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Review ArticleEffectiveness of Cotreatment with Kuntai Capsule and Climen forPremature Ovarian Failure: A Meta-Analysis
Qianwen Ma ,1,2 Yong Tan ,2 and Genlin Mo 3
1Gynecology Department, Zhenjiang Hospital Affiliated to Nanjing University of Chinese Medicine (Zhenjiang Hospitalof Traditional Chinese Medicine), Zhenjiang, China2Reproductive Medicine Department, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China3Advanced Manufacturing Institution, Jiangsu University, Zhenjiang, China
Correspondence should be addressed to Yong Tan; [email protected] and Genlin Mo; [email protected]
Received 28 July 2019; Accepted 31 January 2020; Published 20 February 2020
Academic Editor: Carmen Mannucci
Copyright © 2020 Qianwen Ma et al. /is is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Objective. To compare the treatment efficacy of Kuntai capsule with Climen only in the therapy of premature ovarian failure.Methods. Randomized controlled trials were electronically retrieved from PubMed, Cochrane Library, Web of science, CBM,CNKI, Wanfang, and Weipu database. In addition, some related papers were manually checked. All papers were assessedaccording to the Cochrane Handbook for Systematic Reviews of Interventions, and the effective data were analyzed by Revman 5.3Software. Results. 11 randomized control trials involving 1068 patients were included. Results of meta-analysis showed that E2(estrogen), the total therapeutic effective rate of the group of Kuntai capsule, and hormone were higher than hormone only. /eLH (luteinizing hormone), FSH (follicle-stimulating hormone), and Kupperman score of the group of Kuntai capsule and Climenwere lower than Climen only.Conclusion. Available evidence shows that Kuntai capsule with Climen is more effective than Climenin the therapy of premature ovarian failure. Nowadays, the quality of the research studies is low. More large-scaled randomizedtrials will need to be carried out.
1. Introduction
In recent years, with the economic development, socialprogress, increased mental stress day by day, and the ad-verse living habits lead to a sharp increase in prematureovarian failure (POF) patients [1, 2]. Premature ovarianfailure refers to the ovarian function declining of womenbefore 40 years old, belonging to the polymorphic diseases[3, 4]. /e main performance of the patients is low es-trogen, reduced leucorrhea, amenorrhea, libido, infertility,and emotional abnormal fluctuations. In addition, thepatients also suffer from the elevated level of FSH and LH,reduced E2 level, and elevated gonadotropin concentration.It may be clinically related to genetic, immune, congenitalabsence of enzyme, infection, environment, and iatrogenicfactors [2,5–13]. Currently, the main treatment for thisdisease is hormone therapy, which can improve the
patients’ hormone levels and relieve symptoms [14–16].However, long-term use of hormone drugs has great sideeffects, which can stimulate reproductive organs and in-crease the risk of endometrial cancer. In recent years,traditional Chinese medicine has been gradually applied inthe treatment of premature ovarian failure, and its ad-vantages are gradually highlighted. Some scholars haveproposed that Climen combined with traditional Chinesemedicine can improve the treatment effect and ovarianfunction, and at the same time, the side effects are small andthe medication safety is good [17–27]. In view of this, thepurpose of this study is to conduct a meta-analysis of thecurrent clinical evaluation results of Kuntai capsulecombined with Climen for premature ovarian failure and topreliminarily evaluate the advantages and disadvantages ofKuntai capsule combined with Climen in the treatment ofpremature ovarian failure.
HindawiEvidence-Based Complementary and Alternative MedicineVolume 2020, Article ID 4367359, 7 pageshttps://doi.org/10.1155/2020/4367359
2. Methods
2.1. Inclusion and Exclusion Criteria. We included ran-domized controlled trials of Kuntai capsule with Climencompared with Climen in women with premature ovarianfailure. We included trials no matter where she came from.We eliminated wrong, incomplete, and repeatable articles.We also eliminated the articles of the experimental groupwhich did not use Kuntai capsule with Climen and thecontrol group which did not use Climen monotherapy.
2.2. Intervention and Outcome Indicators. /e experimentalgroup was Kuntai capsule with Climen. /e control groupwas Climen only. Outcome indicators included the totaltherapeutic effective rate, LH, FSH, E2 level, Kuppermanscore, and safety evaluation.
2.3. Systematic Search for Evidence. /e databases ofPubMed, Cochrane Library, Web of science, CBM, CNKI,Wanfang, and Weipu were searched from computer toidentify relevant RCTs. We also performed a hand search toidentify any other articles. /e following search terms wereused: Kuntai capsule, Kuntai, hormone, estradiol, Climen,progesterone, artificial period, artificial cycle, and prematureovarian failure. /e trials should be selected with norestriction.
2.4. Data Extraction and Quality Appraisal of the Evidence.Two independent reviewers extracted the data according tothe inclusion criteria. If the two reviewers disagreed, thedifference was solved through discussion. If a consensuscould not be reached, a third reviewer was consulted. Re-viewers evaluated the evidence according to the Cochranesystem evaluation member handbook on the quality eval-uation criteria of RCT [28]: (1) which random allocationmethod to choose; (2) whether the trial was allocationconcealment; (3) whether the trial used the blindingmethod;(4) whether there was incomplete data bias; (5) whetherthere was selective bias; (6) other bias.
2.5. Data Analysis. All meta-analyses were done in Revman5.3 provided by the Cochrane Collaboration. /e resultswere reported as odds ratios (ORs), with 95% confidenceinterval (95% CI) for dichotomous outcomes, and weightedmean difference (WMD) with 95% CI for continuous out-comes. /e chi-square test was used to test heterogeneityacross studies. Data were analyzed with a fixed effect model ifno statistical heterogeneity was observed (I2≦ 50%). Datawere analyzed with a random effect model if statisticalheterogeneity was observed (I2> 50%). In the presence ofheterogeneity, the two researchers checked the data enteredand explored the variation by conducting sensitivity anal-ysis. Publication bias was examined by the funnel plot. Weused the Z (u)-test to compute statistics. According to the Z(u), the statistic P was obtained. If P< 0.05, there was sta-tistical significance; If P> 0.05, there was no statisticalsignificance.
3. Results
3.1. Included Trials. Searching from each database, we re-ceived 192 citations, including 63 in CNKI, 50 in CBM, 51 inWanfang, 28 in Weipu, 0 in Medline, 0 in Cochrane Library,and 0 in Web of science. Screening the citations, the 178citations were ruled out (including repeating between li-braries and the content which had nothing to do with thestudy). /en, 14 articles were obtained. By reading the fulltext, 3 articles were ruled out because they did not meet theinclusion criteria. Finally, 11 articles were included(Figure 1).
3.2. Methodological Quality. /is study included 11 articles,a total of 1068 patients, which were randomized controlledtrials in China. /is research showed that there were 10articles reporting the FSH and E2 level. 5 articles reported theLH level. 9 articles reported on the total therapeutic effectiverate. 5 articles reported on the Kupperman score. 2 articlesreported the safety analysis. See Table 1 for a summary of keydetails of these studies.
3.3. Analysis of the Level of LH. /e meta-analysis resultsshowed that the difference among the 5 groups was statis-tically significant on the level of LH: the combined effectMD� − 7.01, 95% CI [− 10.77, − 3.24], Z� 3.65, andP � 0.0003. So the level of LH of Kuntai capsule with thehormone group was lower than the hormone group(Figure 2).
3.3.1. Sensitivity Analysis. /is study analyzed the sensitivityof heterogeneity of the 5 articles. Getting rid of Yuan HF’sarticle decreased the heterogeneity obviously, so it was likelyto be the main source of heterogeneity.
3.4. Analysis of the Level of FSH. /e meta-analysis resultsshowed that the difference among the 10 groups was sta-tistically significant on the level of FSH: the combined effectMD� − 8.98, 95% CI[− 11.84, − 6.12], Z� 6.15, andP< 0.00001. So the level of FSH of Kuntai capsule with thehormone group was lower than the hormone group(Figure 3).
3.4.1. Sensitivity Analysis. /is study analyzed the sensitivityof heterogeneity of the 10 articles. Getting rid of Yuan HF’sarticle decreased the heterogeneity obviously, so it was likelyto be the main source of heterogeneity.
3.5. Analysis of the Level of E2. /e meta-analysis resultsshowed that the difference among the 10 groups was sta-tistically significant on the level of E2: the combined effectMD� 11.38, 95% CI [7.11, 15.64], Z� 5.23, and P< 0.00001.So the level of E2 of Kuntai capsule with the hormone groupwas higher than the hormone group (Figure 4).
2 Evidence-Based Complementary and Alternative Medicine
3.5.1. Sensitivity Analysis. /is study analyzed the sensitivityof heterogeneity of the 10 articles. Getting rid of Xiao’sarticle decreased the heterogeneity obviously, so it was likelyto be the main source of heterogeneity.
3.6. Analysis of the 6erapeutic Effective Rate. /e meta-analysis results showed that the difference among the 8groups was statistically significant on the therapeutic ef-fective rate: the combined effect OR� 3.88, 95% CI [2.47,
6.08], Z� 5.90, and P< 0.0001. So the therapeutic effectiverate of Kuntai capsule with the hormone group was higherthan the hormone group (Figure 5).
3.7. Analysis of the Kupperman Score. /e meta-analysisresults showed that the difference among the 5 groups wasstatistically significant on the Kupperman score. /e com-bined effect MD� − 3.86, 95% CI [− 4.92, − 2.80], Z� 7.14,P< 0.00001. So the Kupperman score of Kuntai capsule with
Searching by computer (n = 192), includingCNKI: 63, Wan Fang: 51, CBM: 50, WEI PU:
28, Pubmed: 0, Web of science: 0,Cochrane library: 0
Screening outarticles (n = 14)
Excluding articles a�er readingthe full text not according tothe inclusive criteria (n =3)
Inclusive articles(n = 11)
Excluding (n = 178)Basic experimentBeing not related with theresearch contentsRepeatable articles
(i)(ii)
(iii)
Figure 1: Data screening process.
Table 1: Summary of clinical trials examining the effects of Kuntai capsule with Climen on patients with POF.
Studies Participants Treatment group Controlgroup Main results Course of
treatment
Xu [17] N� 140 Climen+Kuntai capsuleN� 70
ClimenN� 70
Treatment group had a bettereffect 6 months
Xing [18] N� 140 Climen+Kuntai capsuleN� 70
ClimenN� 70
Treatment group had a bettereffect 6 months
Yang [19] N� 126 Climen+Kuntai capsuleN� 63
ClimenN� 63
Treatment group had a bettereffect 6 months
Yuan and Hu [20] N� 80 Climen+Kuntai capsuleN� 40
ClimenN� 40
Treatment group had a bettereffect 3 months
Chen [21] N� 90 Climen+Kuntai capsuleN� 45
ClimenN� 45
Treatment group had a bettereffect 6 months
Zhong et al. [22] N� 70 Climen+Kuntai capsuleN� 35
ClimenN� 35
Treatment group had a bettereffect 3 months
Dai [23] N� 146 Climen+Kuntai capsuleN� 73
ClimenN� 73
Treatment group had a bettereffect 3 months
Xiao et al. [24] N� 90 Climen+Kuntai capsuleN� 45
ClimenN� 45
Treatment group had a bettereffect 3 months
Liang [25] N� 78 Climen+Kuntai capsuleN� 39
ClimenN� 39
Treatment group had a bettereffect 3 months
Liu [26] N� 60 Climen+Kuntai capsuleN� 30
ClimenN� 30
Treatment group had a bettereffect 6 months
Huang [27] N� 48 Climen+Kuntai capsuleN� 23
ClimenN� 25
Treatment group had a bettereffect 3 weeks
Evidence-Based Complementary and Alternative Medicine 3
the Climen group was lower than the Climen group(Figure 6).
3.7.1. Sensitivity Analysis. /is study analyzed the sensitivityof heterogeneity of the 5 articles. Getting rid of Dai SM’sarticle decreased the heterogeneity obviously, so it was likelyto be the main source of heterogeneity.
3.8. Safety Analysis and Publication Bias. Only two articlespresented adverse effects of their studies, and the descrip-tions were not very detailed./us, we were unable to analyzethe safety outcomes. In this study, inverted funnel graphanalysis was performed on the inverse of standard error of
OR of LH, FSH, E2 level, total therapeutic effective rate, andKupperman score./e asymmetrical pattern suggested smallsample studies and possible publication bias, as shown inFigures 7–11.
4. Discussion
/e results of this study showed that the total therapeuticeffective rate, LH, FSH, E2 level, Kupperman score ofKuntai capsule, and Climen group were more effectivethan those of the Climen group in the treatment of pre-mature ovarian failure. POF will not only cause the re-duction of estrogen level, but also lead to the loss of femalefertility in severe cases, which will exert great pressure on
Study or subgroup Mean differenceIV, random, 95% CI
Chen 2017Dai 2016Huang 2014Liu 2015Xiao 2015Xing 2016Xu 2018Yang 2018Yuan 2019Zhong 2015
Total (95% CI)
18.412.39.3419.319.719.119.23.212.7718.9
494
45732330457070634035
46.954.7
42.4147.650.447.347.8
20.1437.7848.4
Weight(%)
7.110.210.55.16.88.98.9
18.218.46.0
100.0
45732530457070634035
496
Mean differenceIV, random, 95% CI
–8.30 [–16.86, 0.26]–12.80 [–18.99, –6.61]
–5.65 [–11.64, 0.34]–10.30 [–21.18, 0.58]
–10.60 [–19.40, –1.80]–8.00 [–15.02, –0.98]–8.40 [–15.45, –1.35]–5.69 [–7.28, –4.10]
–12.00 [–13.49, –10.51]–9.20 [–18.93, 0.53]
–8.98 [–11.84, –6.12]
ExperimentalSD TotalMean
38.641.9
36.7637.339.839.3
14.4525.7839.2
39.4
ControlMean TotalSD
2411.7823.522.823.123.25.573.9422.5
22.8
–100 –50 0 50 100Favours (experimental) Favours (control)Test for overall effect: Z = 6.15 (P < 0.00001)
Heterogeneity: tau2 = 11.02, chi2 = 35.18, df = 9 (P < 0.0001); I2 = 74%
Figure 3: Comparison of the level of FSH.
Mean differenceIV, random, 95% CI
Total (95% CI) 494
Mean differenceIV, random, 95% CI17.98 [2.27, 33.69]
14.90 [10.34, 19.46]12.73 [1.14, 24.32]23.12 [3.63, 42.61]
2.93 [2.01, 3.85]16.49 [3.91, 29.07]16.15 [3.45, 28.85]9.42 [7.07, 11.77]8.26 [4.85, 11.67]
15. 78 [–0.93, 32.49]
11.38 [7.11, 15.64]–100 –50 0 50 100
Test for overall effect: Z = 5.23 (P < 0.00001) Favours (experimental) Favours (control)
Experimental Control
Chen 2017Dai 2016Huang 2014Liu 2015Xiao 2015Xing 2016Xu 2018Yan 2018Yuan 2019Zhong 2015
Study or subgroup
124.5143.86
94.37142.0314.31142
142.442.7284.47
143.13
Mean41.8415.2
21.4541.841.84
41.4741.846.637.7337.8
SD
12.833.76
19.3534.87 2.57
34.1334.56.837.8333.4
SD5.2
14.77.73.8
17.57.06.9
16.715.94.8
100.0
Weight(%)
Heterogeneity: tau2 = 26.84, chi2 = 69.21, df = 9 (P < 0.0001); I2 = 87%
732330457070634035
Total45
109.681.64
118.9111.38
125.51126.25
33.376.21
127.35
Mean125.88
732530457070634035
496
Total45
Figure 4: Comparison of the level of E2.
Study or subgroup Mean differenceIV, random, 95% CI
Dai 2016Huang 2014Liu 2015Yang 2018Yuan 2019
Total (95% CI)
Test for overall effect: Z = 3.36 (P = 0.0008)
–100 –50 0 50 100Favours (experimental) Favours (control)
54.627.5435.5
10.5525.78
12.37.5313.73.9
2.77
229
ExperimentalMean SD Total
7325306340
55.229.9246.4
18.8837.78
13.610.1515.64.353.94
231
7325306340
MeanControl
SD Total
100.0
Weight(%)19.617.712.924.924.9
–7.01 [–10.77, –3.24]
Mean differenceIV, random, 95% CI–0.60 [–4.81, 3.61]–2.38 [–7.41, 2.65]
–10.90 [–18.33, –3.47]–8.33 [–9.77, –6.89]
–12.00 [–13.49, –10.51]
Heterogeneity: tau2 = 18.59, chi2 = 53.28, df = 4 (P < 0.00001); I2 = 92%
Figure 2: Comparison of the level of LH.
4 Evidence-Based Complementary and Alternative Medicine
female physiology and psychology and affect the quality oflife. Climen [29, 30] (estradiol valerate tablets/estradiolcyprogesterone tablets) is the commonly used Westernmedicine treatment of POF, which can simulate the sexhormone levels of the menstrual cycle in the body andinduce menstrual cramps. But long-term use of Climenmay lead to water sodium retention patients and increasethe risk of endometrial cancer and breast cancer. Kuntaicapsule [31–37] originates from Rhizoma coptidis anddonkey-hide gelatin soup of Treatise on Febrile andMiscellaneous Disease, mainly composed of Rhizoma
coptidis, donkey-hide gelatin, radix paeoniae alba, Poriacocos, Radix scutellariae, and Rehmannia glutinosa. It canimprove the symptoms such as amenorrhea, hypo-menorrhea, bradymenorrhea, night sweats, and lumbardebility. /erefore, Kuntai capsule combined with Climencan combine the advantages of the two therapy methodsand make the female reproductive environment moreharmonious.
/e methodological quality evaluation results of theincluded researches showed that there were many low-quality studies./e clinical studies included in this study hadmethodological problems such as randomization, blind
Experimental Odds ratio M-H, fixed, 95% CI
Odds ratio M-H, fixed, 95% CI
6.96 [1.44, 33.51]3.13 [1.15, 8.54]2.11 [0.46, 9.64]
5.55 [1.11, 27.66]2.74 [0.63, 11.82]6.34 [1.35, 29.76]3.47 [1.05, 11.43]3.41 [0.98, 11.85]
3.80 [2.38, 6.07]
0.01 0.1 10 100 Favours (experimental) Favours (control)
Control
4573253930706340
385
Total4573233930706340
383
Total7.5
23.211.77.6
11.48.3
16.014.3
100.0
Weight(%)
357
4367203727685936
Events
302
3457193023595129
EventsChen 2017 Dai 2016 Huang 2014 Liang 2017 Liu 2015 Xing 2016 Yang 2018 Yuan 2019
Total (95% CI)Total events
Study or subgroup
Heterogeneity: chi2 = 2.17, df = 7 (P = 0.95); I2 = 0%Test for overall effect: Z = 5.58 (P < 0.00001)
1
Figure 5: Comparison of the therapeutic effective rate.
Experimental Control Mean differenceIV, random, 95% CI
Chen 2017Dai 2016Xiao 2015Xing 2016Xu 2018
Mean6.287.7
6.266.276.29
SD2.572.4
2.342.552.58
Mean9.6213.59.789.539.57
SD2.87
33.452.852.87
Total (95% CI)
Total4573457070
303
Total4573457070
303
Mean differenceIV, random, 95% CI–3.34 [–4.47, –2.21]–5.80 [–6.68, –4.92]–3.52 [–4.74, –2.30]–3.26 [–4.16, –2.36]–3.28 [–4.18, –2.38]–3.86 [–4.92, –2.80]
–100 –50 0 50 100 Favours (experimental) Favours (control)
19.120.918.520.820.7
100.0
Weight(%)
Heterogeneity: tau2 = 1.20, chi2 = 22.92, df = 4 (P = 0.0001); I2 = 83%Test for overall effect: Z = 7.14 (P < 0.00001)
Study or subgroup
Figure 6: Comparison of the Kupperman score.
SE (MD)
MD5
4
3
2
1
0
50–100 100–50 0
Figure 7: Funnel plot of the level of LH.
SE (MD)
MD10
8
6
4
2
0
50–100 100–50 0
Figure 8: Funnel plot of the level of FSH.
Evidence-Based Complementary and Alternative Medicine 5
method, and follow-up. All of these could lead to the oc-currence of bias and affect the accuracy and reliability of thetrials. Among the 11 references included in this meta-analysis, only 5 references described the specific randomizedmethod (the random number table method or treatmentorder), although all the reports mentioned the randommethod. In most studies, there was no mention of theconcealment of the random scheme, and no specific de-scription of the blind method, loss of follow-up, and
withdrawal cases, which would affect the demonstrationstrength of the study. Meanwhile, LH, FSH, E2 level, andtotal therapeutic effective rate were the main indicators forthe evaluation of efficacy, and the safety analysis of drugs andKupperman score was less concerned. In the future, ran-domized controlled trials should not only be designedreasonably, but also include large samples, rigorous ran-domized methods, and double-blind studies.
/erefore, this study considers that the combination ofKuntai capsule and Climen for premature ovarian failure hasa better curative effect. However, it needs to be supported bymore rigorous double-blind randomized controlled trialswith a larger sample to ensure more convinced researchresults and provide more reliable evidence for the combi-nation of Kuntai capsule and Climen for premature ovarianfailure.
Conflicts of Interest
/e authors declare that they have no conflict of interest.
Acknowledgments
/is research was supported by the Natural Science Foun-dation of China (no. 81873333 and 81373683), and Zhen-jiang Health and Family Planning Science Technology KeyProject (no. SHW2017016).
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SE (MD)
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Figure 9: Funnel plot of the level of E2.
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Figure 10: Funnel plot of the total therapeutic effective rate.
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Figure 11: Funnel plot of the Kupperman score.
6 Evidence-Based Complementary and Alternative Medicine
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