Identifying the most effective Traditional Chinese Medicine treatment modalities for premature ovarian insufficiency: a systematic review and network meta-analysis

Yen Suan Sin; Min Chen; Kim Sia Sng; Jianwei Zhang

doi:10.12688/f1000research.132981.1

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Systematic Review

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]

Yen Suan Sin^1,2, Min Chen¹, Kim Sia Sng², Jianwei Zhang ³

PUBLISHED 27 Apr 2023

Author details Author details

¹ Shandong University of Traditional Chinese Medicine, Jinan, Shandong, 16369, China
² Department of Chinese Medicine, International Medical University, Bukit Jalil, Kuala Lumpur, 57000, Malaysia
³ Shandong University of Traditional Chinese Medicine Affiliated Hospital, Jinan, Shandong, 250014, China

Yen Suan Sin
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Software, Writing – Original Draft Preparation, Writing – Review & Editing

Min Chen
Roles: Formal Analysis, Investigation, Methodology, Validation, Writing – Review & Editing

Kim Sia Sng
Roles: Data Curation, Investigation, Methodology, Validation, Writing – Review & Editing

Jianwei Zhang
Roles: Conceptualization, Supervision, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

This article is included in the Global Public Health gateway.

Abstract

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 (E₂), 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), E₂ (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).

Keywords

Premature ovarian insufficiency, Chinese medicine, Acupuncture, Network meta-analysis, Systematic review

Corresponding author: Jianwei Zhang

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

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

How to cite: Sin YS, Chen M, Sng KS and Zhang J. 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]. F1000Research 2023, 12:450 (https://doi.org/10.12688/f1000research.132981.1) First published: 27 Apr 2023, 12:450 (https://doi.org/10.12688/f1000research.132981.1) Latest published: 27 Apr 2023, 12:450 (https://doi.org/10.12688/f1000research.132981.1)

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 Interventions¹² 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).

Table 1. 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) guideline¹ 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%.
- (i) Recovery: clinical manifestations disappeared, menstrual cycle, serum FSH and E₂ levels returned to normal, total effective rate ≥95%;
- (ii) Effective: clinical manifestations were significantly improved, menstrual cycle, serum FSH and E₂ levels were significantly improved, total effective rate ≥70% and <95%;
- (iii) Efficient: clinical manifestations were slightly improved, menstrual cycle, serum FSH and E₂ levels were slightly improved, total effective rate ≥30% and <70%;
- (iv) Invalid: there was no improvement in clinical signs and symptoms, no improvement in menstrual cycle, no improvement in serum FSH and E₂ levels, total effective rate <30%.
• Secondary outcome measurements: Serum FSH, E₂, 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, I² 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.

Figure 1. PRISMA flowchart showing steps in the selection of relevant trials.

Note: RCT, randomized controlled trials.

Table 2. 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 2022²⁴	From Jan 2019 to Jan 2021	57/57	28.41±5.16/28.75±5.33	HRT + Herbal Medicine + Acupuncture	HRT	①②③④
Peng YL 2022²⁵	From Jan 2019 to Dec 2020	46/46	28.54±3.66/28.21±3.85	Herbal Medicine + Acupuncture	Herbal Medicine	①②③④
Huang YS 2021²⁶	From Mar 2018 to Mar 2020	30/30	31.43±4.48/30.80±5.12	Acupuncture + Moxibustion	HRT	①②③⑤
Chen JM 2021²⁷	From May 2019 to Jan 2020	50/30	30.19±6.55/31.65±7.55	Herbal Medicine	HRT	①②③⑤
Yuan F 2021²⁸	From Dec 2018 to Jun 2020	42/42	36.05±3.48/35.65±3.51	HRT + Herbal Medicine	HRT	①②③④
Chen L 2021²⁹	From May 2017 to May 2019	35/35	38.97±5.52/38.80±4.96	HRT + Herbal Medicine	HRT	①②
Sui J 2021³⁰	From Oct 2017 to Jan 2019	60/62	32.45±0.93/34.61±0.61	Herbal Medicine	HRT	①②③④⑤
Wang XW 2021³¹	From Jul 2019 to Jun 2020	25/25	36.40±1.10/36.50±1.00	Herbal Medicine	HRT	①②③④
Wang YY 2021³²	From Mar 2018 to Mar 2020	26/26	30.22±4.31/30.15±4.23	Herbal Medicine + Acupuncture	HRT	①②③④
Tang HX 2021³³	From Oct 2019 to Oct 2020	40/40	31.63±3.46/32.57±3.60	Herbal Medicine	HRT	①②③④⑤
Lin LL 2021³⁴	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 2021³⁵	From Jan 2019 to Mar 2020	60/60	35.21±2.35/35.17±2.26	HRT + Herbal Medicine	HRT	①②③④⑤
Hou M 2021³⁶	From Nov 2019 to Oct 2020	30/30	35.00±8.26/36.00±3.57	Acupuncture	HRT	①②③
Wu Q 2021³⁷	From Mar 2019 to Oct 2019	30/30	31.57±5.04/31.63±4.54	HRT + Herbal Medicine	HRT	①②③④⑤
Fu WJ 2021³⁸	From Sep 2019 to Nov 2020	30/30	36.43±2.18/35.29±2.43	HRT + Herbal Medicine	HRT	①②③④
Ding AY 2021³⁹	From Mar 2019 to Nov 2019	40/40	35.40±2.50/35.10±2.80	HRT + Herbal Medicine	HRT	①②③
Ma QW 2020⁴⁰	From Sep 2017 to Jan 2019	60/60	31.10±4.30/31.80±4.50	HRT + Herbal Medicine	HRT	①②③④
Zhao JM 2020⁴¹	From Aug 2017 to Dec 2018	52/52	31.17±3.69/31.62±3.75	HRT + Herbal Medicine	HRT	①②③④
Luo C 2020⁴²	From Mar 2017 to Jan 2019	30/30	35.07±2.09/35.27±3.25	Herbal Medicine	HRT	①②③④⑤
Wang TT 2020⁴³	From Mar 2019 to Aug 2020	30/30	32.45±4.15/32.44±4.12	Herbal Medicine + Acupuncture	Herbal Medicine	①
Chi L 2020⁴⁴	From Jun 2017 to Mar 2019	51/54	29.02±3.00/30.18±3.20	Herbal Medicine	HRT	①②③⑤
Liu X 2020⁴⁵	From May 2017 to Oct 2018	35/35	31.55±3.16/30.81±3.25	HRT + Herbal Medicine	HRT	①
Ma K 2019⁴⁶	From Oct 2016 to Sep 2018	43/43	33.81±3.70/32.86±3.96	Herbal Medicine	HRT	①②③④⑤
Zhong WP 2019⁴⁷	From Jun 2016 to Dec 2017	20/20	36.00±2.02/36.20±1.94	Herbal Medicine	HRT	①②③④
Yuan YJ 2019⁴⁸	From Aug 2016 to Nov 2018	45/45	33.18±4.46/32.46±5.45	Herbal Medicine	HRT	①
Li J 2019⁴⁹	From Apr 2017 to Apr 2018	44/44	32.47±4.11/32.45±4.13	HRT + Herbal Medicine	HRT	①②③④⑤
Zhang N 2019⁵⁰	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 2018⁵¹	From Dec 2017 to May 2018	30/30	35.70±2.20/35.40±2.50	HRT + Herbal Medicine	HRT	①②③
Li Xia 2018⁵²	From Mar 2015 to Jul 2018	30/30	22.40±9.08/25.71±7.12	Herbal Medicine + Acupuncture	HRT	①②③④
Li Xiao 2018⁵³	From Feb 2015 to Dec 2016	40/40	31.81±4.29/31.78±4.26	Herbal Medicine	HRT	①②③④
Yao L 2007⁵⁴	From Jan 1988 to Dec 2003	130/130	36.00±2.09/30.80±5.40	Herbal Medicine	HRT	①②③④
Cui LL 2022⁵⁵	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 2021⁵⁶	From Dec 2019 to Jul 2020	48/48	32.60±3.90/33.20±3.90	HRT + Herbal Medicine	HRT	①②③

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.

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 E₂, 20 reported LH and 13 reported AMH.

Table 3. Pairwise meta-analysis.

Outcome measurement	Comparison	N	OR (95%CI)	P	I² (%)
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	I² (%)
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
E₂	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

The forest plot of total effective rate indicates that herbal medicine (OR 2.34, 1.46 to 3.76, I²=38%) and HRT + herbal medicine (OR 3.74, 2.61 to 5.35, I²=0%) were more effective than HRT alone. Herbal medicine and acupuncture (OR 9.22, 2.02 to 42.03, I²=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, I²=0%), herbal medicine (MD 2.68, 0.48 to 4.88, I²=79%), herbal medicine + acupuncture (MD 3.29, 0.51 to 6.07, I²=57%) and HRT + herbal medicine (MD 4.82, 3.61 to 6.02, I²=83%) were more effective in improving FSH levels compared to HRT alone.

The forest plot of E₂ indicates that all treatment modalities involved herbal medicine, including HRT + herbal medicine (MD 9.09, 5.49 to 12.70, I²=96%), HRT + herbal medicine + acupuncture (MD 28.43, 25.92 to 30.94, I²=n/a), herbal medicine (MD 8.52, 0.53 to 16.51, I²=96) and herbal medicine + acupuncture (MD 15.04, 1.06 to 29.01, I²=71%) showed higher effectiveness than HRT alone to improve E₂ 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, I²=92%), herbal medicine (MD 1.36, 0.36 to 2.36, I²=26%) and herbal medicine + acupuncture (MD 0.87, 0.14 to 1.61, I²=0%) were more superior than HRT alone.

The forest plot of AMH indicates that herbal medicine (MD 0.68, 0.22 to 1.14, I²=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.

Figure 3. Network map results of treatment comparisons based on total effective rate, serum FSH, E₂, LH and AMH levels.

A) Total effective rate. B) FSH, C) E₂, D) LH and E) AMH levels. Note: FSH, follicle-stimulating hormone; E₂, estradiol; LH, luteinizing hormone; AMH, anti-Müllerian hormone; HRT, hormone replacement therapy; Herb, herbal medicine; Catgut, catgut-embedding therapy; Acu, acupuncture; Moxa, moxibustion.

Figure 4. League table showing the results of network meta-analysis comparisons based on total effective rates, serum FSH, E₂, LH and AMH levels of all TCM treatment modalities including odds ratios (OR) and 95% credible intervals.

A) Total effective rate. B) FSH, C) E₂, D) LH and E) AMH levels. OR>1 means the top-left treatment is better. Note: FSH, follicle-stimulating hormone; E₂, 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.

Table 4. SUCRA ranking probabilities of all TCM treatment modalities for POI based on total effective rate.

Treatment	SUCRA	PrBest	MeanRank
A. 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
B. 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
C. E₂
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
D. 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
E. 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

Figure 5. SUCRA ranking probabilities of total effective rate, serum FSH, E₂, LH and AMH levels among all TCM treatment modalities.

A) Total effective rate. B) FSH, C) E₂, D) LH and E) AMH levels. Note: SUCRA, surface under the cumulative ranking curves; FSH, follicle-stimulating hormone; E₂, 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 E₂ levels

The results of the NMA showing comparisons of different treatments for the changes of E₂ levels are shown in Figure 3C. The league table results for the E₂ 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.

Table 5. Side-splitting approach of total effective rate, serum FSH, E₂, LH and AMH levels.

Side		Direct		Indirect		Difference		P>\|z\|
Side		Coef.	Std.Err	Coef.	Std.Err	Coef.	Std.Err	P>\|z\|
A. 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
B. 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
C. E₂
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
D. 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
E. 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

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).

Figure 6. Funnel plot of total effective rate, serum FSH, E₂, LH and AMH levels.

A) Total effective rate. B) FSH, C) E₂, D) LH and E) AMH levels. Note: FSH, follicle-stimulating hormone; E₂, estradiol; LH, luteinizing hormone; AMH, anti-Müllerian hormone.

However, among the outcome indicators of E₂, 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 E₂, 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 (I² > 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 studies⁹^,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.

Table 6. Compilation of SUCRA Rank for each outcome measurement in NMA.

SUCRA Rank	Outcome measurement
SUCRA Rank	Total effective rate	FSH	E₂	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

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, E₂, 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, E₂ 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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30. Sui J, Dong L: Enhancing Effect of Zhushi Tiaojing Decoction on Ovarian Blood Supply in POI Patients with Kidney Deficiency and Blood Stasis Syndrome. Shanghai Journal of Traditional Chinese Medicine. 2021; 55(11): 50-3+73.
31. Wang XW, Zhu JH, Gu ZH: Clinical efficacy of Yishen Shugan Decoction in the treatment of premature ovarian insufficiency (kidney deficiency and liver depression syndrome). Inner Mongolia Journal of Traditional Chinese Medicine. 2021; 40(01): 47–48.
32. Wang YY, Shi XH: Clinical Effect of Bushen Huoxue Prescription combined with acupuncture on patients with premature ovarian insufficiency. China Medicine and Pharmacy. 2021; 11(09): 5-8+14.
33. Tang HX, Zhou L, Chen XL, et al.: Efficacy and mechanism of Bushen Huoxue decoction combined with femotone in the treatment of premature ovarian insufficiency (kidney deficiency and blood stasis syndrome). Journal of Chinese Medicinal Materials. 2021; 44(12): 2955–2959.
34. Lin LL: Clinical Analysis of Bushen Shugan Decoction Combined with Acupoint Catgut Embedding in Treatment of Premature Ovarian Insufficiency. Journal of Practical Traditional Chinese Medicine. 2021; 37(01): 36–37.
35. Zhang H, Li WW, Zhang JT: Effects of Yishen Yangruan Decoction on ovarian reserve, expression of Bcl-2/Bax in ovarian granulosa cells and PI3K/AKT signaling pathway in patients with premature ovarian insufficiency. Guiding Journal of Traditional Chinese Medicine and Pharmacy. 2021; 27(09): 108-11+16.
36. Hou M, Gao Y, Wang Y, et al.: Clinical effect of acupuncture and moxibustion combined with piercing to the bone in the treatment of premature ovarian insufficiency. Clinical Research and Practice. 2021; 6(33): 135–137.
37. Wu Q, Liu HP, Li H, et al.: Clinical Observation of Bushenhuoxue Decoction in Treatment of Premature Ovarian Insufficiency of Kidney Deficiency Type. Hubei Journal of Traditional Chinese Medicine. 2021; 43(01): 24–27.
38. Fu WJ, Han FJ, Xu JY, et al.: Clinical Study on Treatment of POI by Harmonizing Nutrient and Defensive. Information on Traditional Chinese Medicine. 2021; 38(04): 63–66.
39. Ding AY, Cheng QL: Exploring the clinical effect of integrated traditional Chinese and Western medicine in the treatment of premature ovarian insufficiency. Diet Health. 2021; 1: 61.
40. Ma QW, Tan Y: Clinical study on sequential therapy of nourishing Yin and tonifying Yang prescription combined with Femoston in the treatment of premature ovarian insufficiency. Guangxi Journal of Traditional Chinese Medicine. 2020; 43(06): 7–10.
41. Zhao JM, Zhang AH: Clinical effect of Ziyin Shugan decoction combined with Clementine in the treatment of premature ovarian insufficiency. Henan Medical Research. 2020; 29(14): 2617–2618.
42. Luo C: Clinical observation on 30 cases of premature ovarian insufficiency with liver depression and kidney deficiency type treated by Yijing Tang. Journal of Gansu University of Chinese Medicine. 2020; 37(02): 61–66.
43. Wang TT: Effectiveness analysis of Zishen Qingxin decoction combined with acupuncture in treating premature ovarian insufficiency. Journal of Oriental Medicated Diet. 2020; 6: 87.
44. Chi L, Zhang Q: The effects of Zishen Yugui decoction on serum anti-Mullerian hormone, estradiol and follicle stimulating hormone in patients with premature ovarian insufficiency. Tianjin Medical Journal. 2020; 48(09): 886–890.
45. Liu X, Fan HF, Yang CG: Clinical effect of Bushen Yangxue Tiaojing Decoction on early-onset ovarian dysfunction. Chinese Community Doctors. 2020; 17(10): 92–104. Publisher Full Text
46. Ma K, Yuan Y, Zhang HX: Clinical efficacy of Bushen Culuan Decoction in treating infertility due to premature ovarian insufficiency. China Journal of Chinese Materia Medica. 2019; 44(06): 1075–1079.
47. Zhong WP, Ye YQ, Wang PJ, et al.: Curative effect of Bushen Huoxue decoction on premature ovarian insufficiency of type of kidney deficiency and blood stasis. Modern Journal of Integrated Traditional Chinese and Western Medicine. 2019; 28(23): 2518–2522.
48. Yuan YJ, Wang XY, Lan L: Observation on the Therapeutic Effect of Erxian Decoction on Early-onset Ovarian Insufficiency of Spleen and Kidney Yang Deficiency Type. Systems Medicine. 2019; 4(18): 130–132.
49. Li J, Zhang Y, Ding ZY: Exploration on the Efficacy and Partial Mechanism of Qingxin Zishen Decoction in Premature Ovarian Insufficiency of Heart-kidney Non-interaction Type Based on the Theory of “Heart-kidney-uterus Axis”. World Chinese Medicine. 2019; 14(09): 2349–2353.
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52. Li X: 30 Cases of Premature Ovarian Insufficiency Treated by Zi Ni Bushen Tiaochong Decoction Combined with Acupuncture. China’s Naturopathy. 2018; 26(13): 44–45.
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56. 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.
57. Sin YS, Sng KS, Chen M, et al.: 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. Publisher Full Text

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Author details Author details

¹ Shandong University of Traditional Chinese Medicine, Jinan, Shandong, 16369, China
² Department of Chinese Medicine, International Medical University, Bukit Jalil, Kuala Lumpur, 57000, Malaysia
³ Shandong University of Traditional Chinese Medicine Affiliated Hospital, Jinan, Shandong, 250014, China

Yen Suan Sin
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Software, Writing – Original Draft Preparation, Writing – Review & Editing

Min Chen
Roles: Formal Analysis, Investigation, Methodology, Validation, Writing – Review & Editing

Kim Sia Sng
Roles: Data Curation, Investigation, Methodology, Validation, Writing – Review & Editing

Jianwei Zhang
Roles: Conceptualization, Supervision, Writing – Review & Editing

Competing interests

No competing interests were disclosed.

Grant information

The author(s) declared that no grants were involved in supporting this work.

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Sin YS, Chen M, Sng KS and Zhang J. 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]. F1000Research 2023, 12:450 (https://doi.org/10.12688/f1000research.132981.1)

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Reviewer Report 04 Jun 2024

Cristina Laguna Benetti-Pinto, Department of Obstetrics and Gynecology, Universidade Estadual de Campinas, Campinas, State of São Paulo, Brazil

Not Approved

https://doi.org/10.5256/f1000research.145942.r266528

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 ... Continue reading

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

No
Is the statistical analysis and its interpretation appropriate?

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

No
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

Competing Interests: No competing interests were disclosed.

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.

CITE

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Reviewer Report 01 Sep 2023

Muhammad Shahzad Aslam, School of Traditional Chinese Medicine, Xiamen University Malaysia, Sepang, Malaysia

Approved with Reservations

https://doi.org/10.5256/f1000research.145942.r196644

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

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

Partly
Is the statistical analysis and its interpretation appropriate?

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

No

Competing Interests: No competing interests were disclosed.

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.

CITE

Report a concern

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Comments on this article Comments (0)

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VERSION 1 PUBLISHED 27 Apr 2023

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Version 1 27 Apr 23	read	read

Muhammad Shahzad Aslam, Xiamen University Malaysia, Sepang, Malaysia
Cristina Laguna Benetti-Pinto, Universidade Estadual de Campinas, Campinas, Brazil

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04 Jun 2024 | for Version 1

Cristina Laguna Benetti-Pinto, Department of Obstetrics and Gynecology, Universidade Estadual de Campinas, Campinas, State of São Paulo, Brazil

6 Views Cite this report Responses(0)

Not Approved

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

No
Is the statistical analysis and its interpretation appropriate?

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

No
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

Competing Interests

No competing interests were disclosed.

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.

Respond to this report

Responses (0)

Back to all reports

Reviewer Report

14 Views

01 Sep 2023 | for Version 1

Muhammad Shahzad Aslam, School of Traditional Chinese Medicine, Xiamen University Malaysia, Sepang, Malaysia

14 Views Cite this report Responses(0)

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

Partly
Is the statistical analysis and its interpretation appropriate?

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

No

Competing Interests

No competing interests were disclosed.

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.

Respond to this report

Responses (0)

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Identifying the most effective Traditional Chinese Medicine treatment modalities for premature ovarian insufficiency: a systematic review and network meta-analysis

Abstract

Keywords

Introduction

Methods

Search strategy and literature screening

Table 1. Search strategy.

Inclusion criteria

Exclusion criteria

Data collection

Literature quality evaluation

Statistical analysis

Results

Study selection

Figure 1. PRISMA flowchart showing steps in the selection of relevant trials.

Table 2. Characteristics and details of the included 33 RCTs.

Risk of bias of the included studies

Figure 2. Graph and summary of the risk of bias.

Results of NMA

Table 3. Pairwise meta-analysis.

Figure 3. Network map results of treatment comparisons based on total effective rate, serum FSH, E2, LH and AMH levels.

Figure 4. League table showing the results of network meta-analysis comparisons based on total effective rates, serum FSH, E2, LH and AMH levels of all TCM treatment modalities including odds ratios (OR) and 95% credible intervals.

Table 4. SUCRA ranking probabilities of all TCM treatment modalities for POI based on total effective rate.

Figure 5. SUCRA ranking probabilities of total effective rate, serum FSH, E2, LH and AMH levels among all TCM treatment modalities.

Table 5. Side-splitting approach of total effective rate, serum FSH, E2, LH and AMH levels.

Figure 6. Funnel plot of total effective rate, serum FSH, E2, LH and AMH levels.

Discussion

Table 6. Compilation of SUCRA Rank for each outcome measurement in NMA.

Conclusions

Data availability

Underlying data

Reporting guidelines

References

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Figure 3. Network map results of treatment comparisons based on total effective rate, serum FSH, E₂, LH and AMH levels.

Figure 4. League table showing the results of network meta-analysis comparisons based on total effective rates, serum FSH, E₂, LH and AMH levels of all TCM treatment modalities including odds ratios (OR) and 95% credible intervals.

Figure 5. SUCRA ranking probabilities of total effective rate, serum FSH, E₂, LH and AMH levels among all TCM treatment modalities.

Table 5. Side-splitting approach of total effective rate, serum FSH, E₂, LH and AMH levels.

Figure 6. Funnel plot of total effective rate, serum FSH, E₂, LH and AMH levels.