Effectiveness and Safety of Guizhi Fuling Wan (Keishibukuryogan) on Prostate Diseases: A Systematic Review and Meta-Analysis

Abstract

Objective:

Aiming at evaluating the effectiveness and safety of Guizhi Fuling Wan or Keishibukuryogan (GZFL) on prostate diseases, to provide available synthesized evidence for clinical application.

Methods:

Randomized controlled trials (RCTs) were identified from English, Chinese, Japanese, and Korean electronic databases, the search date ranged from the inception of databases to July 2024. Rev-Man 5.4.1 software was applied in the analysis of extracted data.

Results:

23 studies were included in the meta-analysis, 12 studies on chronic prostatitis(CP) and 11 studies on benign prostatic hyperplasia (BPH). The synthesized results showed that GZFL had a significantly higher effective rate compared to the control group both in BPH (risk difference [RD] = 0.14, 95% confidence interval [CI] [0.10, 0.18], p < 0.00001) and CP (RD = 0.19, 95% CI [0.14, 0.23], p < 0.00001). It reduced the International Prostate Symptom score (mean difference [MD] = −3.19, 95% CI [−5.35, −1.02], p = 0.004) and NIH Chronic Prostatitis Symptom Index score (MD = −4.09, 95% CI [−5.04, −3.15], p < 0.00001), It also had a significant effect on reducing postvoid residual urine (MD = −6.73, 95% CI [−10.12, −3.33], p = 0.0001), prostate volume (MD = −2.59, 95% CI [−4.39, −0.80], p = 0.005), and increasing maximum urinary flow rate (MD = 1.61, 95% CI [1.11, 2.10], P < 0.00001). A few studies have also reported its therapeutic effects on prostate cancer. No severe adverse effects were reported.

Conclusion:

GZFL is effective and safe for BPH and CP in alleviating symptoms, improving scale scores. Rigorously designed clinical trials are necessary for further clinical application.

Keywords

East Asian traditional medicine Guizhi Fuling Wan Keishibukuryogan prostate diseases meta-analysis

Introduction

Prostate disease is one of the main clinical diseases that threatens the health of male patients. The most common prostate diseases include chronic prostatitis (CP), benign prostatic hyperplasia (BPH), and prostate cancer (PC). Meanwhile, two kinds of prostate diseases can also occur simultaneously in the clinic. It has been found that patients with prostatitis have a higher risk of being diagnosed with BPH¹ and PC² compared with the general population. Prostate diseases have become a significant global health burden. Beyond causing symptoms related to the urinary and reproductive systems, such as frequent urination, pelvic pain, urinary retention, renal insufficiency, and sexual dysfunction, it also causes abnormalities in other systems, leads to gastrointestinal symptoms, and contributes to mental and psychological issues, which have a substantial negative impact on patients’ overall health and quality of life (QoL).

Epidemiological studies indicate that the prevalence of prostatitis symptoms in China ranges from 6.0% to 32.9%.³ In contrast, international reports based on population studies show a prevalence of prostatitis symptoms between 1.7% and 9.7%.^4,5 The incidence of BPH begins to rise around the age of 45, reaching 50%−60% over 60 years old, and increasing to 80%−90% over 70.⁶ According to the Global Cancer Statistics 2020 report,⁷ there were approximately 1.435 million new cases of PC worldwide in 2020, ranking second in the incidence of male malignant tumors. PC was the second leading cause of cancer-related deaths among men in the United States in 2021.⁸ The clinical etiology of prostate diseases is complex, with a wide range of symptoms and associations with various factors, including aging, infections, heredity, neuroendocrine factors, psychological abnormalities, oxidative stress, and pelvic-related disorders. It is also possible for two prostate diseases to occur concurrently in clinical practice.^9–12 The pathogenesis of prostate diseases has not been completely clarified, and in terms of treatment, pharmacotherapy is mainly aimed at alleviating symptoms.^13,14

Medications for CP and BPH include α-receptor blockers, M-receptor blockers, and β3-receptor agonists. Common adverse effects include dizziness, headache, abnormal ejaculation, dry mouth, constipation, dysuria, hypertension, and nasopharyngitis. For BPH, 5α-reductase inhibitors are effective in reducing the production of dihydrotestosterone and prostate volume (PV). Common side effects include sexual dysfunction, decreased libido, gynecomastia, etc. Surgery can be used for the treatment of BPH and PC; however, its use is limited by preoperative contraindications and postoperative complications such as urethral stricture, residual gland hyperplasia, and urinary incontinence.¹⁵ Due to the limited efficacy of single medication or therapy, combined therapy has become a common treatment regimen for prostate disease.

In recent years, a number of clinical and fundamental research on the efficacy of prostate diseases with traditional medicine have been published, which have pointed out that traditional medicine improved patients’ symptoms and related detection indexes through multiple mechanisms and targets.^16–25 Many clinical studies have indicated that the pathogenesis of blood stasis syndrome plays an important role in the occurrence and progression of prostate diseases. One study²⁶ involving 400 patients with prostatitis, investigated the composition proportion of Traditional Chinese Medicine (TCM) syndrome types and found that 146 cases (36.5%) had a blood stasis syndrome, making it one of the predominant syndrome types. Another study²⁷reported that, among 200 patients with BPH, 54 cases (27%) had a blood stasis syndrome, which was positively correlated with the International Prostate Symptom Score (IPSS) and negatively correlated with residual urine volume. The latest Chinese guidelines^28,29 also recognize blood stasis syndrome as one of the major syndrome types in prostate diseases, and Guizhi Fuling Wan (GZFL) is recommended as a Chinese patent medicine for blood stasis syndrome.

GZFL, also known as Keishibukuryogan in Japan and Gyejibokryeonghwan in Korea, is one of the foundational classics guiding syndrome differentiation and treatment in TCM. The formula consists of Cinnamomi Ramulus, Poria, Radix Paeoniae Rubra, Cortex Moutan, and Persicae Semen, and is known for its effects in activating blood circulation, resolving blood stasis, warming the meridians, and relieving obstruction. Pharmacological research has demonstrated that GZFL has sedative, analgesic, anti-tumor, anti-inflammatory, immune-enhancing,^30–33 and neuroprotective effects through mechanisms such as antioxidant activity,³⁴ inhibition of inflammatory cytokines, suppression of adrenaline secretion, inhibition of monoamine oxidase transport, and relaxation of vascular smooth muscle, with no severe adverse effects having been reported.^18,35–37GZFL was initially applied in gynecology and obstetrics for patients with blood stasis syndrome, it has been commonly used in the treatment for menoxenia, dysmenorrhea, menopausal disorders, endometrial myoma and so on.^35,38 In recent years, there has been a growing number of studies reporting the efficacy and mechanisms of GZFL for patients with prostate diseases, most of the researches were conducted in China, Japan, and Korea. This study aims to investigate and evaluate the efficacy and safety of GZFL in the treatment of prostate diseases, providing a reference for further clinical application and research.

Methods

Registration: The protocol of this systematic review has been registered in PROSPERO (Registration Number: CRD42024555323).

Inclusion criteria

Types of trials

The data from randomized clinical trials were extracted to conduct a meta-analysis, and the non-RCTs, comparative observational studies, and case reports were systematically reviewed.

Types of patients

Adult patients with diagnosed prostate diseases according to standardized diagnostic criteria, including IPSS/AUA criteria (for BPH), NIH Chronic Prostatitis Symptom Index (NIH-CPSI) criteria (for prostatitis), Histopathology (for PC), etc.

Types of interventions

The intervention of included trials will be “桂枝茯苓丸” in Chinese and Japanese, Guizhi Fuling Wan; Keishibukuryogan; Gyejibokryeonghwan in English, “계지복령환” in Korean, which was administered alone or combined with other medications.

Types of outcomes

Main outcomes included: (1) Symptom scores, BPH: IPSS; Prostatitis: NIH-CPSI; PC: EPIC-26 urinary domain score. (2) Clinical laboratory indicators, maximum urinary flow rate (Qmax); postvoid residual urine volume (PVR); prostate-specific antigen (PSA); PV. (3) QoL assessments.

Secondary outcomes are as follows: adverse events, compliance, and follow-up.

Search strategy

Literature searching covered English, Chinese, Japanese, and Korean electronic databases, including PubMed, Web of Science, EMBASE, The Cochrane Library, China National Knowledge Infrastructure, Wanfang Data, Japan Medical Abstracts Society, Korea Citation Index, Korean studies information service system, and the search date ranges from the inception of databases to July 2024. Medical subject headings combined with text word searching were performed. Manual searches have been performed to supplement the electronic searches, including screening of reference lists in both included studies and relevant review articles.

Data collection and analysis

Selection of trials and data extraction

Trials selection was performed independently by three researchers (Yunxia Wang, Hongyang Li, Yaxuan Jiang), and the unified scale and cross-checking were conducted (Yunxia Wang, Yaxuan Jiang). The decision to include a controversial trial was made by a fourth researcher (Keiko Ogawa). The entire process was performed according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow diagram.

Assessment of risk of bias

The newest version risks of bias assessment tool (Version 2 of the Cochrane tool for assessing risk of bias in randomized trial, RoB2) was conducted for assessing the risk of bias of the trials included, which consists of randomization process, timing of identification or recruitment of participants, deviations from the intended interventions, missing outcome data, measurement of the outcome, selection of the reported result.

Measures of treatment effect

Extracted data were analyzed by the Rev-Man 5.4 software provided by the Cochrane collaboration, for dichotomous variables, 95%confidence intervals (95% CI), and risk difference (RD) were reported, meanwhile, for a continuous variable, 95% CI and mean difference (MD) were reported.

Assessment of heterogeneity and data synthesis

Q-statistic and I² statistic were performed to evaluate statistical heterogeneity. Data were assessed by the fixed effects model when there was no significant heterogeneity (p >0.10, I² < 50%). Otherwise, the data were assessed by the random effects model (p < 0.10, I² > 50%).

Assessment of reporting bias

When the included trials were more than 10, publication bias was assessed by a funnel plot.

Subgroup analysis and sensitivity analysis

Subgroup analysis and sensitivity analysis will be conducted when there is significant heterogeneity.

Results

Fow of literature screening

The database search results found 521 articles (Fig. 1). After removing duplicates, reviews, and clinical studies that did not meet the inclusion criteria, a total of 31 trials were included, 23 RCTs of which (published in Chinese) were included in the meta-analysis, comprising 11 trials on CP and 12 trials on BPH. Since only one randomized controlled trial (published in English) on PC was identified, a meta-analysis was not conducted (Table 1). While seven trials were case reports and observational studies, three were published in Japanese, two in English, one in Chinese, and one in Korean (Table 2).

FIG. 1.

Flow of literature screening.

Table 1.

Characteristics of the Included Trials

Author (year)	Country	Sample size	Mean age(I/C)	Diagnosis	Intervention	Control	Duration	Outcome measures	Adverse events(I/C)	Drop out (I/C)	Follow-up (I/C)
Benign prostatic hyperplasia
Gong, 2014³⁹	China	286	64.61 ± 5.74/65.73 ± 5.92	BPH	GZFL+EXT^a	Terazosin hydrochloride	28 days	①②⑤⑥⑧	/	N	/
Gao, 2011⁴⁰	China	70	64.50 ± 6.26/65.40 ± 7.04	BPH	GZFL+doxazosin	doxazosin	56 days	②④⑦	5/3	1/2	/
Liu, 2019⁴¹	China	126	52 ± 6/51 ± 6	BPH	GZFL	longBiShuJiaoNang	2 months	①	/	N	/
Zhan, 2006⁴²	China	83	64.3 ± 7.2/64.6 ± 7.5	BPH	GZFL+THCQ^a	Pule’an Pian	14 days	①	/	N	/
Yang, 2014⁴³	China	94	61 ± 12.6/60 ± 12.4	BPH	GZFL+SJS^a	longBiShuJiaoNang	60 days	①	/	N	/
Jing, 2016⁴⁴	China	84	55–84/56–83	BPH	GZFL+Finasteride	Finasteride	56 days	①	/	N	/
Luo, 2023⁴⁵	China	90	55.38 ± 5.39/55.29 ± 5.29	BPH	GZFL+JPBSHXT^a	QianLieShuTongJiaoNang	14 days	①④⑤	/	N	/
Li, 2015⁴⁶	China	40	/	BPH	GZFL+SJS^a	longBiShuJiaoNang	2 months	①	/	N	/
Yu, 2017⁴⁷	China	80	64.6 ± 11.2/63.7 ± 10.6	BPH	GZFL+Tamsulosin Hydrochloride	Tamsulosin hydrochloride	28 days	①④⑤⑥	/	N	/
Liu, 2010⁴⁸	China	80	63.36 ± 5.87/65.65 ± 8.39	BPH	GZFL+ZWT^a	Finasteride	2 months	①	/	N	/
Huang, 2022⁴⁹	China	60	62.65 ± 7.37/62.48 ± 7.26	BPH	GZFL+Finasteride	Finasteride	2 months	②⑤⑥	N	N	/
Zhang, 2017⁵¹	China	82	63.4 ± 4.6/62.6 ± 3.5	BPH	GZFL+ZLT^a+Tamsulosin	Tamsulosin	2 months	①②⑤⑥⑦	/	N	/
Chronic prostatitis
Wu, 2021⁵²	China	104	36.12 ± 5.31/35.92 ± 5.46	CPIII	GZFL+DCH^a	Pule’an Jiaonang	28 days	①⑨	N	N	/
Xie, 2014⁵³	China	102	34.1 ± 5.5/33.6 ± 5.7	CP	GZFL	Levofloxacin	1 month	①	2/7	N	/
Zhang, 2017⁵⁰	China	84	32.18 ± 6.34/31.25 ± 5.21	CPIII	GZFL+ZLT^a	Levofloxacin+Terazosin	2 months	①③	/	N	/
Wang, 2004⁵⁴	China	80	/	CP	GZFL	Levofloxacin	20 days	①	/	N	/
Liu, 2018⁵⁵	China	80	41.21 ± 1.02/40.28 ± 1.02	CP	GZFL+YYFZBJS^a	Wenglitong	/	①	/	N	/
Wang, 2007⁵⁶	China	180	26.09 ± 7.42/26.23 ± 7.37	CP	GZFL+YYFZBJS^a	Wenglitong	56 days	①	N	N	/
Lan, 2013⁵⁷	China	160	33.6/36.5	CP	GZFL+JPY^a	Levofloxacin	1 month	①	/	N	/
Long, 2014⁵⁸	China	120	29.8 ± 7.4/30.2 ± 6.9	CPIII	GZFL	QianlieAnshuan	28 days	③	/	N	/
Hu, 2009⁵⁹	China	120	36.1 ± 10.1/34.6 ± 8.9	CP	GZFL	Qianliekangpian	56 days	①③	/	N	/
Zhao, 2021⁶⁰	China	39	35.47 ± 6.97/32.65 ± 6.74	CPIII	GZFL	Tamsulosin hydrochloride	42 days	①③⑨	0/1	1/0	2 Months 2(16.7%)/3（25.0%）
Jia, 2024⁶¹	China	122	44.21 ± 5.68/43.65 ± 5.42	CP	GZFL+Tamsulosin Hydrochloride	Tamsulosin Hydrochloride	56 days	①③④⑤⑨	N	N	3 Months 3 (7.1%)/7 (24.1%)
Prostate cancer
Koga, 2017⁶²	Japan	70	68/69	CRPC	GZFL+HCEK^a+PPV	personalized peptide vaccination (PPV)	50 days	⑩⑪⑫⑬	No Severe AE	3/4	not clear

Administrated with other traditional patent medicines.

/, not mention.

①Effective rate ②International Prostate Symptom Score ③National Institutes of Health chronic prostatitis symptom index ④maximum urinary flow rate ⑤postvoid residual urine volume ⑥Prostate volume ⑦QOL ⑧MFR ⑨EPS ⑩Peptide-specific ⑪Regulatory T cells ⑫Monocytic myeloid-derived suppressor cells ⑬Interleukin-6.

AE, adverse effect; BPH, Benign prostatic hyperplasia; CP, chronic prostatitis; DCH, Daichaihu Tang; EPS, expressed prostatic secretion; EXT, Erxian Tang; GZFL, Guizhi Fuling Wan; JPBSHXT, Jianpi Buqi Huoxue Tang; JPY, Jinpu Yin; HCEK, Hochu Ekki To; MFR, Maximum Flow Rate; N, none; QOL, quality of life; SJS, Shenjiang San; THCQ, Taohe Chenqi Tang; YYFZBJS, Yiyi Fuzi Baijiang San; ZWT, Zhenwu Tang; ZLT, Zhuling Tang.

Table 2.

Characteristics of Case Reports and non-RCTs

Author (year)	Country	Sample size	Diagnosis	Age	Intervention	Duration	Outcome measures	Results	Adverse events	Follow-up
Ikeuchi, 1990⁶³	Japan	61/82	CP/PLS	36.3/38.5	GZFL	28 days	effect rates	(19)76%/(20)62.5%	5/57	/
Otsuka, 2009⁶⁴	Japan	21	CPIII	49.3 ± 16.2	GZFL+ZLT	56 days	effect rates	(12)85.7%	/	/
Ikeuchi, 1991⁶⁵	Japan	49/55	CP/PLS+anal disease	41.9	GZFL	/	effect rates	(35)71.4%/(32)58.2%	/	/
Lee, 2020⁶⁶	Korea	1	CP/CPPS	41	GZFL	4 months	NIH-CPSI	NIH-CPSI and Pelvic pain decreased significantly	N	/
Shigehara, 2020⁶⁷	Japan^b	30	PC	69.5 ± 6.0	GZFL	12 weeks	VAS, AMS, TT, PSA	VAS* AMS* PSA TT	N	/
Zhang, 2022⁶⁸	China^b	1	PC	69	GZFL+SNS^a	21 days	abdominal CT, PSA	The maximum diameter of the tumor decreased PSA**	/	/
Zhao, 2015⁶⁹	China	60	BPH	44–79	GZFL	40 days	effect rates	(57)95%	/	/

Administrated with other traditional patent medicines.

published in English.

*p < 0.05; **p >0.05.

/, not mention.

AMS, aging male symptoms Scale; BPH, Benign prostatic hyperplasia; CP, chronic prostatitis; CPPS, chronic pelvic pain syndrome; GZFL, Guizhi Fuling Wan; NIH-CPSI, NIH Chronic Prostatitis Symptom Index; PLS, prostatitis-like syndrome; PSA, prostate specific antigen; RCTs, randomized controlled trials; SNS, Sini San; TT, total testosterone; VAS: visual analog Scale; ZLT, Zhuling Tang.

Characteristics of the included studies

Twenty-three of the RCTs were conducted in China, and one was in Japan.^{39–50,51–62} All trials clarified no statistically significant differences in baseline characteristics such as age, gender, and scale scores. Regarding interventions, GZFL was often combined with other traditional medicines in studies on BPH, while approximately half of the studies on CP applied GZFL alone. The most commonly used medications in the control groups were Levofloxacin (n = 4), Tamsulosin (n = 4), Finasteride (n = 3), and the traditional Chinese patent medicine Long Bi Shu Jiao Nang (n = 3). The treatment duration ranged from two weeks to two months, and the dosage and crude drug components of GZFL are sorted in Table 3.

Table 3.

The Dosage Regimen and Crude Drug Components of GZFL

Author (year)	Country	Crude drug components(gram)					Dosage regimen
Author (year)	Country	Cinnamomi ramulus	Poria	Paeoniae radix rubra	Moutan cortex	Persicae semen	Dosage regimen
Benign prostatic hyperplasia
Gao, 2011⁴⁰	China	10	30	15	10	10	1 decoction/day, 8 weeks
Liu, 2019⁴¹	China	15	15	15	10	15	1 decoction/day, 2 months
Zhan, 2006⁴²	China	12	30	15	12	12	1 decoction/day, 2 weeks
Jing, 2016⁴⁴	China	15	15	15	15	15	1 decoction/day, 8 weeks
Luo, 2023⁴⁵	China	equal parts					6g, twice/day, 2 weeks
Yu, 2017⁴⁷	China	exact dosage not specified					6g, twice/day, 4 weeks
Huang, 2022⁴⁹	China	15	15	15	10	10	1 decoction/day, 2 months
Zhang, 2017⁵¹	China	15	25	25	15	15	1 decoction/day, 2 months
Gong, 2014³⁹	China	10	15	10	15	10	1 decoction/day, 28 days
Yang, 2014⁴³	China	10	15	—	—	12	1 decoction/day, 30 days
Li, 2015⁴⁶	China	10	15	—	—	12	1 decoction/day, 1 month
Liu, 2010⁴⁸	China	30	20	10 (Paeoniae Radix Alba)	15	15	1 decoction/day, 2 months
Zhao, 2015⁶⁹	China	12	15	15	10	10	1 decoction/day, 40 days
Chronic prostatitis
Wu, 2021⁵²	China	9	15	15	15	15 + 15(Paeoniae Radix Rubra/Alba)	1 decoction/day, 4 weeks
Xie, 2014⁵³	China	10	15	15	—	15	1 decoction/day, 1 month
Wang, 2004⁵⁴	China	12	12	12	12	12	1 decoction/day, 20 days
Long, 2014⁵⁸	China	12	15	12	10	10	1 decoction/day, 4 weeks
Hu, 2009⁵⁹	China	5	15	15	12	10	1 decoction/day, 8 weeks
Zhao, 2021⁶⁰	China	15	15	15	15	10	1 decoction/day, 6 weeks
Jia, 2024⁶¹	China	15	15	15	15	15	1 decoction/day, 4 weeks
Ikeuchi, 1990^a,63	Japan	exact dosage not specified					3 packets/day, 28 days
Ikeuchi, 1991^a,65	Japan	exact dosage not specified					3 packets/day, 28 days
Lee, 2020^a,66	Korea	0.5	0.5	0.5	0.5	0.5	2.5g, 3 times/day, 4 months
Ohtsuka, 2009^a,64	Japan	exact dosage not specified					3g, twice/day, 8 weeks
Zhang, 2017⁵⁰	China	15	15	25	15	15	1 decoction/day, 1 month
Liu, 2018⁵⁵	China	6	12	16	10	11	1 decoction/day
Wang, 2007⁵⁶	China	5	15	15	15	10	1 decoction/day, 8 weeks
Lan, 2013⁵⁷	China	12	12	12	12	12	1 decoction/day, 1 month
Prostate cancer
Koga, 2017^a,62	Japan	equal parts					2.5g,3 times/day, 50 days
Shigehara, 2020^a,67	Japan	exact dosage not specified					2.5g,3 times/day, 12 weeks
Zhang, 2022⁶⁸	China	5	15	15	10	10	1 decoction/day, 21 days

Paeoniae Radix.

In terms of outcome measures, the effect rate was the most frequently reported indicator. Six trials reported PVR. NIH-CPSI and Qmax were each reported in five trials. four trials reported IPSS, PV, and expressed prostatic secretion. Adverse events were reported in eight trials, with no severe adverse effects pointed out. Dropout rates were reported in three trials, and two trials on CP reported follow-ups, showing lower recurrence rates in the intervention groups compared to the control groups.

Risk of bias of the included trials and methodological quality

In the included trials, one study did not mention the grouping method, and 13 studies claimed to have used random group allocation, but did not specify the random grouping method (Fig. 2). None of the included studies provided details about blinding or its implementation. Except for one study, all included studies reported the predetermined outcomes. Due to the lack of detailed information, the risk of bias in outcome measurement and reporting was difficult to assess accurately.

FIG. 2.

Risk of bias of the included trials. , Low risk; , Some concerns; , High risk; Dla Randomization process; D1b, Timing of identification or recruitment of participants; D2, Deviations from the intended interventions; D3, Missing outcome data; D4, Measurement of the outcome; D5, Selection of the reported result.

Benign prostatic hyperplasia

Effect rates

A total of 10 trials reported the effective rate (Fig. 3), which was calculated as the sum of patients who were either cured or showed improvement, excluding those with no effect. The synthesized results showed that GZFL had a significantly higher effective rate compared to the control group (RD = 0.14, 95% CI [0.10, 0.18], p < 0.00001). The I² test indicated low heterogeneity among the included studies. An analysis of publication bias was conducted for the included trials, the distribution of the included trials was relatively symmetrical, and no significant publication bias was indicated. Subgroup analysis showed that both GZFL monotherapy (one trial of GZFL alone and four trials of GZFL combined with the control Western medications) and GZFL combined with other traditional Chinese medicine formulas (differing from the control groups) demonstrated superior efficacy versus the control groups, and with no significant difference between monotherapy and combination subgroups.

FIG. 3.

Forest plot and Funnel plot of Effect rate for benign prostatic hyperplasia (BPH).

International prostate symptom score

A total of four trials reported the results of IPSS (Fig. 4), and the synthesized results showed that GZFL could reduce the total IPSS (MD = −3.19, 95% CI [−5.35, −1.02], p = 0.004) and storage symptom score (MD = −1.93, 95% CI [−3.66, −0.20], p = 0.03), while no significant reduction was observed in the voiding symptom score (MD = −0.14, 95% CI [−0.60, 0.32], p = 0.55). The I² test indicated high heterogeneity among the studies for the total IPSS (I² = 92%, p < 0.00001) and storage symptom score (I² = 81%, p = 0.02), while low heterogeneity was observed for the voiding symptom score (I² = 0%, p = 0.66). Sensitivity analysis was conducted to explore the sources of high heterogeneity in the total IPSS, after removing Gong 2014, the result of I² test reduced significantly (I² = 59%, p = 0.12), the synthesized results were (MD = −4.24, 95% CI [−5.39, −3.10], p < 0.00001), indicating that the high heterogeneity may be due to the difference in sample sizes between studies. The synthesized results still showed statistical differences, suggesting that the combined results are stable.

FIG. 4.

Forest plot of International Prostate Symptom Score.

Prostate volume, postvoid residual urine volume, and the maximum flow rate

Five trials reported PVR, four trials reported PV and Qmax were reported in three trials (Fig. 5). The synthesized results showed that GZFL significantly reduced PVR (MD = −6.73, 95% CI [−10.12, −3.33], p = 0.0001) and decreased prostate volume (MD = −2.59, 95% CI [−4.39, −0.80], p = 0.005), while it increased Qmax (MD = 1.61, 95% CI [1.11, 2.10], P < 0.00001). The I² test revealed high heterogeneity in the PVR (I² = 94%, p < 0.00001), and in the PV (I² = 76%, p = 0.005), while low heterogeneity in the Qmax (I² = 43%, P = 0.15).

FIG. 5.

Forest plot of postvoid residual urine volume (PVR), prostate volume (PV), maximum urinary flow rate (Qmax).

A sensitivity analysis was performed where trials were removed one by one. In the synthesized results for PVR, the heterogeneity significantly decreased after the study by Huang (2022) was excluded (I² = 61%, p = 0.05). In the synthesized results for PV, the heterogeneity significantly decreased after the study by Zhang (2017) was removed (I² = 65%, p = 0.06), suggesting that the differences in sample sizes and the limited number of the included trials were most likely the main source of heterogeneity. After removing specific studies, the synthesized results for PVR and PV were (MD = −5.41, 95% CI [−7.02, −3.81], p < 0.00001) and (MD = −3.27, 95% CI [−4.96, −1.58], p = 0.0002), respectively, which were still significantly decreased, indicating that the synthesized results are stable.

Chronic prostatitis

Effect rates

A total of 10 CP trials reported an effective rate (Fig. 6). The synthesized results indicated that GZFL had a better effective rate compared to the control group (RD = 0.19, 95% CI [0.14, 0.23], p < 0.00001). The I² test showed low heterogeneity among the included studies. An analysis of publication bias was conducted for the included studies. Except for the study Zhao (2021) at the lower end, which had a small sample size and might cause bias, the distribution of the other studies was relatively symmetrical, indicating no significant publication bias. Subgroup analysis showed that both GZFL monotherapy (five trials of GZFL alone and one trial of GZFL combined with the control Western medications) and GZFL combined with other traditional Chinese medicine formulas (differing from the control groups) demonstrated superior efficacy versus the control groups, and with no significant difference between monotherapy and combination subgroups.

FIG. 6.

Forest plot and Funnel plot of Effect rate for chronic prostatitis (CP).

The National Institutes of Health CP symptom index

A total of five trials reported the NIH-CPSI (Fig. 7). The synthesized results showed that GZFL could significantly reduce the NIH-CPSI total score (MD = −4.09, 95% CI [−5.04, −3.15], p < 0.00001), improve urinary function scores (MD = −0.64, 95% CI [−1.15, −0.13], p = 0.01), and enhance QoL scores (MD = 0.93, 95% CI [0.34, 1.52], p = 0.002). However, there was no significant reduction in pain symptom scores (MD = −0.67, 95% CI [−2.63, 1.29], p = 0.50). The I² test indicated moderate heterogeneity among the included studies for the NIH-CPSI total score and pain scores, while urinary function scores and QoL scores showed lower heterogeneity. All trials included involved GZFL monotherapy, except one trial that combined GZFL with tamsulosin hydrochloride (control: tamsulosin hydrochloride).

FIG. 7.

Forest plot of National Institutes of Health chronic prostatitis symptom index.

Case reports

Since all the included RCTs were conducted in China, to provide a comprehensive perspective, the non-RCTs and case reports conducted in countries outside of China, as well as those conducted in China within the past 10 years, were summarized^63–69 (Table 2). For BPH and CP, GZFL was reported to have an effective rate ranging from 58.2% to 95%. A case report from Korea on CP found significant reductions in NIH-CPSI scores and pelvic pain after administration of GZFL. A study from Japan on PC reported that GZFL effectively improved indicators related to hot flushes in PC patients receiving androgen deprivation therapy, significantly reducing their intensity, frequency, and duration, while PSA and total testosterone levels remained unchanged. A case report from China on PC observed symptom improvement and a reduction in tumor size after the administration of GZFL.

Side effects

A total of 11 trials reported adverse effects (5 trials employed GZFL only, three trials applied GZFL combined with control Western medication). No adverse effects were observed in six trials. A study on BPH of Gao (2011) noted mild dizziness in 3 patients from the intervention group and the control group, as well as mild diarrhea in two patients from the intervention group. A study on CP by Zhao (2021) reported mild dizziness in one patient from the control group, while another study by Xie (2014) did not specify the details of the observed adverse effects. A Japanese study of Ikeuchi (1990) reported two cases of gastrointestinal symptoms, and one case each of glossitis, facial warmth, and increased skin eczema. Another Japanese RCT on PC of Koga (2017) provided a detailed report on adverse effects, including appetite loss, fever, and fatigue, while no severe adverse effects were reported.

Compliance and Follow-Up

In the included trials, three trials reported dropout rates of 1–4 patients. The study on BPH by Gao (2011) did not specify the reasons for dropout. In the study on CP by Zhao (2021), one patient in the control group dropped out due to visiting relatives. The study on PC of Koga (2017) reported that three patients in the intervention group and four patients in the control group dropped out due to disease progression and death. A total of three trials has been conducted follow-up, including two trials on CP and one trial on PC. Zhao (2021) conducted a follow-up for two months, and Jia (2024) for three months. The recurrence rates for the intervention and control groups were 16.7% (n = 2)/25% (n = 3) and 7.1% (n = 3)/24.1% (n = 7), respectively, with the intervention group showing lower rates than the control group. The PC study of Koga (2017) did not specify the follow-up duration, disease progression or death occurred in 63% (19) of patients in the intervention group and 74% (26) of patients in the control group.

Limitations

The retrieved literatures were published in Chinese, English, Korean, and Japanese, suggesting the common use of GZFL for prostate disease in East Asian countries. However, the RCTs included in the Meta-analysis are all published in China, and due to the limited number of trials, the subgroup analysis related to country differences was not conducted in our research.

Discussion

Clinical research has identified blood stasis as one of the main pathogenic factors and a common syndrome type in prostate diseases. In clinical practice, it is often seen in combination with syndromes such as qi stagnation syndrome and damp-heat syndrome. As shown in the characteristics table of the trials included in this research, in the intervention group, GZFL was also usually combined with other TCM formulas, most of which had the effect of clearing heat and eliminating dampness, regulating qi flow, tonifying the kidney, and strengthening the spleen. It also reflects the pathological characteristics of prostate diseases of the internal accumulation of qi stagnation and damp-heat due to urinary obstruction and inflammation, which also highlights the principles of syndrome differentiation.

From the perspective of modern medicine, with aging, changes in blood rheology and microcirculation disorders can lead to a blood stasis constitution. Unhealthy lifestyles, excessive stress, emotional depression, and anxiety can also cause chronic congestion in the prostate and pelvic region, leading to fibrous tissue proliferation and glandular duct obstruction. This results in poor drainage of inflammatory substances from the prostatic acini, increased internal pressure, and worsened local blood circulation in the prostate, contributing to associated symptoms. This condition is considered related to the concept of “blood stasis” in East Asian traditional medicine. A study involving 466 patients identified D-dimer as a potential biomarker for diagnosing PC, a finding validated by clinical investigation and Mendelian Randomization analysis. In the prescription of GZFL, blood-activating and stasis-dissolving herbs such as Radix Paeoniae Rubra, Moutan Cortex have been shown to reduce plasma viscosity, improve blood circulation, inhibit platelet aggregation,⁷⁰ and repair damage caused by tissue ischemia and hypoxia,⁷¹ which also have been proved to reduce capillary permeability in inflammatory areas,⁷² suggesting that they may accelerate the excretion of inflammatory secretions in prostate tissue. Furthermore, a study⁷³ reported that GZFL increased the diameter of arterioles and arteries after administration, enhanced blood flow speed and rate in arterioles and small arteries, and increased nitric oxide production in vascular endothelial cells, while expanding the small artery diameter in a mesenteric artery stasis model. GZFL is recommended for patients with blood stasis syndrome. However, there is still insufficient reporting on the stage of the disease course during which blood stasis syndrome typically occurs, which needs further investigation in future research to provide better guidance for clinical application.

According to the meta-analysis of the included trials, the GZFL intervention group showed a higher effectiveness rate than the control group for both BPH and CP. As for the evaluation criteria for effective rate, among the nine BPH trials included, symptom improvement (n = 9), prostate ultrasound results and residual urine volume (n = 5), IPSS (n = 3), digital rectal examination (DRE) (n = 2), and Qmax (n = 1). Among the 10 CP trials, symptom improvement (n = 9), DRE and prostatic fluid test results (n = 5) and NIH-CPSI scores (n = 4), and prostate ultrasound (n = 1). These results indicate that the efficacy criteria cover both subjective symptoms and objective diagnostic indicators, providing a comprehensive and credible assessment for the effectiveness rate. However, the lack of a standardized efficacy criterion may lead to some variation in the results assessment across different trials. Standardizing the criteria for evaluating effectiveness is one of the key issues that needs to be addressed in further clinical research. The low heterogeneity in the synthesized results of the effective rate and no significant issues in the publication bias, suggest the stability of the meta-analysis results.

In terms of symptom scales, IPSS is selected in most trials of BPH, and NIH-CPSI is reported in most trials of CP, both of these two scales are currently internationally recognized tools for assessing symptom severity in patients. IPSS is currently recognized globally as the best scale for assessing the severity of symptoms in patients with BPH. NIH-CPSI was proposed in 1999⁷⁴ to objectively evaluate symptoms and QoL in CP/CPPS patients, which is also applied in evaluating treatment efficacy during follow-up. The IPSS can be divided into storage and voiding symptom scores. Based on the results, GZFL was more effective in improving the total IPSS and storage symptoms compared to the control group. The NIH-CPSI scale can be divided into pain, urinary function, and QoL scores. The synthesized results showed that the GZFL intervention group outperformed the control group in improving the total NIH-CPSI score, urinary function score, and QoL score. In the improvement of commonly used clinical indicators, studies on BPH showed that compared to the control group, the GZFL intervention group reduced PVR, PV, and Qmax. Sensitivity analysis identified potential sources of heterogeneity and confirmed the stability of the combined result, and further research is needed to validate these findings. GZFL may improve BPH through potential mechanisms involving estrogen signaling inhibition. Experimental evidence suggests that its active component Mairin reduces Estrogen Receptor α, Androgen Receptor mRNA, and protein expression in BPH tissue.⁷⁷ Another study⁷⁶ found that GZFL significantly reduced the prostate wet weight and prostate index in a BPH rat model by downregulating the expression of Dihydrotestosterone and Vascular Endothelial Growth Factor in serum and prostate tissue, while upregulating Transforming Growth Factor-β1 in prostate tissue. Liu et al.⁷⁵ pointed out that the formula plays an anti-inflammatory, anti-angiogenesis, and pro-apoptotic role in BPH treatment by regulating the expression of Bcl-2-associated X protein, B-cell lymphoma-2, Tumor Necrosis Factor, Interleukin-6, Epidermal Growth Factor Receptor and pathways like Phosphatidylinositol 3-kinase-Protein kinase B.

It was reported in several studies that GZFL prevented immunosuppression during immunotherapy, improved hot flashes, and was effective in alleviating symptoms and reducing tumor size in patients with PC. GZFL contains complex active ingredients. Pharmacological studies indicate that it is composed of cinnamic acid, cinnamaldehyde, paeoniflorin, albiflorin, gallic acid, ethyl gallate, benzoyl-paeoniflorin, and benzoic acid.^32,33,37 A study⁷⁸ suggested that GZFL may improve hot flashes by reducing plasma Calciotonin Gene-Related Peptide levels. In terms of its anti-tumor effects, the active components of Poria in the GZFL have been reported to significantly inhibit the proliferation of PC cells and induce apoptosis, showing both dose and time-dependent effects.⁷⁹ Other herbs in the formula, such as Radix Paeoniae Rubra, reduce the number of cells in the G1 phase and significantly increase sub-G0 cells, thereby inhibiting tumor cell proliferation.⁸⁰ Additionally, the amygdalin extracted from Persicae Semen is considered the main active ingredient for its anti-inflammatory and anti-tumor effects,⁸¹ while Cinnamon has also been reported to have anti-tumor properties.⁸²

Regarding the adverse reactions of GZFL, no reports of serious adverse effects were found in the included trials, which provides a certain extent of validation for its safety. Toxicological research³⁵ also indicated that GZFL did not cause any toxicologically significant adverse events at doses as high as 2000 mg/kg/day. The reported mild adverse effects were mostly related to gastrointestinal symptoms and dizziness. Attention still should be paid to the occurrence of adverse effects in clinical practices, and methods such as administering the medication after meals may help reduce the occurrences. The summarized results show a low dropout rate and recurrence rate in the intervention group. In the PC study, the intervention group even demonstrated a lower disease progression and mortality rate. However, further research is needed to confirm these findings.

The formulation in these three countries is primarily composed of the five herbal ingredients as recorded in the original text. However, there are differences in dosage and formulation types. Among the included studies published in China, decoctions were commonly used, with some studies utilizing pills or granules, and prescriptions were often adjusted based on the patient’s specific syndrome differentiation. Studies conducted in Japan consistently use granules, with fixed ingredients and dosages, allowing slight adjustments depending on the pharmaceutical company. A case report published in Korean used the original formula as a decoction. Due to the limited number of studies, the subgroup analysis related to country differences was not conducted in our research. However, variations in formulation and dosage across countries may introduce bias, representing an issue to be addressed in future research.

Conclusion

GZFL is effective and safe for BPH and CP in alleviating symptoms, improving scale scores, reducing postvoid residual urine, decreasing prostate volume, and increasing maximum urinary flow rate. A few studies have also reported its therapeutic effects on PC. However, due to the limited number of studies and methodological concerns of the included trials, more high-quality, multicenter, large-sample clinical trials are necessary to further support its clinical application.

Authors’ Contributions

Y.W.: Conceptualization, methodology, software, and writing—original draft preparation. H.L.: Visualization, investigation, and software. Y.J.: Investigation and validation. K.O.O.: Supervision and writing—reviewing and editing. H.K.: Writing—reviewing and editing. N.H.: Writing—reviewing and editing.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

Ethical Statement

No ethical approval was required as this study did not involve human participants or laboratory animals.

Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Supplemental Material

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