小鼠子宫内膜异位症模型英文文献
子宫内膜异位症大鼠模型研究进展
doi:10.3969/j.issn.l674-5817.2019.01.014子宫内膜异位症大鼠模型研究进展纟己莲I,马铁2,刘冬妍I(中国医科大学附属盛京医院1.实验研究中心，2.病理科，沈阳110004)［摘要］为临床深入研究子宫内膜异位症(EMs)的病因、发病机制、治疗药物和预防对策提供合理的大鼠模型。
本文对EMs大鼠模型的发病机制、建模方法、优化措施、评价标准以及模型应用等进行综合阐述和比较，研究者可根据实验需要选择合适的建模方法，使其更加贴合实验及临床研究的需要。
［关键词］子宫内膜异位症(EMs);大鼠；建模方法［中图分类号］Q95-33［文献标志码］A［文章编号］1674-5817(2019)01-0072-05子宫内膜异位症(endometriosis,EMs)，简称内异症，是一种常见的妇科疾病。
其发病率高达10%~15%,复发率也很髙，并有逐渐增加的趋势且存有一定的恶变率⑴。
尽管该病的研究历程很长，但其发病机制还不清楚、治疗于段有限。
山于伦理道德的原因，很难对患病妇女进行全程观察，也不能反复进行创伤性、侵袭性或对照性实验研究。
因此，动物模梨成为研究该病的重要手段。
目前，国内外已建立灵长类、家兔、鼠类、巴马香猪、鸡胚囊尿膜等多种EMs动物模型⑷。
本文就EMs的发病机制、大鼠模型的建模方法、优化措施、评价标准以及模型应用等进行综合阐述和比较，研究者可根据实验需要选择合适的建模方法，使其更加贴合实验及临床研究的需要。
1发病原因、发病机制目前公认的EMs的发病机制主要有：经血逆流的种植学说⑼，即月经周期中脱落的子宫内膜碎片经过输卵管倒流至盆腔，在腹膜或者器官表面种植；全能细胞化生学说，即认为EMs的发生是子宫内膜干细胞和骨髓干细胞的异常增生、分化所致;［收稿日期］2018-06-15［作者简介］纪莲(1982-),女，助理实验师。
E-mail:37243816@［通信作者］刘冬妍(1969-),女,教授,研究员，主要从事肠道粘膜研究。
子宫内膜异位症动物模型制备方法研究概况
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子宫内膜异位症动物模型制备方法研究概况Research progress on preparation methods of animal models of endometriosis孙瑞英，崔轶凡（山西中医药大学，山西晋中030619）摘要子宫内膜异位症（EMT）是一种严重影响妇女生活质量的妇科常见疾病，当前的手术及激素治疗效果不彻底，复发率高，可能与EMT的病因和发生机制尚不清晰有关，已成为妇产科领域研究的热门，EMT动物模型的构建是探求EMT的发生、发展以及诊治方法的重要方式，为EMT的研究提供了实验载体。
选取适当的动物模型有利于进一步揭露EMT的病因、发病机制和临床疗效评判。
因为仅有人和非人灵长类可以自觉形成EMT,制约了对EMT的探索，所以构建规范的动物模型已是探索EMT机制的重要因素的一部分。
关键词子宫内膜异位症;动物模型；造模方法中图分类号:R711.71文献标识码：A D01:10.19763/ki.2096-7403.2020.06.20子宫内膜异位症（endometriosis,EMT）是一种具有活性的子宫内膜组织在宫腔被覆盖的黏膜外生长的雌激素依赖性疾病。
在中医学里并无EMT 的病名，根，病=症”=病”“癥范畴。
目前对该病的发病机尚，西药，具有的发，大的生活。
学的，在EMT患发病的，能对对照研究，也能性研究。
，创的EMT，有一研究病学亍学，对发病机制、研发新药中药用机的用，有该疾病。
EMT的，性，EMT的发病机尚，的一的。
并EMT在一的题，用范畴潜在的限性都要充分考虑。
研究总结近20年来EMT的发展经验，对各种EMT动物的现状题作出简述。
Endometriosis子宫内膜异位症
doi:10.1136/bmj.39073.736829.BE2007;334;249-253BMJCynthia FarquharEndometriosis/cgi/content/full/334/7587/249Updated information and services can be found at:These include:Data supplement/cgi/content/full/334/7587/249/DC1"References"References/cgi/content/full/334/7587/249#otherarticles 4 online articles that cite this article can be accessed at:/cgi/content/full/334/7587/249#BIBL This article cites 13 articles, 2 of which can be accessed free at: Rapid responses/cgi/eletter-submit/334/7587/249You can respond to this article at:/cgi/content/full/334/7587/249#responses free at:4 rapid responses have been posted to this article, which you can access forservice Email alertingbox at the top left of the articleReceive free email alerts when new articles cite this article - sign up in the Topic collections(308 articles)Other Surgery (571 articles) Other Women's health - otherArticles on similar topics can be found in the following collectionsNotesTo order reprints follow the "Request Permissions" link in the navigation box/bmj/subscribers go to:BMJ To subscribe toCliniCal ReviewGynaecology, National Women’s Hospital, University of Auckland, Auckland, New Zealand Correspondence to:c.farquhar@aucklanBMJ 2007:334:249-53doi: 10.1136/bmj.39073.736829.BEEndometriosisCynthia FarquharFor the full versions of these articles see What is endometriosis?Endometriosis is a chronic condition characterised by growth of endometrial tissue in sites other than the uter-ine cavity, most commonly in the pelvic cavity, includ-ing the ovaries, the uterosacral ligaments, and pouch of Douglas (fig 1). Common symptoms include dysmenor-rhoea, dyspareunia, non-cyclic pelvic pain, and subfertil-ity (table 1). The clinical presentation is variable, with some women experiencing several severe symptoms and others having no symptoms at all. The prevalence in women without symptoms is 2-50%, depending on the diagnostic criteria used and the populations stud-ied.1 The incidence is 40-60% in women with dysmenor-rhoea and 20-30% in women with subfertility.w1-w3 The severity of symptoms and the probability of diagnosis increase with age.w4 The most common age of diagno-sis is reported as around 40, although this figure came from a study in a cohort of women attending a family planning clinic.w5 Symptoms and laparoscopic appear-ance do not always correlate.2 The American Society for Reproductive Medicine has published a classification of severity of endometriosis at laparoscopy.w6What are the causes of endometriosis?Several factors are thought to be involved in the development of endometriosis. Retrograde menstrua-tion remains the dominant theory for the develop-ment of pelvic endometriosis, though as this is almost universal it is unlikely to be the sole explanation.w7-w9 The quantity and quality of endometrial cells, failure of immunological mechanisms, angiogenesis, and the production of antibodies against endometrial cells may also have a role.w10 w11 Embryonic cells may give rise to deposits in distant sites such as the umbilicus, the pleural cavity, and even the brain.w8 w9What are the risk factors for endometriosis?Risk factors generally relate to exposure to menstrua-tion: early menarche and late menopause increase the risk whereas the use of oral contraceptives reduces.w5What is the natural course of endometriosis?Studying the natural course is difficult because of the need for repeat laparoscopy. T wo studies in whichl aparoscopy was repeated after treatment in women given placebo, however, reported that over 6-12 months, endometrial deposits resolved spontaneously in up to a third of women, deteriorated in nearly half, and were unchanged in the remainder.w12 w13BMJ | 3 fEBRUARY 2007 | VolUME 334249SuMMaRy pointSMedical treatmentAvoid prescribing medical treatment for women who are trying to conceiveThe simpler treatments—such as the combined oral contraceptive pill, oral or depot medroxyprogesteroneacetate, and the levonorgestrel intrauterine system—are as effective as the gonadotrophin releasing hormone (GnRH) analogues and can be used long termSurgical treatmentLaparoscopic excision or ablation at time of diagnostic laparoscopy if possibleEndometriomata (large cysts of endometriosis) are best stripped out instead of drainage and ablationRecurrencesIn the five years after surgery or medical treatment 20-50% of women will have a recurrenceLong term medical treatment (with or without surgery) has the potential to reduce recurrence but evidence based research is lackingtable 1 | Common presentations of endometriosisSymptomAlternative diagnoses Recurrent painful periods Adenomyosis, physiologicalPainful intercourse Psychosexual problems, vaginal atrophy Painful micturitionCystitisPainful defecation during menstruation Constipation, anal fissuresChronic lower abdominal pain Irritable bowel syndrome, neuropathic pain, adhesions Chronic lower back pain Musculoskeletal strainAdnexal masses Benign and malignant ovarian cysts, hydrosalpingesInfertilityUnexplained (assuming normal ovulation and semen parameters with patent tubes)CliniCal ReviewDiagnosis of endometriosisWhat features of history and examination are important?In women of reproductive age who present with recurrent dysmenorrhoea or pelvic pain you should take a full history of reproduction and carry out a pelvic examination. The cyclical nature of the pain and the relation of the pain to menstruation points to the diagnosis of endometriosis. Painful micturition, defecation, and dyspareunia are also associated. In young women you should consider other diagnoses such as pelvic infection, problems in early preg-nancy, ectopic pregnancy, ovarian cyst torsion, and appendicitis (table 1). During pelvic examination, tenderness in the posterior fornix or adnexa, nod-ules in the posterior fornix, or adnexal masses may indicate endometriosis. Adolescents presenting with dysmenorrhoea do not require a pelvic examination as disease is uncommon.How is endometriosis diagnosed?Transvaginal ultrasonography can reliably detect endometriomata (cysts of endometriosis), but fail-ure to reveal cystic structures does not exclude the diagnosis of endometriosis.3 w14 Magnetic resonanceimaging is increasingly used to identify subperitoneal deposits, although retroversion, endometriomata, and bowel structures may mask small nodules.4 w15Although concentrations of the cancer antigen CA125 are slightly raised in some women with endometriosis, the test neither excludes nor diag-noses endometriosis and is not considered useful in establishing the diagnosis.5 The threshold for surgery is unlikely to be influenced by the CA125 concentra-tion, and the guidelines from the Royal College of Obstetricians and Gynaecologists described CA125 as having only limited value as either a screening or a diagnostic test.6 Laparoscopy is the only diagnostic test that can reliably rule out endometriosis. It is also accurate in detecting endometriosis and is considered the standard investigation.6What are the indications for laparoscopy?Many young women experience dysmenorrhoea (about 60-70%), and unless there are other features to indicate endometriosis laparoscopy is not recom-mended.w16 Some women will require further inves-tigation to guide management. For adolescents who present with dysmenorrhoea, the recommended approach is to first prescribe non-steroidal anti-inflammatory drugs (NSAIDs) and oral contracep-tives.w17 w18 The lack of measurable pain relief with these drugs is usually an indication for further inves-tigation.w19 Other indications for laparoscopy include severe pain over several months, pain requiring sys-temic therapy, pain resulting in days off work or school, or pain requiring admission to hospital.What are the effective medical treatments?Treatment options for medical therapy include oral contraceptives, progestogens, androgenic agents, and gonadotrophin releasing hormone (GnRH) analogues. All suppress ovarian activity and menses and atrophy of endometriotic implants, although the extent to which they achieve this varies. There have been few randomised controlled trials of medical treatment versus placebo, although many trials have250 BMJ | 3 fEBRUARY 2007 |VolUME 334Fig 1 | Mild pelvic endometriosis seen at the time ofdiagnostic laparoscopy. Arrows show typical endometriotic deposits (reproduced with permission of dr d A Hill)table 2 | Medical treatment* for endometriosisdrugMechanism of actionlength of treatment recommended Adverse eventsnotesMedroxyprogesterone acetate/progestagens Ovarian suppression Long termWeight gain, bloating, acne, irregular bleedingMay be given orally or byintramuscular or subcutaneous depot injectionDanazol Ovarian suppression 6-9 months Weight gain, bloating, acne, hirsutism, skin rashes Adverse effects on lipid profiles Oral contraceptiveOvarian suppressionLong termNausea, headachesCan be used to avoidmenstruation by skipping the placebo pillsGnRH analogueOvarian suppression bycompetitive inhibitor of GnRH analogue6 monthsHot flushes, other symptoms of hypo-oestrogenism By injection or nasal spray onlyLevonorgestrel intrauterine systemEndometrial suppression; ovarian suppression in some womenLong term use but change every 5 years in women <40 yearsIrregular bleedingAlso reduces menstrual blood lossGnRH=gonadotrophin releasing hormone.*Decisions about medical therapy will depend on patient’s choice, available resources, plans for fertility, and ongoing symptoms. Side effect profile may influence choice.on 21 April 2008 Downloaded fromCliniCal Reviewcompared different types of medical treatment.7-10 All medical treatments are similarly effective in relieving pain during treatment (table 2).The side effect profiles are important in decid-ing treatment choices. Progestogens are associated with irregular menstrual bleeding, weight gain, mood swings, and decreased libido. The side effectsa ssociated with danazol include skin changes, weight gain, and occasionally deepening of the voice, and it is infrequently prescribed now. GnRH analogues dramatically lower oestrogen concentrations, and side effects include the development of menopausal symptoms and the loss of bone mineral density with long term use (both reversible). Oestrogen therapy in an add back regimen is useful for preventing side effects with GnRH analogues.10 In the randomised controlled trials comparing subcutaneous depot medroxyproges-terone acetate (SC-DMPA) with GnRH analogues the bone loss was less with the progesterone during treat-ment.w20 w21Recurrence of painful symptoms after six months of medical treatment may be as high as 50% in the 12-24 months after the treatment is stopped.w22 w23 Recur-rence may in part be because large lesions respond poorly to medical treatment. It is generally accepted that endometriomata are not amenable to medical treatment, although temporary clinical relief may be achieved.The levonorgestrel intrauterine system (LNG-IUS) is an established treatment for heavy menstrual bleed-ing but can also be used for dysmenorrhoea and endometriosis.11 w24 In one study only 10% of women who had a levonorgestrel intrauterine system after surgery for endometriosis had moderate or severe dysmenorrhoea compared with 45% of the women who had surgery only.12 In a trial of 82 women with endometriosis the levonorgestrel intrauterine system had similar effectiveness to GnRH analogues, but the potential for long term use of this system is advanta-geous if the woman does not want to conceive.13 It has also been used in women with rectovaginal disease.14 In the future aromatase inhibitors may have a thera-peutic role in endometriosis as they inhibit oestrogenproduction selectively in endometriotic lesions, without affecting ovarian function.w25is surgery or medical treatment more effective?There are no randomised controlled trials comparing medical versus surgical treatments for the management of endometriosis, and the decision about medical or surgical treatment at the time of diagnosis will depend on several factors including patient’s choice, the avail-ability of laparoscopic surgery, the desire for fertility, and concerns about long term medical therapy.What are the effective surgical strategies?Surgery for endometriosis can be performed laparo-scopically or as an open procedure. It entails exci-sion or ablation (by laser or diathermy), or both, of the endometriotic tissue with or without adhesiolysis. There are few trials of laparoscopic treatment.14 15 Surgi-cal excision of endometriosis results in improved pain relief and improved quality of life after six months compared with diagnostic laparoscopy only.14 In one of the trials laparoscopic treatment also included uter-ine nerve ablation (LUNA),15 and pain improvement persisted for up to five years in more than half of the women.w26 About 20% of women do not report any improvement after surgery.14No randomised controlled trials have compared laser versus electrosurgical removal of endometriosis, and only one small trial, with inconclusive results, com-pared excision versus ablation.w27How often does endometriosis recur after surgery?Recurrence of endometriosis after laparoscopic surgery is common.16 w26 Even with experienced laparoscopic surgeons, the cumulative rate of recurrence after five years is nearly 20%.17 Another study reported recur-rence of dysmenorrhoea in almost a third of women within one year of laparoscopic surgery in women who received no other treatment.16What is the role of uterine nerve ablation at the time of laparoscopy?Randomised controlled trials of laparoscopic uterine nerve ablation at the time of laparoscopic excisionBMJ | 3 fEBRUARY 2007 | VolUME 334251Fig 2 | laparoscopy of an enlarged ovary containing an endometriotic cyst leaking “chocolate” fluid (arrow)(reproduced with permission from Professor Peter Braude)on 21 April 2008 Downloaded fromCliniCal Reviewof endometriosis compared with laparoscopic exci-sion only showed no evidence of benefit, although there was limited evidence of benefit with presacral neurectomy.18What is the evidence for surgery in women with endometriomata?Randomised controlled trials comparing excision or drainage and ablation for endometriomata ≥3 cm reported that recurrences were reduced and subsequent spontaneous pregnancy increased in the women who underwent excision (fig 2).19 Although excisional surgery of the capsule could lead to removal of normal ovarian tissue and result in reduced ovarian reserve,20 w28 there is no evidence that this occurs, whereas a recurrence of the endometriomata will inevitably mean further surgery.19What is the best approach in women with rectovaginal disease?Rectovaginal endometriosis presents surgical challenges because of difficult access and the possibility of injury to the bowel. Although reported long term outcomes are encouraging with advanced laparoscopic techniques, there are few prospective studies and no randomised controlled trials.16 17 One small study of the levonor-gestrel intrauterine system in women with rectovaginal endometriosis found improved dysmenorrhoea, pelvic pain, and dyspareunia after one year.w29 A trial com-paring oestrogen and progesterone combination with low dose progestogen in 90 women with rectovaginal disease reported substantial reductions at 12 months in all types of pain without major differences between groups.21 Overall, two thirds of patients were satisfied with this approach.Should women have hormonal treatment before surgery for endometriosis?Only one study has examined this question. There was no evidence of a difference in the difficulty of surgery in the women who had received preoperative hormonal treatment.w30Should women have hormonal treatment after conserva-tive surgery?There was no evidence of improved pain relief with postoperative hormonal treatment (including danazol, GnRH analogues, oral contraceptives, and medroxy-progesterone acetate) up to 24 months after surgery.11 The studies to date are small, however, and there is insufficient follow-up to rule out a benefit.What are the effects of hormonal treatment after oophorectomy (with or without hysterectomy)?There was no evidence of increased rates of recur-rence in women who had both ovaries removed and who were given nearly four years of combined hor-mone therapy, but the study was underpowered to detect clinically important differences.22What is the impact of endometriosis on fertility?Although management of pain may be the more immediate issue, the long term outcome of fertility should not be overlooked. Few studies have exam-ined this. A systematic review of medical treatment for women with infertility and endometriosis did not find evidence of benefit,7 and it is not recommended for women trying to conceive.6 23 A systematic review of laparoscopic treatment of endometriosis in women with subfertility suggested an improvement in pregnancy rate in the 9-12 months after surgery.w31 A second systematic review of laparoscopic excision compared with ablation endometriomata reported a fivefold increase in rate of pregnancy.19 There is the ongoing concern about ovarian reserve in women who have laparoscopic excision.20 w28 The other con-cern is the impact of endometriomata on artificial reproductive techniques.w32 The European Society for Human Reproduction and Embryology recommends surgery if endometriomata are ≥4 cm.23ConclusionEndometriosis should be suspected in any woman of reproductive age who presents with dysmenor-rhoea or chronic pelvic pain. Only laparoscopy can reliably identify endometriosis. If endometriosis is diagnosed at the time of laparoscopy, laparoscopic surgery should be the first choice of treatment, espe-cially in women of reproductive age with an endome-triomata. In women with endometriomata, the cyst252BMJ | 3 fEBRUARY 2007 | VolUME 334on 21 April 2008 Downloaded fromCliniCal Reviewwall should be stripped out, instead of drainage and ablation, as the recurrences are fewer and pregnancy rates improved. At present, there is no evidence of benefit of postoperative medical treatment but the levonorgestrel intrauterine system has the potential for long term use. In women who wish to conceive surgical, rather than medical, treatment should be offered.1 Fauconnier A, Chapron C. Endometriosis and pelvic pain:epidemiological evidence of the relationship and implications. Human Reprod Update 2005;11:595-606.2 Vercellini P, Trespidi L, De Giorgi O, Cortesi I, Parazzini F, CrosignaniGP. Endometriosis and pelvic pain:relation to disease stage and Endometriosis and pelvic pain: relation to disease stage and localization. Fertil Steril 1996;65:299-304.3 Alcazar JL, Laparte C, Jurado M, Lopez-Garcia G. The role oftransvaginal ultrasonography combined with color velocity imaging and pulsed Doppler in the diagnosis of endometrioma. Fertil Steril 1997;67:487-91.4 Kinkel K, Brosens J, Brosens I. Preoperative investigations. In:Sutton C, Jones K, Adamson D, eds. Modern management of endometriosis . Basingstoke: Taylor & Francis, 2006:71-85. 5 Mol BW, Bayram N, Lijmer JG, Wiegerinck MA, Bongers MY, vander Veen F, et al. The performance of CA-125 measurement in the detection of endometriosis: a meta-analysis. Fertil Steril 1998;70:1101-8.6 Royal College of Obstetricians and Gynaecologists. The investigationand management of endometriosis . London: Royal College ofObstetricians and Gynaecologists, 2006. (Green Top Guideline No 24.) /resources/Public/pdf/endometriosis_gt_24_2006.pdf7 Hughes E, Fedorkow D, Collins J, Vandekerckhove P. Ovulationsuppression for endometriosis. Cochrane Database Syst Rev 2003;(3):CD000155.8 Prentice A, Deary AJ, Bland E. Progestagens and anti-progestagensfor pain associated with endometriosis. Cochrane Database Syst Rev 2000;(2):CD002122.9 Selak V, Farquhar C, Prentice A, Singla A. Danazol for pelvic painassociated with endometriosis. Cochrane Database Syst Rev 2001;(4):CD000068.10 Sagsveen M, Farmer JE, Prentice A, Breeze A. Gonadotrophin-releasing hormone analogues for endometriosis: bone mineral density. Cochrane Database Syst Rev 2003;(4):CD001297.11 Yap C, Furness S, Farquhar C. Pre and post operative medicaltherapy for endometriosis surgery. Cochrane Database Syst Rev 2004;(3):CD003678.12 Vercellini P, Frontino G, De Giorgi O, Aimi G, Zaina B, Crosignani PG.Comparison of a levonorgestrel-releasing intrauterine device versus expectant management after conservative surgery for symptomatic endometriosis: a pilot study. Fertil Steril 2003;80:305-9.13 Petta CA, Ferriani RA, Abrao MS, Hassan D, Rosa E, Silva JC, et al.Randomized clinical trial of a levonorgestrel-releasing intrauterine system and a depot GnRH analogue for the treatment of chronic pelvic pain in women with endometriosis. Human Reprod 2005;20:1993-8.14 Abbott J, Hawe J, Hunter D, Holmes M, Finn P, Garry R. Laparoscopicexcision of endometriosis: a randomized, placebo-controlled trial. Fertil Steril 2004;82:878-84.15 Sutton CJ, Ewen SP, Whitelaw N, Haines P. Prospective, randomized,double-blind, controlled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal, mild and moderate endometriosis. Fertil Steril 1994;62:696-700.16 Fedele L, Bianchi S, Zanconato G, Bettoni G, Gotsch F. Long-termfollow-up after conservative surgery for rectovaginal endometriosis. Am J Obstet Gynecol 2004;190:1020-4.17 Redwine DB, Wright JT. Laparoscopic treatment of completeobliteration of the cul-de-sac associated with endometriosis: long-term follow-up of en bloc resection. Fertil Steril 2001;76:358-65.18 Proctor ML, Latthe PM, Farquhar CM, Khan KS, Johnson NP. Surgicalinterruption of pelvic nerve pathways for primary and secondary dysmenorrhoea. Cochrane Database Syst Rev 2005;(4):CD001896.19 Hart RJ, Hickey M, Maouris P, Buckett W, Garry R. Excisional surgeryversus ablative surgery for ovarian endometriomata. Cochrane Database Syst Rev 2005;(3):CD004992.20 Wong BC, Gillman NC, Oehninger S, Gibbons WE, Stadtmauer LA.Results of in vitro fertilization in patients with endometriomas: is surgical removal beneficial? Am J Obstet Gynecol 2004;191:597-607.21 Vercellini P, Pietropaolo G, De Giorgi O, Pasin R, ChiodiniA, Crosignani PG. Treatment of symptomatic rectovaginalTreatment of symptomatic rectovaginal endometriosis with an estrogen-progestogen combination versus low-dose norethindrone acetate. Fertil Steril 2005;84:1375-87.22 Matorras R, Elorriaga MA, Pijoan JI, Ramon O, Rodriguez-Escudaro FJ.Recurrence of endometriosis in women with bilateral adnexectomy (with or without total hysterectomy) who received hormone replacement therapy. Fertil Steril 2002;77:303-8.23 European Society for Human Reproduction and Embryology. ESHREguideline for diagnosis and treatment of endometriosis . /guidelines.BMJ | 3 fEBRUARY 2007 | VolUME 334 253on 21 April 2008 Downloaded from。
子宫内膜异位症动物模型再评价
子宫内膜异位症动物模型再评价子宫内膜异位症（内异症）是指有生长功能的子宫内膜组织出现在子宫腔被覆黏膜以外的身体其他部位的疾病。
是一种激素依赖性、出血性、炎症性、遗传性疾病，临床症状可表现为盆腔痛、月经失调、不孕、盆腔包块等[ 1]。
自1860年首次报道该病以来，其发病机理至今尚未完全明了，它仍是令妇科专家们“迷惑的疾病”。
根据近年来的研究显示，内分泌异常改变有利于子宫内膜移位种植，未成熟卵泡黄素化可能是发生内异症的病因之一。
患者常伴有细胞和体液免疫功能的异常，有部分免疫球蛋白与补体的变化及细胞免疫反应异常，患者的血中与腹腔液中可发现多种自身抗体。
加强对本病的基础研究，特别是建立理想的动物模型模拟人类内异症，以便进行反复的、可控的实验，在动物身上进行病因病理、药物治疗等的研究，才能有助于尽快地攻克此病。
文献一子宫内膜异位症动物模型的构建1、材料与方法1. 1标本来源2002 年4月至2002年7 月因EM 入我院妇产科行腹腔镜诊治的患者8 例。
术后病理均证实为EM, 取其在位内膜及腹腔内膜异位囊肿壁。
1. 2实验动物[ 1]SCID 小鼠, 雌性, 8 周龄, 体重20～25g,46只, 由军事医学科学院实验动物中心提供SPF(specific -pathogen free) 条件饲养。
1. 3方法1. 3. 1标本处理标本置入盛有4ml DMEM 培养液(含100U/ml 青霉素, 100U/ml链霉素) 无菌瓶后, 置于冰壶, 快速送入实验室接种( 1h 内, 否则影响接种成功率)[ 1]。
标本用0. 1mol/L 的无菌PBS 漂洗3 次, 尽量洗去血块和粘液。
然后于无菌培养皿内等量分置, 分装入盛有 D MEM 液的无菌管内, 准备接种。
1. 3. 2动物处理用1%的戊巴比妥钠约0. 07ml 腹腔注射麻醉SCID 小鼠, 待小鼠麻醉后固定于操作板上, 腹部酒精消毒备皮, 夹起腹部皮肤, 用无菌小弯剪剪开0. 5cm 长的小口,将已备标本种植于皮下, 无菌丝线缝合及纱布包裹。
浅论二 ■ 英对小鼠异位子宫内膜影响的分子机制研究
浅论二■ 英对小鼠异位子宫内膜影响的分子机制研究【摘要】【目的】探讨四氯二苯并二■英(TCDD)对子宫内膜异位症小鼠模型的影响及其分子学机制。
【方法】采用小鼠自体子宫内膜移植法建立小鼠子宫内膜异位症模型，分别给予TCDD 0、l、3、10 μg/kg 剂量灌胃，每21 d 1次，于建模术后3、6、9周处死，鉴定异位病灶的形成，测量异位病灶体积。
采用免疫组化法和RT-PCR法检测各组小鼠异位子宫内膜组织中芳香烃受体(AhR)和细胞色素P450 1A1(CYP1A1)表达水平。
【结果】①染毒组小鼠异位病灶体积的增加与染毒剂量和时间具有明显的正相关性(r = 为、，均P );②染毒组小鼠异位子宫内膜AhR蛋白较对照组增强(P );且随染毒剂量增加和染毒时间延长，AhR蛋白表达相应增加(r分别为、，均P );③随染毒剂量增加，CYP1A1蛋白表达相应增加(r = ，P )，对照组未检测到CYP1A1蛋白表达;④染毒组小鼠异位子宫内膜AhR mRNA较对照组增强(P )。
随染毒剂量增加和暴露时间延长，AhR mRNA表达相应增加(r分别为、，P );⑤随染毒剂量的增加，CYP1A1 mRNA表达明显增加(r = ，P )，对照组小鼠异位子宫内膜病灶中未检测到CYP1A1mRNA。
【结论】 TCDD可促进小鼠模型异位子宫内膜病灶的发展，其机制可能与AhR及其下游基因CYP1A1激活有关。
AhR及CYP1A1的表达增强是二■英暴露的生化指标。
【关键词】四氯二苯并二■英; 子宫内膜异位症; 小鼠; AhR; CYP1A1Abstract：【Objective】 To investigate the effect of 2，3，7，8-tetrachlorodibenzo-p-dioxin (TCDD) on development of endometriosis in a mouse model from perspective of molecular mechanism. 【Methods】 The endometriosis mouse model was established with autotransplantation of endometrium. Twenty-one days prior to induction surgery which produces endometriosis， female mice werepretreated with 2，3，7，8-tetrachlorodibenzo-p-dioxin (TCDD) at 0， 3， or 10 mg TCDD/kg. Animals were treated again at the time of surgery and at 3， 6， and 9 weeks following surgery. Evaluation of ectopic focuses diameter were made at 3， 6， 9 weeks post surgery. The AhR and CYP1A1 expression on ectopic endometrium were identified by immunohistochemistry and RT-PCR assays. 【Results】①With increased time and dose of TCDD exposure， it produced a dose-dependent increase in endometriotic site diameter when all time points were pooled within each dose in mice (r = and respectively， both P ). ②The expression of AhR protein on ectopic focuses in mice were higher in the TCDD exposure group than those in control group， and presented time-dose dependent increase (r = and ， both P ). ③The higher dose of exposureincreased， the higher CYP1A1 protein expressions enhanced (r = ， P ). ④As compared with the control group， the expression of AhR mRNA in ectopic focuses of mice were higher in the TCDD exposure group， and show time-dose dependent increase (r = and ， both P ). ⑤The higher dose of exposure increased， the higher CYP1A1 mRNA expression enhanced (r = ， P ). 【Conclusion】 TCDD can promote progression of ectopic focus of endometriosis in the mouse 子宫内膜异位症(endometriosis，EMS)是育龄妇女的常见病，但其发病机制尚不清楚。
活血消异方对子宫内膜异位症模型小鼠子宫内膜容受性的影响研究
活血消异方对子宫内膜异位症模型小鼠子宫内膜容受性的影响研究吴天思;崔阳阳;孙伟伟;赵瑞华;徐彩【摘要】Objective To investigate the effects of Huoxuexiaoyi recipe on endometrial receptivity in mice models with endometriosis , and to explore its action mechanism .Methods The animal models with endometriosis pregnancy hypofunction were established in mice through the method of abdominal cavity +subcutaneous injections , and the mice in sham-operation group were injected with same volume of 0.9% sodium chloride solution .After the success of modeling, the mice were randomly divided into traditional Chinese medicine group ( TCM group) and modelgroup .The mice in TCM group were treated by Huoxuexiaoyirecipe ,however ,the mice in model group and sham-operation group were given same volume of 0.5% CMC by gavage.After three menstrual cycles, the mice in the three groups were put in the cage with infertile male mice (2:1), then the vaginal plug was observed at 8:00 am in the next day(D1).The detection specimens were taken at 10:30 pm on D4 after false pregnant ,and the expression levels of endometrial integrin-αvβ3 and leukaemia inhibitory factor ( LIF) were detected by Western Blot .Results The expression levels of endometrial integrin-αvβ3 and LIF at implantation window phase in model group were significantly decreased ,as compared with those in sham-operation group ( P <0.05).However the expression levels of endometrial integrin-αvβ3 and LIF at implantation window phasein TCM group were significantly increased,as compared with those in model group ( P <0.05 ), but which were significantly lower than those in sham-operation group ( P <0.05 ).Conclusion The endometriosis has adverse effects on endometrial receptivity . Huoxuexiaoyi recipe can significantly increase the expression levels of endometrial i ntegrin αvβ3 and LIF at implantation window phase so as to improve endometrial receptivity in mice with endometriosis .%目的探讨子宫内膜异位症对子宫内膜容受性的影响机制以及活血消异方对子宫内膜异位症模型小鼠子宫内膜容受性的作用.方法通过"皮下+腹腔"同系异体子宫内膜注射的方法建立子宫内膜异位症妊娠功能低下小鼠模型,假手术予等量0 Z.9%氯化钠溶液注射.建模成功后,随机分为中药组和模型组,中药组予活血消异方干预治疗,模型组和假手术组予等量0.5%羧甲基纤维素钠(CMC)灌胃.连续治疗3个周期后,3组分别与不育雄鼠合笼,次日清晨8:00观察阴栓,见栓者定为假孕第1天,于假孕第4天晚上10:30取材,运用Western blot法检测小鼠子宫内膜整合素αvβ3和LIF的蛋白表达.结果模型组小鼠种植窗口期子宫内膜整合素αvβ3和LIF的蛋白表达量较假手术组显著降低,差异有统计学意义(P<0.05);中药组小鼠种植窗口期子宫内膜整合素αvβ3和LIF的蛋白表达量较模型组显著升高,差异有统计学意义(P<0.05),但均低于假手术组(P<0.05).结论子宫内膜异位症对子宫内膜容受性存在不良影响.活血消异方能够显著提高小鼠围着床期子宫内膜着床因子整合素αvβ3和LIF的蛋白表达量,从而改善子宫内膜异位症模型小鼠子宫内膜容受性.【期刊名称】《河北医药》【年(卷),期】2017(039)007【总页数】4页(P965-967,972)【关键词】子宫内膜异位症;子宫内膜容受性;活血消异方;整合素αvβ3;LIF【作者】吴天思;崔阳阳;孙伟伟;赵瑞华;徐彩【作者单位】100053 北京市,中国中医科学院广安门医院妇科;100053 北京市,中国中医科学院广安门医院妇科;100053 北京市,中国中医科学院广安门医院妇科;100053 北京市,中国中医科学院广安门医院妇科;北京中医药大学【正文语种】中文【中图分类】R711.71子宫内膜异位症(endometriosis，EM)简称内异症，是指活性的子宫内膜腺体和间质种植于子宫腔以外的部位浸润性生长，引起慢性盆腔痛、不孕、月经失调等一系列临床表现的一种雌激素依赖性疾病。
ERβ对子宫内膜异位症小鼠模型的影响
ERβ对子宫内膜异位症小鼠模型的影响关铮;李亚里;宫庭钰;晏红;高贞贞【期刊名称】《中国实验动物学报》【年(卷),期】2009(17)4【摘要】目的通过建立子宫内膜异位症小鼠模型探讨雌激素β受体对子宫内膜异位症的影响.方法利用雌激素β基因敲除小鼠建立自体子宫内膜异位模型;应用人不同的组织在SCID小鼠建立子宫内膜异位症模型后,注射雌激素β受体激动剂WAY-200070,观察其对异位病灶生长的影响.结果比较30只雌激素β受体基因敲除小鼠及22只同源未敲除小鼠异位病灶生长及组织细胞形态无明显差异(P>0.05);雌激素β受体激动剂WAY-200070对不同类型的SCID小鼠内异症病灶生长影响无明显差异(P>0.1).结论雌激素β受体对子宫内膜异位病灶的形成影响作用微弱.【总页数】5页(P270-274)【作者】关铮;李亚里;宫庭钰;晏红;高贞贞【作者单位】中国人民解放军总医院妇科,北京,100853;中国人民解放军总医院妇科,北京,100853;中国人民解放军总医院妇科,北京,100853;中国人民解放军总医院妇科,北京,100853;中国人民解放军总医院妇科,北京,100853【正文语种】中文【中图分类】R-71【相关文献】1.二恶英对小鼠模型子宫内膜异位症的影响 [J], 刘娟;任慕兰2.子宫内膜异位症中ER-α和ER-β研究进展 [J], 龙晓宇;关咏梅;傅松滨3.ERα、ERβ、pS2及其在子宫内膜异位症中表达的研究现状 [J], 卢静;冯鸽;迟小岩4.ERα、ERβ、pS2及其在子宫内膜异位症中表达的研究现状 [J], 卢静; 冯鸽; 迟小岩5.子宫内膜异位症患者在位和异位内膜上皮细胞ER-α、ER-β的检测 [J], 龙晓宇;关咏梅因版权原因，仅展示原文概要，查看原文内容请购买。
子宫内膜异位症小鼠巨噬细胞移动抑制因子变化规律的研究
化 情况 ， 以期 揭示 ＭＩ Ｆ在 Ｅ Ｍｓ发 病 过 程 中 可 能存 在 的作 用．
１ ３ 样 品收 集 ． 颈椎 脱 臼法处死 小 鼠， 腹腔 注射 ３ｍＬ无 菌 Ｐ Ｓ Ｂ，
型普 通 Ｐ Ｒ 仪 和 Ｓ ＧＭＡ １１ Ｃ Ｉ —４离 心 机 分 别 为 美 国
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激 素并对激 素产 生 反应 的活性 病 灶 ［ ． ２ 巨噬 细胞 移 动 ］ 抑制 因子 （ Ｆ 是 一 种 重 要 的免 疫 和促 血 管 生 成 因 ＭＩ ） 子 ， 献报道 ， Ｍｓ 者腹 腔液 中 ＭＩ 文 Ｅ 患 Ｆ的水 平显 著 高 于正 常妇 女 ， 提示 ＭＩ Ｆ在 Ｅ Ｍｓ发病 过 程 中发 挥 了重 要 作用［ ］ 但是 ， Ｅ ３． 在 Ｍｓ发 生发 展 过 程 中 ＭＩ Ｆ发 生 怎样 的变化 ， 目前 未见 报道 ． 研究 构建 Ｅ 本 Ｍｓ小 鼠模 型， 分别运用 实 时荧 光 定 量 Ｐ Ｒ（ Ｔ Ｐ Ｒ） Ｃ Ｒ — Ｃ 和酶 联 免
量 １ ￣２ ， ９ １ｇ 性周期 ４ ， 门大学 生命 科 学 院实 验 ～５ｄ 厦
动 物 中心 提供 ． 室 温 ２ ～ ２ 在 １ ３℃ 、 湿度 ６ ～ ７ 、 Ｏ ５ １ ２ｈ光 照交 替的条 件下 喂养． 仪 器 ： ｔｒＧｅ ｅ０ ０荧 光 定 量 Ｐ Ｒ 仪 为 澳 大 Ｒｏｅ－ ｎ ３ ０ Ｃ
著 ． 示 ＭＩ 提 Ｆ与 Ｅ Ｍｓ 发 生 发展 过 程 关 系密 切 ， 能参 与早 期 的病 理 活 动 过 程 ． 的 可
关键 词 ： 子宫 内膜异位症 ； 巨噬细胞移 动抑 制因子 ； 时荧光定量 Ｐ Ｒ； 实 Ｃ 酶联免疫吸附试验
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IMPLANTATION AND DEVELOPMENT OF MOUSE EGGS TRANSFERRED TO THE UTERI OF NON-PROGESTATIONAL MICE
THOMAS P. COWELL
Department of JÇoology, University of Oxford, and Department of Anatomy, University of California Medical Center, San Francisco
mice.
Bilateral ovariectomy was performed on the recipient mice by excising the ovarian fat pad. Vaginal smears of all cyclic recipient mice were taken before the transfer operation.
that the endometrium was damaged in focal areas, most of which were in the ovarian end of the left uterine horn. Although the epithelium covered most of the endometrium, it was very attenuated in many areas, especially where the endometrium was very oedematous. There was usually oedema, and leucocytic infiltration occurred in the endometrium underlying broken epithelium. In some areas, the myometrium was degenerative and oedematous.
(Received 16th May 1968)
Summary. Four-day-old mouse embryos were transferred to the uterine lumen of virgin cyclic and ovariectomized mice; the eggs 'implanted' and developed only in mice whose endometrium was previously traumatized with a glass scraper. The histology of the mechanically induced implantation sites is described and similarities to normal implan-
Transplantation of the egg to extra-uterine sites such as the anterior chamber of the eye (Fawcett, Wislocki & Waldo, 1947 ; Runner, 1947), kidney (Fawcett, 1950), spleen (Kirby, 1963b) and testis (Kirby, 1963a) demonstrates that the egg is capable of 'implantation' and limited development in a variety of nonendometrial tissues, apparently regardless of the hormonal environment.
at 8 µ and stained with Haematal 8 and Bieb damage Examination of the cyclic uterus 12 to 14 hr after traumatization revealed
the tear to about two-thirds of the way down the uterine lumen. Then, with the
cutting edge pressed against the uterine lining, the scraper was withdrawn. The instrument was rotated and the process repeated four more times. The size of the scraper used was, as a rule, as large as possible, while still allowing its free movement down the uterine lumen. Immediately after scraping, six to twenty eggs were introduced into the left uterine horn by means of a transfer apparatus described by Kirby (1963b). The tip of the micropipette used in the transfer of the eggs was flame polished to reduce the chance of its insertion into the endometrium. All instruments were sterilized before the operation.
240
Thomas P. Cowell
and, if so, to study the process of implantation, the development of the conceptus, and the effect of the developing conceptus on the uterus in this abnormal conceptus-endometrium relationship.
transfer.
INTRODUCTION
Experimental separation of maternal and embryonic elements provides a valuable means for studying the embryo-endometrial relationship during implantation and placentation.
The comparative ease of egg implantation in the extra-uterine sites contrasts with implantation in the uterus which occurs only during an endocrinologically controlled receptive period (Doyle, Gates & Noyes, 1963; Psychoyos, 1966). However, several investigators have observed implantation of tumours in cyclic mice (Hall, 1940; Stein-Werblowsky, 1962). Hall (1940) thought that sarcoma implantation in the cyclic uterus occurred at sites where the trocar used for transfer had damaged the uterine lining.
Haemangio-endotheliomata were taken from 129/J mice and placed in Pannett-Compton saline. The tumours were cut into 1-mm pieces and trans¬ ferred to the traumatized left uterine horn of each of eight ovariectomized
The recipient mouse was anaesthetized with an intraperitoneal injection of Avertin (Winthrop), and the left uterine horn exposed through a dorsolateral incision. A small tear was made in the uterus near the utero-tubal junction and a scraper, fashioned from a glass pipette (PI. 1, Fig. 1), was inserted through
tation sites are discussed.
Implanted embryos developed only to stages equivalent to 5 to 9 days of normal pregnancy, but the trophoblast continued to proliferate and invaded the endometrium, eroding maternal blood vessels and distending the uterus. In five of eight ovariectomized mice, plaques of decidual-like cells were found near the trophoblast 7 to 12 days after