Efficacy and Safety of Coenzyme Q10 in Idiopathic Male Infertility: A Systematic Review and Meta-Analysis of Randomized Trials

Abstract

Purpose

Despite numerous studies on coenzyme Q10 (CoQ10) as a treatment for idiopathic male infertility (IMI), clear clinical guidance remains lacking. This systematic review and meta-analysis (SRMA) aimed to evaluate the efficacy of CoQ10 and determine the optimal dose, formulation, and treatment duration compared to placebo or other therapies.

Materials and Methods

We searched PubMed, Science Direct, and Cochrane Library using relevant keywords to identify studies assessing CoQ10’s effects on sperm parameters, seminal CoQ10 levels, and clinical pregnancy rates in men with IMI. Study quality was assessed using the Revised Cochrane Risk of Bias tool (RoB2), and meta-analyses were conducted using Review Manager 5.4. The protocol was registered in PROSPERO (CRD42024513515).

Results

Nine studies comprising 781 participants (430 treatment, 351 control) met the inclusion criteria. CoQ10 supplementation significantly improved sperm concentration (mean differences [MD]: 10.22×10⁶/mL [3.51–16.93], p=0.003), seminal volume (MD: 0.17 mL [0.03–0.31], p=0.02), total sperm motility (MD: 4.95% [1.15–8.75], p=0.01), and seminal CoQ10 levels (MD: 37.04 ng/ml [31.24–42.84], p<0.001). It also significantly increased clinical pregnancy odds (odds ratio: 6.02 [1.97–18.41], p=0.002). Subgroup analysis showed that treatment duration >3 months significantly improved sperm morphology (p<0.05). Three studies reported no adverse effects, while one noted mild, transient side effects.

Conclusions

CoQ10 supplementation in men with IMI significantly improves semen quality, seminal CoQ10 levels, and clinical pregnancy rates, particularly when used for over 3 months. CoQ10 therapy in infertile men with IMI is generally safe, whether used alone or in combination with other antioxidants.

INTRODUCTION

Approximately 8% to 12% of couples in the world encounter infertility, 30% to 50% due to male infertility. Male infertility refers to the inability to conceive due to male-related causes after one year of unprotected sexual intercourse [1,2]. Impaired fertility in a man can be caused by congenital or acquired conditions such as urogenital tract abnormalities, varicoceles, genital tract infections, genetic disorders, immunological problems, hormonal problems, cancer, or systemic diseases. However, around 37% to 58% of all male infertility cases present with a decrease in semen quality without an unknown etiology are defined as idiopathic male infertility (IMI) [3].

Oxidative stress (OS) has been identified as the underlying mechanism of IMI conditions [3]. OS occurs when the levels of reactive oxygen species (ROS) surpass the antioxidant capacity, which leads to damage to sperm cell membranes and DNA [4]. Increased ROS is found in 30% to 80% of IMI patients [5]. Therefore, antioxidant therapy aims to increase the semen antioxidant capacity can help in preventing the occurrence of OS [2].

Coenzyme Q10 (CoQ10) is a fat-soluble antioxidant and is an essential component of mitochondrial energy metabolism. Several randomized controlled trials (RCTs) have reported that CoQ10 supplementation in IMI patients significantly improves semen parameters and antioxidant capacity in seminal fluid [6,7,8]. However, robust data on the pooled effects of COQ10 on the reproductive outcomes of patients with IMI are lacking. Additionally, there has been no systematic review and meta-analysis (SRMA) that includes all RCT studies on the effectiveness of CoQ10 in IMI and examines dose variability, duration of administration, and safety of this supplement. Therefore, the current SRMA aims to evaluate the efficacy and safety of CoQ10 supplementation—administered alone or in combination with other antioxidants—on semen quality, seminal CoQ10 levels, and pregnancy outcomes in men with IMI, compared to placebo or alternative treatments.

MATERIALS AND METHODS

1. Protocol

The SRMA protocol has been registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42024513515).

2. Eligibility criteria (PICOS Criteria)

The PICO (Population, Intervention, Control, and Outcome) criteria of this SRMA are provided in Table 1, following the original model [9].

Table 1. Patients, intervention, control, and outcome (PICO) of the current systematic review and meta-analysis.

Acronym	Definition	Description
P	Population	Infertile men with idiopathic male infertility who received intervention
I	Intervention	Supplementation with coenzyme Q10 at varying doses and durations, either alone or combined with other antioxidants
C	Control	Infertile men with idiopathic male infertility who received a placebo or other supplements
O	Outcome	Primary outcomes:
			Semen parameters (sperm concentration, total sperm motility, morphology, and seminal volume)
			Seminal coenzyme Q10 levels
			Spontaneous pregnancy rate
		Secondary outcomes:
			Adverse effects

3. Literature search

This systematic review conducted a literature search on February 17, 2024, from various databases, PubMed, Science Direct, and Cochrane Library. The search was limited to articles published in the English language. The search was carried out using the following keywords: (“Coenzyme Q10” OR “coenzyme Q 10” OR “CoQ10” OR “Co Q10”) AND (“Male Infertility” OR “asthenozoospermia” OR “oligozoospermia” OR “oligoasthenozoospermia” OR “teratozoospermia”). During the literature search process, we did not use the filter features provided by each database to maintain the sensitivity of the search results.

4. Selection process

The study selection process was carried out by three investigators independently using a web-based application (rayyan.ai). One investigator (ATFZ) initially screened records for inclusion based on predetermined inclusion criteria by screening titles and abstracts, followed by a full-text assessment for eligibility. Two investigators (SB and MAGM) independently checked the decisions. Disagreements were discussed to reach a consensus. The screening results were reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) [10].

5. Data collection

Data were extracted by one investigator (ATFZ), including information on the study design (RCT), participant characteristics (e.g., age and grouping), and the definition of IMI according to the World Health Organization (WHO) criteria [11], CoQ10 intervention characteristics (e.g., dose, duration of intervention, intervention status [single or combination]), and outcomes of the study (sperm concentration, total sperm motility, morphology, and seminal volume, seminal CoQ10 levels, and spontaneous pregnancy rate). Two investigators (SB and MAGM) checked the extracted data. Differences of opinion were discussed to reach a consensus. The collected data was recorded in an Excel spreadsheet.

6. Risk of bias (quality) assessment

The methodological quality of eligible studies was independently evaluated by two investigators (ATFZ and MAGM) according to the Cochrane risk of bias tool (RoB 2). Specifically, we assessed the risk of bias of five domains: bias arising from the randomization process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in the measurement of the outcome, and bias in the selection of the reported result. Then, the overall risk of bias was decided in each included study. Disagreement in evaluating the risk of bias was resolved by discussion to reach a consensus.

7. Statistical analysis

The analysis of this study was performed using RevMan 5.4 (Cochrane Collaboration) and Comprehensive Meta-Analysis V3 (Biostat). For continuous data (sperm concentration, seminal volume, normal morphology, total sperm motility, and seminal CoQ10 level), we calculated the mean differences (MDs) with 95% confidence intervals (CIs). We used odds ratios (ORs) with 95% CI for dichotomous data (clinical pregnancy rate). We conducted the meta-analysis and subgroup analysis using the actual values representing the change from pre-treatment to post-treatment. However, several studies reported only the pre- and post-treatment means and standard deviations (SD), without providing the difference or its SD. To address this, we applied the Cochrane formula [12] to estimate the SD of the change (SD_C) using the following equation:

[SDC=[SD₁+SD₂–2r(SD₁)(SD₂)]

Fixed-effect models were used for meta-analyses when the heterogeneity value (I²) was low (<50%), while random-effect models were used when the heterogeneity value (I²) was high (>50%). We performed subgroup analysis based on the treatment duration (≤3 months and >3 months), type of control group (placebo or non-placebo), and CoQ10 status (single or in combination). For all meta-analyses that used random-effect models, a sensitivity analysis was conducted to assess whether the removal of a study is capable of changing the outcome.

8. Publication bias

Publication bias was evaluated subjectively by looking at the funnel plot. If the study distribution in the funnel plot was not symmetrical, publication bias was considered high.

RESULTS

1. Literature search and results of screening

After searching for studies from various databases using appropriate keywords, we found 543 studies. Before the screening, 79 duplicate studies were excluded, leaving 464 studies that underwent title and abstract screening. A total of 413 studies were excluded because they did not meet the eligibility criteria. Following the assessment of the full text of the remaining 51 studies, 41 studies were excluded because they did not meet the inclusion criteria. Additionally, two studies were excluded due to unresolved concerns by the publishing journal regarding the presented data. Hence, eight studies were found eligible for inclusion in the final analysis (Fig. 1).

Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow-chart for inclusion/exclusion of studies. RCT: randomized controlled trial. Supplement Table 1 includes the list of excluded articles.

2. Characteristics of the included studies

This SRMA included 8 RCTs, with a total of 781 IMI patients involved (treatment group: 430 and control group: 351). The classification of male infertility was variable, but the majority of studies were per the WHO 2010 criteria [11]. Out of 9 studies, five studies used a single CoQ10 formulation at a dose of 100 to 200 mg/day [6,7,8,13,14], while the remaining four studies used combinations of antioxidants containing CoQ10 at a lower dose of 20 to 90 mg/day [15,16,17,18]. The duration of CoQ10 therapy for patients with IMI was recorded as 3 months in 4 studies [6,8,14,18] and 6 or more months in 3 studies [7,13,15]. The remaining 2 studies [16,17] assessed outcomes at two points during the whole treatment period to evaluate differences in the outcomes based on intervention. Semen parameters were assessed in all studies included in this meta-analysis, while only two studies assessed levels of seminal CoQ10 [6,13], and two studies reported their results on clinical pregnancy outcomes [15,16]. Characteristics of the included studies are presented in Table 2.

Table 2. Characteristics of studies included in the current systematic review and meta-analysis.

No.	Author (publication year)	Participants	No. of participants		Age (y), mean±SD		Intervention	Duration of intervention (mo)	Comparison/control	Outcome					Adverse event
			CoQ10	Control	CoQ10	Control				SV	SC	SMT	SMP	SQ10
1	Alahmar and Singh (2022) [6]	Idiopathic oligoasthenospermia	65	65	33.6±14.1	36.4±15.2	CoQ10 (200 mg)	3	Centrum Multivitamins	√	√	√	√	√	NR
2	Alkumait et al (2020) [7]	Idiopathic oligoasthenoteratozoospermia	50	50	32.2±10.2	30.1±7.6	CoQ10 (200 mg)	6	Glutathione Placebo	√	√	√	√	-	NR
3	Balercia et al (2009) [13]	Idiopathic asthenozoospermia	30	30	32 (27–39)		CoQ10 (200 mg)	6	Placebo	-	√	√	√	√	CoQ10 was generally well tolerated, no laboratory abnormalities were observed
4	Busetto et al (2018) [15]	Idiopathic oligo- and/or astheno- and/or teratozoospermia	52	52	32.5±6.7	32.5±6.7	Proxeed Plus (two sachets daily)	6	Placebo	√	√	√	√	-	Not serious AE Nausea (4); Headache (2); Vertigo (1); GERD (1)
5	Kopets et al (2020) [16]	Idiopathic oligoasthenoteratozoospermia	42	41	32.5±6.1	32.7±5.2	Verum TDS	4	Placebo	-	√	√	√	-	There were no adverse events.
6	Micic et al (2019) [17]	Idiopathic oligoasthenozoospermia	125	50	31.5 (19–44)		ProXeed Plus (two sachets daily)	6	Placebo	√	-	√	-	-	NR
7	Nadjarzadeh et al (2014) [14]	Idiopathic oligoasthenoteratozoospermia	23	24	34.17± 4.52	34.67±6.69	CoQ10 (200 mg)	3	Placebo (Lactose)	-	√	√	√	-	There were no side effects
8	Terai et al (2020) [18]	Idiopathic Infertile male with oligozoospermia and/or asthenozoospermia	15	16	39.4±6.8	38.4±5.8	Antioxidant supplementa	3	Chinese Herbal	√	√	√	-	-	NR

CoQ10: coenzyme Q10, NR: not recorded, SC: sperm concentration, SD: standard deviation, SMP: sperm morphology, SMT: sperm motility, SQ10: seminal coenzyme Q10 level, SV: semen volume.

ProXeed Plus, Netherlands, containing: CoQ10 (20 mg); L-carnitine (1,000 mg); fumarate (725 mg); L-acetyl-carnitine (500 mg); fructose (1,000 mg); vitamin C (90 mg); Zinc (10 mg); folic acid (200 mcg); vitamin B12 (1.5 mcg).

Verum Test dietary supplement (TDS), containing: CoQ10 (40 mg); L-carnitine (1990 mg); L-arginine (250 mg); glutathione (100 mg); Zinc (7.5 mg); vitamin B9 (234 mcg); vitamin V12 (2 mcg); Selenium (50 mcg).

^aAntioxidant supplement, containing: CoQ10 (90.26 mg); L-carnitine (750.1 mg); Zinc (30 mg); astaxanthin (16.05 mg); vitamin C (1000 mg); vitamin B12 (60.1 mcg); vitamin E (150 mg).

3. Results of quality assessment

In the fifth domain (bias in selection of the reported result), three studies [7,14,16] did not stick to the original research plan and were, therefore, marked as having “high risk” of bias. Overall, two included studies were in the “low risk” of bias category, three studies were in the “some concern” category, and three studies were in the “high risk” of bias category as demonstrated in Fig. 2.

Fig. 2. Risk of bias assessment using the revised Cochrane risk of bias tool for randomized trials (RoB 2.0).

4. Results of meta-analysis

1) Sperm concentration

The meta-analysis of sperm concentration outcome was conducted in 7 studies [6,7,13,14,15,16,18], with one study having two consecutive results [16]. The meta-analysis results show a significantly higher sperm concentration in IMI patients who received CoQ10 therapy compared to the control group (MD=10.22×10⁶/mL [95% CI: 3.51–16.93, p=0.003, I²=92%]) (Fig. 3A). Subgroup analysis based on the duration of intervention showed significantly higher sperm concentrations when CoQ10 therapy was administered for more than 3 months (MD=13.61×10⁶/mL [95% CI: 5.15–22.06, p=0.002]) [7,13,15,16], while the increase in sperm concentration following 3 months or less of CoQ10 therapy was not statistically significant (MD=6.07×10⁶/mL [95% CI: -3.04–15.18, p=0.19]) (Fig. 3A) [6,14,16,18]. However, no significant differences were found between the two subgroups (p=0.23) (Fig. 3A). Subgroup analysis based on the type of control group showed significantly higher sperm concentration when a placebo was used as a control (MD=12.86×10⁶/mL [95% CI: 6.36–19.35, p<0.001]) [7,13,14,15,16] while no significant difference was found in studies that used other supplements as a control (MD=-0.29×10⁶/mL [95% CI: -1.95–1.37, p=0.92]) (subgroup difference, p<0.001) (Supplement Fig. 1A) [6,18]. Meanwhile, in the subgroup meta-analysis based on the CoQ10 formulation, no significant differences were found between the single [6,7,13,14] or combination CoQ10 subgroups (p=0.13) (Supplement Fig. 1B, Table 3) [15,16,18]. The results of the sensitivity analysis in the meta-analysis assessing the outcomes of sperm concentration showed consistent results (Supplement Fig. 1C). The results of the funnel plot in the meta-analysis on the outcome of sperm concentration showed a symmetrical distribution (Supplement Fig. 1D).

Fig. 3. Subgroup meta-analysis (CoQ10 vs Control) based on the duration of intervention (≤3 months or >3 months); (A) sperm concentration; (B) seminal volume; (C) normal morphology of sperm; (D) sperm total motility. SD: standard deviation, CI: confidence interval.

Table 3. Summary of results of subgroup meta-analyses of the effects of coenzyme Q10 on semen parameters.

Outcome	Covariate	Subgroup	No. of studies	MD (95% CI)	p-value	I2 (%)	Subgroup analyses
							I2 (%)	p-value
Sperm concentration (×106/mL)	Overall		8	10.22 (3.51–16.93)	0.003a	92
	Duration of intervention	≤3 months	4	6.07 (-3.04–15.18)	0.19	80	29.2	0.23
		>3 months	4	13.61 (5.15–22.06)	0.002	87
	Type of control group	Placebo	6	12.86 (6.36–19.35)	<0.001	82	93.2	<0.001b
		Non-placebo	2	-0.29 (-1.95–1.37)	0.92	0
	Coenzyme Q10 formulation	Single	4	4.93 (-2.22–12.09)	0.18	91	55.6	0.13
		Combination	4	16.78 (3.05–30.51)	<0.001	86
Seminal volume (mL)	Overall		5	0.17 (0.03–0.31)	0.02a	0
	Duration of intervention	≤3 months	3	0.18 (-0.05–0.42)	0.13	0	0	0.88
		>3 months	3	0.16 (-0.02–0.34)	0.08	0
	Type of control group	Placebo	4	0.18 (0.03–0.33)	0.02	0	0	0.67
		Non-placebo	2	0.17 (-0.34–0.51)	0.69	0
	Coenzyme Q10 formulation	Single	2	0.10 (-0.18–0.38)	0.48	0	0	0.56
		Combination	4	0.20 (0.03–0.36)	0.02	0
Normal morphology (%)	Overall		6	1.10 (-0.88–3.09)	0.28	73
	Duration of intervention	≤3 months	3	-0.59 (-1.04 to -0.14)	0.001	0	78.1	0.03b
		>3 months	3	3.34 (-0.24–6.93)	0.07	60
	Type of control group	Placebo	5	1.78 (-0.92–4.49)	0.20	68	65.6	0.09
		Non-placebo	1	-0.60 (-1.06 to -0.14)	NA	NA
	Coenzyme Q10 formulation	Single	3	0.20 (-1.88–2.27)	0.85	71	0	0.33
		Combination	3	2.40 (-1.55–6.34)	0.23	65
Total motility (%)	Overall		7	4.95 (1.15–8.75)	0.01a	89
	Duration of intervention	≤3 months	5	2.80 (-4.42–10.01)	0.45	91	7.9	0.30
		>3 months	4	7.07 (3.53–10.60)	<0.001	80
	Type of control group	Placebo	7	6.45 (3.11–9.78)	<0.001	84	20.7	0.26
		Non-placebo	2	-0.89 (-13.25–11.47)	0.89	84
	Coenzyme Q10 formulation	Single	3	1.43 (-8.51–11.38)	0.78	93	0	0.35
		Combination	6	6.59 (2.55–10.64)	0.001	86

MD: mean difference, CI: confidence interval.

^aSignificant for overall test; ^bSignificant for subgroup differences.

2) Seminal volume

The meta-analysis of seminal volume outcomes was conducted in 5 studies [6,7,15,17,18], with one study having two consecutive results [17]. The meta-analysis results show a significantly higher seminal volume in IMI patients who received CoQ10 therapy compared to the control group (MD=0.17 mL [95% CI: 0.03–0.31, p=0.02, I²=0%]) (Fig. 3B). Subgroup analysis based on the intervention duration showed no significant difference in seminal volume outcome (p=0.88) (Fig. 3B). Subgroup analysis based on the control group also showed no significant difference (p=0.76) (Supplement Fig. 2A). Additionally, in the subgroup meta-analysis based on the CoQ10 formulation, no significant differences were found between the single or combination CoQ10 subgroups (p=0.56) (Supplement Fig. 2B, Table 3). The funnel plot results in the meta-analysis on the outcome of seminal volume showed a symmetrical distribution (Supplement Fig. 2C).

3) Normal morphology

The meta-analysis of normal morphology outcomes was conducted in 5 studies [6,13,14,15,16], with one study having two consecutive results [16]. The meta-analysis results show no significant difference in the mean percentage of normal sperm morphology between IMI patients receiving CoQ10 therapy and the control group. (MD=1.10 [95% CI: -0.88–3.09, p=0.28, I²=73%]) (Fig. 3C). Subgroup analysis based on the duration of intervention showed insignificantly higher normal morphology when CoQ10 therapy was administered for more than 3 months (MD=3.34 [95% CI: -0.24–6.93, p=0.07]) [6,14,16], while the increase in normal morphology percentage following 3 months or less of CoQ10 therapy was significantly lower (MD: -0.59 [95% CI: -1.04 to -0.14, p=0.01]) (Fig. 3C) [13,15,16]. Significant differences were found between the two subgroups (p=0.03) (Fig. 3C). Subgroup meta-analysis based on the control group showed that the “placebo subgroup” [13,14,15,16] showed no significant result compared to the “non-placebo control” subgroup (p=0.09) (Supplement Fig. 3A). Meanwhile, in the subgroup meta-analysis based on the CoQ10 formulation, there was also no significant difference between the single or combination CoQ10 subgroups (p=0.33) (Supplement Fig. 3B, Table 3). The sensitivity analysis results in the meta-analysis assessing the outcomes of normal morphology showed consistent results. The funnel plot results in the meta-analysis on the outcome of normal morphology showed a symmetrical distribution. (Supplement Fig. 3D).

4) Total sperm motility

The meta-analysis of total motility outcomes was conducted in 7 studies [6,13,14,15,16,17,18], with two studies having two consecutive results [16,17]. The meta-analysis results show a significantly higher total sperm motility in IMI patients who received CoQ10 therapy compared to the control group (MD=4.95% [95% CI: 1.15–8.75, p=0.01, I²=89%]) (Fig. 3D). Subgroup analysis based on the intervention duration showed no significant difference in total motility outcome (p=0.30) (Fig. 3D). The subgroup meta-analysis based on the control group also showed no significant difference (p=0.26) (Supplement Fig. 4A). Meanwhile, in the subgroup meta-analysis based on the CoQ10 formulation, there was also no significant difference between the single or combination CoQ10 subgroups (p=0.35) (Supplement Fig. 4B, Table 3). The sensitivity analysis results in the meta-analysis assessing the outcomes of total motility showed consistent results (Supplement Fig. 4C). The funnel plot results in the meta-analysis on the outcome of total motility showed a symmetrical distribution (Supplement Fig. 4D).

5) Seminal CoQ10 levels

The meta-analysis of Seminal CoQ10 levels outcomes was conducted in 2 studies [6,13]. The meta-analysis results show a significantly higher seminal CoQ10 level in IMI patients who received CoQ10 therapy compared to the control group (MD=37.04 [95% CI: 31.24–42.84, p<0.0001, I²=37%]) (Fig. 4). The funnel plot results in the meta-analysis on the outcome of total motility showed a symmetrical distribution (Supplement Fig. 5).

Fig. 4. Meta-analysis of seminal CoQ10 levels (CoQ10 vs Control). CoQ10: coenzyme Q10, SD: standard deviation, CI: confidence interval.

6) Clinical pregnancy rate

The meta-analysis of pregnancy rate outcomes was conducted in 2 studies [15,16]. The meta-analysis results show a significantly higher clinical pregnancy rate in IMI patients who received CoQ10 therapy compared to the control group (OR=6.02 [95% CI: 1.97–18.41, p=0.002, I²=0%]) (Fig. 5). The funnel plot results in the meta-analysis on the outcome of total motility showed a symmetrical distribution (Supplement Fig. 6).

Fig. 5. Meta-analysis of clinical pregnancy rate (CoQ10 vs Control). CoQ10: coenzyme Q10, M-H: Mantel-Haenszel, CI: confidence interval.

7) Adverse events of CoQ10

A total of 4 out of 8 RCT studies evaluated side effects that occurred during the administration of CoQ10 supplements [13,14,15,16]. Of the four studies, 3 reported no side effects while receiving CoQ10 supplementation (Table 2) [13,14,16]. However, in the study by Busetto et al [15], mild side effects were reported in the form of nausea in 4 patients, headache in 2 patients, vertigo, and gastroesophageal reflux disease (GERD) in 1 patient each. These side effects disappeared immediately after the intervention was stopped. However, the intervention given in the latter study was a combination of several antioxidants, namely CoQ10 (20 mg); L-carnitine (1,000 mg); fumarate (725 mg); L-acetyl-carnitine (500 mg); fructose (1000 mg); vitamin C (90 mg); Zinc (10 mg); folic acid (200 mcg); vitamin B12 (1.5 mcg); so the side effects that arise may not be from the effects of CoQ10 alone [15]. The results of our qualitative analysis indicated that CoQ10 is generally well tolerated and does not cause serious side effects in IMI patients.

5. Meta-regression

The relationship between the duration of intervention and semen parameter outcomes was evaluated by meta-regression analysis. The results showed no significant correlation between semen parameters and duration of intervention (p>0.05) (Supplement Table 1, Supplement Fig. 7).

DISCUSSION

The results of the current meta-analysis showed that CoQ10 supplementation significantly increased sperm concentration, seminal volume, total sperm motility, CoQ10 levels in the seminal fluid, and increased pregnancy rates in IMI. Vishvkarma et al [19] previously conducted a meta-analysis assessing the effect of CoQ10 on semen parameters, and the results showed that CoQ10 supplementation significantly increased sperm motility but had no effect on sperm concentration, seminal volume, and seminal CoQ10 levels. Based on population size and homogeneity, this study included a larger population, with 781 participants in 9 RCTs, compared to Vishvkarma et al’s study [19], which included only three studies. Broader representation increases the level of evidence on the topic. Additionally, subgroup meta-analyses and meta-regression may provide new insights into the effectiveness of CoQ10 in patients with IMI.

In 40% of infertile men, the specific cause remains unidentified, which is classified as IMI [20]. Several recent studies have reported that the involvement of OS greatly influences the incidence of infertility in men; in fact, 30% to 80% of male infertile patients were found to have increased ROS in their semen [5]. ROS are free radicals produced from oxidative metabolic pathways and the activity of mitochondrial respiratory chain enzymes. In semen, ROS are also produced by abnormal or immature leukocytes or spermatozoa. ROS in small amounts also have cellular functions such as sperm capacitation, hyperactivation, and acrosome reaction, and are also involved in sperm-oocyte fusion during fertilization [21]. Semen is also rich in antioxidants, which are produced in two systems: the enzymatic system (glutathione peroxidase, superoxide dismutase, catalase) and the non-enzymatic system, which is obtained from compounds consumed through food or supplements [21,22]. However, when ROS levels exceed antioxidant levels, OS will occur in sperm fluid, which causes damage to sperm DNA. Spermatozoa are susceptible to OS because their plasma membrane contains many polyunsaturated fatty acids, which can undergo lipid peroxidation by ROS. Lipid peroxidation causes a chain reaction that produces further mutagenic and genotoxic molecules, which in turn increase ROS production, DNA fragmentation, and sperm apoptosis [23]. Therefore, increasing antioxidant levels in semen may help prevent OS and reduce sperm damage, although the effectiveness of this approach is still under debate [23].

CoQ10 is an exogenous antioxidant that transports electrons from complexes I and II to complexes III. This effect is influential in preventing membrane phospholipid peroxidation and free radical oxidation [24]. CoQ10 plays a vital role in cellular energy production, but its reduced form, ubiquinol, primarily confers antioxidant properties. Ubiquinol can donate electrons, neutralizing ROS and thereby reducing OS [25]. This form of CoQ10 is considered more effective in mitigating oxidative damage in sperm cells [6]. The results of this meta-analysis showed that CoQ10 supplementation significantly increased CoQ10 levels in semen in IMI patients. Increasing CoQ10 levels in seminal fluid may enhance the antioxidant capacity of seminal fluid [13,26,27,28]. This could help reduce OS and protect sperm DNA from ROS-induced damage. Several previous studies suggest that antioxidant therapy may reduce sperm damage [29,30,31]. Research conducted by Humaidan et al [32] showed that a three-month lifestyle modification program, in conjunction with antioxidant treatment, decreased DNA fragmentation index in infertile males exhibiting increased sperm DNA fragmentation and a history of unsuccessful in vitro fertilization/intracytoplasmic sperm injection. However, controlled trials assessing reproductive outcomes are needed before a definitive conclusion can be established. Increasing the antioxidant capacity of seminal fluid can help reduce the risk of lipid peroxidation due to OS, thereby increasing sperm count due to inhibited apoptosis due to the lipid peroxidation process [22]. This is also proven by Tavilani et al [33], which indicates that antioxidant enzymes in seminal plasma have a protective function against lipid peroxidation in spermatozoa. Another effect of increasing CoQ10 in semen is improvement of mitochondrial function [22]. Increasing mitochondrial function in sperm will provide more energy, thereby increasing sperm motility [34]. CoQ10 accepts electrons from various substrates, thereby preventing the formation of high ROS such as superoxide radicals and hydrogen peroxide, and donating electrons to these reactive intermediates. CoQ10 helps convert them into water, reducing OS within cellular membranes and mitochondria [35,36]. In addition, giving CoQ10 supplements can also increase inhibin B levels [22]. Inhibin B is produced by Sertoli cells as a marker of Sertoli cell activity. Increased levels of inhibin B in serum reflect increased spermatogenesis in the testes. This increase is supported by previous studies reporting that serum levels of inhibin B were strongly and positively correlated with testicular volume and sperm count [37]. Increasing spermatogenesis in the testicles will increase the number of sperm in the semen.

Positive effects of CoQ10 supplementation on spermatogenic function and semen parameters may be mediated by several mechanisms that include; 1) Enhancing the antioxidant ability of semen to limit lipid peroxidation caused by OS, which may prevent damage to spermatozoa and apoptosis; 2) Increasing mitochondrial function in spermatozoa results in increased energy, which promotes motility in sperm; 3) Increasing spermatogenesis, which is characterized by increasing levels of inhibin B as the main product of Sertoli cells, which describes the process of spermatogenesis in the testes. A summary of the suggested mechanisms by which CoQ10 supplementation enhances sperm parameters is shown in Fig. 6. However, new research is needed to explore the exact mechanisms of improved semen parameters and men’s fertility potential following CoQ10 supplementation.

Fig. 6. Mechanism of the effect of coenzyme Q10 (CoQ) on increasing semen parameters. ROS: reactive oxygen species.

The high variability of CoQ10 dosage remains a significant challenge in providing the best dosage recommendation. Three of the eight studies included in this systematic review gave CoQ10 alone at a daily dose of 100 to 200 mg, while the other four studies gave CoQ10 in combination with other antioxidants, but the dose of CoQ10 tended to be lower, around 20 to 100 mg. In Alahmar’s study [26], a comparison was made between a single administration of CoQ10 at a dose of 400 mg/day and 200 mg/day. The results revealed that a dose of CoQ10 400 mg/day provides better outcomes than 200 mg/day. Apart from the varied dosage, the timing of CoQ10 supplementation is also variable, but from the results of the subgroup meta-analysis, we found a significant difference between giving CoQ10 for 3 months or less and giving it for more than 3 months. Giving CoQ10 for more than 3 months increased the percentage of normal sperm morphology significantly compared to giving CoQ10 only for 3 months or less. The study of Micic et al [17] conducted assessments at two points with different intervention durations, 12 weeks and 24 weeks. The results showed sperm volume and motility were higher after being given the intervention for 24 weeks. Likewise, the study of Kopets et al [16] reported an increase in sperm concentration and motility, and the percentage of normal morphology was higher after patients received intervention for 16 weeks compared to 8 weeks. For instance, in humans, each seminiferous epithelium cycle lasts approximately 10 to 16 days, resulting in a total spermatogenesis time of approximately 70 to 75 days. This duration is based on the fact that approximately 4.5 cycles are necessary to complete the entire spermatogenesis process [38]. Longer treatment duration is hypothesized to be advantageous over shorter cycles because it aligns with the natural duration of total spermatogenesis time. Based on the meta-regression results in this study, we did not find a significant relationship between the duration of CoQ10 administration and semen parameters in patients with IMI. However, the results of the subgroup meta-analysis showed significantly better outcomes in patients who were given CoQ10 for 6 months or more in terms of the percentage of normal morphology. Therefore, we still recommend giving CoQ10 for at least 6 months to provide more optimal results.

The main goal of infertility therapy is to achieve pregnancy. The results of our meta-analysis indicate that the likelihood of clinical pregnancy in patients who received CoQ10 supplements is six times greater than in patients who did not receive CoQ10 supplementation. However, this data is limited by the low number of studies, which may not adequately represent the broader population of men experiencing infertility. It became crucial to emphasize the need for additional studies that specifically evaluate the impact of CoQ10 on pregnancy rates in larger and more diverse populations.

In terms of safety, only one in four studies reported side effects that included nausea in 4 patients, headache in 2 patients, vertigo in 1 patient, and one patient with GERD [15]. However, in this study, the supplement given was a combination of several antioxidants and other vitamins, including L-carnitine, fumarate, fructose, vitamin C, Zinc, folic acid, and vitamin B12. Therefore, the side effects that occur are not necessarily due to the effects of CoQ10 [15]. Meanwhile, three other studies assessed side effects and found that CoQ10 administration was well tolerated [13,14,16]. CoQ10 supplementation is generally safe to use and well tolerated for IMI patients.

Despite the interesting findings of this SRMA, we realize that this study still has shortcomings, namely the heterogeneity of interventions, which is still very varied, even though we have tried to overcome this by creating a subgroup analysis model. However, different combinations can bias the results, especially in subgroup analysis based on status (single vs combination). Apart from that, the limited number of RCTs, especially those reporting pregnancy rate outcomes, is also an important limitation of exploring the potential impact of CoQ10 therapy on reproductive outcomes. Several included studies have a high risk of reporting bias because they do not report all outcomes that should be reported. But besides these limitations, the results of SRMA provide the most recent evidence that can be used as a clinical consideration for using CoQ10 in IMI patients. However, while acknowledging the need for further research, it is also important to highlight that CoQ10 supplementation could represent a valuable addition to fertility treatment regimens for men with idiopathic infertility.

CONCLUSIONS

CoQ10 supplementation in patients with IMI significantly improves sperm concentration, seminal volume, total motility, and seminal CoQ10 levels, particularly when administered for six months. It has also been shown to increase the likelihood of achieving clinical pregnancy and is generally safe, whether used alone or in combination with other antioxidants. While further research is warranted to refine dosing strategies and confirm long-term outcomes, the findings of this SRMA suggest that CoQ10 is a promising therapeutic option for men with IMI.

Supplementary Materials

Supplementary materials can be found via https://doi.org/10.5534/wjmh.250159.

Supplement Fig. 1

Sub-group analysis of sperm concentration outcome. (A) Based on type of control group, (B) based on the CoQ10 formulation (single or combination), (C) sensitivity analysis of sperm concentration outcome, (D) publication bias. CoQ10: coenzyme Q10, SD: standard deviation, CI: confidence interval, SE: standard error, MD: mean difference.

Supplement Fig. 2

Sub-group analysis of seminal volume outcome. (A) Based on type of control group, (B) based on the CoQ10 formulation (single or combination), (C) funnel plot. CoQ10: coenzyme Q10, SD: standard deviation, CI: confidence interval, SE: standard error, MD: mean difference.

Supplement Fig. 3

Sub-group analysis of normal sperm morphology outcome. (A) Based on type of control group; (B) based on the CoQ10 formulation (single or combination), (C) sensitivity analysis of normal sperm morphology outcome, (D) publication bias. CoQ10: coenzyme Q10, SD: standard deviation, CI: confidence interval, SE: standard error, MD: mean difference.

Supplement Fig. 4

Sub-group analysis of sperm total motility outcome. (A) Based on type of control group, (B) based on the CoQ10 formulation (single or combination), (C) sensitivity analysis of sperm total motility outcome, (D) publication bias. CoQ10: coenzyme Q10, SD: standard deviation, CI: confidence interval, SE: standard error, MD: mean difference.

Supplement Fig. 5

Funnel plots of meta-analysis of seminal coenzyme Q10 levels. SE: standard error, MD: mean differences.

Supplement Fig. 6

Funnel plots of meta-analysis of clinical pregnancy rates. SE: standard error, OR: odds ratio.

Supplement Fig. 7

Meta-regression between semen parameters and duration of intervention.

Supplement Table 1

List of excluded studies