【作者】 黄惠玲；

【导师】 罗颂平；

【作者基本信息】 广州中医药大学 ， 中医妇科学， 2010， 博士

【摘要】 目的：子宫内膜异位症是不孕的主要原因之一,发病率正在上升,是目前妇科一个疑难病。在不孕的患者中,大约30%～58%合并子宫内膜异位症。在诊断为子宫内膜异位症的患者,不孕的发生率约为30%～50%,而自然流产的发生率亦有约40%,严重影响育龄患者的生活质量和健康。目前未有系统性对本病所致不孕的中医方药证治规律研究。本研究旨在系统收集及整理近20年有关治疗子宫内膜异位症的临床研究文献,对该病所引致不孕的中医治疗处方用药,特别是高频数的中医方药进行统计分析、归纳及总结,为今后对子宫内膜异位症及其不孕的治疗及下一步临床用药提供系统化思路和理据。方法与结果：1.子宫内膜异位症及其不孕的理论研究收集及整理现代中、西医文献中对子宫内膜异位症与其不孕的论述、病因病机、临床资料和研究进展,分析研究现状,探求新的研究思路。2.子宫内膜异位症及其不孕的疗效评价：2.1方法：2.1.1制定检索策略：检索对象为中国期刊全文数据库(中国知识基础设施工程,CNKI)。为了更全面地检索到符合研究标准的论文,将根据每篇论文的主题词、关键词与摘要等元素交叉搜寻所有“子宫内膜异位症”文献,并对涉及该病所引致不孕的治法及方药,作出收录及分析。2.1.2制定纳入、排除标准：文章的内容与“子宫内膜异位症”及“不孕”有关,患者症状被诊断为子宫内膜异位症,当中有要求妊娠或确诊不孕患者(统称为“不孕患者”)。中药治疗组病例数目≥25例,其中因本病引致不孕的例数不少于25%,所选方药疗效明确,以不孕患者受孕或妊娠情况为重要的观察指标(疗效标准：中药治疗组妊娠率≥25%,妊娠率=不孕患者在3年内妊娠或生育例数／不孕患者总数),主要治疗方法为中医药疗法或保守性手术(腹腔镜手术为主)结合中医药疗法；排除病例中无不孕患者,在疗效中无明确指出不孕患者妊娠率(文献无明确指出不孕消失率、痊愈率或治愈率当妊娠率计的,予以排除),治疗方法以中医针灸或以灌肠、外敷、直肠滴注等中医外治法为主要疗法。2.1.3数据分析：利用Excel软件及STATA统计学软件,通过编写程式,对数据进行频数分析和药对分析。通过频数分析,对治疗子宫内膜异位症的各类中药的使用频率进行比较,并根据其差异,认识到不同种类药物的运用情况,以致推论出用药的主导趋势,为进一步全面、系统地掌握子宫内膜异位症及其不孕的证治规律提出证据。2.2结果：2.2.1收集及排除研究：通过中国期刊全文数据库共检出与子宫内膜异位症相关文献11,298篇,根据题目作出初步筛选与中医药治疗或保守性手术结合中医药治疗的文献共435篇。为了防止文献的遗漏,对每篇文献进行阅读及整理,去掉个案报道、重复报告及无记录妊娠情况的,得到95篇中医临床研究文献。然后再进行另一次筛选,排除文献35篇(14篇含仅为子宫腺肌病患者,19篇中药治疗组不孕例数少于25%,5篇中药治疗组妊娠率少于25%)2.2.2纳入研究：符合诊断标准、排除、纳入条件的临床研究文献共共60篇,包括中医药疗法文献47篇及保守性手术(腹腔镜手术为主)结合中医药疗法文献13篇。在中医药疗法文献中,有一篇的不孕患者属于要求妊娠者；对于她们的不孕年限,文献没有作出交待。47篇文献共报告了3,686例子宫内膜异位症患者,其中不孕患者有1,778例(48.2%)；治疗组的子宫内膜异位症患者共2,593例,其中不孕患者为1,264例(48.7%)。在47篇文献中,全部有不孕症状患者的有13篇合共664例；其中治疗组的不孕患者有518例(78%)。不孕患者来自生殖中心或不孕不育专科的少于10%。治疗组的样本量≥100例的只有5篇(11%),18篇(38%)的样本量在50-99例之间,24篇(51%)的样本量在25-49例之间。13篇保守性手术结合中医药疗法文献共报告了1,144例子宫内膜异位症患者,其中不孕患者估787例(68.8%)；治疗组的子宫内膜异位症患者共613例,其中不孕患者估398例(64.9%)。在13篇文献中,有5篇合部440例患者合并不孕；其中治疗组的不孕患者有213例(48.4%)。只有1篇文献共127例不孕患者来自生殖医院。治疗组的样本量≥100例的只有1篇(8%),3篇(23%)的样本量在50-99例之间,9篇(69%)的样本量在25-49例之间。2.2.3入选文献评价：在47篇中医药疗法文献中,设有对照组的有28篇,其中一篇以正常妇女为对照观察对象,但所对照观察的项目并不包括受孕情况,所以,实际上设有对照组的只有27篇(57.4%),其余20篇为非对照文献(42.6%)；在13篇保守性手术结合中医药疗法文献中,全部为RCT试验(100%)。2.2.4妊娠率：47篇文献(100%)都有列明治疗期间或治疗后的受孕情况。治疗组3年内妊娠率≥50%的有18篇(38.3%),其它的妊娠率为25%-49%之间；13篇文献(100%)都有列明治疗期间或治疗后的受孕情况。治疗组3年内妊娠率≥50%的有7篇(53.8%),其它的妊娠率为25%-49%之间。2.2.5中医证治规律2.2.5.1中医药疗法文献排名前三位的药类为活血化瘀药(41.3%)、补虚药(22.7%)和清热药(13.3%)累积频率为77.3%。其中活血化瘀药和补虚药累积频率高达64%,是治疗子宫内膜异位症性不孕的主要药物。使用频次≥7的活血化瘀药依次为：莪术、三棱、丹参、延胡索、川芎、桃仁、水蛭、蒲黄、穿山甲、血竭、郁金、五灵脂、红花。使用频次≥7的补虚药依次为：当归、菟丝子、甘草、淫羊藿、黄芪、续断。活血化瘀药中出现频率最高的前3味药物依次分布。活血止痛药：延胡索、川芎、蒲黄。活血调经药：丹参、桃仁、红花。破血消癥药：莪术、三棱、水蛭。在活血化瘀药中破血消癥药最为常用,占活血化瘀药总频数的37%。2.2.5.2子宫内膜症异位症合并不孕患者的中医药疗法文献为了更清晰地反映子宫内膜异位症合并不孕的治疗用药规律,在47篇的中医药疗法文献中选出其中不孕患者达100%的文献共13篇进行用药规律分析。排名前三位的药类为活血化瘀药(42.9%)、补虚药(27.6%)和清热药(11.7%),累积频率为82.2%。其中活血化瘀药和补虚药累积频率高达70.6%,是治疗子宫内膜异位症性不孕的主要药物；排名第三位的是清热药。使用频数(次)≥4的活血化瘀药依次为：丹参、莪术、三棱、水蛭、延胡索、郁金、蒲黄、五灵脂。使用频数(次)≥4的补虚药依次为：当归、菟丝子、淫羊藿、续断。活血化瘀药中出现频率最高的前3味药物依次分布。活血止痛药：延胡索、郁金、五灵脂。活血调经药：丹参、桃仁、红花。破血消癥药：莪术、三棱、水蛭。在活血化瘀药中破血消癥药最为常用,占活血化瘀药总频数的40%。2.2.5.3根据不同比例的不孕率作药物分类比较比较两组不同比例的不孕患者的用药情况,结果发现子宫内膜异位症不孕患者达100%的文献,补虚药的使用百分点轻微提高(27.6%比22.7%),而清热药的使用百分点相对降低(11.7%比13.3%)。活血化瘀药仍然是排名首位的药物,使用的百分点没有明显改变(42.9%比41.3%),理气药的使用率亦稍为增加(9.2%比8.5%)。2.2.5.4保守性手术(腹腔镜手术为主)结合中医药疗法文献排名前三位的药类为活血化瘀药(45.6%)、补虚药(25.6%)和理气药(8.1%),累积频率为79.4%。其中活血化瘀药和补虚药累积频率高达71.3%,依然是治疗子宫内膜异位症不孕的主要药物;排名第三位的是理气药,而清热药则排名第四位。丹参和三七这类有活血化瘀生新作用的活血化瘀药取代了破血散瘀消癥力强的虫类药如水蛭、穿山甲及蟅虫等,成为使用比例最高的药物。三棱和莪术仍然是本病的常用药。使用频数(次)≥4的活血化瘀药依次为：丹参、三七、莪术、延胡索、三棱、血竭、川芎。使用频数(次)≥4的补虚药依次为：菟丝子、当归、甘草、黄精。活血化瘀药中出现频率最高的前3味药物依次分布。活血止痛药：三七、延胡索、血竭。活血调经药：丹参、桃仁、益母草。破血消癥药：莪术、三棱、水蛭。活血止痛药取代了破血消癥药,成为使用率最高的活血化瘀药物,占活血化瘀药总频数的45%。2.2.5.6.常用药物上述三组出现频率最高的6味药物：赤芍、当归、莪术、三棱、丹参、延胡索。累积频数分别为171味次、50味次和49味次。累积频率超过30%。2.2.5.7.常用药对①活血消癥药对：三棱与莪术；②活血调经药对：当归与川芎；③活血止痛药对：蒲黄与五灵脂；④补肾调冲药对：淫羊藿与菟丝子结论：1.运用医学统计学方法对中医药治疗子宫内膜异位症及其不孕的临床研究文献进行系统评价与分析,提示子宫内膜异位症及其所致不孕症的主要病机是血瘀和肾虚,活血化瘀、补肾化瘀是其主要治法,其次为理气与清热。活血化瘀有轻重之分,当血瘀症状比较重时,多以破血消癥为主。2.研究发现,随着不孕患者的比例增加,理气药的使用率亦稍为增加(9.2%比8.5%),提示疏肝解郁对子宫内膜异位症不孕的治疗是有帮助的。常用理气药是香附。3.研究子宫内膜异位症及其不孕的方药证治规律及用药频数,发现最常用的6味中药是赤芍、当归、莪术、三棱、丹参、延胡索。而破血消癥亦常用虫类药,如水蛭。常用药对为活血消癥之三棱与莪术,活血调经之当归与川芎,活血止痛之蒲黄与五灵脂,补。肾调冲之淫羊藿与菟丝子。更多还原

【Abstract】 Objective:Endometriosis is one of the main reasons for infertility, with increasing morbidity, is a complicated gynecological disease. About 30%～58% of infertile women are found to have this disease. For those having endometriosis, the chance of infertility is about 30% to 50%, while the chance of miscarriage is about 40 percent, seriously affecting the health and quality of life of women of reproductive age. At present, there is no systematic study on the rules of syndrome differentiation and treatment in Chinese Medicine on endometriosis and its related infertility. This study aims at systematically collect and reviews the clinical research literatures on endometriosis of the latest 20 years, analyze and summarize those prescriptions and herbs with high frequencies in the treatment of endometriosis and its related infertility as a means to provide data support and thoughts for clinical application.Methods and Results:1. Academic research on endometriosis and its related infertility: Collection and collation of contemporary discussions, pathogenesis, clinical data and research reviews of Chinese Medicine and Western medicine literatures on endometriosis and its related infertility, analysis of the current situation, and exploration of new research approach.2. Evaluation on the efficacy of endometriosis and its related infertility2.1 Methods:2.1.1 Develop search strategies:Collect papers published in the China Journals Full-text Database (CNKI). In order to get more relevant papers, each "endometriosis" related paper is reviewed according to its topic, key words and abstract. Treatment, prescriptions and drugs relating to endometriosis and infertility will be collected and reviewed.2.1.2 Develop inclusion and exclusion criteria:Select only those papers related to "endometriosis" and "infertility". Patients confirmed having endometriosis, among them with request for medical treatment of fertility or infertile (called the "Infertile"). The number of participants of the Chinese medicine trial group≥25 cases, not less than 25% of them infertile). The prescriptions and drugs used were effective. Pregnancy rate is a key measurement. (Required results:The pregnancy rate of the Chinese medicine trial group≥25%, pregnancy rate= number of successful pregnancy of those infertile within three years after treatment/the total number of infertile), the treatment was mainly Chinese Medicine, or combined conservative surgery (mainly laparoscopic surgery) with Chinese Medicine. Some papers were excluded due to one of the following reasons:no infertile patient, the pregnancy rate was not stated specifically, using acupuncture, enema, external application, rectal infusion as the key treatment.2.1.3 Data Analysis:Using Excel software and STATA statistical software, and programming formulae, to conduct frequency analysis and paired herbs analysis. By using frequency analysis, the data can be compared and reviewed so that the medicinal herbs most in use can be identified.2.2 Results:2.2.1 Collection and exclusion of literatures:During the search of literatures,11,298 papers related to Endometriosis were obtained. After the first screening,435 papers were identified as related to the Chinese Medicine treatment or the conservative surgery (mainly laparoscopic surgery) with Chinese Medicine treatment. To ensure that there was no missing of relevant paper, each of them was read and analyzed. By screening out the case reports, repeated reports and those with no pregnancy record,95 papers left. Further screening was conducted with 35 papers being screened out (14 papers with adenomyosis only cases,19 papers with number of infertile patient less that 25% in the Chinese Medicine treatment group,5 papers with the pregnancy rate of the experimental group less that 25%).2.2.2 Included literatures:A total of 60 studies matched the diagnostic, inclusion and exclusion criteria were identified of which 47 were treated with Chinese Medicine,13 with combined conservative surgery (mainly laparoscopic surgery) and Chinese Medicine.A total of 3,686 participants were reported in the 47 Chinese Medicine trials,1,778 (48.2%) of which were infertile. The experimental group consisted of 2,593 participants with 1,264 participants (48.7%) infertile. 13 trials with all 664 participants infertile, of which the experimental group has a total of 518 participants (78%). Less than 10% of the participants were from the Reproductive Center or Specialized Center for Infertility Treatment. In the experimental group,5 trials (11%) with sample size≥100 participants, 18 trials (38%) with sample size between 50-99,24 trials (51%) with sample size between 25-49.A total of 1,144 participants were reported in the 13 combined conservative surgery (mainly laparoscopic surgery) with Chinese Medicine trials, of which 787 participants(68.8%) requested treatment for infertility. The experimental group totaling 613 participants with 398 participants (64.9%) infertile.5 out of the 13 trials with all 440 participants infertile while the experimental group has a total of 213 participants (48.4%). Only 1 trial with 127 cases was from the Reproductive Center or Specialized Center for Infertility Treatment. In the experimental group,1 trial (8%) with sample size^100≥participants,3 trials (23%) with sample size between 50-99, trials (69%) with sample size between 25-49.2.2.3 Evaluation of quality:28 out of 47 with controlled trials. As 1 controlled trial did not measure pregnancy rate, making the number of controlled trials reduced to 27(57.4%). The remaining 20 (42.6%) were self-controlled trials. All 13 combined conservative surgery (mainly laparoscopic surgery) with Chinese Medicine were randomized-controlled trials (100%).2.2.4 Rate of Pregnancy:47 trials (100%) reported pregnancy situation during and after treatment.18 trials reported the pregnancy rate of the experimental group≥50% within 3 years. The others with the pregnancy rate between 25%-49%; 13 trials (100%) reported pregnancy situation during and after treatment.7 trials reported pregnancy rate of the experimental group≥50% within 3 years while others with pregnancy rate between 25%-49%2.2.5 Rule of the use of Chinese medicinal herbs of Endometriosis and its related infertility 2.2.5.1 Chinese Medicine treatmentThe top 3 Chinese medicinal herbs were herbs for activating blood and stasis-dissolving (41.3%), tonics (22.7%) and heat-clearing (13.3%); the cumulative frequency was 77.3%. The cumulative frequency of herbs for activating blood and stasis-dissolving and tonics reached 64%, were the most popular herbs for treatment of endometriosis and its related infertility. Those herbs for activating blood and stasis-dissolving with frequency≥7: rhizoma curcumae, rhizoma curcuma, radax salviae miltiorrhizae, rhizoma corydalis, rhizoma chuanxion, semen persicae, hirudo, pollen typhae, squama manis, sanguis draxonis, radix curcumae, faeces trogopterori, flos carthami. Those herbs for tonics with frequency≥7:radix angelicae sinensi, semen cuscutae, radix glycyrrhizae, herba epimedii, radix astragali, radix dipsaci. The top 3 Chinese medicinal herbs for activating blood and stasis-dissolving were:activating blood to relieve pain:rhizoma corydalis, rhizoma chuanxion, pollen typhae; blood-activating and menstruation-regulating:radax salviae miltiorrhizae, semen persicae, flos carthami;removing blood stasis and eliminating mass:rhizoma curcumae, rhizoma sparganii, hirudo. Removing blood stasis and eliminating mass was the most popular one among the three, accounted for 37% of activating blood and stasis-dissolving herbs.2.2.5.2 Chinese Medicine treatment for endometriosis and its related infertility patientsIn order to reflect more accurately the rules of syndrome differentiation and its related infertility, the 13 trials with all infertile participants were selected for separate study. The top 3 Chinese medicinal herbs were herbs for activating blood and stasis-dissolving (42.93%), tonics (27.6%) and heat-clearing (11.7%); the cumulative frequency was 82.2%. The cumulative frequency of herbs for activating blood and stasis-dissolving and tonics reached 70.6%, were the most popular herbs for treatment of endometriosis and its related infertility. The third one was heat-clearing herbs. Those herbs for activating blood and stasis-dissolving with frequency≥4:radax salviae miltiorrhizae, rhizoma curcumae, rhizoma curcuma, hirudo, rhizoma corydalis, radix curcumae, pollen typhae, faeces trogopterori. Those herbs for tonics with frequency≥4:radix angelicae sinensi, semen cuscutae, herba epimedii, radix dipsaci. The top 3 Chinese medicinal herbs for activating blood and stasis-dissolving were:activating blood to relieve pain:rhizoma corydalis, radix curcumae, faeces trogopterori; blood-activating and menstruation-regulating:radax salviae miltiorrhizae, semen persicae, flos carthami:removing blood stasis and eliminating mass:rhizoma curcumae, rhizoma sparganii, hirudo. Removing blood stasis and eliminating mass was the most popular one among the three, accounted for 40% of activating blood and stasis-dissolving herbs.2.2.5.3 Comparison of the use of herbs based on different infertility rateBy comparing the above 2 groups that containing different ratios of infertile patients, it was found that when the clinical trials with infertile participants reached 100%, there were more use of the tonics herbs (27.6% vs. 22.7%) while the use of heat-clearing was decreased by certain percentage points (11.7% vs.13.3%). Activating blood and stasis-dissolving was still the most popular type (42.9% vs.41.3%).2.2.5.4 Combined conservative surgery (mainly laparoscopic surgery) with Chinese Medicine treatmentThe top 3 Chinese medicinal herbs were herbs for activating blood and stasis-dissolving (45.6%), tonics (25.6%) and qi-regulating medicinal (8.1%); the cumulative frequency was 79.4%. The cumulative frequency of herbs for activating blood and stasis-dissolving and tonics reached 71.6%, remained as the most popular herbs for treatment of endometriosis and its related infertility. The third one was qi-regulating medicinal while the fouth was heat-clearing. Radax salviae miltiorrhizae and radix notoginseng have replaced those insects like hirudo, squama manis and eupolyphaga seu steleophaga that with higher power of removing blood stasis and eliminating mass. Rhizoma sparganii and rhizoma curcumae remained the most popular herbs. Those herbs for activating blood and stasis-dissolving with frequency≥4:radax salviae miltiorrhizae, radix notoginseng, rhizoma curcumae, rhizoma corydalis, rhizoma sparganii, sanguis draxonis, rhizoma chuanxion. Those herbs for tonics with frequency≥4:semen cuscutae, radix angelicae sinensis, radix glycyrrhizae, rhizoma polygonati. The top 3 Chinese medicinal herbs for activating blood and stasis-dissolving were:activating blood to relieve pain:radix notoginseng, rhizoma corydalis, sanguis draxonis.; blood-activating and menstruation-regulating:radax salviae miltiorrhizae, semen persicae, herba leonuri;removing blood stasis and eliminating mass: rhizoma curcumae, rhizoma sparganii, hirudo. Activating blood to relieve pain, accounted for 45% of activating blood and stasis-dissolving drug, has replaced removing blood stasis and eliminating mass to become the most popular herbs in the group.2.2.5.6. The medicinal herbs most in use There were 6 herbs that were commonly and widely used in all the above 3 groups of patients. They were: radix paroniae rubra, radix angelicae sinensis, rhizoma curcumae, rhizoma sparganii, radax salviae miltiorrhizae, rhizoma corydalis. Cumulative frequencies of all the 6 herbs were 171,50 and 49 respectively. Cumulative percentage exceeded 30% in each group.2.2.5.7 Paired herbs①Paired herbs for removing blood stasis and eliminating mass:rhizoma sparganii and rhizoma curcumae;②Paired herbs for blood-activating and menstruation-regulating:radix angelicae sinensis and rhizoma chuanxion;③Paired herbs for activating blood to relieve pain:pollen typhae and faeces trogopterori④Paired herbs for nourishing kidney and regulating thoroughfare and conception vessels:herba epimedii and semen cuscutae.Conclusion1. By application of statistical method to review and analyse the clinical research literatures, a conclusion can be drawn that blood stasis and kidney deficiency are the key pathogenesis of Endometriosis and its related infertility. The key therapeutic methods are treatment with promoting Qi and removing blood-statis, and replenishing kidney and dissolving blood. Followed by regulating Qi, and heat-clearing method. When the blood stasis is serious, the more application of removing blood stasis and eliminating mass,2. Regulating Qi helps to sooth the liver and alleviating depression of the infertile. Rhizoma cyperi is the most commonly used herb.3. Throughout this study, six most commonly used herbs are identified:radix paroniae rubra, radix angelicae sinensis, rhizoma curcumae, rhizoma sparganii, radax salviae miltiorrhizae, rhizoma corydalis are found. Herbs of removing blood stasis and eliminating mass have been used very widely, especially those insects like hirudo. There are 4 popular pared herbs like①Paired herbs for removing blood stasis and eliminating mass:rhizoma sparganii and rhizoma curcumae;②Paired herbs for blood-activating and menstruation-regulating: radix angelicae sinensis and rhizoma chuanxion;③Paired herbs for activating blood to relieve pain:pollen typhae and faeces trogopterori④Paired herbs for nourishing kidney and regulating thoroughfare and conception vessels: herba epimedii and semen cuscutae.更多还原