Comparative Effectiveness and Safety of East Asian Traditional Medicine for Adolescents with Polycystic Ovary Syndrome: A Protocol for Systematic Review and Bayesian Network Meta-Analysis

Article information

J Korean Med. 2025;46(4):139-147

Publication date (electronic) : 2025 December 1

doi : https://doi.org/10.13048/jkm.25057

Ha-Rin Kwon ¹^,^§

, Soo-Bo Shim ²^,^§

, So-Yeong Yun ¹^,³

, Eun-Young Choi ²

, Min-Kyung Kim ²

, Hye-Lim Lee ²

, Song-Baek Kim ¹^,³^,

¹Department of Obstetrics and Gynecology, College of Korean Medicine, Wonkwang University

²Department of Pediatrics, College of Korean Medicine, Daejeon University

³Department of Obstetrics and Gynecology, Wonkwang University Korean Medicine Hospital

Correspondence to: Song-Baek Kim, Dept. of Korean Medicine OB & GY, Wonkwang University Korean Medicine Hospital, 99 Garyeonsan-ro, Deokjin-gu, Jeonju-si, Jeollabuk-do, Repubic of Korea, Tel: +82-63-270-1018, Fax: +82-63-270-1594, E-mail: ksb9714@nate.com

^§

The authors contributed equally to this work as co-first authors.

Received 2025 September 8; Revised 2025 October 28; Accepted 2025 November 11.

Abstract

Objectives

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder in adolescents with significant reproductive and metabolic implications. Although East Asian traditional medicine (EATM) has shown potential in managing PCOS, no study has comprehensively compared its modalities in adolescents.

Methods

This protocol outlines a Bayesian network meta-analysis of randomized controlled trials assessing herbal medicine, acupuncture, and other EATM interventions versus conventional treatment or placebo in adolescents (≤19 years) diagnosed with PCOS. Comprehensive database searches will include PubMed, Embase, CENTRAL, and East Asian sources. Risk of bias will be evaluated using RoB2, and the certainty of evidence using CINeMA.

Results

The primary outcome will be improvement in menstrual irregularity, assessed by cycle frequency, duration, and regularity. Secondary outcomes will include changes in serum hormone levels (luteinizing hormone, follicle-stimulating hormone, estradiol, testosterone, anti-Müllerian hormone) and the incidence of treatment-related adverse events. Comparative effectiveness and safety will be estimated using a Bayesian network meta-analysis under a random-effects model; the analysis will report mean differences with 95% credible intervals, assess inconsistency with node-splitting and heterogeneity with χ² (Q), τ², and I², and rank interventions via the surface under the cumulative ranking curve.

Conclusions

This review will be the first to provide a ranked comparison of EATM interventions in adolescent PCOS. The findings are expected to guide clinical decision-making, promote safer and more effective individualized care, and support integrative approaches in adolescent PCOS management.

Keywords: Polycystic ovary syndrome; Adolescents; Traditional Korean medicine; Complementary and alternative medicine; Network meta-analysis; Protocol

Background

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that can emerge during adolescence and affect reproductive, metabolic, and psychological health¹⁾. According to recent meta-analytic findings, the prevalence of adolescent PCOS based on the Rotterdam diagnostic criteria is estimated at 11.04%²⁾, and the number of pediatric and adolescent patients receiving treatment for PCOS in Korea has shown a continuous upward trend. Notably, the total reimbursed healthcare expenditure for adolescent PCOS in Korea increased approximately 2.93-fold from 2015 to 2024³⁾.

Adolescents with PCOS frequently present with clinical signs of hyperandrogenism—such as menstrual irregularities, acne, and hirsutism—as well as metabolic abnormalities including obesity and insulin resistance^4–6). These manifestations tend to become more prominent during adolescence, a period marked by the maturation of the hypothalamic–pituitary–ovarian axis⁷⁾. Consequently, PCOS in adolescence may lead to a higher risk of long-term complications, including infertility, type 2 diabetes, dyslipidemia, non-alcoholic fatty liver disease, and hypertension. In addition, many patients experience psychological distress, such as depression, anxiety, and low self-esteem, resulting in a diminished quality of life^8–11).

Early diagnosis and intervention for PCOS during adolescence are essential for improving long-term outcomes. In recognition of this, diagnostic criteria and clinical guidelines have undergone continuous updates in recent years^12–14). However, despite these efforts, diagnostic and treatment guidelines for adolescents remain inconsistent and fragmented, with significant variability across countries and medical societies, and challenges in clinical application.

Conventional treatments include combined oral contraceptive pills as the first-line therapy, with metformin added in cases of insulin resistance or obesity. In cases where monotherapy is insufficient, anti-androgenic agents such as spironolactone or flutamide may be used as adjuncts¹⁵⁾. However, concerns regarding adverse effects and long-term safety—particularly in adolescent patients—remain a challenge in clinical decision-making¹⁶⁾.

In this context, East Asian traditional medicine (EATM)—including herbal medicine, acupuncture, and moxibustion—has garnered increasing attention as a complementary and potentially safer treatment approach. EATM emphasizes personalized, constitution-based care and addresses a wide range of symptoms such as menstrual irregularity, fatigue, acne, and emotional distress^17,18). Due to its relatively low incidence of adverse effects, EATM has attracted increasing interest among adolescents and caregivers seeking integrative and individualized options^7,19).

Although several systematic reviews have examined the effectiveness of traditional therapies in managing PCOS, most have focused on adult populations or single interventions^18,19). To date, no study has systematically compared multiple EATM modalities in adolescents using a network meta-analysis (NMA) framework. Therefore, the present study aims to evaluate the comparative effectiveness and safety of East Asian traditional medicine interventions, such as herbal medicine and acupuncture, versus conventional treatments or placebo in improving menstrual regularity and ovulation in adolescents with PCOS.

2. Methods/design

1) Study registration

This protocol for systematic review and NMA is registered on PROSPERO platform (CRD42025110 5229). This protocol was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Protocols guidelines.

2) Eligibility criteria

① Types of studies

This review will include randomized controlled trials (RCTs) only. There will be no restrictions on publication status, study setting, country, or language. Non-randomized studies, observational studies, reviews, and protocols will be excluded.

② Types of participants

We will include adolescents aged 19 or younger who have been diagnosed with PCOS according to the recommendations for adolescent in international evidence-based PCOS guideline or equivalent criteria consistent with these recommendations²⁰⁾. Trials that include both adolescents and adults will be eligible only if adolescent targeted diagnosis and treatment are specified and adolescent data are reported separately.

③ Types of interventions

Eligible interventions will include any form of EATM, such as:

- Herbal medicine (e.g., decoctions, capsules, tablets, pills, powders, or extracts),
- Acupuncture (manual, electro-, auricular),
- Moxibustion,
- Cupping therapy,
- Chuna manual therapy,
- Pharmacopuncture, Bee venom acupuncture,
- Meditation or qigong,
- Or combinations of the above.

Interventions must be administered alone or in combination with other EATM modalities, and they may also be combined with conventional treatments if the effects of EATM can be separately assessed.

④ Types of comparators

Comparators may include:

- Placebo or sham interventions,
- Conventional medical treatments, such as: Combined oral contraceptive pills (COCPs), Insulin sensitizers (e.g., metformin), Ovulation inducers (e.g., clomiphene, letrozole), Anti
-androgenic agents (e.g., spironolactone),
- Or other traditional interventions.

⑤ Types of outcome measurement

- Primary outcome: Improvement in menstrual irregularity, as measured by cycle frequency, duration, and regularity.
- Secondary outcomes: Changes in serum hormone levels (Luteinizing hormone, Follicle-stimulating hormone, Estradiol and possibly others (e.g., testosterone, AMH).), improvement in ovulatory function, reduction of hyperandrogenic symptoms (e.g., acne and hirsutism).
- Incidence of adverse events related to treatment.

3) Data sources and search strategy

We will search the following electronic bibliographic databases: MEDLINE (via PubMed), Embase.com, Cochrane Central register of controlled trials (CENTRAL), and CINAHL. Additional searches will be conducted in East Asian databases, including OASIS, KMbase, KISS, RISS, Korean Medical Database, KCI, CNKI, Wanfang Data, CQVIP, CiNii, and J-Stage. There will be no restrictions on publication language or start date. Articles published up to 21 July 2025 will be considered. Other sources will include citation tracking, checking reference lists of included studies, searching trial registries and dissertation databases, and contacting study authors or field experts. Only published studies will be included in the final analysis.

Two researchers will independently search the electronic bibliographic databases. The Medline database search strategy is described in Table 1, and the modified search strategy will be used in other databases (Supplementary table S1).

Table 1

Search Strategy for Medline

4) Study selection

Two reviewers will independently screen titles and abstracts for eligibility, followed by full-text assessment of potentially eligible studies. Disagreements will be resolved through discussion or by consulting a third reviewer. The selection process will follow the PRISMA guideline for NMA (Figure 1). This flow diagram will be updated and finalized during the actual literature screening and selection process.

Fig. 1

A PRISMA flow diagram of the literature screening and selection process.

* Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers).

** If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools.

5) Data extraction

Data will be extracted independently by at least two reviewers using a standardized form. Extracted data will include study characteristics (authors, year, country), participant characteristics, diagnostic criteria, intervention and comparator details, outcomes, and adverse events. Authors will be contacted to provide missing or unclear data when necessary. Discrepancies will be resolved by consensus.

6) Assessment of risk of bias in included studies

The Cochrane Risk of Bias tool version 2 will be used to assess the methodological quality of each included RCT. Two reviewers will perform this assessment independently, and any disagreements will be resolved through discussion. For studies with missing information, study authors will be contacted for clarification.

7) The conventional pairwise meta-analysis

Pairwise meta-analyses will be conducted using R software (version 4.2.3) with the ‘meta’ (version 8.2-0) and the ‘metafor’ package (version 4.8-0). For dichotomous outcomes, relative risks with 95% confidence intervals (CIs) will be calculated. For continuous outcomes, mean differences (MDs) with 95% CIs will be used. Heterogeneity will be assessed using the χ² test and I² statistic. A fixed-effect model will be used if heterogeneity is low (I² < 50%), and a random-effects model will be adopted when heterogeneity is substantial (I² ≥ 50%). Subgroup or meta-regression analyses will be considered only if substantial heterogeneity (I² > 75% or τ² large) is observed.

8) The network meta-analysis

The network meta-analysis will be performed using a Bayesian approach with the ‘gemtc’ (version 1.1-0) and ‘rjags’ (version 4-17), ‘XML’ (version 3.99-0.18), “slam” (version 0.1-55), and “netmeta” (version 3.2-0) R packages. Markov Chain Monte Carlo simulation will be used to generate pooled effect estimates. A random-effects model will be used for data synthesis to account for potential between-study variability. The effects of interventions will be summarized using MDs with 95% credible intervals (CrI). Inconsistency will be assessed using the node-splitting method. Statistical heterogeneity will be assessed using the χ² test of Q, τ², and I² statistics. Herbal medicine will be classified as individual nodes according to each single or compound formula, while acupuncture, moxibustion, cupping, chuna, pharmacopuncture, and bee venom acupuncture will be treated as separate nodes. If considerable differences in dosage or administration are identified within the same intervention, they will be analyzed as distinct nodes. Rankings of interventions will be evaluated using the surface under the cumulative ranking curve. If sufficient studies are available, funnel plots will be constructed to assess potential publication bias.

9) Meta-biases

We will assess the risk of reporting bias due to missing results, including publication bias and selective outcome reporting. If sufficient studies are available, we will explore the possibility of small-study effects through visual inspection of funnel plots and relevant statistical methods.

10) Rating the confidence in estimates of the effect in Network meta-analysis

The certainty of evidence for each outcome will be assessed using the CINeMA (Confidence in Network Meta-Analysis) framework, which is based on GRADE principles. The following six domains will be evaluated: within-study bias, reporting bias, indirectness, imprecision, heterogeneity, and incoherence.

11) Ethical statement

This study is a systematic review and bayesian NMA of previously published data. As it does not involve human subjects or the collection of personal information, institutional review board review was not required.

Discussion

This study is the first network meta-analysis to compare the effectiveness and safety of EATM interventions for managing PCOS in adolescents. By integrating both direct and indirect evidence, it aims to offer a ranked comparison of herbal medicine, acupuncture, and conventional treatments, addressing the current gap in adolescent-specific PCOS management. Prior systematic reviews have primarily relied on pairwise meta-analyses^21,22), limiting their ability to compare multiple interventions concurrently. Although a few studies have employed network meta-analysis^23,24), these have predominantly focused on adult women, and a comprehensive evaluation specific to adolescents has not yet been reported.

Clinically, this study is expected to support personalized traditional medicine approaches for managing adolescent PCOS. By comparing and ranking interventions at a network level across multidimensional domains—including not only menstrual irregularities but also emotional distress, metabolic imbalance, and quality of life—it may provide actionable guidance for clinical decision-making.

A potential limitation is the restricted eligibility of randomized controlled trials exclusively targeting adolescents. Given the diagnostic complexities unique to this age group, our preliminary scoping suggests that some trials applied adult-based criteria, which may not align with adolescent-appropriate definitions and could ultimately reduce the number of studies included. Moreover, for herbal interventions, clinical heterogeneity is anticipated due to differences in formula composition, dosage, formulation, and treatment duration. Accordingly, network inconsistency will be assessed using node-splitting analyses, and sensitivity and subgroup analyses will be performed to test the robustness of the findings.

Despite these limitations, this study constitutes the first protocol to systematically evaluate the comparative effectiveness and safety of East Asian traditional medicine interventions in adolescents with PCOS. It will help build the evidence base for future trials and guideline development and provides a foundational step toward identifying appropriate and safe therapeutic alternatives for adolescents affected by PCOS.

Supplementary Information

jkm-46-4-139-Supplementary-Table-S1.pdf

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