
==== Front
Heliyon
Heliyon
Heliyon
2405-8440
Elsevier

S2405-8440(24)12711-9
10.1016/j.heliyon.2024.e36680
e36680
Research Article
L-carnitine combined with traditional Chinese medicine for male infertility: A systematic review and meta-analysis
Yang Yang a
Xue Xinyu b
Zhou Jun c
Qiu Zerui a
Wang Biao a
Yin Ziwei a
Ou Guangyang a
Zhou Qing supergoon@163.com
c⁎
a The First Clinical College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
b Hunan University of Chinese Medicine, Changsha, China
c The First Hospital of Hunan University of Chinese Medicine, Changsha, China
⁎ Corresponding author. The First Hospital of Hunan University of Chinese Medicine, No. 95 Shaoshan Middle Road, Yuhua District, Changsha, Hunan Province, 410001, China. supergoon@163.com
24 8 2024
15 9 2024
24 8 2024
10 17 e3668015 2 2024
13 8 2024
20 8 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Background

Fertility rates are declining globally, and male infertility is increasingly recognized as a significant challenge. This study aims to present the latest findings on the effectiveness and safety of combining traditional Chinese medicine (TCM) with L-carnitine (LC) for treating male infertility.

Methods

We searched 8 databases. Randomized controlled trials of TCM combined with LC therapy versus LC alone in the treatment of male infertility. The outcome included: pregnancy rate, sperm motility, concentration, volume, viability and liquefaction time. Subgroup analyses were also performed according to type of TCM, type of dosage form, and different TCM treatments, and the source of the high heterogeneity was explored. The study is registered on PROSPERO (CRD42023421497).

Results

1129 subjects from 12 of the 1833 eligible studies fulfilled the criteria. Compared with LC treatment alone, the combination of TCM and LC significantly improved pregnancy rate [RR = 1.65, 95 % CI (1.37–2.00)], grade (a+b) sperm motility [SMD = 1.56, 95 % CI (1.12, 2.01)], grade (a) sperm motility [SMD = 1.04, 95 % CI (0.69, 1.38)], sperm concentration [SMD = 1.39, 95 % CI (0.91, 1.86)], and sperm viability [SMD = 1.72, 95 % CI (0.83, 2.60)]. Subgroup analyses indicated that Compound Xuanju Capsule and Yougui Capsule demonstrated better efficacy. And the decoction and not-decoction each had their own advantages.

Conclusions

The combination of TCM with LC can have a dual effect: increasing pregnancy rates and sperm quality. Therefore, this combination is a recommended therapeutic strategy and a more appropriate type of TCM can be selected according to the patient's own characteristics.

Keywords

Male Infertility
L-carnitine
Traditional Chinese Medicine
Meta-analysis
Sperm quality
Abbreviations

TCM traditional Chinese medicine

LC L-carnitine

MI male infertility

RR risk ratio

CI confidence interval

SMD standardized mean difference

CXJC Compound Xuanju Capsule

WZYZP Wuziyanzong Prescription

YGC Yougui Capsule

RCT randomized controlled trial
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pmc1 Introduction

Male infertility (MI) is defined as the inability to achieve natural conception due to male factors, persisting after one year of regular sexual activity without contraception which influenced by various factors including environmental pollution, societal expectations, changes in lifestyle, and the demands of a fast-paced life,. Furthermore, the implications of MI extend beyond the biological aspect and can significantly influence the mental health, overall quality of life, and dynamics within family. Moreover, it imposes a substantial economic and emotional burden on the affected individuals [1]. The World Health Organization reports showed that the global prevalence of infertility ranges from 8 to 12 %, with approximately 50 % of the cases being due to male factors [2]. Notably, prevalence rates are relatively elevated in regions such as the Americas, Western Pacific, Africa, and Europe [3]. Therefore, understanding MI comprehensively and developing effective strategies to deal with its multifaceted impact on individuals and societies is meaningful. MI can result from various causes, including hereditary diseases, infectious diseases, and anomalies in the development of reproductive organs [[4], [5], [6], [7], [8], [9], [10], [11], [12], [13]]. However, unified understanding of the mechanisms underlying the causation of MI is probably still relatively lacking. The diagnosis and treatment of MI exhibit characteristics of multidisciplinary intersection [14], Clinical interventions primarily focus on symptomatic relief and employ hormonal, antioxidant, and nutritional drugs [15], Among the commonly used medications are L-carnitine (LC), pancreatic kininogenase, coenzyme Q [16], lipoic acid, and vitamin E. These drugs aim to address specific aspects of MI and provide a targeted approach to enhance reproductive health. As the understanding of the intricate mechanisms involved continues to evolve, advancements in diagnostic techniques and therapeutic strategies are essential to improve the overall management of MI.

LC, recognized as a natural antioxidant with anti-inflammatory and anti-apoptotic properties, plays a crucial role in sperm metabolism, optimizing both routine and functional parameters in seminal plasma [17,18]. Despite these beneficial effects, the metabolism of LC produces trimethylamine, leading to adverse reactions such as dry mouth, fatigue, diarrhea, and gastrointestinal discomfort [19]. Simultaneously, challenges persist, including the limited effectiveness of individual drugs, inappropriate administration of treatment courses, and non-standardized medication usage. While LC has demonstrated effectiveness in treating endocrine and cardiovascular disorders, peripheral neurogenic pain, and MI [20], its impact on the percentage of malformed spermatozoa remains unclear, and there is no significant improvement in sperm volume or sperm concentration. Consequently, the therapeutic effect of LC is not entirely satisfactory. Addressing these limitations and refining treatment protocols are essential for advancing the effectiveness of interventions aimed at ameliorating MI. For more than 2,000 years, Traditional Chinese Medicine (TCM) has been applied in the treatment of MI, with numerous studies highlighting its efficacy in improving sperm quality [[21], [22], [23], [24], [25]]. Recent clinical investigations have explored the combination of TCM with LC for MI treatment [[26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37]], revealing significant synergistic effects, enhanced efficacy, and reduced adverse effects. Despite existing clinical studies and meta-analyses [[38], [39], [40], [41], [42]] focusing on specific TCM combined with LC in MI treatment, many meta-analyses [[40], [41], [42]] primarily report the efficacy of individual formulas combined with LC. This results in variations in intervention form and content, inconsistent findings, and predominantly longitudinal comparisons for outcome indexes. The lack of horizontal comparisons across different TCM classes and comprehensive assessment of interventions leads to non-uniform outcomes. The current clinical landscape for MI treatment involves a spectrum of TCM with varying efficacies, and the therapeutic system lacks completeness and standardization. Consequently, previous meta-analyses may not comprehensively address this issue mentioned above. Efforts to refine the understanding and standardization of TCM interventions are essential for advancing the holistic treatment of MI.

This meta-analysis seeks to assess the effectiveness and safety of diverse TCM species when combined with LC for MI treatment, and focus on exploring potential combination strategies to harness their comprehensive and multi-level advantages in the treatment of MI. The findings of this study may provide a reference for standardizing and promoting the clinical application of TCM and LC in the treatment of MI and valuable evidence-based medical evidence for the synergistic effectiveness and safety of LC based combination treatment protocols.

2 Matertials and methods

The meta-analysis was reported according to the Preferred Reporting Items for Meta-analysis (PRISMA) statement (Supplementary material 1), and we registered it to the PROSPERO database summary (CRD42023421497).

2.1 Literature searching strategies

We searched in MEDLINE, PubMed, Cochrane Library, Web of Science, EMBASE, China National Knowledge Infrastructure (CNKI), Wanfang Database, and VIP database. Relevant randomized controlled trials (RCTs) were collected and selected from the beginning of library construction to November 25, 2023. The references of relevant reviews and articles were also manually searched, and the language was limited to Chinese or English. We used the following combined text and MeSH terms: “Infertility”, “Male” and “L-carnitine” and adjusted to the requirements of different databases. We have improved the search formula according to the PICOS principle, which has been added in the supplementary materials (Supplementary material 2).

2.2 Study selection and inclusion criteria

Eligible articles were evaluated by two independent researchers based on the following inclusion and exclusion criteria, and discrepancies between them were resolved by negotiation. The inclusion criteria included (1) publicly published RCT; (2) male patients with a diagnosis of infertility considered according to international authoritative guidelines [43,44] and Chinese domestic multidisciplinary guidelines for the diagnosis and treatment of MI [14], with no restriction on age, nationality, or duration of the disease; and (3) a control group: treatment with only LC. (4) Observation group: combined treatment with TCM on the basis of the control group, with no limitation on the type and composition. (5) The spouses of the subjects were all healthy. Exclusion criteria included: (1) animal experiments, reviews and basic studies; (2) studies with own control or no control group; (3) incomplete or incorrect data. If studies were repeated, only published studies with the most comprehensive data required were included. All retrieved articles were imported into EndNote X9, and two researchers assessed the full text to independently select eligible studies and documented the original exclusion of the excluded studies. Sections where disagreements existed were resolved by a third researcher who acted as the final reviewer to resolve the disagreements. Fig. 1 provides the full screening process. We also adapted the search strategy appropriately for different databases. The reference lists of retrieved literature were manually screened for potential missing literature. For articles with missing data, we proactively contacted the authors to obtain the missing data.Fig. 1 Flow diagram of literature search and study selection.

Fig. 1

2.3 Data extraction and quality assessment

Two researchers independently extracted data from each included study using a standardized data extraction form. Extracted information included: basic information, participant characteristics, and the intervention. We assessed trials for selection bias, execution bias, detection bias, attrition bias, reporting bias, and other biases using the Cochrane Risk of Bias Assessment Tool. Each study was categorized as low risk (green), unclear risk (yellow), or high risk (red) of bias. Literature quality was evaluated using the modified Jadad scale by scoring randomization concealment, blinding, and withdrawal and exit from the literature, as described in the Supplementary material 3.

2.4 Statistical analysis

We analyzed the effects of TCM combined with LC and LC treatment alone on the following outcomes: pregnancy rate, sperm motility [grade (a+b) sperm/grade (a) sperm], sperm concentration, sperm viability, sperm liquefaction time, and sperm volume. The continuous data were reported as the standardized mean difference (SMD), and the discontinuous data were reported as risk ratio (RR) with 95 % confidence intervals (CI).I2 testing was used to assess the heterogeneity. Substantial heterogeneity was revealed if the I2 was >50 %, and the random-effects model was used. A funnel plot was drawn to examine the publication bias if the study included ≥10 RCTs. Egger's test and Begg's test was used to evaluate the symmetry of the funnel plot.We also conducted further analysis using the sensitivity analysis method. When publication bias is present, further research should be conducted using the trim-and-fill method. We conducted subgroup and sensitivity analysis to explore the source in studies with high heterogeneity. All statistical analyses were performed using Stata/MP (version 15.0).

3 Results

3.1 Study selection and characteristics

1833 articles were initially generated from 8 databases and manual searches. Critically reviewed based on title and abstract by two independent reviewers after removing duplicate studies. The detailed literature screening process is presented in Fig. 1. Ultimately, 12 studies [[26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37]] containing 1129 subjects participated in this meta-analysis, and the major characteristics of the included studies are shown in Table 1. Risk of bias summary is shown in Fig. 2. The basic demographic data (age, disease duration) of the experimental and control groups in all the included studies were not statistically significant (P > 0.05).Table 1 Main characteristics of the 12 randomized controlled trials in this meta-analysis.

Table 1First author	Year	T/C Sample	Interventions	Period (week)	Observation target	
Treatment group	Control group	
LIN W	2019	40/40	TCM(YGC) + LC	LC	12	1; 2;3; 5;6; 9;10; 11; 12; 13	
LIU PY	2023	47/46	TCM(CXJC) + LC	LC	12	1; 2;5; 6;9; 10; 13; 14	
LI Z	2018	78/86	TCM(WZYZP) + LC	LC	12	1; 2;5; 6;7; 15; 16	
LUO F	2021	30/30	TCM(YGC) + LC	LC	12	1; 2;3; 5;18	
TAN XL	2023	43/43	TCM(CXJC) + LC	LC	12	1; 2;3; 5;7; 9;10; 11; 13; 14; 19; 20	
WANG HZ	2021	48/48	TCM(QJD) + LC	LC	12	1; 2;4; 5;8; 21	
WANG YC	2021	48/48	TCM(WZYZP) + LC	LC	12	1; 5	
WANG YC	2023	40/42	TCM(WZYZP) + LC	LC	12	1; 2;4; 5;7; 8;22	
XIA HX	2021	40/42	TCM(QLP) + LC	LC	12	1; 2;3; 5;7; 21	
ZENG F	2022	55/56	TCM(BSSJD) + LC	LC	12	1; 2;4; 5;6; 7	
ZHANG CD	2012	30/30	TCM(CXJC) + LC	LC	12	1; 2;4; 5;6	
ZHANG HY	2018	59/60	TCM(HSC) + LC	LC	12	1; 2;3; 5;7; 17	
TCM: traditional Chinese medicine; YGC: Yougui Capsule; CXJC: Compound Xuanju Capsule; WZYZP: Wuziyanzong Prescription; QJD: Qiangjing Decoction; QLP: Qilin Pill; BSSJD: Bushen Shengjing Decoction; HSC: Huanshao Capsule.

1: Sperm concentration; 2: Pregnancy rate; 3: Sperm motility; 4: Sperm vitality; 5: Grade (a+b) sperm motility; 6: Grade (a) sperm motility; 7: Semen volume; 8: Sperm liquefaction time; 9: Testosterone; 10: Follicle-stimulating Hormone; 11: Prolactin; 12: Progesterone; 13:Luteinising Hormone; 14: Estradiol 15: Mitochondrial membrane potential; 16: Succinate dehydrogenase; 17: morphologically abnormal sperm; 18: Egg fertilization rate; 19: Sperm acrosome integrity rate; 20:Seminal plasma NO; 21: Total number of spermatozoa; 22: Sperm total motility.

Fig. 2 Risk of bias summary.

Fig. 2

3.2 Effect of TCM with LC on pregnancy rate compared with LC alone

Out of the 12 papers included, 11 [[26], [27], [28], [29], [30], [31],[33], [34], [35], [36], [37]] reported on the effect of TCM combined with LC treatment on pregnancy outcomes, with a total of 1033 cases. Among the 523 patients treated with TCM combined with LC, 195 pregnancy events were observed. In contrast, the control group, which consisted of 510 patients treated with LC only, observed 115 pregnancy events. The study found that the pregnancy rate was significantly higher in the group that received TCM combined with LC treatment compared to the control group [RR = 1.65, 95 % CI (1.37–2.00), I2 = 0 %] (Fig. 3).Fig. 3 Effect of combined treatment of TCM and LC on pregnancy rate in comparison with the treatment of LC alone.

Fig. 3

Subgroup analyses based on the control treatment was conducted for different types of TCM groups (Supplementary Material 4(A)). No significant heterogeneity (I2 = 0 %) was observed in the Compound Xuanju Capsule group (CXJC) [RR = 1.77, 95 % CI (1.22–2.57)]. In the Wu Zi Yan Zong Prescription (We collectively refer to Wuzi Yanzong Capsule and Wuzi Yanzong Decoction both as the Wuzi Yanzong Prescription, WZYZP) group [RR = 1.31, 95 % CI (0.88–1.96)], although there was no significant heterogeneity (I2 = 29.8 %), the result did not reach statistical significance (P = 0.19). Similarly, in the Yougui Capsule (YGC) group [RR = 2.13, 95 % CI (1.31–3.45)], no significant heterogeneity (I2 = 0 %) was observed. For other groups [RR = 1.65, 95 % CI (1.37–2.00)], there was no significant heterogeneity (I2 = 0 %).

Subgroup analyses was also performed for the difference in dosage forms (Supplementary Material 4(B)), revealing variations in efficacy between the two. In the decoction group, no statistical significance was observed [RR = 1.32, 95 % CI (0.91–1.93)], while better efficacy was noted in the not-decoction group [RR = 1.81, 95 % CI (1.45–2.25)].

3.3 Effect of TCM with LC on sperm parameters compared with LC alone

3.3.1 Sperm motility

A total of 12 papers [[26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37]] were comprehensively analyzed to assess the impact of TCM combined with LC treatment on grade (a+b) sperm motility, involving a total of 1129 patients. The result demonstrated high heterogeneity. (I2 = 90.8 %), and a random-effects model was utilized to calculate the combined effect value for grade (a+b) sperm motility. The result indicated a substantial improvement [SMD = 1.56, 95 % CI (1.12–2.01)] (Fig. 4).Fig. 4 Effect of combined treatment of TCM and LC on grade (a+b) sperm motility in comparison with the treatment of LC alone.

Fig. 4

Subgroup analyses was conducted based on the type of TCM administered (Supplementary Material 5(A)). The heterogeneity was high in the following three groups: the CXJC group [SMD = 1.97, 95%CI(0.73–3.20), I2 = 93.4 %)]; the WZYZP group [SMD = 1.63, 95 % CI (0.40–2.86), I2 = 95.6 %)]and the YGC group [SMD = 2.09, 95 % CI (0.46–3.72), I2 = 92.7 %)]. The other TCM group [SMD = 1.03, 95%CI (0.82–1.24)] displayed no heterogeneity (I2 = 0 %), all of which were statistically significant.

Regarding the dosage form, it demonstrated high heterogeneity. observed in the not-decoction group [SMD = 1.86, 95 % CI (1.21–2.52), I2 = 92 %], and similarly in the decoction group [SMD = 1.01 95 % CI (0.67–1.35), I2 = 66.9 %], both of which reached statistical significance (Supplementary Material 5(B)). Subgroup analyses was performed based on different treatment methods of TCM. It was categorized into the Tonifying Kidney Yang group, Tonifying Kidney and Nourishing Essence group, and Others' group. In the Tonifying Kidney Yang group [SMD = 2.01, 95 % CI (1.17–2.85)], the heterogeneity decreased (I2 = 90.9 %). In the Tonifying Kidney and Nourishing Essence group [SMD = 1.40, 95 % CI (0.73–2.06)], the heterogeneity did not change significantly (I2 = 91.5 %). Meanwhile, in the Others’ group, the heterogeneity significantly decreased. [SMD = 0.95, 95 % CI (0.67–1.23), I2 = 0 %] (Supplementary Material 5(C)).

No obvious symmetry was found by plotting a funnel plot (Supplementary Material 11(A)), and the results of the sensitivity analysis were stable. Besides, the risk of bias was assessed through Egger's test (P = 0.000 < 0.05) (Supplementary material 12(A)) and Begg's test (P = 0.011 < 0.05) (Supplementary material 12(B)), indicating publication bias. (95 % CI (2.191–5.760). Therefore, it is necessary to use the trim-and-fill method to evaluate the stability of the combined results. After including 2 virtual studies and applying a random effects model, the results did not reverse, indicating that the combined results are robust. [Q = 179.965, P = 0.000] (Supplementary Material 15(A)).

5 papers [[26], [27], [28],35,37] reported the effect of combination therapy on grade (a) sperm motility, with a total of 288 cases utilizing TCM in combination with LC and 279 cases using LC only. The results showed a slight heterogeneity (I2 = 73.2 %). A random effects model was applied to analyze the results [SMD = 1.04, 95 % CI (0.69–1.38)] (Fig. 5).Fig. 5 Effect of combined treatment of TCM and LC on grade (a) sperm motility in comparison with the treatment of LC alone.

Fig. 5

Subgroup analyses, based on the type of TCM, included 1 literature in the CXJC group, 1 literature in the WZYZP group, 1 literature in the YGC group, and 2 literatures in the other TCM group. The analysis revealed a significant reduction in heterogeneity after combining the other groups [SMD = 1.08, 95 % CI (0.12–2.03), I2 = 91.3 %) (Supplementary Material 6(A)).

Besides, regarding the dosage forms, the decoction group demonstrated better efficacy. revealing superior efficacy in the decoction group [SMD = 1.29, 95 % CI (0.79–1.79)] and slightly reduced efficacy in the not-decoction group [SMD = 0.86, 95 % CI (0.43–1.28)] (Supplementary Material 6(B)).

3.3.2 Sperm concentration

A total of 12 papers [[26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37]] investigated the impact of TCM combined with LC treatment on sperm concentration in patients, encompassing a total of 1129 participants. Substantial heterogeneity was observed (I2 = 92.2 %), and the effect value was calculated using a random-effects model [SMD = 1.30, 95 % CI (0.91–1.86)] (Fig. 6). Symmetry was noted in the funnel plot (Supplementary material 11(B)), and the results of the sensitivity analysis were stable. Besides, the risk of bias was assessed through Egger's test (P = 0.008 < 0.05) (Supplementary material 12(B)) and Begg's test (P = 0.011 < 0.05) (Supplementary material 13(B)), indicating publication bias. Therefore, it is necessary to use the trim-and-fill method to evaluate the stability of the combined results. After including 3 virtual studies and applying a random effects model, the results did not reverse, indicating that the combined results are robust. [95 % CI (2.484–6.435),Q = 263.968, P = 0.000] (Supplementary Material 15(B)).Fig. 6 Effect of combined treatment of TCM and LC on sperm concentration in comparison with the treatment of LC alone.

Fig. 6

Following subgroup analyses, heterogeneity was significantly reduced (I2 = 48.9 %) in the CXJC group [SMD = 1.36, 95 % CI (0.96–1.76)]. The heterogeneity did not show significant changes in the YGC group [SMD = 1.76, 95 % CI (−0.03-3.55)], WZYZP group [SMD = 1.18, 95 % CI (0.35–2.02), I2 = 91.7 %]and other groups [SMD = 1.41, 95 % CI (0.18–2.63), I2 = 96.6 %] (Supplementary material 7(A)).

The decoction group, comprising 4 papers [28,31,32,35] with a total of 467 patients, indicated a reduction in heterogeneity [SMD = 0.99, 95 % CI (0.47–1.50), I2 = 85.7 %]. In contrast, the not-decoction group, consisting of 8 papers [26,27,29,30,33,34,36,37] with 662 patients [SMD = 1.60, 95 % CI (0.9–2.29)] (I2 = 93.4 %) (Supplementary material 7(B)).

As for different treatment methods of TCM, there was a significant change in heterogeneity within these subgroups. In the Tonifying Kidney Yang group [SMD = 1.49, 95 % CI (0.94–2.03)], the heterogeneity decreased (I2 = 81.9 %). In the Tonifying Kidney and Nourishing Essence group [SMD = 1.05, 95 % CI (0.40–1.69)], the heterogeneity did not change significantly. (I2 = 91.6 %). Meanwhile, in the Others’ group, the results of the decoction group were not statistically significant. (I2 = 98.1 %) [SMD = 1.98, 95 % CI (−0.54–4.51), P = 0.124 ] (Supplementary material 7(C)).

3.3.3 Sperm viability

Sperm viability is a crucial metric in assessing sperm quality and plays a pivotal role in determining pregnancy outcomes. In a comprehensive evaluation, five papers [27,31,33,35,36]reported the impact of two distinct treatments on sperm survival, involving a total of 442 patients. The observed heterogeneity was significant (I2 = 93.6 %) yet statistically considerable. A random-effects model was employed for the analyses, revealing a significant improvement [SMD = 1.72, 95 % CI (0.83–2.60)] (Fig. 7). Subgroup analyses demonstrated that both the decoction group [SMD = 1.09, 95 % CI (0.42–1.77), I2 = 81.0 %] and the not-decoction group [SMD = 2.16, 95 % CI (0.61–3.71), I2 = 95.4 %] exhibited enhanced effectiveness (Supplementary material 8).Fig. 7 Effect of combined treatment of TCM and LC on sperm viability in comparison with the treatment of LC alone.

Fig. 7

3.3.4 Sperm liquefaction time

Only two [31,33] papers reported this outcome indicator. Substantial heterogeneity was observed in the calculations (I2 = 94.5 %), and a combined effects analysis was conducted using a random-effects model [SMD = −2.19, 95%CI (−3.86 to −0.52)] (Supplementary material 9).

3.3.5 Sperm volume

Six papers [28,30,[33], [34], [35],37] reported the impact of LC combined with TCM treatment on sperm volume in patients. Significant heterogeneity was observed (I2 = 82 %), and a random-effects model was applied for pooled analysis [SMD = 0.80, 95 % CI (0.41–1.19)] (Fig. 8). In subgroup analyses, one literature was included in the CXJC group, no literature was included in the YGC group, and two articles were included in the WZYZP group [SMD = 0.54, 95 % CI (0.23–0.85)], demonstrating a significant decrease in heterogeneity (I2 = 27.7 %). However, no significant change in heterogeneity was detected in the other TCMs group [SMD = 0.93, 95 % CI (0.18–1.69), I2 = 90 %]. (Supplementary material 10(A)). Categorization based on dosage form revealed both no significant change heterogeneity in the decoction group [SMD = 0.87, 95 % CI (−0.04–1.07), I2 = 91.9 %], and not-decoction group [SMD = 0.77, 95 % CI (0.28–1.26), I2 = 82 %] (Supplementary material 13(B)), Additionally, the results of the decoction group were not statistically significant.Fig. 8 Effect of combined treatment of TCM and LC on sperm volume in comparison with the treatment of LC alone.

Fig. 8

4 Discussion

The global decline in fertility has generated social challenges, including labour shortages, increasing ageing of societies and demographic imbalances. Projections suggest that by 2100, a total of 183 countries may experience below-replacement fertility rates [45]. MI emerges as a potential contributor to this global fertility decline, with research indicating a 76.9 % increase in its prevalence from 1990 to 2019. This rise is notable across various regions, forming a widespread global trend [46]. Compounding the issue, MI has historically received limited attention, and its diagnostic and therapeutic challenges remain unresolved [47]. LC is recognized as the supplement that can enhance sperm quality [18,48] and has been widely used in the field of pharmacotherapy. However, there are some limitations based on its lack of specificity and numerous adverse events [49]. Additionally, artificially assisted reproduction techniques face limitations due to their high costs and associated risks of preterm labor [50] and birth defects [51]. Hence, there is a critical need to explore novel clinical strategies for MI treatment. As a representative of the Oriental world and a treasure of Chinese cultural heritage, TCM has garnered increasing recognition in recent years for its role in treating MI [[21], [22], [23], [24], [25],52]. TCM interventions focus on enhancing antioxidative stress capabilities, safeguarding sperm DNA integrity, improving sperm quality, promoting sperm maturation, enhancing the spermatogenic microenvironment, and optimizing the function of accessory gonads. Building on these insights, we posit that combining TCM with LC in the treatment of MI may yield enhanced efficacy.

In the current study, the combination therapy involving TCM has displayed promising clinical therapeutic perspectives when compared to the use of LC alone. Notably, the pregnancy rates in the combination group were significantly higher, indicating a positive outcome. The improvement in grade (a+b) sperm motility in the TCM combination group was substantial [SMD = 1.56, 95 % CI (1.12–2.01)]. Additionally, there was a surprising increase of 1.39*106/ml in sperm concentration in the combination group compared to the control group. These outcomes serve as crucial benchmarks for assessing clinical efficacy, and it is gratifying to observe a distinctly positive impact from the combination group. Furthermore, the combination group exhibited superior improvements in grade (a) sperm motility and sperm viability. The sperm liquefaction time was notably shortened by 2.19 min in the experimental group. These findings provide support for the therapeutic strategy of combining TCM with LC, offering additional treatment options utilizing TCM. Consequently, we posit that the combination of TCM will yield more significant results in the treatment of MI and can be considered a clinical treatment strategy worthy of widespread adoption. While some previous studies have reported similar results, a majority of them were confined to exploring the combination of specific types of TCM with LC. These studies often relied on before-and-after controls for their own interventions, lacking the comprehensive cross-sectional comparison of the efficacy of various TCM interventions. As a result, the evidence from these studies may lack generalizability and universality. Therefore, this study incorporated a wider range of TCM categories, aiming to provide more comprehensive and robust evidence for the clinical diagnosis and treatment by comparing their efficacy and advantages in outcome indicators when combined with LC in the treatment of MI. Additionally, in order to comprehensively evaluate the effectiveness of TCM as an adjunctive therapy and explore optimal treatment strategies, this study included factors such as dosage form and therapeutic methods in the scope of discussion, conducting subgroup analyses.

Firstly, grouping was conducted based on the types of TCM used, and the results revealed significant advantages associated with CXJC and YGC. This aligns with consistent and robust conclusions drawn from studies by Zhao Jun [53], Wang Zhen [38], and others. Both groups exhibited remarkable advantages in pregnancy rates and grade (a+b) sperm motility.

TCM has a rich history spanning over 2,000 years in addressing the issue of MI. Within the TCM theoretical framework, MI is predominantly classified under categories such as “less sperm”, “thin sperm”, “cold sperm” and “childlessness”. According to TCM principles, the kidney serves as the primary reservoir of sperm, representing the foundation of innate nature. It plays vital roles in promoting the development of reproductive organs and maintaining reproductive functions. The spleen, considered the root of the acquired body in TCM, is responsible for transporting nutrients and converting them into reproductive essence, nourishing the essence stored in the kidney. Chinese medicine practitioners often attribute the causes of MI to deficiencies in kidney qi and kidney essence resulting from congenital factors, chronic illnesses, emotional disturbances, dietary imbalances, and immoral sexual practices. Notably, our findings indicate that the efficacy of CXJC and YGC aligns with TCM's understanding of the etiology and pathogenesis of MI.

To delve deeper into the remarkable efficacy of CXJC and YGC, we explore their composition and the reasons behind their effectiveness. CXJC consists mainly of four components: black ant, Fructus Lycii (Gouqizi), Herba Epimedii (Yinyanghuo), and Fructus cnidii (Shechuangzi). This formulation aims to warm the kidney, strengthen yang, benefit the kidney, and replenish essence. Clinical studies have demonstrated that CXJC effectively improves sperm quality [54], increases sex hormone levels, promotes sperm secretion, enhances sexual organ function [55], significantly boosts sperm concentration and total sperm count, and improves sperm motility [56].

Despite CXJC's simple composition, modern medical research reveals that black ants and Epimedium are rich in vitamins, lignans, flavonoids and other components [57]. Notably, Herba Epimedii, a valuable component, has been employed for centuries to treat infertility. It possesses kidney-tonifying and yang-warming properties [58] and is widely distributed in Asia and Europe [59]. Oxidative stress has been shown to be a central factor contributing to MI [18,60]. Icariin, a major flavonoid in Epimedium, serves as a natural source of antioxidants [57]. Experimental evidence indicates that Icariin regulates gene expression, influences spermatogenesis, and improves sexual function through various pathways [[61], [62], [63]]. Furthermore, Icariin II contributes to the differentiation of ADSCs into SCs, promoting erectile function restoration [64]. The supplementation of Icariin also attenuates testicular damage by modulating the hypothalamus-pituitary-testis axis [65,66]. showcasing its diverse medicinal effects [67]. In conclusion, we attribute the efficacy of CXJC in this study to Herba Epimedii. Subgroup analyses revealed that both CXJC and YGC fall under the kidney yang category, and this subgroup exhibited significantly lower heterogeneity. The treatment rules of TCM may contribute to the observed high heterogeneity in sperm concentration, emphasizing the importance of individualized symptom differentiation in clinical practice. Additionally, both CXJC and YGC contain Fructus Lycii. Exploring Fructus Lycii in-depth, it has been extensively used in Asian countries, particularly China [68], for its “tonifying the kidney, nourishing the liver, and brightening the eyes” effects [69]. Researchers have found that Fructus Lycii possesses significant antioxidant potential, effectively mitigating oxidative stress on reproductive function [70]. Experimental studies with rats [71] and rabbits [72] have demonstrated improvements in antioxidant capacity, sperm concentration, and viability. Fructus Lycii is rich in biologically active molecules such as Lycium barbarum polysaccharide (LBP), carotenoids, polyphenols, and betaine [73,74]. LBP, particularly, has garnered attention for its historical significance and modern bioactivities [75]. Studies have shown that polysaccharides isolated from LBP exhibit antioxidant and aging-delaying abilities [76]. In a mouse model of oxidative stress, LBP at 20 mg/kg effectively improved testicular histopathological structure, increased sperm concentration and viability, decreased sperm malformation rate, and reduced apoptotic cells in testicular spermatogonial cells [77].

Analyses of clinical medication patterns for MI treatment reveal that Fructus Lycii is the most frequently prescribed drug [78], contributing to anti-oxidative stress, free radical scavenging, inhibition of spermatogonial cell apoptosis, enhancement of cellular immunity, and regulation of sex hormone homeostasis [79]. The antioxidant effects of Epimedium and Lycium are crucial contributors to the efficacy of the drug.

As the study progressed, our attention was drawn to the specific herbal pairing contained in the YGC. Herbal pairs typically consist of various TCM. They closely align with the etiology and mechanism of diseases, reflecting the characteristic advantages of TCM with intrinsic patterns of change and scientific connotation [[80], [81], [82], [83]]. Notably, the “Semen Cuscutae-Fructus Lycii” herbal pair emerged as having a beneficial effect on sperm quality. Both components exhibit the efficacy of tonifying the liver and kidney, fixing essence, and consolidating urine [84]. Semen Cuscutae focuses on tonifying kidney yang, while Fructus Lycii focuses on tonifying kidney yin. The combination of the two aims to harmonize yin and yang.

Research has identified that this herbal pair has 83 potential targets for treating MI and can effectively repair the blood-testis barrier, as revealed through network pharmacology studies [85]. Animal experiments further verified its capability to significantly increase sperm concentration and survival rate in rats. Moreover, improvements were observed in the structural morphology of testicular supporting cells and seminiferous tubules, accompanied by a notable increase in the number of spermatogenic cells. Additionally, a study identified 11 targets related to regulating weak spermatozoa by YGC, involving 14 biological processes [86]. A meta-analysis supported the therapeutic effect of YGC on MI [87], aligning with the findings of this study.

These insights provide valuable reference points for the future clinical treatment of MI when considering TCM. In summary, the positive effects of CXJC and YGC, particularly through the use of Herba Epimedii, Fructus Lycii, and the “Semen Cuscutae - Fructus Lycii” herbal pair, contribute to the enhancement of sperm quality and improvement in pregnancy outcomes. Therefore, the inclusion of these herbal medicines in the diagnosis and treatment of MI could theoretically result in more favorable therapeutic effects.

In addition to the above results, subgroup analyses yielded some notable findings. When comparing the efficacy of the decoction and not-decoction groups, it was found that the heterogeneity in the grade (a+b) sperm motility decreased in the decoction group, while the heterogeneity in grade(a) sperm motility showed more significant changes in the non-decoction group. This led us to posit that the differences in the dosage forms of TCM are the source of the aforementioned heterogeneity, which is a novel and intriguing result. The suspicion that the choice of dosage form may impact clinical efficacy was, to some extent, confirmed by this study's results.

The not-decoction group demonstrated greater efficacy for pregnancy rate [RR = 1.81, 95 % CI (1.45–2.25)], grade (a+b) sperm motility [SMD = 1.86, 95 % CI 1.21–2.52)], sperm concentration [SMD = 1.60, 95 % CI (0.90–2.29)], and sperm viability [SMD = 2.16, 95 % CI (0.61–3.71)]. In contrast, the decoction group proved more beneficial in improving grade (a) sperm motility [SMD = 1.29, 95 % CI (0.79–1,79)]. Dosage forms are integral to the administration of drugs, significantly influencing drug dosage, efficacy, safety, and adherence [76]. Both TCM and modern medicine employ similar formulations in various dosage forms for clinical treatment. The inappropriate selection of dosage forms may not only affect efficacy but can also lead to adverse outcomes.

The TCM dosage forms considered in this meta-analysis include decoction and not-decoction (both pill and capsule). We believe that drug dosage form is a crucial reference factor, and choosing the correct TCM dosage form tailored to the severity of the disease is a direction worth further exploration. The group is committed to investigating this issue further. Building on the preceding discussion, future research will delve into the pharmacological mechanisms of CXJC and YGC in treating MI. We aim to conduct a more comprehensive and systematic analysis of the efficacy differences caused by different dosage forms. Our overarching goal is to identify the optimal therapeutic solution and combination strategy for MI, providing comprehensive evidence-based medical support for clinical application and dissemination.

Although the included studies compared the age and disease duration of the two groups of patients and found no statistical significance, the original studies did not scientifically account for factors such as patients'sex hormone levels, weight, lifestyle habits (e.g., smoking, drinking, staying up late), as well as work and sleep patterns, which may affect sperm quality. This lack of data collection and analysis is one of the potential sources of heterogeneity in our study and a possible cause of publication bias. We look forward to future related studies that will collect and analyze more comprehensive and detailed demographic information to minimize the impact of these factors on the results, thus ensuring scientific rigor. However, we also acknowledge another possibility: studies demonstrating the effectiveness of TCM may be more likely to be published, while studies showing no significant benefit or effectiveness might be underrepresented. This tendency could result in a disproportionate number of studies highlighting the efficacy of TCM in the literature. We recognize this potential issue and suggest that future research should pay closer attention to this bias to ensure a more comprehensive and balanced representation of research findings.

Finally, we found that only four studies [26,33,35,37] among the included research reported results on adverse reactions and side effects of the drugs. None of these studies observed significant adverse reactions or side effects in the subjects. We believe that further research on drug side effects is necessary to ensure that new treatment strategies are both safe and effective.

The observed publication bias may be related to the aforementioned factors. Additionally, inaccuracies in article selection and small sample sizes can introduce bias, which should be avoided in future research. Overall, this study identified CXJC and YGC as effective treatments for male infertility and discussed the scientific basis of their efficacy. It also highlighted key factors influencing the treatment of this condition, aiming to provide more diverse and personalized treatment options in the future. Furthermore, this study offers data support for future experimental designs. We anticipate more precise and rigorous scientific research on the integration of traditional Chinese and Western medicine for treating this condition.

5 Limitations

This meta-analysis has some limitations:1 .The sample size included in this analysis was not large enough and all of them were from Chinese regions, and the efficacy of patients from other regions could not be evaluated uniformly;

2 .This paper proposes the influence of TCM dosage form on the efficacy, but the variables are not unique in the evaluation of group effects;

3 .In terms of the quality of the literature: some studies did not provide explanatory notes on adverse reactions, and most of the literature did not emphasize the position of allocation concealment and blinding in RCTs.

6 Conclusions

According to the findings of the meta-analysis, the combined use of TCM and LC in the treatment of male infertility exhibited superior outcomes in terms of pregnancy rates and sperm parameters when compared to LC alone. Notably, Compound Xuanju Capsule and Yougui Capsule displayed enhanced efficacy in this regard. Furthermore, the impact of different dosage forms on efficacy showed variability. The combination of Traditional Chinese Medicine with LC emerges as a promising therapeutic option with heightened effectiveness, warranting further exploration through multicenter, large-sample, and long-term clinical studies to delineate the optimal approach.

Funding

We would like to acknowledge funding from Hunan Provincial Department of Education Scientific Research (Outstanding Youth) Project (22B0368), “Hunan Provincial Traditional Chinese Medicine Clinical Medicine Research Center for Sexual and Reproductive Health” (Xiangkeji 2020SK4014), Hunan Provincial Key Specialty in Traditional Chinese Medicine (Traditional Chinese Medicine Andrology) (Letter of Hunan Traditional Chinese Medicine [2023] No.4), Hunan University of Chinese Medicine Graduate Innovation Project “Yifang” (2024YF05 ).

Data availability statement

Data included in article/supplementary material/referenced in article can be found.

CRediT authorship contribution statement

Yang Yang: Writing – review & editing, Writing – original draft, Visualization, Validation, Software, Resources, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Xinyu Xue: Writing – original draft, Resources, Methodology, Investigation. Jun Zhou: Writing – review & editing, Supervision. Zerui Qiu: Visualization, Software. Biao Wang: Visualization. Ziwei Yin: Writing – review & editing, Software, Data curation. Guangyang Ou: Visualization, Validation. Qing Zhou: Supervision, Project administration, Funding acquisition.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A . Supplementary data

The following is the Supplementary data to this article:Multimedia component 1

Multimedia component 1

Acknowledgments

The authors thank the assistance from the staff at The First Hospital of Hunan University of Chinese Medicine for this study.

Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.heliyon.2024.e36680.
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