and the control group received NS above.The treatment regimen lasted 14 days.Measure the weight of the lesion after killing the mices.HE and Immunohistochemistry and RT-PCR were used to determine the interstitial substance and gland and the expression of ERβand ERαin ectopic tissue.
Results:Compared with the control group,the weight of lesions that were obtained from Eutopic endometrium of endometriosis,ovarian endometriotic cysts and normal endometrium were not reduced in mices treated with WAY-200070(P＞0. 05).Compared with the control group,the weight of lesions that were obtained from adenomyotic focus were reduced in mice treated with WAY-200070(P＜0.05). Expressions of ERβfrom these four groups were alike in the groups using drug and the control groups,and Expressions of ERαfrom the first three groups were alike in the groups using drug and the control groups.Otherwise,On light microscopy,the interstitial substance and gland of adenomyotic ectopic lesions were significantly different in the group using WAY-200070 than the control group(P＜0.05).At last, the macrophage and nature killer cells were tested in adenomyotic focus and they were all alike in the groups using drug and the control groups(P＞0.05).
Conclusions:selective estrogen receptor-βagonist can not effectively interfere with the growth of endometiosis.In contrast,It may make some effects on the growth of adenomyosis,otherwise,It is an puzzle that how make these changes.It is obvious that the macrophage and nature killer cells make no use on these changes in this experiment.
方法:将子宫腺肌病异位病灶、子宫内膜异位症在位内膜、卵巢巧克力囊肿囊壁以及正常子宫内膜四种不同组织分别种植于SCID小鼠颈背部皮下,建立其相应的鼠模型。移植后第2天给予药物,实验组颈背部皮下注射WAY-200070 5mg/kg/d,对照组颈背部皮下注射等体积生理盐水(NS),连用14天,后将小鼠处死,移植物取出后称重,采用HE染色观察子宫内膜腺体和间质的成活率,免疫组化法半定量腺体和间质,逆转录聚合酶连反应(RT-PCR)测定ERβ以及ERα表达。
结果:子宫腺肌病异位病灶、子宫内膜异位症在位内膜、卵巢巧克力囊肿囊壁以及正常子宫内膜四种不同组织移植到SCID小鼠后均可成活,正常子宫内膜、在位内膜及卵巢异位囊肿壁模型组异位病灶重量在种植后有明显缩小(P＜0.05),但与对照组比较无显著差异(P＞0.05);而子宫腺肌病异位病灶用药组重量缩小的差值与对照组比较有差异(P＜0.05)。四组移植物取出后RT-PCR测定ERβmRNA含量,同时除腺肌病组以外的其他三组分别测定实验组与对照组的ERαmRNA含量,差异均也无统计学意义(P＞0.05)。腺肌病组免疫组化半定量后实验组和对照组腺体和间质的差异有统计学意义(P＜0.05),随后,又测定了腺肌病组异位病灶内巨噬细胞和自然杀伤细胞的含量,结果实验组和对照组差异无统计学意义。
结论:选择性雌激素β受体激动剂WAY-200070对子宫内膜异位症动物模型无明显治疗作用,而对子宫腺肌病的动物模型产生了一定影响,但作用途径与巨噬细胞和自然杀伤细胞没有关系,可能通过其他途径发生作用,具体作用机制有待进一步研究。
Objective:To investigate the effects of selective estrogen receptor-βagonist (WAY-200070) on focus development of endometriosis(EM) and adenomyosis (AM),provide the data of treating endometriosis(EM) and adenomyosis(AM).
Methods:Eutopic endometrium of endometriosis,ovarian endometriotic cysts,adenomyotic focus and normal endometrium were subcutaneously transplanted into SCID mice,and the SCID mice models were established.Then the next day the mices were randomized into treatment group received WAY-200070(5mg/kg·d) by subcutaneous injection and the control group received NS above.The treatment regimen lasted 14 days.Measure the weight of the lesion after killing the mices.HE and Immunohistochemistry and RT-PCR were used to determine the interstitial substance and gland and the expression of ERβand ERαin ectopic tissue.
Results:Compared with the control group,the weight of lesions that were obtained from Eutopic endometrium of endometriosis,ovarian endometriotic cysts and normal endometrium were not reduced in mices treated with WAY-200070(P＞0. 05).Compared with the control group,the weight of lesions that were obtained from adenomyotic focus were reduced in mice treated with WAY-200070(P＜0.05). Expressions of ERβfrom these four groups were alike in the groups using drug and the control groups,and Expressions of ERαfrom the first three groups were alike in the groups using drug and the control groups.Otherwise,On light microscopy,the interstitial substance and gland of adenomyotic ectopic lesions were significantly different in the group using WAY-200070 than the control group(P＜0.05).At last, the macrophage and nature killer cells were tested in adenomyotic focus and they were all alike in the groups using drug and the control groups(P＞0.05).
Conclusions:selective estrogen receptor-βagonist can not effectively interfere with the growth of endometiosis.In contrast,It may make some effects on the growth of adenomyosis,otherwise,It is an puzzle that how make these changes.It is obvious that the macrophage and nature killer cells make no use on these changes in this experiment.
引文
[1]宗利丽,马骊,王小宁,等.乙酰肝素酶基因在子宫内膜异位症患者在位与异位子宫内膜组织中的表达[J].中华妇产科杂志,2004,39(1):24-26.
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[28]Kuiper G,Enmark E,Tujague M et al.Cloning of a novel receptor expressed in rat prostate and ovary.Proc Natl Acad Sci USA,1996,93:5925-5930.
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[3]Koshiyama M,Okamoto T,Ueta M.The relationship between endometrial carcinoma and coexistent adenomyosis uteri,endometriosis externa and myoma uteri.Cancer Detect Prey.2004,28:94-98.
[4]D'Hooghe TM.Clinical relevance of the baboon as a model for the study of endometriosis.Fertil Steril,1997,68(4):613-625.
[5]Bailey MT,Coecl,Endometriosis is associated with an attered profile of irrtestinal microftore in female rhesus monkeys.Hum Reprod,2002,17(7):1704-1708.
[6]Berkley KJ,Dmitrieva N,Curtis Ks,et al.Innervation of ectopic endometriume in a rat model of endometriosis,Proc Natl Acad Sci USA,2004,101(30):11094-11098.
[7]Guo SW,Olive DL.Two unsuccessful clinical trials on endometriosis and a few lessons learned.Gynecol Obstet Invest.2007,64(1):24-35.
[8]Pace P,Taylor J,Suntharalingam S,et al.Human estrogen receptor beta binds DNA in a manner similar to and dimerizes with estrogen receptor alpha[J].J Biol Chem,1997,272(41):258322-258381.
[9]Harris HA.Estrogen receptor,Recent lessons from in vivo studies.Molecular Endocrinology 2006,23:459-463.
[10]Claudia R,Vanesa A,Werner von W.et al.Expression of co-stimulatory molecules,chemokine receptors and proinflammatory cytokines in dendritic cells from normal and chronically inflamed rat testis.Mol Hum Reprod.2007,13(12):853-861.
[11]Grummer,Ruth.Animal models in endometriosis research.Hum Reprod Update.2006.12(5):641-649.
[12]Roesch DM.Effects of selective estrogen receptor agonists on food intake and body weight gain in rats.Physiol Behav,2006,87:39-44.
[13]Miller NR,Jover T,Cohen HW,et al.Estrogen can act via estrogen receptor alpha and beta to protect hippocampal neurons against global ischemia-induced cell death.Endocrinology 2005,146:3070-3079.
[14]Harris HA,Bruner-Tran KL,Zhang XCH.et al.A selective estrogen receptor-beta agonist causes lesion regression in an experimentally induced model of endometriosis Hum Reprod,2005,20(4):936-941.
[15]Meresman GF,Auge L,Baranao RI.Oral contraceptives suppress cell proliferation and enhance apoptosis of eutopic endometrial tissue from patients with endometriosis.Fertil Steril 2002,77,1141-1147.
[16]Yang JH,Chen MJ,Chen HF.et al.Decreased expression of killer cell inhibitory receptors on natural killer cells in eutopic endometrium in women with adenomyosis.Hum Reprod 2004,19,1974-1978.
[17]Yang JH,Wu MY,Chang DY,et al.Increased interleukin-6 messenger RNA expression inmacrophage-cocultured endometrial stromal cells in adenomyosis.Am J Reprod Immun (2006a)55,181-187.
[18]Yang JH,Chen MJ,Wu MY,et al.Decreased suppression of interleukin-6 after treatment with medroxyprogesterone acetate and danazol in endometrial stromal cells of women with adenomyosis.(2006b),Fertil Steril 86,1459-1465.
[19]Mahutte NG,Arici A.Medical management of endometriosis-associated pain[J].Obstet Gynecol Clin N Am,2003,30:133-501.
[20]Vercellini P,Fedele L,Pietropaolo G,et al.Progestogens for endometriosis:forward to the past[J].Hum Reprod Update,2003,9:387-396.
[21]Aanicki TI.Treatment of the pelvic pain associated with endometrio sis using danazol vaginal suppositories.Two year follow-up [J].Fertil Stertil,2002,77:S52-53.
[22]苏丽,岳瑛．子宫内膜异位症的药物治疗[J]．现代生物医学进展,2007,7(2)：318-321．
[23]IraharaM,Uemura H,Yasui T,et al.Efficacy of every other day administration ofconjugated equine estrogen and medroxyprogesterone acetate on gonadotropin releasing hormone agonists treatment inwomenwith endometriosis[J J.Gynecol Obstet invest,2001,52 (4):217-222.
[24]CobellisL,Razzi S,Smione S,et al.The treatmentwith a COX-2 specific inhibitor is effective in the management of pain related to endometriosis[J].Eur J Obstet Gynecol Reprod Biol,2004,116(1):100-102.
[25]M ahutte N G,A rici A.Medical management of endonetriosis-associated pain[J].O bstet Gynecol C lin N Am,2003,30(1):133-150.
[26]Chlouber R O,O live D L,Pritts E A.Investigational drugs for endometriosis[J].Expert Op in Investi D rugs,2006,15(4):399-407.
[27]Bulun SE,Lin Z,Imir G,et al.Regulation of aromatase expression in estrogen-responsive breast and uterine disease:from bench to treatment.Pharmacol Rev 2005;57:359-383.
[28]Kuiper G,Enmark E,Tujague M et al.Cloning of a novel receptor expressed in rat prostate and ovary.Proc Natl Acad Sci USA,1996,93:5925-5930.
[29]黄心璇,马妍,郑永添等,雌激素的心脏保护作用——与β1-肾上腺素受体的相互作用及其信号通路,生理学报,2007,59(5):571-577.
[30]Hudelist G,Keckstein J,Czerwenka K et al.Estrogen receptor beta and matrix metalloproteinase are coexpressed in uterine endometrium and endometriotic lesions of patients with endometriosis.Fertil Steril.2005,84:1249-1256.
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