F1000Research F1000Research 2046-1402 F1000 Research Limited London, UK 10.12688/f1000research.132981.1 Systematic Review Articles Identifying the most effective Traditional Chinese Medicine treatment modalities for premature ovarian insufficiency: a systematic review and network meta-analysis

[version 1; peer review: 1 approved with reservations, 1 not approved]

 Sin Yen Suan Conceptualization Data Curation Formal Analysis Investigation Methodology Project Administration Resources Software Writing – Original Draft Preparation Writing – Review & Editing https://orcid.org/0000-0002-2392-0489 1 2 Chen Min Formal Analysis Investigation Methodology Validation Writing – Review & Editing https://orcid.org/0000-0002-8074-897X 1 Sng Kim Sia Data Curation Investigation Methodology Validation Writing – Review & Editing 2 Zhang Jianwei Conceptualization Supervision Writing – Review & Editing https://orcid.org/0000-0002-0532-9580 a 3 Shandong University of Traditional Chinese Medicine, Jinan, Shandong, 16369, China Department of Chinese Medicine, International Medical University, Bukit Jalil, Kuala Lumpur, 57000, Malaysia Shandong University of Traditional Chinese Medicine Affiliated Hospital, Jinan, Shandong, 250014, China zhangjianwei1970@gmail.com

No competing interests were disclosed.

 27 4 2023 2023 12 450 11 4 2023 Copyright: © 2023 Sin YS et al. 2023 This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background: This study aimed to systematically evaluate and compare the clinical efficacy of different modalities of Traditional Chinese Medicine (TCM) for the treatment of premature ovarian insufficiency (POI) and identify the most effective treatment modality.

Methods: Six electronic databases (PubMed, OVID, Scopus, CNKI, VIP and WanFang) were screened from their inception until 20/01/2022. This network meta-analysis (NMA) incorporated hormone replacement therapy (HRT) as the placebo and six different TCM treatment modalities as interventions. The primary outcome was total effective rate; the secondary outcomes were improvement in serum follicle-stimulating hormone (FSH), estradiol (E 2), luteinizing hormone (LH) and anti-Müllerian hormone (AMH) levels. The Cochrane risk of bias tool was used to appraise the quality of the included studies. Random effect model was used for pairwise meta-analysis using RevMan 5.4. NMA was performed in STATA. The surface under the cumulative ranking curves (SUCRA) and mean rank (MR) were used as evaluation indexes.

Results: Overall, 37 randomized clinical trials involving 2,597 subjects that conformed to the inclusion criteria were included. Herbal medicine combined with catgut-embedding therapy was concluded to achieve the highest total effective rate (MD 4.35; 95% CI 1.32, 14.38) and improvement in AMH level (MD 0.74; 95% CI -0.74, 2.22). HRT combined with herbal medicine and acupuncture was determined to be the most effective treatment model for POI in improving their FSH (MD -13.17; 95% CI -18.17, -8.17), E 2 (MD 34.29; 95% CI 14.41, 54.18) and LH (MD -15.01; 95% CI -19.95, -10.06) levels.

Conclusions: Combination of HRT, herbal medicine and acupuncture was the most effective treatment modality for patients with POI. We also found that combination of herbal medicine with conventional HRT for patients with POI could effectively improve the clinical effectiveness in all aspects. This result may provide guidance for future treatment guideline implementation for POI.

Registration: PROSPERO ( CRD42020163873; 28/04/2020).

 Premature ovarian insufficiency Chinese medicine Acupuncture Network meta-analysis Systematic review The author(s) declared that no grants were involved in supporting this work. Introduction

Premature ovarian insufficiency (POI) is a pathological state of a woman below the age of 40 years suffering from irreversible diminished ovarian function in her reproductive age, it mainly manifests as oligomenorrhoea, hypomenorrhea, amenorrhea, elevated follicle-stimulating hormone (FSH) level (>25 U/L) and short or long term effects of estrogen deficiency. 1 The ovarian reserve can be measured by serum anti-Müllerian hormone (AMH) levels. According to the Bologna criteria, a low ovarian reserve is defined as an AMH level below 0.5–1.1 ng/mL (3.6–7.9 pmol/L). 2 Review data from 2020 reported that the prevalence of POI is about 10% among women below 40 years old. 3 The occurrence of this disease has been increasing among populations living in urban cities. This has captured the attention of public health policy makers and a timely and appropriate preventive measure is urged to be implemented.

Hormone replacement therapy (HRT) is the most recommended medical intervention for patients with POI, referring to the European Society of Human Reproduction and Embryology (ESHRE) and International Menopause Society (IMS) guidelines, as well as the Chinese Medical Experts’ Consensus on Clinical Diagnosis and Treatment of POI, stipulated by the Obstetrics and Gynecology Society of Chinese Medical Association. 1 , 4 – 6 However, there are risks of adverse reactions and associated diseases after HRT application. 7 , 8 Hence, patients often seek out complementary medicine to improve their ovarian functions and increase chances of conception.

Various Traditional Chinese Medicine (TCM) treatments such as herbal medicine, acupuncture, moxibustion and catgut-embedding therapy have been applied as the treatment for patients with POI. These treatment modalities have been proven to be effective and safe to improve ovarian functions among patients with POI through numerous clinical trials and direct comparison by using meta-analysis. 9 – 11 However, there are inadequate direct and indirect comparisons between different TCM treatment modalities that contribute to clinical health promotion and selection of the optimal therapeutic procedure. Therefore, there is a need to systematically evaluate and analyze the efficacy of these alternatives in order to provide a strong theoretical basis and scientific evidence for clinical practice and research. In this study, we compared the efficacy of different TCM treatment modalities for patients with POI by conducting network meta-analysis (NMA) to rank the therapeutic measures in line with their treatment effect through direct and indirect comparisons of the means, with the prospective to provide an evidence-based guidance for future clinical guidelines.

 Methods

The study method is compliant with the Cochrane Handbook for Systematic Reviews of Interventions 12 and the methods outlined in Lei Zhang et al. 13 It followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension statement for network meta-analyses (PRISMA-NMA). 14 , 57 It was registered in the International Prospective Systematic Registration Review (PROSPERO) with registration number CRD42020163873 on 28 April 2020.

Search strategy and literature screening

Records identified from six electronic databases, which included three English databases ( PubMed (RRID:SCR_004846), OVID, Scopus (RRID:SCR_022559)) and three Chinese databases ( CNKI, VIP, WanFang). Reported studies from the inception of each database until 20 January 2022 were screened. Search terms used were a combination of text words and medical subject headings (MeSH), including “Premature Ovarian Insufficiency”, “POI”, “Premature Ovarian Failure” or “Primary Ovarian Insufficiency”. Table 1 shows the search strategy details for each database. Only English and Chinese articles were included. Additionally, the reference lists of all eligible studies were screened to avoid missing eligible studies. The electronic search and literature screening were executed by two researchers (SYS and CM) independently. Any potential disagreement was assessed and discussed with a third reviewer (SKS).

Search strategy.
Databases Search term
PubMed (Premature ovarian insufficiency OR primary ovarian insufficiency OR premature ovarian failure OR primary ovarian failure OR ovarian insufficiency OR premature menopause OR premature ovarian dysfunction OR amenorrhoea OR “POI” OR “POF”) AND (Chinese medicine OR herbal medicine OR Chinese herb* OR Chinese drug OR traditional medicine OR alternative medicine OR complementary medicine OR acupuncture OR needling OR acupoint* OR “point, acupuncture” OR electroacupuncture OR warm* needle OR warm needling OR fire needling OR auricular acupressure OR auricular point* OR auricular needle OR ear acupuncture OR acupoint catgut embedding OR acusector OR moxibustion OR cupping OR massage OR tuina) Article type: Clinical trial OR randomized controlled trial Publication date: From the beginning until on 20 Jan 2022 Search result: 99 articles
OVID MEDLINE ((Premature ovarian insufficiency or primary ovarian insufficiency or premature ovarian failure or primary ovarian failure or ovarian insufficiency or premature menopause or premature ovarian dysfunction or amenorrhoea or POI or POF) AND (Chinese medicine or herbal medicine or Chinese herb* or Chinese drug or traditional medicine or alternative medicine or complementary medicine or acupuncture or needling or acupoint* or electroacupuncture or warm* needle or warm needling or fire needling or auricular acupressure or auricular point* or auricular needle or ear acupuncture or acupoint catgut embedding or acusector or moxibustion or cupping or massage or tuina)) Publication type: Randomized controlled trial Search result: 22 articles
Scopus ALL (((premature AND ovarian AND insufficiency OR primary AND ovarian AND insufficiency OR premature AND ovarian AND failure OR primary AND ovarian AND failure OR ovarian AND insufficiency OR premature AND menopause OR premature AND ovarian AND dysfunction OR amenorrhoea OR poi OR pof) AND (Chinese AND medicine OR herbal AND medicine OR Chinese AND herb* OR Chinese AND drug OR traditional AND medicine OR alternative AND medicine OR complementary AND medicine OR acupuncture OR needling OR acupoint* OR electroacupuncture OR warm* AND needle OR warm AND needling OR fire AND needling OR auricular AND acupressure OR auricular AND point* OR auricular AND needle OR ear AND acupuncture OR acupoint AND catgut AND embedding OR acusector OR moxibustion OR cupping OR massage OR tuina))) Document type: Clinical trial Search result: 0 articles
CNKI Professional search: ((TI=premature ovarian insufficiency OR TI=premature ovarian failure OR TI=premature ovarian diminished OR TI=ovarian insufficiency OR TI=ovarian failure) OR (KY=premature ovarian insufficiency OR KY=premature ovarian failure OR KY=premature ovarian diminished OR KY=ovarian insufficiency OR KY=ovarian failure) OR (AB=premature ovarian insufficiency OR AB=premature ovarian failure OR AB=premature ovarian diminished OR AB=ovarian insufficiency OR AB=ovarian failure)) AND ((TI=Chinese medicine OR TI=herbal medicine OR TI=integrative medicine OR TI=herb OR TI=acupuncture OR TI=moxibustion OR TI=acupoint OR TI=tuina OR TI=catgut-embedding OR TI=cupping) OR (KY=Chinese medicine OR KY=herbal medicine OR KY=integrative medicine OR KY=herb OR KY=acupuncture OR KY=moxibustion OR KY=acupoint OR KY=tuina OR KY=catgut-embedding OR KY=cupping) OR (AB=Chinese medicine OR AB=herbal medicine OR AB=integrative medicine OR AB=herb OR AB=acupuncture OR AB=moxibustion OR AB=acupoint OR AB=tuina OR AB=catgut-embedding OR AB=cupping)) Search result: 1,135 articles (Note: Search was done in Chinese language.)
WanFang ((TITLE=premature ovarian insufficiency OR TITLE=premature ovarian failure OR TITLE=premature ovarian diminished OR TITLE=ovarian insufficiency OR TITLE=ovarian failure) OR (KEYWORDS=premature ovarian insufficiency OR KEYWORDS=premature ovarian failure OR KEYWORDS=premature ovarian diminished OR KEYWORDS=ovarian insufficiency OR KEYWORDS=ovarian failure)) AND ((TITLE=Chinese medicine OR TITLE=herbal medicine OR TITLE=integrative medicine OR TITLE=herbal medicine OR TITLE=acupuncture OR TITLE=moxibustion OR TITLE=acupoint OR TITLE=tuina OR TITLE=catgut-embedding OR TITLE=cupping) OR (KEYWORDS=Chinese medicine OR KEYWORDS=herbal medicine OR KEYWORDS=integrative medicine OR KEYWORDS=herb OR KEYWORDS=acupuncture OR KEYWORDS=moxibustion OR KEYWORDS=acupoint OR KEYWORDS=tuina OR KEYWORDS=catgut-embedding OR KEYWORDS=cupping)) Source: Journal, conference report Search result: 978 articles (Note: Search was done in Chinese language.)
VIP (M=(premature ovarian insufficiency OR premature ovarian failure OR premature ovarian diminished OR ovarian insufficiency OR ovarian failure) AND (herbal medicine OR herb OR integrative medicine OR acupuncture OR moxibustion OR acupoint OR tuina OR catgut-embedding OR cupping)) Search result: 368 articles (Note: Search was done in Chinese language.)
Inclusion criteria

All relevant TCM randomized controlled trials (RCTs) for POI were included according to the inclusion criteria.

Types of participant (P): Patients diagnosed with POI according to the European Society of Human Reproduction and Embryology (ESHRE) guideline 1 or “Chinese expert consensus on premature ovarian insufficiency”. 4

Types of Intervention (I): The treatment group received TCM treatment modalities, such as herbal medicine, acupuncture, moxibustion and catgut embedding therapy alone or in combination.

Comparisons (C): The control group received HRT or one of the aforementioned TCM treatments.

Outcomes (O):

Primary outcome measurement: Total effective rate.

Total effective rate = (number of recovery cases + number of effective cases + number of efficient cases)/total number of cases × 100%.

Recovery: clinical manifestations disappeared, menstrual cycle, serum FSH and E 2 levels returned to normal, total effective rate ≥95%;

Effective: clinical manifestations were significantly improved, menstrual cycle, serum FSH and E 2 levels were significantly improved, total effective rate ≥70% and <95%;

Efficient: clinical manifestations were slightly improved, menstrual cycle, serum FSH and E 2 levels were slightly improved, total effective rate ≥30% and <70%;

Invalid: there was no improvement in clinical signs and symptoms, no improvement in menstrual cycle, no improvement in serum FSH and E 2 levels, total effective rate <30%.

Secondary outcome measurements: Serum FSH, E 2, luteinizing hormone (LH) and AMH levels.

Type of studies (S): RCTs.

 Exclusion criteria

Studies were omitted if the studies did not meet the inclusion criteria, for instance animal studies, review articles, case reports, editorials, letters and comments.

 Data collection

The name of authors, year of publication, subject age group, course of disease, types of TCM treatment modalities, number of subjects in intervention and comparison groups, were extracted into a spreadsheet. Two researchers (SYS and CM) performed the data extraction individually. In case of any discrepancies, another researcher (SKS) were asked to resolve the discrepancies via discussion.

 Literature quality evaluation

The Cochrane risk of bias tool was used to appraise the quality and risk of bias of the included studies. The assessment was done independently by two researchers (SYS and CM). 15 In this tool, the random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome reporting, incomplete outcome data, selective reporting, and other items were being evaluated in all the included studies. Low, unclear and high risk of bias were used to evaluate each element. In case of discrepancies, discussion among the researchers (SYS, CM and SKS) were done to resolve it.

 Statistical analysis

For pairwise meta-analysis of each intervention pair, a random effect model was used, with RevMan (RRID:SCR_003581) 5.4 (Nordic Cochrane Centre, Cochrane Collaboration, 2020) being employed. Continuous outcomes between intervention groups can be compared by using standard mean differences (SMDs), while dichotomous outcomes can be analyzed using odds ratios (OR). The relative treatment effectiveness between each intervention pair were estimated using 95% confidence intervals.

A NMA was performed in Stata (RRID:SCR_012763) 14.0 (free alternative, RStudio) and the network evidence graph was generated using the ‘netplot’ command. To compare direct and indirect comparisons of each intervention, I 2 and P-value of the global consistency were evaluated, and then the node-splitting analysis method was applied to detect inconsistencies. The inconsistency factor within each closed loop of evidence was used to detect inconsistency among studies. The evaluation indexes included surface under the cumulative ranking curves (SUCRA) and mean rank (MR). The SUCRA value reflected the possibility of the intervention measures, and the intervention was considered more effective if the MR was closer to 0. P<0.05 was considered statistically significant. 11

To determine if there was a small sample effect or publication bias in the network, a comparison-adjusted funnel plot was used.

 Results Study selection

The selection procedure was recorded in Figure 1 according to the most updated PRISMA 2020 flow diagram for new systematic review. 16 A total of 2,602 studies were firstly identified through six databases, including three English databases (PubMed, OVID and Scopus), as well as three Chinese databases (CNKI, VIP and WanFang). Of those, 586 duplicate records were eliminated using EndNote X9 (RRID:SCR_014001) (Clarivate Analytics, USA). By assessing the title and abstract, 1,940 studies were subsequently removed. Full articles of the remaining 76 studies were screened, of which 43 were removed for not reporting relevant outcome data, non-RCT, no full-text access, not relevant to TCM intervention, or intervention only included in one trial, which may lead to small study effects in a NMA. Eventually, 33 RCTs involving 2,597 subjects that conformed to the inclusion criteria were selected into this study and proceed with data extraction and analysis. Among them, all RCTs were Chinese articles. This NMA incorporated HRT as the placebo and six TCM treatment modalities. The characteristics and details of the included 33 RCTs are listed in Table 2.

PRISMA flowchart showing steps in the selection of relevant trials.

Note: RCT, randomized controlled trials.

 Characteristics and details of the included 33 RCTs.
Author name, year (ref.) Admission time Sample size (T/C) Mean age/course of disease (T/C) Intervention group Control group Outcome
Xie Q 2022 24 From Jan 2019 to Jan 2021 57/57 28.41±5.16/28.75±5.33 HRT + Herbal Medicine + Acupuncture HRT ①②③④
Peng YL 2022 25 From Jan 2019 to Dec 2020 46/46 28.54±3.66/28.21±3.85 Herbal Medicine + Acupuncture Herbal Medicine ①②③④
Huang YS 2021 26 From Mar 2018 to Mar 2020 30/30 31.43±4.48/30.80±5.12 Acupuncture + Moxibustion HRT ①②③⑤
Chen JM 2021 27 From May 2019 to Jan 2020 50/30 30.19±6.55/31.65±7.55 Herbal Medicine HRT ①②③⑤
Yuan F 2021 28 From Dec 2018 to Jun 2020 42/42 36.05±3.48/35.65±3.51 HRT + Herbal Medicine HRT ①②③④
Chen L 2021 29 From May 2017 to May 2019 35/35 38.97±5.52/38.80±4.96 HRT + Herbal Medicine HRT ①②
Sui J 2021 30 From Oct 2017 to Jan 2019 60/62 32.45±0.93/34.61±0.61 Herbal Medicine HRT ①②③④⑤
Wang XW 2021 31 From Jul 2019 to Jun 2020 25/25 36.40±1.10/36.50±1.00 Herbal Medicine HRT ①②③④
Wang YY 2021 32 From Mar 2018 to Mar 2020 26/26 30.22±4.31/30.15±4.23 Herbal Medicine + Acupuncture HRT ①②③④
Tang HX 2021 33 From Oct 2019 to Oct 2020 40/40 31.63±3.46/32.57±3.60 Herbal Medicine HRT ①②③④⑤
Lin LL 2021 34 From Jan 2018 to Jan 2020 20/20 33.98±2.08/33.70±2.13 Herbal Medicine + Cat-gut Embedding Therapy HRT ①②③
Zhang H 2021 35 From Jan 2019 to Mar 2020 60/60 35.21±2.35/35.17±2.26 HRT + Herbal Medicine HRT ①②③④⑤
Hou M 2021 36 From Nov 2019 to Oct 2020 30/30 35.00±8.26/36.00±3.57 Acupuncture HRT ①②③
Wu Q 2021 37 From Mar 2019 to Oct 2019 30/30 31.57±5.04/31.63±4.54 HRT + Herbal Medicine HRT ①②③④⑤
Fu WJ 2021 38 From Sep 2019 to Nov 2020 30/30 36.43±2.18/35.29±2.43 HRT + Herbal Medicine HRT ①②③④
Ding AY 2021 39 From Mar 2019 to Nov 2019 40/40 35.40±2.50/35.10±2.80 HRT + Herbal Medicine HRT ①②③
Ma QW 2020 40 From Sep 2017 to Jan 2019 60/60 31.10±4.30/31.80±4.50 HRT + Herbal Medicine HRT ①②③④
Zhao JM 2020 41 From Aug 2017 to Dec 2018 52/52 31.17±3.69/31.62±3.75 HRT + Herbal Medicine HRT ①②③④
Luo C 2020 42 From Mar 2017 to Jan 2019 30/30 35.07±2.09/35.27±3.25 Herbal Medicine HRT ①②③④⑤
Wang TT 2020 43 From Mar 2019 to Aug 2020 30/30 32.45±4.15/32.44±4.12 Herbal Medicine + Acupuncture Herbal Medicine ①
Chi L 2020 44 From Jun 2017 to Mar 2019 51/54 29.02±3.00/30.18±3.20 Herbal Medicine HRT ①②③⑤
Liu X 2020 45 From May 2017 to Oct 2018 35/35 31.55±3.16/30.81±3.25 HRT + Herbal Medicine HRT ①
Ma K 2019 46 From Oct 2016 to Sep 2018 43/43 33.81±3.70/32.86±3.96 Herbal Medicine HRT ①②③④⑤
Zhong WP 2019 47 From Jun 2016 to Dec 2017 20/20 36.00±2.02/36.20±1.94 Herbal Medicine HRT ①②③④
Yuan YJ 2019 48 From Aug 2016 to Nov 2018 45/45 33.18±4.46/32.46±5.45 Herbal Medicine HRT ①
Li J 2019 49 From Apr 2017 to Apr 2018 44/44 32.47±4.11/32.45±4.13 HRT + Herbal Medicine HRT ①②③④⑤
Zhang N 2019 50 From Dec 2016 to Jun 2018 45/45 28.20±4.60/30.20±4.10 HRT + Herbal Medicine + Acupuncture HRT + Herbal Medicine ①②③④
Zhou QY 2018 51 From Dec 2017 to May 2018 30/30 35.70±2.20/35.40±2.50 HRT + Herbal Medicine HRT ①②③
Li Xia 2018 52 From Mar 2015 to Jul 2018 30/30 22.40±9.08/25.71±7.12 Herbal Medicine + Acupuncture HRT ①②③④
Li Xiao 2018 53 From Feb 2015 to Dec 2016 40/40 31.81±4.29/31.78±4.26 Herbal Medicine HRT ①②③④
Yao L 2007 54 From Jan 1988 to Dec 2003 130/130 36.00±2.09/30.80±5.40 Herbal Medicine HRT ①②③④
Cui LL 2022 55 From Sep 2018 to Jan 2020 39/38 36.00±6.00/37.00±6.00 Herbal Medicine + Cat-gut Embedding Therapy Herbal Medicine ①②③④⑤
Zeng X 2021 56 From Dec 2019 to Jul 2020 48/48 32.60±3.90/33.20±3.90 HRT + Herbal Medicine HRT ①②③

Note: ①, total effective rate; ②, FSH; ③, E 2; ④, LH.

RCT, randomized controlled trial; T, Treatment; C, Control; HRT, hormone replacement therapy; FSH, follicle-stimulating hormone; E 2, estradiol; LH, luteinizing hormone.

 Risk of bias of the included studies

For the random sequence generation element, 21 studies reported an appropriate method for randomization, thus “low risk”. There were two studies allocated participants to interventions based on participants’ preference and hospital record number therefore “high risk”. The rest only reported random, so it is “unclear”.

In terms of allocation concealment, 30 studies were judged as having “high risk” of bias as there were inadequate concealment of allocations prior to assignment. Only one study reported clear allocation concealment by using sequentially numbered, opaque and sealed envelope, therefore it was judged as “low risk”. There were two studies reported using assignment envelopes but sufficient details such as whether the envelopes were sequentially numbered, opaque and sealed were not mentioned, thus “unclear”.

In terms of blinding of participants and personnel, only one study was stated as single-blinded design but did not address the outcome, therefore “unclear”. The rest of the studies were judged as “high risk” as there were no blinding and due to different treatment modalities, participants might have the wrong belief that the intervention was more effective for their treatment.

In terms of outcome assessment, all studies were judged as “unclear” due to inadequate information for evaluation. In terms of incomplete outcome data, only one study was judged as “high risk” of bias as there were missing outcome data across the intervention groups. The rest were “low risk”. In terms of selective reporting, only one study was judged as “high risk” of bias due to incomplete outcome of interest in the study. The rest were “low risk”. In terms of other bias, all studies were “low risk” except two, in which there were incorrect reported data and discrepancies found in the studies. The graph and summary of the risk of bias are listed in Figure 2.

Graph and summary of the risk of bias.

Risk of bias A) graph and B) summary.

 Results of NMA

Pairwise meta-analysis

Table 3 presents the results of the pairwise meta-analysis and heterogeneity estimates. All 33 studies reported total effective rate, 30 reported FSH, 29 reported E 2, 20 reported LH and 13 reported AMH.

Pairwise meta-analysis.
Outcome measurement Comparison N OR (95%CI) P I 2 (%)
Total Effective Rate G vs. A 2 3.42 [1.02, 11.46] 0.05 0
D vs. A 11 2.34 [1.46, 3.76]* 0.0004 38
E vs. A 2 2.43 [0.16, 36.61] 0.52 80
F vs. A 1 10.32 [1.12, 93.34]* 0.04 N/A
B vs. A 14 3.74 [2.61, 5.35]* <0.0001 0
C vs. A 1 5.17 [1.61, 16.64]* 0.006 N/A
C vs. B 1 1.54 [0.24, 9.66] 0.65 N/A
E vs. D 2 9.22 [2.02, 42.03]* 0.004 0
F vs. D 1 4.04 [1.17, 13.96]* 0.03 N/A
Outcome measurement Comparison N SMD (95%CI) P I 2 (%)
FSH G vs. A 2 3.70 [2.18, 5.23]* <0.00001 0
D vs. A 9 2.68 [0.48, 4.88]* 0.02 79
E vs. A 2 3.29 [0.51, 6.07]* 0.02 57
F vs. A 1 4.24 [-0.53, 9.01] 0.08 N/A
B vs. A 13 4.82 [3.61, 6.02]* <0.00001 83
C vs. A 1 12.00 [8.43, 15.57]* <0.00001 N/A
C vs. B 1 10.20 [4.96, 15.44]* 0.0001 N/A
F vs. D 1 1.38 [-0.11, 2.87] 0.07 N/A
E 2 G vs. A 2 -11.97 [-45.01, 21.08] 0.48 94
D vs. A 9 8.52 [0.53, 16.51]* 0.04 96
E vs. A 2 15.04 [1.06, 29.01]* 0.03 71
F vs. A 1 8.56 [3.44, 13.68]* 0.001 N/A
B vs. A 12 9.09 [5.49, 12.70]* <0.00001 96
C vs. A 1 28.43 [25.92, 30.94]* <0.00001 N/A
C vs. B 1 13.20 [9.06, 17.34]* <0.00001 N/A
F vs. D 1 22.89 [20.44, 25.34]* <0.00001 N/A
LH D vs. A 7 1.36 [0.36, 2.36]* 0.008 26
E vs. A 2 0.87 [0.14, 1.61]* 0.02 0
B vs. A 8 5.20 [2.51, 7.88]* 0.0001 92
C vs. A 1 18.10 [15.75, 20.45]* <0.00001 N/A
C vs. B 1 5.90 [1.57, 10.23]* 0.008 N/A
F vs. D 1 1.57 [1.12, 2.02]* <0.00001 N/A
AMH G vs. A 1 0.09 [-0.12, 0.30] 0.39 N/A
D vs. A 6 0.68 [0.22, 1.14]* 0.004 99
B vs. A 5 0.54 [-0.04, 1.13] 0.07 99
F vs. D 1 0.15 [0.02, 0.28]* 0.03 N/A

Note: Data are reported as odds ratios (OR)/standard mean differences (SMDs) and 95% confidence intervals. N, number of studies; A, HRT; B, HRT + Herbal Medicine; C, HRT + Herbal Medicine + Acupuncture; D, Herbal Medicine; E, Herbal Medicine + Acupuncture; F, Herbal Medicine + Catgut-embedding Therapy; G, Acupuncture + Moxibustion; * indicates for P<0.05.

N/A, not applicable; HRT, hormone replacement therapy; FSH, follicle-stimulating hormone; E 2, estradiol; LH, luteinizing hormone; AMH, anti-Müllerian hormone.

The forest plot of total effective rate indicates that herbal medicine (OR 2.34, 1.46 to 3.76, I 2=38%) and HRT + herbal medicine (OR 3.74, 2.61 to 5.35, I 2=0%) were more effective than HRT alone. Herbal medicine and acupuncture (OR 9.22, 2.02 to 42.03, I 2=0%) was more effective than herbal medicine alone.

The forest plot of FSH indicates that acupuncture + moxibustion (MD 3.70, 2.18 to 5.23, I 2=0%), herbal medicine (MD 2.68, 0.48 to 4.88, I 2=79%), herbal medicine + acupuncture (MD 3.29, 0.51 to 6.07, I 2=57%) and HRT + herbal medicine (MD 4.82, 3.61 to 6.02, I 2=83%) were more effective in improving FSH levels compared to HRT alone.

The forest plot of E 2 indicates that all treatment modalities involved herbal medicine, including HRT + herbal medicine (MD 9.09, 5.49 to 12.70, I 2=96%), HRT + herbal medicine + acupuncture (MD 28.43, 25.92 to 30.94, I 2=n/a), herbal medicine (MD 8.52, 0.53 to 16.51, I 2=96) and herbal medicine + acupuncture (MD 15.04, 1.06 to 29.01, I 2=71%) showed higher effectiveness than HRT alone to improve E 2 levels among patients with POI.

The forest plot of LH indicates that therapeutic effects of HRT + herbal medicine (MD 5.20, 2.51 to 7.88, I 2=92%), herbal medicine (MD 1.36, 0.36 to 2.36, I 2=26%) and herbal medicine + acupuncture (MD 0.87, 0.14 to 1.61, I 2=0%) were more superior than HRT alone.

The forest plot of AMH indicates that herbal medicine (MD 0.68, 0.22 to 1.14, I 2=99%) showed better efficacy compared to only HRT in improving AMH levels.

NMA on total effective rate

The results of the NMA showing comparisons of different treatments based on total effective rate are shown in Figure 3A. The total effective rate are presented in the form of a league table can be found in Figure 4A. A total of 33 RCTs (2,862 participants) with seven different treatment modalities were analyzed. The results of NMA indicate that herbal medicine combined with catgut-embedding therapy have the highest efficiency. According to the SUCRA, which presents treatment ranking to offer the most important benefit outcome (the highest total effective rate), herbal medicine combined with catgut-embedding therapy (87.8%) had the highest effective rate, followed by combination of HRT with herbal medicine and acupuncture (76.8%), HRT combined with herbal medicine (67.1%), acupuncture combined with moxibustion (63.1%), herbal medicine combined with acupuncture (27.3%), HRT alone (16.1%) and herbal medicine only (11.9%). This also showed that combination of TCM treatments with HRT are more effective than HRT alone. Table 4 (part A) and Figure 5A depict the rankings of these seven treatments.

Network map results of treatment comparisons based on total effective rate, serum FSH, E <sub>2</sub>, LH and AMH levels.

A) Total effective rate. B) FSH, C) E 2, D) LH and E) AMH levels. Note: FSH, follicle-stimulating hormone; E 2, estradiol; LH, luteinizing hormone; AMH, anti-Müllerian hormone; HRT, hormone replacement therapy; Herb, herbal medicine; Catgut, catgut-embedding therapy; Acu, acupuncture; Moxa, moxibustion.

 League table showing the results of network meta-analysis comparisons based on total effective rates, serum FSH, E <sub>2</sub>, LH and AMH levels of all TCM treatment modalities including odds ratios (OR) and 95% credible intervals.

A) Total effective rate. B) FSH, C) E 2, D) LH and E) AMH levels. OR>1 means the top-left treatment is better. Note: FSH, follicle-stimulating hormone; E 2, estradiol; LH, luteinizing hormone; AMH, anti-Müllerian hormone; TCM, Traditional Chinese medicine; HRT, hormone replacement therapy; Herb, herbal medicine; Catgut, catgut-embedding therapy; Acu, acupuncture; Moxa, moxibustion.

 SUCRA ranking probabilities of all TCM treatment modalities for POI based on total effective rate.
Treatment SUCRA PrBest MeanRank

Total effective rate

HRT 16.1 0.0 6.0
HRT + Herb 67.1 3.9 3.0
HRT + Herb + Acu 76.8 21.4 2.4
Herb 11.9 0.0 6.3
Herb + Acu 27.3 0.1 5.4
Herb + Catgut 87.8 66.2 1.7
Acu + Moxa 63.1 8.5 3.2

FSH

HRT 5.8 0.0 6.7
HRT + Herb 67.4 0.0 3.0
HRT + Herb + Acu 99.9 99.5 1.0
Herb 23.1 0.0 5.6
Herb + Acu 49.6 0.1 4.0
Herb + Catgut 49.3 0.2 4.0
Acu + Moxa 54.9 0.1 3.7

E 2

HRT 15.1 0.0 6.1
HRT + Herb 51.6 0.0 3.9
HRT + Herb + Acu 92.6 66.4 1.4
Herb 40.8 0.0 4.6
Herb + Acu 66.7 10.3 3.0
Herb + Catgut 80.1 23.3 2.2
Acu + Moxa 3.2 0.0 6.8

LH

HRT 12.3 0.0 5.4
HRT + Herb 71.0 0.0 2.4
HRT + Herb + Acu 99.9 99.7 1.0
Herb 40.4 0.0 4.0
Herb + Acu 22.3 0.0 4.9
Herb + Catgut 53.9 0.3 3.3

AMH

HRT 16.7 0.0 4.3
HRT + Herb 66.7 24.1 2.3
Herb 65.8 16.5 2.4
Herb + Catgut 67.2 45.5 2.3
Acu + Moxa 33.6 13.9 3.7

Note: SUCRA, surface under the cumulative ranking curves; TCM, Traditional Chinese Medicine; POI, premature ovarian insufficiency; FSH, follicle-stimulating hormone; E 2, estradiol; LH, luteinizing hormone; AMH, anti-Müllerian hormone; HRT, hormone replacement therapy; Herb, herbal medicine; Catgut, catgut-embedding therapy; Acu, acupuncture; Moxa, moxibustion.

 SUCRA ranking probabilities of total effective rate, serum FSH, E <sub>2</sub>, LH and AMH levels among all TCM treatment modalities.

A) Total effective rate. B) FSH, C) E 2, D) LH and E) AMH levels. Note: SUCRA, surface under the cumulative ranking curves; FSH, follicle-stimulating hormone; E 2, estradiol; LH, luteinizing hormone; AMH, anti-Müllerian hormone; TCM, Traditional Chinese medicine; HRT, hormone replacement therapy; Herb, herbal medicine; Catgut, catgut-embedding therapy; Acu, acupuncture; Moxa, moxibustion.

NMA on FSH levels

The results of the NMA showing comparisons of different treatments based on improvements of FSH levels are shown in Figure 3B. The league table results of the NMA on FSH levels are presented in Figure 4B. A total of 28 RCTs (2,384 participants) with seven different treatment modalities were analyzed. The results of NMA indicate that the combination of HRT with herbal medicine and acupuncture achieved the highest efficiency in improving the FSH levels. According to SUCRA, the combination of HRT with herbal medicine and acupuncture (99.9%) had the highest effective rate, followed by HRT combined with herbal medicine (67.4%), acupuncture combined with moxibustion (54.9%), herbal medicine combined with acupuncture (49.6%), herbal medicine combined with catgut-embedding therapy (49.3%), herb alone (23.1%) and HRT only (5.8%). Table 4 (part B) and Figure 5B depict the rankings of these seven treatments.

NMA on E 2 levels

The results of the NMA showing comparisons of different treatments for the changes of E 2 levels are shown in Figure 3C. The league table results for the E 2 comparison are shown in Figure 4C. A total of 26 RCTs (2,108 participants) with seven different treatment modalities were analyzed. The results of NMA indicate that the combination of HRT with herbal medicine and acupuncture had the highest efficiency. It was also found that the combination of different treatment modalities pairing with herbal medicine were more effective than HRT alone. According to SUCRA, the combination of HRT with herbal medicine and acupuncture (92.6%) had the highest effective rate, followed by herbal medicine combined with catgut-embedding therapy (80.1%), herbal medicine combined with acupuncture (66.7%), HRT combined with herbal medicine (51.6%), herbal medicine alone (40.8%), HRT alone (15.1%) and acupuncture combined with moxibustion (3.2%). Table 4 (part C) and Figure 5C depict the rankings of these seven treatments.

NMA on LH levels

The results of the NMA showing treatment comparisons based on the difference of LH levels are shown in Figure 3D. The league table results of the NMA for LH levels are shown in Figure 4D. A total of 19 RCTs (1,505 participants) with six different treatment modalities were analyzed. The results of NMA indicate that the combination of HRT with herbal medicine and acupuncture have the highest efficacy. It was also discovered that treatment modalities combined with herbal medicine are more useful than HRT alone. According to SUCRA, the combination of HRT with herbal medicine and acupuncture (99.9%) had the highest effective rate, followed by HRT combined with herbal medicine (71.0%), herbal medicine combined with catgut-embedding therapy (53.9%), herbal medicine alone (40.4%), herbal medicine combined with acupuncture (22.3%) and HRT alone (12.3%). Table 4 (part D) and Figure 5D presents the ranking of these six treatments.

NMA on AMH levels

The results of the NMA showing treatment comparisons based on the improvement of AMH levels in five treatment modalities are shown in Figure 3E. The league table results regarding the comparison of the AMH levels are presented in Figure 4E. A total of 11 RCTs with reported AMH levels (1,030 participants) were analyzed. The results of NMA indicate that herbal medicine combined with catgut-embedding therapy had the highest efficiency and treatment modalities with the presence of herbal medicine are more effective compared to treatment without herbal medicine. According to SUCRA, herbal medicine combined with catgut-embedding therapy (67.2%) had the highest effective rate, followed by HRT combined with herbal medicine (66.7%), herbal medicine alone (65.8%), acupuncture combined with moxibustion (33.6%) and HRT alone (16.7%). Table 4 (part E) and Figure 5E depict the rankings of these five treatments.

Evaluation of statistical inconsistency

Although global inconsistency showed there that were no significant statistical differences for the outcomes, the node-splitting method was employed to further evaluate on the local inconsistency ( Table 5). Overall, no statistical inconsistency for the outcomes were seen from the node-splitting outcome, except between direct and indirect comparisons of HRT with combination of HRT and herbal medicine, HRT with herbal medicine, HRT with combination of herbal medicine and acupuncture, herbal medicine with combination of HRT and herbal medicine, herbal medicine with combination of herbal medicine and acupuncture, as P<0.05 indicates for local inconsistency between the local comparisons. These might be due to ineffective sample size for the particular treatment comparisons.

Side-splitting approach of total effective rate, serum FSH, E <sub>2</sub>, LH and AMH levels.
Side Direct Indirect Difference P>|z|
Coef. Std.Err Coef. Std.Err Coef. Std.Err

Total effective rate

A B 1.302018 0.1869113 2.694049 0.6192193 -1.392031 0.6308563 0.027
A C 1.643014 0.6890454 1.839627 1.020893 -0.1966132 1.231668 0.873
A D 0.7736507 0.2225935 -0.5922928 0.6084046 1.365943 0.6440799 0.034
A E 0.2745474 0.5314991 2.925095 0.8082094 -2.650548 0.9568743 0.006
A F 2.3254 1.177303 2.042871 0.7480681 0.2825286 1.394865 0.839
A G - - - - - - -
B C 0.4290022 0.9997119 0.2323267 0.7194375 0.1966755 1.231671 0.873
B D -1.561014 0.4246506 -0.4012063 0.3030283 -1.159807 0.5189197 0.025
D E 2.221581 0.7822485 -0.4290057 0.551082 2.650587 0.9568655 0.006
D F 1.395881 0.7169363 1.678198 1.196491 -0.2823171 1.394837 0.840

FSH

A B -4.385776 .8296878 -7.019813 3.360363 2.634038 3.463264 0.447
A C -12 3.379563 -14.80831 3.988823 2.808312 5.228016 0.591
A D -1.330655 1.152858 .4646895 3.094725 -1.795344 3.301872 0.587
A E - - - - - - -
A F -4.24 3.754363 -2.397674 3.16034 -1.842325 4.907443 0.707
A G - - - - - - -
B C -10.19999 3.902824 -7.3909 3.478562 -2.809093 5.228043 0.591
B D 5.876125 1.997919 2.04132 1.518885 3.834806 2.509528 0.126
D F -1.379984 2.959344 -3.219893 3.914674 1.839909 4.907389 0.708

E 2

A B 9.092383 2.721332 20.20191 9.597002 -11.10953 9.975317 0.265
A C 28.43 9.621474 22.89342 10.14843 5.536579 13.9844 0.692
A D 8.621667 3.561098 -1.652434 9.294642 10.2741 9.953024 0.302
A E - - - - - - -
A F 8.560001 9.168995 31.61203 9.457669 -23.05203 13.17262 0.080
A G - - - - - - -
B C 13.20007 9.767265 18.7195 10.00883 -5.519434 13.98484 0.693
B D -5.415176 6.761988 -1.062784 5.045681 -4.352393 8.437178 0.606
D F 22.89007 8.877762 -0.207172 9.733271 23.09724 13.17386 0.080

LH

A B -4.632461 1.104242 -12.19775 4.807764 7.565293 4.932953 0.125
A C -18.1 3.135893 -10.5318 3.808109 -7.568203 4.933104 0.125
A D -2.089832 1.392677 0.7951949 31.73015 -2.885027 31.7607 0.928
A E - - - - - - -
B C -5.899871 3.644604 -13.46706 3.32461 7.567194 4.93318 0.125
D F -1.57 3.060984 4.200054 63.4475 -5.770054 63.52132 0.928

AMH

A B 0.5447631 0.326256 1.227886 1.155475 -0.6831228 1.200393 0.569
A C 0.68482 0.2711292 -0.9716826 1.105524 1.6565503 1.138173 0.146
A E - - - - - - -
B C -0.4066692 0.4828313 0.4681092 0.5217627 -0.8747784 0.7108789 0.218
C D 0.15 0.7004296 -1.18702 18.80401 1.33702 18.81704 0.943

Note: FSH, follicle-stimulating hormone; E 2, estradiol; LH, luteinizing hormone; AMH, anti-Müllerian hormone.

Small-study effects

There was a lack of strong evidence on the small-study effects across outcomes based on total effective rate and FSH level ( Figure 6A and B).

Funnel plot of total effective rate, serum FSH, E <sub>2</sub>, LH and AMH levels.

A) Total effective rate. B) FSH, C) E 2, D) LH and E) AMH levels. Note: FSH, follicle-stimulating hormone; E 2, estradiol; LH, luteinizing hormone; AMH, anti-Müllerian hormone.

However, among the outcome indicators of E 2, LH and AMH ( Figure 6C, D and E), it could be inferred that heterogeneity between studies were one of the reasons for those studies located on the lateral side of the funnel plot. Comparison-correction funnel plots based on E 2, LH and AMH levels were made upon 26, 19 and 11 included studies, respectively (involving seven, six and five interventions, respectively). The asymmetrical funnel plots suggest probability of small-study effects in this study.

Sensitivity analysis

For the paired studies with significant heterogeneity (I 2 > 50%), a sensitivity analysis was done by removing any single study one by one. Results showed that there were no significant changes, stipulating that the pooled results were consistent.

 Discussion

Previous studies 9 , 10 , 17 have demonstrated the efficacy of herbal medicine and acupuncture in treating POI. In this study, we utilized the advantages of NMA method to compare the efficacy of various TCM treatment modalities for this condition. Our findings revealed the comparative efficacy of six treatment modalities: HRT combined with herbal medicine and acupuncture, HRT combined with herbal medicine, herbal medicine combined with acupuncture, herbal medicine combined with catgut-embedding therapy, acupuncture combined with moxibustion and herbal medicine alone. Table 6 shows the compilation of SUCRA rank for each outcome measurement in NMA. Our results indicated that the combination of HRT with herbal medicine and acupuncture was the most effective treatment modality for patients with POI in the present study. These findings suggest that TCM treatment approaches could be considered as a promising therapeutic option for women with POI.

Compilation of SUCRA Rank for each outcome measurement in NMA.
SUCRA Rank Outcome measurement
Total effective rate FSH E 2 LH AMH
1 Herb + Catgut HRT + Herb + Acu HRT + Herb + Acu HRT + Herb + Acu Herb + Catgut
2 HRT + Herb + Acu HRT + Herb Herb + Catgut HRT + Herb HRT + Herb
3 HRT + Herb Acu + Moxa Herb + Acu Herb + Catgut Herb
4 Acu + Moxa Herb + Acu HRT + Herb Herb Acu + Moxa
5 Herb + Acu Herb + Catgut Herb Herb + Acu HRT
6 HRT Herb HRT HRT
7 Herb HRT Acu + Moxa

Note: SUCRA, surface under the cumulative ranking curves; NMA, network meta-analysis; FSH, follicle-stimulating hormone; E 2, estradiol; LH, luteinizing hormone; AMH, anti-Müllerian hormone; HRT, hormone replacement therapy; Herb, herbal medicine; Catgut, catgut-embedding therapy; Acu, acupuncture; Moxa, moxibustion.

To the best of our knowledge, this study is the first systematic evaluation covering all treatment modalities in TCM to provide reliable evidence to determine the efficacy and feasibility of TCM treatment for patients with POI. There are a variety of different treatment modalities in TCM and all seem effective in treatment. 11 , 18 However, until now there have been no consensus or standard procedure of TCM treatment recommended for POI. This scientific direct and indirect comparison can provide important guidance on the pros and cons of each intervention and their treatment priority.

There is no record about POI found in the TCM literature. However, comparing its clinical manifestations, POI can be categorized as “amenorrhoea”, “oligomenorrhoea” and “infertility” based on TCM perspective. The pathogenesis is mainly related to malnourishment of the thoroughfare and conception vessels, as well as the uterus, which might be due to congenital insufficiency, physical and mental overwork, or sexual overstrain. TCM treats a disease based on syndrome differentiation. Different treatment modalities such as oral administration of herbal decoction, acupuncture, catgut-embedding therapy, moxibustion, electroacupuncture, ear acupressure and herbal enema, are suitable for the treatment of POI. In our study, 33 clinical trials using TCM treatment were screened and the therapeutic effect of seven treatment modalities were analyzed. It has been proven that comprehensive treatment models are more effective in improving ovarian function, compared to just using HRT as sole treatment. This would provide clinical practitioners with strong and reliable evidence, as well as a useful alternative during clinical decision-making.

We also found that the integration of herbal medicine into POI treatment, such as its combination with HRT, acupuncture or catgut-embedding therapy, can significantly improve the ovarian functions by observing on indicators including total effective rate, FSH, E 2, LH and AMH levels. Therefore, herbal medicine may be considered as an intervention when HRT alone, the standard procedure recommended by recognized guidelines worldwide, 1 , 4 , 5 cannot effectively cure POI. This study possesses significance in providing clinical guidance.

Acupuncture has been widely applied on POI treatment particularly in China. 10 , 11 , 18 It has been demonstrated that acupuncture is safe and effective. 19 – 21 Through early intervention of acupuncture, it has also been found that acupuncture can increase pregnancy rate significantly. 22 , 23 Our study has demonstrated that application of acupuncture in the treatment of POI is also useful to observe clinical improvement. However, it is suggested that acupuncture must be combined with herbal medicine and even HRT in order to optimize the therapeutic effects. This recommended treatment modality not only demonstrates the advantage of TCM treatment, it also provides a potential practical, safe and low-cost treatment option for both the patients and clinicians.

In this study, we found a shortage of rigorous clinical trials adhering to the international requirements, as well as a paucity of heterogeneity of study candidates, interventions, controls, and outcome measures, which challenge the process of systematic review and NMA. Due to inadequate data from the included studies, the safety of each intervention could not be evaluated. The risk of bias assessment in this study indicates that most of the studies did not clearly state the blinding of outcome assessors, which might impact on the reliability of data analysis outcome.

 Conclusions

In conclusion, herbal medicine combined with catgut-embedding therapy was shown to be the most effective treatment model to improve total effective rate and AMH levels in the present study. The combination of HRT, herbal medicine and acupuncture was demonstrated to be the most effective treatment model for improving serum FSH, E 2 and LH levels. An overview on SUCRA analysis outcomes showed that comprehensive treatment models with the integration of herbal medicine seemed more prone to improve ovarian functions. Monotherapies, such as solely using HRT or herbal medicine treatment, were found to have no obvious advantages on their curative effect for POI. The integration of herbal medicine to conventional HRT may be a favorable approach for enhancing the clinical utility of HRT in the management of POI. RCTs involving multiple centers and different countries are essential to further verify the conclusions of this study, which can also create international awareness on the efficacy of TCM treatments for POI.

 Data availability Underlying data

All data underlying the results are available as part of the article and no additional source data are required.

 Reporting guidelines

Figshare: PRISMA-NMA checklist for ‘Identifying the most effective Traditional Chinese Medicine treatment modalities for premature ovarian insufficiency: a systematic review and network meta-analysis’. https://doi.org/10.6084/m9.figshare.22567846. 57

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

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Cui LL Kang MX Peng B : Efficacy Observation of Acupoint Thread Embedding Combined with Yun Zhong Ding Kun Tang for Premature Ovarian Insufficiency. Shanghai Journal of Acupuncture and Moxibustion. 2022;41(06):573–578. Zeng X : Clinical Efficacy of Kuntai Capsules Combined with Estradiol Tablets/Estradiol and Dydrogesterone Tablets in the Treatment of Patients with Premature Ovarian Insufficiency. China Journal of Pharmaceutical Economics. 2021;16(10):97–100. Sin YS Sng KS Chen M : PRISMA checklist for ‘Identifying the most effective Traditional Chinese Medicine treatment modalities for premature ovarian insufficiency: a systematic review and network meta-analysis’.[Dataset]. figshare. 2023. 10.6084/m9.figshare.22567846 10.5256/f1000research.145942.r266528 Reviewer response for version 1 Laguna Benetti-Pinto Cristina 1 Referee https://orcid.org/0000-0001-6198-5593 Department of Obstetrics and Gynecology, Universidade Estadual de Campinas, Campinas, State of São Paulo, Brazil

Competing interests: No competing interests were disclosed.

 4 6 2024 Copyright: © 2024 Laguna Benetti-Pinto C 2024 This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. recommendation reject

I reviewed the manuscript “ Identifying the most effective Traditional Chinese Medicine treatment modalities for premature ovarian insufficiency: a

systematic review and network meta-analysis” . The authors aimed to evaluate and compare the clinical efficacy of different modalities of Traditional Chinese Medicine (TCM) for the treatment of POI and identify the most effective treatment.

The authors registered the systematic review  and declared to follow the PRISMA-NMA. They used 6 databases (three English databases and three Chinese databases). Only Traditional Chinese Medicine randomized controlled trials were included, with women treated with herbal medicine, acupuncture, moxibustion and catgut embedding therapy alone or in combination with conventional HT.

The effectiveness of treatments was to be evaluated according to clinical manifestation, menstrual cycle, FSH and Estradiol levels, and LH and AMH levels.

The issue is interesting and there are gaps in the knowledge of effectiveness of complementary IOF treatment.

My major concern is on the outcomes of the treatments. It is not clear who were the POI-women investigated.  Why analyze the AMH levels in POI due to gonadal dysgenesis or after an oophorectomy, for example? Is mandatory to identify the causes of POI in each study included. Furthermore, the reduction in FSH, LH are not good outcomes to evaluate the best treatment. The global consensus indicates to evaluate clinical aspects as hot flushes, improvement in sexual function or in vaginal dryness, improvement in bone mass. Theses aspects were not showed. Hence, my suggestion is to change the aim and the title of the reviewed to “Identifying the effectiveness of TCM treatment in changing some hormonal aspects related to POI”

I have some other concerns that are listed below:

1.Title – see comments above

2.Abstract – see comments above and change

3.Introduction

-

-Page 3, first paragraph: the authors included a POI prevalence of about 10%. This rate is not in accordance with the literature or even with the reference cited [3]. Please review and correct (in reference number 3, the prevalence of POI is 1-3%). The authors also cited the use of AMH levels to measure ovarian reserve. AMH measurement is only indicated in specific cases of POI, if the final diagnosis is not completely certain, especially when FSH levels are not stable and above 25 U/L. I suggest a review of these concepts.

Page 3: “Hence, patients often seek out complementary medicine to improve their ovarian functions and increase chances of conception” – what is the idea of ​​this paragraph? HT is the first and best treatment whenever the woman has no absolute contraindication, which is not frequent. In these cases, complementary treatment or alternative treatment generally aims to minimize the effects of hypoestrogenism. In most POI etiologies, it is unfortunately not possible to improve ovarian function. Please, clarify/rewrite the paragraph.

4.Methodology and Results

Page 6, PRISMA flowchart – please, in the studies included, mention in the figure which database they are from.

The authors mentioned that the diagnosis criteria were according to ESRHE guideline OR according Chinese expert consensus on POI. Please, include in the manuscript these criteria (the last article was published in Chinese. These criteria are important to comprehension of systematic review.

Discussion:

Page 19.  “Our findings revealed the comparative efficacy of six treatment modalities: HRT combined with herbal medicine and acupuncture, HRT combined with herbal medicine, herbal medicine combined with acupuncture, herbal medicine combined with catgut-embedding therapy, acupuncture combined with moxibustion and herbal medicine alone.”  - see “major concern”.  And what kind of HT?

Page 19: “However, comparing its clinical manifestations, POI can be categorized as “amenorrhoea”, “oligomenorrhoea” and “infertility” based on TCM perspective. The pathogenesis is mainly related to malnourishment of the thoroughfare and conception vessels, as well as the uterus, which might be due to

congenital insufficiency, physical and mental overwork, or sexual overstrain. TCM treats a disease based on syndrome  differentiation.”  Please, make clear these concepts. I am not able to understand, according to global consensus of POI.

Page 19. “Therefore, herbal medicine may be considered as an intervention when HRT

alone, the standard procedure recommended by recognized guidelines worldwide,1,4,5 cannot effectively cure POI” – This conclusion is not supported bye the results of this review or by the global consensus. The idea is not clear to me. Please, reviewed.

Although the systematic review was methodologically well done, there are conceptual errors, and conclusions aren’t in line with the recommendations of global consensus. If there is by the authors an extensive revision of the study, with changes in the concepts, aims and conclusions, the manuscript can be submitted to a new analysis.

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes

Is the statistical analysis and its interpretation appropriate?

Partly

If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.)

Yes

Are sufficient details of the methods and analysis provided to allow replication by others?

No

Are the conclusions drawn adequately supported by the results presented in the review?

No

Reviewer Expertise:

premature ovarian insufficiency

I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.

 10.5256/f1000research.145942.r196644 Reviewer response for version 1 Aslam Muhammad Shahzad 1 Referee https://orcid.org/0000-0003-2728-6726 School of Traditional Chinese Medicine, Xiamen University Malaysia, Sepang, Malaysia

Competing interests: No competing interests were disclosed.

 1 9 2023 Copyright: © 2023 Aslam MS 2023 This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. recommendation approve-with-reservations

According to authors: Acupuncture has been widely applied on POI treatment particularly in China. 10 , 11 , 18  It has been demonstrated that acupuncture is safe and effective. 19 – 21  I suggest to broaden the discussion in context to use of Acupuncture in Malaysia, US. We all know its effectiveness on POI treatment in China. Please read literature and include more reference from different geography. If no study in other geography found then given give rational. 

Provide rational to use SUCRA Rank for each outcome measurement in NMA..I suggest to compare it with Bayesian Model and Averaging, Rank-Heat Plot.

The study conclusion must present with future direction. Please include more paragraph.

Is there any comparison given with best TCM TM for POI with pharmacotherapy? The discussion must contain a couple of paragraph to provide rational and treatment comparison.

Please provide in-depth study limitation in separate paragraph. 

 Please provide Prisma Checklist as supplementary file.

Please suggest to include one heading how to improve the quality reporting of POI. Most of TCM treatment has similar issues. It is mandatory to provide solution. Please elaborate your discussion and specify to POI treatment. Acceptability of TCM treatment is a big issues. I hope you understand my point and add some heading inside discussion.

 If possible i recommend to include proposed Hypothetical mechanism of TCM TM in POI disease. 

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Partly

Is the statistical analysis and its interpretation appropriate?

Yes

Are sufficient details of the methods and analysis provided to allow replication by others?

Partly

Are the conclusions drawn adequately supported by the results presented in the review?

No

Reviewer Expertise:

Phytochemistry, Complementary and alternative medicine

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.