Efficacy Of Kidney-tonifying Traditional Chinese Medicine Prescriptions in Hypoplastic Uterus Treatment
Mar 05, 2022
Contact: emily.li@wecistanche.com
Efficacy of kidney-tonifying traditional Chinese medicine prescriptions in hypoplastic uterus treatment: A systematic review and meta-analysis
Xichuang Chen1 et al.
Abstract
Aim: To review and evaluate the efficacy of kidney-tonifying traditional Chinese medicine prescriptions (KT-TCMP) in hypoplastic uterus (HU) treatment.
Methods: We searched MEDLINE, the Cochrane Library, CNKI (China National Knowledge Infrastructure), WAN FANG, and VIP databases until 14 December 2013 independently with two investigators. Randomized controlled trials (RCT) involving KT-TCMP as a combined or monotherapy in the treatment of HU were reviewed and analyzed. Meta-analysis was performed by the Review Manager (version 5.2). Results: Nine RCT of 1745 patients were eligible for this review and meta-analysis, of which eight RCT described the primary outcome of clinical efficacy and three RCTs drew the secondary outcome of uterine size. Meta-analyzed 'recovery' clinical efficacy of KT-TCMP in seven RCT was conducted which considered diethylstilbestrol therapy alone as a control, as well as three RCT that meta-analyzed the effect of KT-TCMP on uterine diameter enlargement. As a result, KT-TCMP therapy had a significantly improved difference in increasing ‘recovery’ clinical efficacy (risk ratio, 2.34; 95% confidence interval [CI], 1.90–2.89) and enlarging the uterine diameter (standardized mean difference, 1.62; 95% CI, 1.39–1.84). One study reported adverse reactions as an important outcome and found it was safe during KT-TCMP therapy.
Conclusion: The therapy of applying KT-TCMP as a combined or monotherapy in the treatment of HU may be more efficacious. However, this RCT was of moderate methodological quality and a small sample size; thus, the results should be confirmed with more rigorously controlled further studies.
Keywords: herb, hypoplastic uterus, infantile uterus, kidney-tonifying traditional Chinese medicine prescriptions, meta-analysis, review.
Introduction
From the viewpoint of Western medicine, the hypoplastic uterus (HU, also known as the infantile uterus) is usually considered a rare congenital problem caused by disruption of the development of the Müllerian duct.1 This anomaly is part of the spectrum of Mayer–Rokitansky–Küster–Hauser syndrome (MRKHS), and represents the most severe form of Müllerian anomalies.2 Patients generally have no phenotypic abnormalities at birth, while usually present with primary amenorrhea at puberty in the clinic,3 or may present at menarche with an obstructed uterus or later in life if there are investigations for fertility or miscarriages.4 As these women may experience challenges in conceiving,5 the diagnosis can arouse painful emotions and/or have life-changing effects.
In conventional Western medicine, most of these patients should take hormonal drugs chronically as HU is commonly associated with hormonal dysfunction. On the other hand, the patient can be treated surgically if she represents a suitable operation indication and has no operation contraindication. Generally, an intrauterine device will be applied in these patients to gradually promote the development of the uterus, or other correctional operations performed. However, the clinical efficacy of these methods is undesirable and may even sometimes be seriously harmful if the uterus is accidentally perforated during the operation.6,7 In addition, another assistant method named hysteroscopic metroplasty has been applied successfully to some patients, while it is still a high-risk operation that the patient will have less hope to recover from if it fails.8,9 In China, HU belongs in the spectrum of kidney deficiencies according to the basic theory of traditional Chinese medicines (TCM).10 Except for those conventional Western therapies, there is an alternate method of applying kidney-tonifying TCM prescriptions (KTTCMP) for treatment in China, which has achieved a notable effect in natives.10 Regrettably, however, there was still no large-scale clinical trial studying and confirming its efficacy further. Therefore, we conducted a systematic review and metanalysis of randomized controlled trials (RCT) to evaluate the efficacy of KT-TCMP as a combined or monotherapy in the treatment of HU in order to provide important information to expand our current knowledge and spawn new research.
Methods
Search strategy
Studies were searched by two investigators browsing the following electronic databases independently (X. C. C., Y. H.), supplemented by scanning reference lists of identified original articles and the volumes of abstracts of scientific meetings: PubMed/MEDLINE, the Cochrane Library, and especially the Chinese periodical databases of CNKI (China National Knowledge Infrastructure), WAN FANG and VIP were used to search until 25 March 2013. The search strategy was: 'hypoplastic uterus' OR 'uterine dysplasia' OR 'hypoplasia of uterus' OR 'infantile uterus' in the title/abstract item for searching the databases of PubMed/ MEDLINE and the Cochrane Library, while full-text items were used for searching the Chinese periodical databases. No language restrictions were imposed. The data were updated to 14 December 2013.
Selection of studies
Potentially relevant studies were independently evaluated by two reviewers (X. C. C. and Y. H.). Reviewers screened all titles and abstracts when available and they examined the full text and considered it eligible if the published study met the following criteria: (i) was an RCT; (ii) included participants diagnosed with HU only without having any other serious diseases; (iii) applied KT-TCMP as a combined or monotherapy in the experimental treatment of HU; (iv) included no restriction on the race or nationality with an average age ranging 19–35 years; and (v) the primary outcome was clinical efficacy and the secondary was uterine diameter. However, studies with the following criteria were excluded: (i) was a published work review, duplicate or a repeated data article (when two or more publications reported data from the same study populations, we would only keep the most detailed and/or the most recent publication); (ii) included poor methodological quality or incomplete data; and (iii) the number of participants was less than 15 in either group.
Data exaction
Two authors (X. C. C., Y. H.) independently reviewed all the studies that met our inclusion criteria, which was guided by the Cochrane Handbook for Systematic Reviews and the PRISMA statement.11,12 Disagreement was finally resolved by discussion with a third author (J. H. F.). A general statement of the studies (e.g. author and year of publication), comprehensive information of patients (e.g. sample size, age, ethnicity, disease course, and therapy history), and information of the reported outcomes (e.g. clinical efficacy, the proportion of uterine body and cervix, uterine size, values of sex hormone, basal body temperature, and adverse reaction) were extracted from the included trials.
Quality of the studies
The methodological quality of the trials was evaluated as suggested in the Cochrane Handbook on the following areas: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective outcome reporting were classified into low risk, high risk or unclear risk of bias for each item.11 Two authors (P. P. Z. and J. L. Y.) were independently involved in quality assessment. All discrepancies were resolved by consensus with a third author (X. Y. Z.).
Statistical analysis
The verified data was analyzed by using Review Manager version 5.2 (the Nordic Cochrane Center, Copenhagen, Denmark). Risk ratio (RR; Mantel–Haenszel), standardized mean difference (SMD; inverse variance), and their corresponding 95% confidence intervals (95% CI) were computed for dichotomous or continuous outcome data respectively. Statistical heterogeneity between the trials was evaluated by using the I2-test as well as the χ2-test.11 An I2 value of more than 50% was considered as substantial heterogeneity. A fixed-effect model was used in case of no relevant statistical heterogeneity, while a random effect model was used oppositely. Significance was assumed if the 95% CI did not include the value 1.0 for RR or zero for SMD. Egger’s precision weighted linear regression tests and Begg’s funnel plots were used to test potential publication bias by using Stata/SE version 12.0 (Stata Corp, College Station, Texas, The USA).13
Results
Study selection and characteristics
The systematic database search yielded 2443 studies, of which 102 papers were from PubMed and the Cochrane Library. Among these papers, 73 were English language and the rest were non-Englishlanguage articles (e.g. Japanese, Polish and French), while each one of these papers had an English title and/or an English abstract that we could easily exclude from these studies by inclusion criteria. On the other hand, there were 2341 papers from Chinese periodical databases in total, of which 40 papers were reviewed in full after screening all titles and abstracts when available (Fig. 1). Finally, nine studies that fulfilled the criteria were included in our review, and eight of them for meta-analysis, including information for 1745 participants in total.14–22 The process of study selection is shown in the flow chart (Fig. 1), and the study characteristics are listed in Tables 1 and 2. All the studies were RCT published from 1997 to 2011 with a similar baseline and consisted of eight studies of KT-TCMP therapy (KT-TCMT) with15,21 or without14,16–19,22 diethylstilbestrol (DES) therapy in the treatment group versus the same regimen of DES therapy in the control group and one study23 of KT-TCMT and conventional Western medicine therapy (CWMT; e.g. hormone administration, operation treatment, and intrauterine devices placement) in the treatment group versus the same regimen of CWMT in the control group. The sample size was in the range of 64–730, and all the inclusive participants were diagnosed with HU and all were Chinese. The reported outcomes consisted of eight studies of clinical efficacy,14–21 three studies of uterine size,14,15,19 one study of adverse reaction and the proportion of uterine body and cervix,14 and another single study of values of sex hormone and basal body temperature (Table 1).18 In addition, the compositions of KT-TCMP in each included study are listed in Table 3.
Quality assessment
Among these nine RCT, three were at low risk for bias for allocation sequence generation, while the remaining studies did not report their randomization methods clearly. In addition, none of the included studies reported the use of allocation concealment and blinding. However, we regarded the risk of bias associated with lack of blinding and allocation concealment to be minimal, as the primary outcomes were of objective nature. Otherwise, all studies had a low risk of bias in items of selective outcome reporting and incomplete outcome data, except that one study15 had a high risk of bias in the item of incomplete outcome data for loss of the description about the proportion of uterine body and cervix in the article. In summary, we considered the overall risk of bias amongst our included studies to be moderate (Table 4).
Outcome measures
Categorization of clinical efficacy
Clinical efficacy was the main outcome assessed in almost every included study in this review. As shown in Table 5, eight studies reported the outcome of clinical efficacy, of which one study grouped the result of clinical efficacy into two items (recovery and inefficiency),14 four studies into three items (recovery, effectiveness/improvement, and inefficiency),18–21 and the other three studies into four items (recovery, effectiveness, improvement, and inefficiency).15–17 While the criteria were not quite the same in the same item of Outcome measures Categorization of clinical efficacy was the main outcome assessed in almost every included study in this review. As shown in Table 5, eight studies reported the outcome of clinical efficacy, of which one study grouped the result of clinical efficacy into two terms (recovery and inefficiency),14 four studies into three items (recovery, effectiveness/improvement, and inefficiency),18–21 and the other three studies into four items (recovery, effectiveness, improvement, and inefficiency).15–17 While the criteria were not quite the same in the same item of categorization in every individual study as listed in Table 5. From the item of 'recovery', we could see that the indicator of pregnancy or the uterine size returning to normal was an index of 'recovery' criterion in seven studies,14–19,21 while one relatively large sample study (730 participants enrolled) considered the efficacy of conceived and delivered healthy term infants finally as a target, which a much more difficult criterion to meet.20
'Recovery' clinical efficacy of KT-TCMT in HU treatment
As we know, 'recovery' clinical efficacy had a greater clinical significance than other categories. There were seven studies (including 987 patients)14–19,21 that followed the similar criteria of 'recovery' efficacy as listed in Table 5 and, meanwhile, their treatments in both groups were quite similar (KT-TCMT with or without DES therapy in the treatment group vs the same regimen of DES therapy in the control group). Thus, we produced a meta-analysis about the 'recovery' efficacy of KT-TCMT with or without DES versus DES therapy alone in the treatment of infantile uterus (Fig. 2). As a result, there was no statistical heterogeneity between these studies (P = 0.66, I2 = 0%), so we used a fixed-effect model for meta-analysis. Figure 2 shows an RR of 2.34 (95% CI, 1.90–2.89) and P < 0.01 by Z-test; thus, the administration of KT-TCMP in treatment of HU had an improved significant difference versus controls. In addition, the study by Qi et al. (730 participants enrolled)20 compares KT-TCMT with CWMT (e.g. hormone administration, placement of intrauterine device or operations) versus the same regimen of CWMT; the rate of 'recovery' and 'inefficacy' was 72.02% and 8.93% in the KT-TCMT with CWMT group, respectively, and 31.97% and 51.02% in the CWMT alone group, respectively (Table 6). Thus, we would also conclude that the additional treatment of KT-TCMP to CWMT could improve the curative effect in HU therapy.
Effect of KT-TCMP on uterine diameter enlargement
The secondary outcome was uterine diameter. There were three studies that described the uterine size as an outcome, of which one study reported the value of the average diameter of the uterus before treatment and after two consecutive courses in both groups directly;22 while the other two studies reported uterine area17 and size,18 respectively; thus, we transformed these data into the value of the average diameter of the uterus. Next, we calculated the mean difference of the uterus before and after the treatment in both groups and produced a meta-analysis (Fig. 3). A heterogeneity test showed P = 0.15 and I2 = 47% that we used a fixed-effect model to calculate. As a result, the KT-TCMT group had a more improved significance in enlarging the diameter of the uterus versus controls (SMD = 1.62 [95% CI, 1.39–1.84], Z = 13.99 [P < 0.01]).
Safety of KT-TCMP in HU treatment
Only one study reported adverse reaction as an important outcome in the treatment of HU in both groups.14 It was found that approximately 11.65% of patients in the DES therapy control group had gastrointestinal reactions such as alexithymia, while patients in the KT-TCMT group did not have any obvious adverse reactions.
Publication bias
Visual inspection through Begg’s funnel plot and quantitative evaluation through Egger’s test (P = 0.599) did not reveal any evidence of significant publication bias of the studies that included the outcome of clinical efficacy (Fig. 4).
Discussion
To our knowledge, this manuscript has reviewed the efficacy of the therapy of KT-TCMP as a combined or monotherapy for HU treatment relatively early. This review has collected nine RCT of 1745 patients (Fig. 1) and the pooled results show that KT-TCMP had an improved significant difference in increasing the clinical efficacy of 'recovery' (Fig. 2) and enlarging uterine diameter (Fig. 3).
As we know, women physiologically menstruate and become pregnant, and these two complex physiological processes in which Tiangui, a kind of refined nutritious substance transformed from kidney essence, plays the most important role.23 Therefore, kidneys dominate reproduction chiefly in the basic theory of TCM.24 As described in Table 3, the principal ingredients of TCM prescriptions in every included study were kidney-tonifying and nourishing blood herbs such as Radix Rehmanniae Preparata (Shudihuang), Radix Angelicae Sinensis (Danggui), and Rhizoma Chuanxiong (Chuanxiong), and the remaining herbs were intended to soothe the liver and regulate Qi such as Rhizoma Cyperi (Xiangfu), promote blood circulation for removing blood stasis such as Flos Carthami (Honghua), or strengthen the spleen and eliminate dampness such as Poria (Fuling) in order to form a harmonizing effect according to the basic theory of TCM.25
Recent pharmacological studies of TCM have suggested that kidney-tonifying herbs have revealed hormone-like actions,26 which could regulate feedback of the hypothalamus-pituitary–sexual gland axis with increased contents of follicle-stimulating hormone, luteinizing hormone, and estradiol (E2) in blood serum and raise the wet weight of the ovaries with the significant difference in adult female rats.27 Another report described an improved sex-hormone level of E2 after applying kidney-tonifying herbs versus controls in female patients.18 In addition, it was reported that there was an obvious efficacy of kidney-tonifying herbs on improving ovulation and pregnancy rate when combined with clomiphene citrate in infertility treatment compared with the patients taking clomiphene citrate alone.28 It may be that it enhances the expression of the cathepsin-L protein,29 which plays an important role in the ovulation process.30 However, the exact mechanisms of KT-TCMP in HU treatment were still not clear and an authoritative conclusion could not be found. In the present study, the clinical efficacy of KT-TCMP in HU treatment is assured (Fig. 2, Table 6). A prescription of TCM is usually a combination of ‘master’ herbs (for principal diseases or symptoms), 'adviser' herbs (for boosting the 'master' and treating accompanying symptoms), 'soldier' herbs (for enhancing the therapeutic effects and modulating the adverse effects of the 'master' and 'adviser' herbs and restoring the body to pre-illness equilibrium) and 'guide' herbs (for guiding the active constituents of other herbs to the specific meridian and coordinating the actions of other herbs).31 It may be that the synergistic drug combinations improve the therapeutic selectivity and targets.32
Moreover, multiple targets can reside in the same or different pathways and tissues, and their modulation can produce more than additive effects triggered by actions converging at a specific pathway site.33 In addition, our review and meta-analysis are based on the results of previous studies; hence, its objectivity and accuracy depend on the quality of these selected articles. We considered the overall risk of bias amongst our included studies to be moderate according to the tool of Cochrane Handbook (Table 4). However, nine RCT and 1745 patients in total were still a small sample; on the other hand, all patients included here were Chinese; therefore, the result may be restricted by race. Thus, we need more high-quality, multicenter studies and randomized double-blind clinical trials to compare, analyze and confirm the findings further.
Disclosure
All of the authors declare that there are no sources of financial support or relationships that may pose a conflict of interest related to this manuscript.
From: ' Efficacy of kidney-tonifying traditional Chinese medicine prescriptions in hypoplastic uterus treatment: A systematic review and meta-analysis' by Xichuang Chen1 et al.
---J Sleep Res. (2018) 27, 283–291
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