Evaluation On The Efficacy And The Rules Of Syndrome Differentiation And Treatment In Chinese Medicine Of Ovulatory Disorder Infertility

Objective:Ovulation problem accounts for about 25-30 percent of female infertility. The number of relevant clinical trials of Chinese Medicine is increasing, and the research methods become more standardized gradually. This study aims at evaluating the clinical trials of the treatment of Ovulatory Disorder Infertility by Chinese Medicine in the past sixteen years with the use of Systematic Review, assessing the quality of clinical research studies, evaluating and comparing the efficacy and safety of the treatments by using Chinese Medicine treatment methods versus Western medicine, and determining the most effective and safest way for the treatment of Ovulatory Disorder Infertility. Besides, rule of syndrome differentiation of Chinese Medicine; rule of use of Chinese medicinal herbs and rule of use of acupuncture points of Ovulatory Disorder Infertility were evaluated.Methods and Results:1. Academic research on ovulatory disorder infertility:Collection and collation of ancient and contemporary discussions, pathogenesis, clinical data and research reviews of Chinese Medicine and Western medicine literatures on infertility and Ovulatory Disorder Infertility, analysis of the current situation, and exploration of new research approach.2. Evaluation on the efficacy of ovulatory disorder infertility(1) Methods:①Develop search strategies:Chinese Biological Medicine Database (CBM disc) of Chinese Medical Academy, WEIPU Periodical Database (VIP Chinese Periodical Database), China Journals Full-text Database (CNKI), Cochrane Library, Medline and Pubmed were searched electronically from 1994 to December 2009. Randomized control trials concerning Ovulatory Disorder Infertility treated by Chinese Medicine method were searched manually from January 2007 to December 2009.②Develop inclusion and exclusion criteria:Select only the randomized control trials (RCTs), which meet the inclusion and exclusion criteria, include only the trials that compare rate of pregnancy, rate of ovulation and safety. Exclude trials that compare other physiological indices only. Four types of trials were included, namely:Chinese Medicine versus Western medicine, Combined Chinese and Western medicine versus Western medicine, Acupuncture versus Western medicine and Combined Chinese Medicine and Acupuncture versus Western medicine.③The quality of Research methods of the included trials should match with the guidelines of Cochrane Collaboration for the evaluation of control trials and JADAD scale method. In Meta analysis, quantitative data is analyzed by using Odd Ratio (OR), with 95% confidence interval (CI).Meta View 5.0.2 of Review Manager 5.0 in Cochrane Collaboration was used for analysis in this evaluation.④Data analysis:Apart from the overall effect (z) comparison between the treatment groups (includes:Combined Chinese and Western medicine, Chinese Medicine, Acupuncture, and Combined Chinese Medicine and Acupuncture) and the control groups of Western medicine were done, a Q test (Mantel-Haenszel chi-square) will also be done to evaluate the homogeneity of the included trials. The test of heterogeneity can be evaluated by sensitivity test and sub-group analysis. Fixed Effects Model will be used if the heterogeneity could be neglected, whereas Random Effects Model will be used if heterogeneity existed. The calculation of overall effect and Significance Testing were demonstrated by the Forest Plot of Review Manager 5.0. Sensitivity analysis (Funnel plot analysis) between Fixed Effects Model and Random Effects Model can be demonstrated by establishing Funnel plot, which uses odd ratio (OR) as x-axis and log OR as y-axis. Analysis on the distribution pattern of the collected clinical data was made to determine whether there is existence of publication bias. The results will be demonstrated with the use of charts.(2) Results: ①Collection of literatures:During the search of literatures,661 papers related to Ovalulatory Disorder Infertility were obtained; most of the literatures were published on Chinese Medication Journals. There are totally 117 clinical trials; of which 71 were controlled clinical trials (61.74%) and 44 were self-controlled trials (38.26%).②Excluded literatures:544 of non-clinical studies were excluded,44 of self-controlled trials,3 of Chinese Medicine versus Chinese Medicine,1 of combined acupuncture and Western medicine versus Western medicine,10 of case control trials and 37 of randomized control trials, which were not matched with the diagnosis, inclusion and exclusion criteria. Total excluded literatures were 639.③Included literatures:A total of 22 randomized control trials matched the diagnostic, inclusion and exclusion criteria were identified (treatment group accounted for 1,191 participants whereas control group accounted for 1,031 participants, as a total of 2222 participants), of which 10 comparisons treated with Combined Chinese and Western medicine versus Western medicine, 9 treated with Chinese Medicine versus Western medicine,2 treated with Acupuncture versus Western medicine,1 treated with Combined Chinese Medicine and Acupuncture versus Western medicine.④Rate of Pregnancy:There were totally 2222 participants in 22 trials, the treatment group had 1191 participants, of which 729(61.20%) became pregnant after treatment. The treatment group consisted of 4 divisions, namely group of Combined Chinese and Western medicine, Chinese Medicine, Acupuncture and Combined Chinese Medicine and Acupuncture, of which 262/458(57.2%), 382/609(62.72%),65/94(69.14%) and 20/30(66.66%) were pregnant after treatment respectively. In the control group, all participants were treated with Western medicine,372/1031(36.08%) participants became pregnant after treatment.⑤Rate of Ovulation:There were totally 2294 participants or cycles in 18 trials, the treatment group had 1216 participants or cycles, of which 962(79.11%) had ovulation after treatment. The treatment group consisted of 4 divisions, namely group of Combined Chinese and Western medicine, Chinese Medicine, Acupuncture and Combined Chinese Medicine and Acupuncture, of which 374/454(82.37%),388/514(75.48%),172/218(78.89%),28/30(93.33%) had ovulation after treatment respectively. In the control group, all participants were treated with Western medicine,809/1078(75.04%) had ovulation after treatment.⑥Adverse reaction:There was only one paper which mentioned adverse reaction(罗志娟2007, Chinese Medicine versus Western medicine) in 22 included trials. For Luteinizing Unruptured Follicle Syndrome (LUFS):Treatment group: 6.59%(12/182 cases), Control group:19.60%(30/153 cases); for Ovarian hyper-stimulation syndrome (OHSS):Treatment group:0%, Control group:0.65% (1/153 cases); for Ovarian Follicular Dysplasia:Treatment group: 25.82%(47/182 cases), Control group:20.26%(31/153 cases).The result indicated that the incidence of LUFS of the treatment group is lower than the control group(P<0.05).⑦Evaluation of quality:The assessment by JADAD's scale showed that 2 of the trials got 3 points (which were classified as high-quality trials), 9 of the trials got 2 points (which were classified as medium-low-quality trials), and 11 of the trials got 1 point (which were classified as low-quality trials).⑧Evaluation of efficacy and safety:The efficacy of the included paper can be divided into rate of pregnancy and rate of ovulation. Rate of pregnancy were described in all 22 clinical trials, whereas rate of ovulation were described in only 18 clinical trials. There are only 2 clinical trials mentioned about the reasons for withdrawal, both are Acupuncture versus Western medicine trials. According to the different treatment strategies, the 22 included clinical trials were divided into 4 groups, namely:group of Combined Chinese and Western medicine (10 trials), Chinese Medicine (9 trials), Acupuncture (2 trials) and Combined Chinese Medicine and Acupuncture (1 trial) to implement Meta analysis.1. Combined Chinese and Western medicine versus Western medicine (10 papers). Regarding to the rate of pregnancy, since the 10 included trials are very similar in nature, this is regarded as homogeneity, so Fixed Effects Model was used. The average odds ratio (OR) was 3.05,95% Confidence Intervals (CI): 2.31,4.02; Chi2:5.60, P:0.78, heterogeneity (I2):0%; the total effect (z): 7.87, P<0.00001. The result of Meta analysis indicated that there was a statistically significant difference between the treatment and control group. The rate of pregnancy of the treatment group is significantly better than the control group (P<0.05). Regarding to the rate of ovulation, since the 8 included trials are very similar in nature, this is regarded as homogeneity, so Fixed Effects Model was used also. The average odds ratio (OR) was 1.76, 95% Confidence Intervals (CI):1.27,2.44; Chi2:2.12, P:0.96, heterogeneity (I2):0%; the total effect (z):3.41, P<0.0006. The result of Meta analysis indicated that there was a statistically significant difference between the treatment and control group. The rate of Ovulation of the treatment group is significantly better than the control group (P<0.05).2. Chinese Medicine versus Western medicine (9 papers). Regarding to the rate of pregnancy, since the 9 included trials are not very similar in nature, this is regarded as heterogeneity, so Random Effects Model was used. The average odds ratio (OR) was 2.73,95% Confidence Intervals (CI):1.92,3.90; Tau2:0.11, Chi2:13.52, P:0.1, heterogeneity (I2):41%; the total effect (z): 5.56, P<0.00001. The result of Meta analysis indicated that there was a statistically significant difference between the treatment and control group. The rate of pregnancy of the treatment group is significantly better than the control group (P<0.05). Regarding to the rate of ovulation, since the 7 included trials are not very similar in nature, this is regarded as heterogeneity, so Random Effects Model was used. The average odds ratio (OR) was 1.31,95% Confidence Intervals (CI):0.72,2.41; Tau2:0.41, Chi2:17.49, P:0.008,, heterogeneity (I2):66%; the total effect (z):0.89, P=0.38. The result of Meta analysis indicated that there was not a statistically significant difference between the treatment and control group in the rate of Ovulation(P>0.05).3. Acupuncture versus Western medicine (2 papers). Regarding to the rate of pregnancy, since the 2 included trials are very similar in nature, this is regarded as homogeneity, so Fixed Effects Model was used. The average odds ratio (OR) was 2.29,95% Confidence Intervals (CI):1.26,4.16; Chi2:0.00, P:0.96, heterogeneity (I2):0%; the total effect (z):2.71, P=0.007. The result of Meta analysis indicated that there was a statistically significant difference between the treatment and control group. The rate of pregnancy of the treatment group is significantly better than the control group (P<0.05). Regarding to the rate of ovulation, since the 2 included trials are not very similar in nature, this is regarded as heterogeneity, so Random Effects Model was used. The average odds ratio (OR) was 0.57,95% Confidence Intervals (CI): 0.16,2.03; Tau2:0.69, Chi2:5.56, P:0.02, heterogeneity (I2):82%; the total effect (z):0.87, P=0.38. The result of Meta analysis indicated that there was not a statistically significant difference between the treatment and control group for the rate of Ovulation(P>0.05).4. Combined Chinese Medicine and Acupuncture versus Western medicine (1 paper) Since there is only one paper, Meta analysis cannot be performed.3. Evaluation on the rules of syndrome and treatment in TCM of ovulatory disorder infertility(1) Methods:①Develop search strategies:Same as above (2. Evaluation on the efficacy of Ovulatory Disorder Infertility).②Develop inclusion and exclusion criteria:Select only the randomized control trials (RCTs) or quasi-randomized control trials that included case control trials (CCT). The treatment group should choose Chinese Medicine methods for treatment, which included:Syndrome Differentiation of Chinese Medicine, Cycle Therapy of Chinese Medicine, Single Prescription of Chinese Medicine, Acupuncture, Moxibustion and Combination treatment. Exclude all Non-Ovulatory Disorder Infertility trials, and also exclude case reports and all other studies without control groups.③Data analysis:Adopt descriptive statistics, use frequency and percentage as statistical methods.(2) Results:①Rule of Treatment of Chinese Medicine of Ovulatory Disorder Infertility:For the 69 included trials, there are four papers (5.79%) concerning Syndrome Differentiation of Chinese Medicine,20 papers (28.98%) concerning Cycle Therapy of Chinese Medicine and 41 papers (59.42%) concerning Single Prescription of Chinese Medicine. There are nine papers (13.04%) concerning Acupuncture Treatment, of which five papers used Combined Chinese Medicine and Acupuncture; three (4.34%) used Acupuncture only and one (1.44%) used Moxibustion only for treatment.②Rule of the use of Chinese medicinal herbs of Ovulatory Disorder Infertility:There were 107 prescriptions in 69 Control Trials, which involved 119 kinds of Chinese medicinal herbs, the total frequency of Chinese medicinal herbs used was 1096, and average numbers of Chinese medicinal herbs used per prescription was 10.24 kinds. The total frequency of the top 10 Chinese medicinal herbs was 480 that is equivalent to 43.79%. There were 37 prescriptions in the 22 randomized control trials which were matched with the included and excluded criteria, the number of Chinese medicinal herbs involved was 74, the total frequency was 357, and average numbers of Chinese medicinal herbs used per prescription was 9.65 kinds. The total frequency of the top 10 Chinese medicinal herbs was 166 that is equivalent to 46.49%. There were 60 prescriptions in the 37 randomized control trials which were not matched with the included and excluded criteria, the number of Chinese medicinal herbs involved was 99, the total frequency was 633, and average numbers of Chinese medicinal herbs used per prescription was 10.55 kinds. The total frequency of the top 10 Chinese medicinal herbs was 281 that is equivalent to 44.39%. There were 10 prescriptions in the 10 case control trials which were not matched with the included and excluded criteria, the number of Chinese medicinal herbs involved was 61, the total frequency was 106, and average numbers of Chinese medicinal herbs used per prescription was 10.60 kinds. The total frequency of the top 10 Chinese medicinal herbs was 47 that is equivalent to 44.33%. 16 Chinese medicinal herbs were found by summarizing the top 10 Chinese medicinal herbs of the above four different types of researches. Those with frequency of 4 were:Angelica sinensis, Cuscuta chinensis Lam., Rehmannia glutinosa Libosch, Epimedium brevicornum Maxim. Lycium barbarum L.; with frequency of 3 were:Ligusticum chuanxiong Hort. and White peony root; frequency of 2 were:Cyperus rotundus L., Ligustrum lucidum, Salvia, Cornus Officinalis Sieb. et Zucc., Dioscorea opposita Thunb.; frequency of 1 were: Cistanche, Peony, Raspberry and Red flowers. Cistanche, Peony, Raspberry and Red flowers were removed from the above list as they were only found in the 10 excluded case control trials, so the remaining 12 Chinese medicinal herbs were:Cyperus rotundus L., Ligustrum lucidum, Salvia, White peony root, Angelica sinensis, Cuscuta chinensis Lam., Rehmannia glutinosa Libosch, Epimedium brevicornum Maxim., Lycium barbarum L., Ligusticum chuanxiong Hort. Cornus Officinalis Sieb. et Zucc., Dioscorea opposita Thunb.. In the above 12 Chinese medicinal herbs, Angelica sinensis, Cuscuta chinensis Lam., Rehmannia glutinosa Libosch, Epimedium brevicornum Maxim., Lycium barbarum L., Ligusticum chuanxiong Hort., Cornus Officinalis Sieb. et Zucc., Dioscorea opposita Thunb. were found in the top 10 Chinese medicinal herbs of all the 59 randomized control trials.③Rule of the use of Acupuncture points of Ovulatory Disorder Infertility:There were nine control trials treated by using acupuncture,8 out of 9 were randomized control trials and one was non-randomized control trials. In the eight trials treated by acupuncture,16 acupoints were chosen in the seven trials (as a trial from陈雪松didn't mention about the acupoints and the technique used), the total frequency was 45 and average acupoints used per trial was 6.43. The acupoints of Guanyuan(RN4), Zigong(EX-CA1), Sanyinjiao(SP6) were used in all trials, which was equivalent to 100%; the proportion of Zhongji(RN3)and Zusanli(ST36) being used was 71.4%; the proportion of the rest of acupoints were used was only 14.3%～28.6%. The priority of acupoints to be selected for the treatment of Ovulatory Disorder Infertility was in a descending order as shown below:Guanyuan(RN4), Zigong(EX-CA1), Sanyinjiao(SP6), Zhongji(RN3), Zusanli(ST36), Baihui(DU20), Shenshu(BL23), Taixi(KI3), Minmen(DU4), Pishu(BL20), Tianshu(ST25), Xuehai(SP10), Shuidao(ST28), Guilai(ST29), Hegu(LI4) and Taichong(LR3). In the 7 trials, which used Moxibustion for treatment,2 trials(陈雪松与郑惠颖)didn't describe the acupoints to be used,3 acupoints were selected in the rest 5 trials, the total frequency was 8 and the average acupoints to be selected per trial was 1.6. Shenque(RN8) was the acupoint to be selected in all trials, which was equivalent to 100%; the proportion of Sanyinjiao(SP6) being used was 40%, one trial selected Baihui (DU20). So the priority of acupoints to be selected by using Moxibustion for the treatment of Ovulatory Disorder Infertility was in a descending order as shown below:Shenque(RN8), Sanyinjiao(SP6) and Baihui(DU20).Conclusion1. Infertility has profound theoretical and clinical origin in Traditional Chinese medicine. In the past decade, there were many reports and progress on the clinical trials of the usage of Chinese medicine and integrative medicine for the treatment of Ovulatory Disorder Infertility.2. Meta analysis of the clinical trials of Chinese Medicine in the past 16 years showed that when Chinese medicine or Combined Chinese and Western medicine, acupuncture or combination of Chinese medicine and acupuncture were used, the rates of pregnancy were significantly better than the use of Western medicine alone as control groups. But there was not a statistically significant difference between the treatment and control group for the rate of Ovulation. 3. Regarding the rule of treatment, Chinese medicinal herbs treatment is the most popular way among all Chinese Medicine treatment methods for treating Ovulatory Disorder Infertility, followed by acupuncture, and then Moxibustion. In Chinese medicinal herbs treatment, Single Prescription of Chinese Medicine came first, Cycle Therapy of Chinese Medicine came after, and then Syndrome Differentiation of Chinese Medicine.4. Regarding the rule of the use of Chinese medicinal herbs, frequency data of herbs and analysis showed that among the 59 randomized control trials, the eight most popular Chinese medicinal herbs for the treatment of Ovulatory Disorder Infertility are:Angelica sinensis, Cuscuta chinensis Lam., Rehmannia glutinosa Libosch, Epimedium brevicornum Maxim., Lycium barbarum L., Ligusticum chuanxiong Hort., Cornus Officinalis Sieb. et Zucc. and Dioscorea opposita Thunb. etc. For clinical application, with the use of these 8 Chinese medicinal herbs together with combined methods of Cycle Therapy and Syndrome Differentiation of Chinese Medicine, better therapeutic effect may be obtained. Most Chinese Medicine Practitioners tend to choose herbs with property of either warm or neutral and which are belonged to kidney or liver meridians, and avoid using the herbs with property of very hot or very cold.5. Regarding the rule of the use of Acupuncture points, acupoints on Ren Meridian such as Guanyuan (RN4), Zhongji (RN3), Shenque(RN8) were chosen first, and aided with acupoints on Spleen and Stomach Meridians such as Sanyinjiao(SP6), Zusanli (ST36). An extra point related to female reproductive organ, which is called Zigong(EX-CA1), was chosen as well.