Current treatment for male infertility: an umbrella review of systematic reviews and meta-analyses

Abstract

This umbrella review aimed to summarize and provide a general evaluation of the effectiveness of current treatments for male infertility and assess the quality of evidence and possible biases. An umbrella review of systematic reviews and meta-analyses available in PubMed, Web of Science, and Scopus, covering studies published up to October 2023, was conducted. Sperm concentration, morphology, and motility were used as endpoints to evaluate the effectiveness of the treatments. Of 2998 studies, 18 published meta-analyses were extracted, yielding 90 summary effects on sperm concentration (n = 36), sperm morphology (n = 26), and sperm motility (n = 28) on 28 interventions. None of the meta-analyses were classified as having low methodological quality, whereas 12 (66.7%) and 6 (33.3%) had high and moderate quality, respectively. Of the 90 summary effects, none were rated high-evidence quality, whereas 53.3% (n = 48), 25.6% (n = 23), and 21.1% (n = 19) were rated moderate, low, and very low, respectively. Significant improvements in sperm concentration, morphology, and motility were observed with pharmacological interventions (N-acetyl-cysteine, antioxidant therapy, aromatase inhibitors, selective estrogen receptor modulators, hormones, supplements, and alpha-lipoic acid) and nonpharmacological interventions (varicocele repair and redo varicocelectomy). In addition, vitamin supplementation had no significant positive effects on sperm concentration, motility, or morphology. Treatments for male infertility are increasingly diverse; however, the current evidence is poor because of the limited number of patients. Further well-designed studies on single treatment and high-quality meta-analysis of intertreatment comparisons are recommended.

INTRODUCTION

According to the World Health Organization (WHO), human infertility is defined as the failure to obtain a clinical pregnancy despite 1 year of unprotected intercourse with the same partner.1 Approximately one in six couples has been troubled by infertility, with male infertility being the primary or contributing factor in half of these cases.2,3 Many studies have been made to investigate the causes of male infertility, and the reported risk factors include reproductive system disease (such as varicocele, chronic prostatitis, bilateral sperm ducts, and testicular cancer), bacterial and viral infections (such as herpes simplex virus, urogenital mycoplasmas, coronavirus disease 2019, Chlamydia trachomatis, and human papillomavirus), specific genetic abnormalities (such as chromosomal aberrations, gene mutations, congenital anomalies, and polymorphisms), and lifestyles (such as smoking, coffee, cannabis, and dietary patterns),4,5,6,7,8,9,10 primarily on the basis of decreased and inferior sperm quality.

To alleviate this global burden, many retrospective and prospective studies have revealed the effects of different interventions, which can be broadly classified into pharmacological, nonpharmacological, and combined interventions, on male infertility. Numerous systematic reviews and meta-analyses have pooled and summarized the results of each intervention.11,12,13 The effectiveness of the intervention is usually assessed by the degree of improvement in semen or sperm quality, with sperm concentration, morphology, and motility ranking as the top three most frequently used endpoints. A comprehensive overview of the association of effectiveness between male infertility and artificial intervention is urgently needed to make clinically individual recommendations; however, such an overview remains unavailable.

Therefore, this umbrella review aimed to summarize and provide a general evaluation of the effectiveness of current treatments on male infertility and assess the quality of evidence and possible biases.

MATERIALS AND METHODS

Umbrella review method and literature search

Umbrella reviews summarize and evaluate the strength and validity of evidence in published reports and assess the potential risk of bias.14 In this study, we conducted an umbrella review in accordance with the reporting guidance provided in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P).15

Systematic reviews and meta-analyses regarding treatments for male infertility were systematically searched, and their results were comprehensively evaluated. According to the reporting criteria of umbrella reviews, reviews without pooled quantitative assessment results were excluded.

To obtain systematic reviews and meta-analyses of interest, medical databases, including PubMed, Web of Science, and Scopus, were searched from their inception to October 2023, following the Scottish Intercollegiate Guidelines Network (SIGN) guidelines.16 The predefined search terms were “male infertility”, “male sterility”, “male subfertility”, “aspermia”, “azoospermia”, “oligospermia”, “teratozoospermia”, “asthenozoospermia”, “meta-analysis”, “meta-analyses”, and “systematic review”. Synonyms were combined using the Boolean operator (OR), and paratactic terms were combined using the Boolean operator (AND). The detailed strategy is presented in Supplementary Table 1.

Supplementary Table 1.

Search term of this umbrella review

Medical databases	The predefined search terms
Pubmed	#1. (male infertility[Title/Abstract]) OR (male sterility[Title/Abstract]) OR (male subfertility [Title/Abstract]) OR (aspermia [Title/Abstract]) OR (azoospermia [Title/Abstract]) OR (oligospermia [Title/Abstract]) OR (teratozoospermia [Title/Abstract]) OR (asthenozoospermia [Title/Abstract])
	#2. (meta-analysis[Title/Abstract]) OR (meta-analyses[Title/Abstract]) OR (“systematic review” [Title/Abstract])
	#3. #1 and #2
Web of Science	#1. (TS=(male infertility) OR TS=(male sterility) OR
	TS=(male subfertility) OR TS=(aspermia) OR
	TS=(azoospermia) OR TS=(oligospermia) OR
	TS=(teratozoospermia) OR TS=(asthenozoospermia))
	#2. (TS=(meta-analysis) OR TS=(meta-analyses) OR
	TS=(systematic review)) #3. #1 and #2
Scopus	#1. TITLE-ABS-KEY ( ( “male infertility” ) OR ( “male sterility” ) OR ( “male subfertility” ) OR ( “aspermia” ) OR ( “azoospermia” ) OR ( “oligospermia” ) OR (“teratozoospermia” ) OR ( “asthenozoospermia” ) )
	#2. TITLE-ABS-KEY ( ( “meta-analysis” ) OR (“meta-analyses” ) OR ( “systematic review” ) )
	#3. #1 and #2

Two investigators (JJY and QHW) independently screened titles and abstracts and selected eligible articles for subsequent full-text review. Relevant references in all eligible reviews were also manually screened. Any disagreements were resolved by consensus following the addition of a third investigator (ZYC).

Eligibility criteria

Systematic reviews with meta-analyses about treatment inventions for male infertility were included without any restriction on the research types (including cohort or case–control observational studies and randomized or nonrandomized controlled interventional studies), race, sex, or region of the participants. The involved interventions were as follows: (1) pharmacological interventions, including phosphodiesterase-5 inhibitors, N-acetyl-cysteine (NAC), antioxidant therapy, aromatase inhibitors (AIs), clomiphene citrate, hormones, selective estrogen receptor modulators (SERMs), tamoxifen, follicle-stimulating hormone (FSH) therapy, testosterone, recombinant-human FSH, highly purified FSH, Qilin Pill, Wuzi Yanzong Pill, Indian ginseng, supplements, vitamins, alpha-lipoic acid, coenzyme Q10 (CoQ10), selenium, L-carnitine, and zinc sulfate; (2) nonpharmacological interventions, including varicocele repair (VR), redo varicocelectomy, subclinical varicocelectomy, and acupuncture; and (3) combined interventions, including vitamins plus traditional Chinese medicine (TCM) and adjuvant drug therapy after varicocelectomy.

Studies were excluded if they met the following criteria: (1) without summary estimates or corresponding 95% confidence intervals (CIs), for example, systematic reviews without meta-analysis; (2) endpoints without sperm concentration, morphology, or motility, for example, a meta-analysis that only reported sperm volume but not sperm concentration, morphology, or motility; (3) published in languages other than English; or (4) animal or laboratory studies. If more than one study focused on the same intervention, only one meta-analysis with the largest number of primary studies was selected to avoid the inclusion of duplicate studies. Furthermore, if two or more studies were conducted on the same number of primary studies, the study with the largest number of participants was selected.

Data extraction

One reviewer (JJY) independently extracted the following data, and another reviewer (QHW) was responsible for double-checking: (1) intervention, (2) name of the first author, (3) publication year, (4) study design, (5) population, (6) sperm parameter, (7) number of included studies, (8) number of participants, (9) standard mean difference (SMD) and corresponding 95% CI, (10) effect model, (11) I² statistic, and (12) the P-value of Egger’s test.

Methodological and evidence quality

The Assessment of Multiple Systematic Reviews (AMASTAR), a valid tool for umbrella reviews, was used to evaluate the methodological quality of each included meta-analysis.17,18 It is a numerical scoring system consisting of 11 items (11 total points) and grades studies into high, moderate, and low quality with cutoff values of 8 points and 3 points.

The quality of evidence for each intervention in the umbrella review was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE),16 and the results were presented as high, moderate, low, and very low grades for recommendation.

Data analyses

Data on the effectiveness of treatments on male infertility were extracted, and the summary effect with 95% CI was reported in each meta-analysis if available. To allow the pooled effect estimates for each endpoint to be displayed on the same axis, the mean differences were transformed into SMD. If multiple treatments existed in one article, data were extracted separately if possible. Heterogeneity among studies was estimated using the I² statistic and Cochran’s Q test. To calculate the publication bias in each meta-analysis, Egger’s regression test was performed.19 Significant heterogeneity was defined as P < 0.10 in Egger’s regression test, whereas P < 0.05 was considered significant for other tests. Evidence synthesis was performed using Review Manager 5.3 version (Cochrane Collaboration, Oxford, UK), and the results were presented using the software package R (http://www.R-project.org; The R Foundation, Boston, MA, USA).

RESULTS

Characteristics of the included studies

A flowchart of the screening process is presented in Figure 1. According to the predefined search strategy, 2998 studies were initially identified from 3 standard databases, and 71 studies were finally selected for further full-text screening. Subsequently, the following were extracted: 90 estimated summary effects on sperm concentration, morphology, and motility on 28 interventions from 18 published studies, among which 36 estimated summary effects from 18 studies were reported on sperm concentration, 26 estimated summary effects from 12 studies were reported on sperm morphology, and 28 estimated summary effects from 13 studies were reported on sperm motility. With the exception of Qilin Pill, Wuzi Yanzong Pill, Indian ginseng, and alpha-lipoic acid, more than one meta-analysis was published for each intervention. Detailed information is presented in Supplementary Table 2.

Figure 1.

The flow diagram for identification and selection of studies.

Supplementary Table 2.

The effectiveness of treatments on sperm parameters

Intervention	Author	Year	Study design	Population	Sperm parameter	Study (n)	Cases/total	SMD	95% CI	Effects model	I2	Q-test	Egger test (P)	AMSATR evaluation	GRADE evaluation
Pharmacological intervention
Phosphodiesterase-5 inhibitors	Dong et al.1	2021	RCT	Infertility	Sperm concentration	3	83/82	0.39	0.24–0.54	Random	83	<0.01	NA	9	Moderate
					Sperm morphology	3	83/82	0.15	0.01–0.31	Fixed	0	0.57	NA	9	Moderate
NAC	Wei et al.2	2021	RCT and non-RCT	Idiopathic infertility	Sperm concentration	3	431	0.25	0.15–0.34	Random	52	0.13	NA	7	Very low
					Sperm morphology	3	431	0.18	0.08–0.27	Random	100	<0.01	NA	7	Moderate
					Sperm motility	3	431	0.20	0.10–0.29	Random	96	<0.01	NA	7	Very low
Antioxidant therapy	Agarwal et al.3	2023	RCT	Infertility	Sperm concentration	36	2407/1903	0.12	0.09–0.15	Random	94	<0.01	0.50	9	Moderate
					Sperm morphology	18	975/853	0.17	0.12–0.22	Random	96	<0.01	0.04	9	Low
					Sperm motility	36	2516/1936	0.05	0.02–0.08	Random	100	<0.01	<0.01	9	Moderate
Supplements*	Shahid et al.4	2021	RCT	Infertility	Sperm concentration	13	825/1789	0.07	0.03–0.11	Random	91	<0.01	NA	9	Low
					Sperm morphology	13	825/1789	0.05	0.01–0.09	Random	89	<0.01	NA	9	Moderate
					Sperm motility	13	826/1789	0.07	0.04–0.11	Random	96	<0.01	NA	9	Moderate
Vitamins	Shahid et al.4	2021	RCT	Infertility	Sperm concentration	4	332/3400	0.01	−0.03–0.03	Fixed	0	0.99	NA	9	Moderate
					Sperm morphology	4	332/3400	0.01	−0.03–0.03	Fixed	0	0.99	NA	9	Moderate
					Sperm motility	4	332/3400	0.01	−0.04–0.03	Fixed	0	0.98	NA	9	Low
Alpha-lipoic acid	Dong et al.5	2022	RCT	Infertility	Sperm concentration	3	84/84	0.36	0.20–0.51	Fixed	47	0.11	NA	9	Moderate
					Sperm morphology	2	54/54	0.89	0.70–1.08	Fixed	0	0.32	NA	9	Moderate
					Sperm motility	3	84/84	0.56	0.41–0.71	Random	65	0.02	NA	9	Moderate
CoQ10	Shahid et al.4	2021	RCT	Infertility	Sperm concentration	4	245/246	0.12	0.04–0.21	Random	94	<0.01	NA	9	Moderate
					Sperm morphology	4	245/246	0.07	−0.01–0.16	Random	73	0.01	NA	9	Moderate
					Sperm motility	4	245/246	0.12	0.03–0.21	Random	98	<0.01	NA	9	Moderate
Selenium	Sharma et al.6	2022	RCT	Idiopathic infertility	Sperm concentration	3	176/153	0.14	0.03–0.24	Random	70		NA	8	Moderate
L-carnitine	Wei et al.2	2021	RCT and non-RCT	Idiopathic infertility	Sperm concentration	4	190	0.08	−0.06–0.23	Random	99	<0.01	NA	7	Very low
					Sperm morphology	2	139	0.23	0.07–0.40	Random	88	<0.01	NA	7	Very low
					Sperm motility	4	190	0.16	0.02–0.30	Random	98	<0.01	NA	7	Very low
Zinc sulfate	Shahid et al.4	2021	RCT	Infertility	Sperm concentration	4	144/147	0.07	−0.04–0.19	Random	81	<0.01	NA	9	Moderate
					Sperm morphology	4	144/147	0.07	−0.04–0.19	Random	86	<0.01	NA	9	Moderate
					Sperm motility	4	144/147	0.76	0.65–0.88	Fixed	0	0.76	NA	9	Moderate
AIs	Guo et al.7	2022	RCT and non-RCT	Infertility	Sperm concentration	8	605	0.15	0.07–0.23	Random	98	<0.01	NA	9	Very low
					Sperm morphology	6	498	0.39	0.30–0.48	Random	82	<0.01	NA	9	Very low
					Sperm motility	10	666	0.19	0.11–0.26	Random	93	<0.01	NA	9	Very low
Antioxidant therapy for 3 months or less	Agarwal et al.3	2023	RCT	Infertility	Sperm concentration	36	986/865	0.12	0.07–0.16	Random	95	<0.01	NA	9	Moderate
					Sperm morphology	24	1018/838	0.14	0.10–0.19	Random	99	<0.01	NA	9	Moderate
					Sperm motility	18	434/370	0.12	0.05–0.19	Random	96	<0.01	NA	9	Moderate
Antioxidant therapy for 6 months	Agarwal et al.3	2023	RCT	Infertility	Sperm concentration	22	1014/659	0.14	0.09–0.18	Random	89	<0.01	NA	9	Moderate
					Sperm morphology	14	1192/821	0.20	0.16–0.25	Random	76	0.45	NA	9	Moderate
					Sperm motility	7	435/378	0.13	0.06–0.20	Fixed	0	<0.01	NA	9	Moderate
Antioxidant therapy for 9 months or more	Agarwal et al.3	2023	RCT	Infertility	Sperm concentration	8	407/379	0.09	0.02–0.16	Random	69	<0.01	NA	9	Moderate
					Sperm motility	4	306/277	0.06	−0.02–0.14	Random	72	<0.01	NA	9	Moderate
Clomiphene citrate	Huijben et al.8	2023	RCT and non-RCT	Infertility	Sperm concentration	15	566	0.22	0.13–0.30	Random	87	<0.01	NA	8	Very low
					Sperm morphology	6	221	0.10	−0.04–0.23	Fixed	42	0.13	NA	8	Very low
					Sperm motility	13	537	0.16	0.08–0.24	Random	76	<0.01	NA	8	Very low
Hormones	Shahid et al.4	2021	RCT	Infertility	Sperm concentration	15	608/500	0.13	0.07–0.19	Random	87	<0.01	NA	9	Moderate
					Sperm morphology	15	608/500	0.08	0.02–0.14	Random	83	<0.01	NA	9	Low
					Sperm motility	15	608/500	0.09	0.03–0.15	Random	78	<0.01	NA	9	Low
SERMs	Shahid et al.4	2021	RCT	Infertility	Sperm concentration	9	323/262	0.67	0.59–0.75	Fixed	1	0.43	NA	9	Low
					Sperm morphology	9	323/261	0.09	0.01–0.17	Random	93	<0.01	NA	9	Moderate
					Sperm motility	9	323/262	0.18	0.10–0.26	Random	63	<0.01	NA	9	Moderate
Tamoxifen	Shahid et al.4	2021	RCT	Infertility	Sperm concentration	7	237/186	0.62	0.53–0.72	Fixed	0	0.50	NA	9	Low
					Sperm motility	7	237/186	0.16	0.07–0.26	Random	71	<0.01	NA	9	Moderate
FSH therapy	Cannarella et al.9	2020	RCT	Idiopathic infertility	Sperm concentration	9	372/294	0.14	0.07–0.22	Random	92	<0.01	NA	7	Moderate
					Sperm morphology	8	310/244	0.09	0.01–0.17	Random	85	<0.01	NA	7	Moderate
Low dose of FSH therapy	Cannarella et al.9	2020	RCT	Idiopathic infertility	Sperm concentration	3	111/75	0.11	−0.04–0.25	Random	82	<0.01	NA	7	Moderate
					Sperm morphology	3	111/75	0.03	−0.11–0.17	Random	96	<0.01	NA	7	Moderate
Intermediate-dose of FSH therapy	Cannarella et al.9	2020	RCT	Idiopathic infertility	Sperm concentration	4	180/159	0.34	0.24–0.45	Random	0	0.56	NA	7	Moderate
					Sperm morphology	3	118/109	0.17	0.04–0.30	Fixed	0	0.54	NA	7	Moderate
High dose of FSH therapy	Cannarella et al.9	2020	RCT	Idiopathic infertility	Sperm concentration	2	81/60	0.48	0.31–0.64	Random	76	0.04	NA	7	Moderate
					Sperm morphology	2	81/60	0.14	−0.03–0.30	Fixed	0	0.94	NA	7	Moderate
rhFSH	Cannarella et al.9	2020	RCT	Idiopathic infertility	Sperm concentration	4	157/144	0.17	0.06–0.28	Random	67	0.03	NA	7	Low
					Sperm morphology	3	95/94	0.06	−0.08–0.21	Random	90	<0.01	NA	7	Low
hpFSH	Cannarella et al.9	2020	RCT	Idiopathic infertility	Sperm concentration	5	215/90	0.15	0.03–0.26	Random	93	<0.01	NA	7	Low
					Sperm morphology	5	215/150	0.07	−0.03–0.17	Fixed	47	0.15	NA	7	Low
Qilin Pill	Jin et al.10	2017	RCT	Oligoasthenozoospermia	Sperm concentration	8	778	0.20	0.13–0.27	Random	91	<0.01	0.715	7	Low
					Sperm motility	4	500	0.35	0.26–0.43	Random	53	0.10	NA	7	Low
Wuzi Yanzong Pill	Zhao et al.11	2018	RCT	Oligoasthenozoospermia	Sperm concentration	5	509/451	0.10	0.03–0.16	Random	95	<0.01	NA	8	Low
					Sperm morphology	2	66/56	−0.11	−0.28–0.06	Fixed	0	0.38	NA	8	Low
					Sperm motility	5	509/451	0.07	0.01–0.13	Random	97	<0.01	NA	8	Low
Indian ginseng	Durg et al.12	2018	RCT and non-RCT	Infertility	Sperm concentration	3	315	0.61	0.50–0.72	Random	67	<0.01	NA	8	Very low
Testosterone	Shahid et al.4	2021	RCT	Infertility	Sperm morphology	2	135/134	0.13	0.01–0.25	Random	83	0.01	NA	9	Moderate
Nonpharmacological intervention
Surgical intervention
VR	Agarwal et al.13	2023	RCT and non-RCT	Clinical varicocele-associated infertility	Sperm concentration	14	1347/920	0.12	0.08–0.16	Random	98	<0.01	<0.01	9	Very low
					Sperm morphology	11	818/585	0.11	0.06–0.16	Random	99	NA	>0.05	9	Very low
					Sperm motility	7	659/467	0.06	0.01–0.12	Random	97	NA	>0.05	9
Redo varicocelectomy	Mahdi et al.14	2022	RCT and non-RCT	Recurrent varicocele-associated infertility	Sperm concentration	5	175	0.29	0.14–0.44	Fixed	35	0.19	NA	7	Very low
					Sperm morphology	3	93	0.42	0.22–0.63	Fixed	0	0.64	NA	7	Very low
					Sperm motility	5	175	0.24	0.09–0.39	Fixed	31	0.21	NA	7	Very low
Subclinical varicocelectomy	Kim et al.15	2016	RCT	Sub-clinical varicocele-associated infertility	Sperm concentration	7	276/272	0.06	−0.02–0.14	Fixed	37	0.15	NA	6	Moderate
					Sperm morphology	7	276/272	0.03	−0.06–0.11	Fixed	68	<0.01	NA	6	Moderate
					Sperm motility	4	189/183	0.15	0.05–0.25	Random	76	<0.01	NA	6	Moderate
Nonsurgical intervention
Acupuncture	Jia et al.16	2021	RCT	Oligoasthenozoospermia	Sperm concentration	2	134	0.09	−0.08–0.26	Random	95	0.09	NA	8	Moderate
					Sperm motility	2	134	0.11	−0.06–0.28	Random	95	<0.01	NA	8	Moderate
					Sperm motility	4	144/147	0.76	0.65–0.88	Fixed	0	0.76	NA	9	Moderate
Combined intervention
Vitamins plus TCM	Wang et al.17	2020	RCT	Infertility	Sperm concentration	12	658/630	0.11	0.05–0.16	Random	99	<0.01	0.03	8	Low
					Sperm motility	13	685/659	0.15	0.10–0.20	Random	97	<0.01	0.01	8	Low
Vitamins plus HSC	Wang et al.17	2020	RCT	Infertility	Sperm concentration	3	151/145	0.17	0.06–0.28	Random	98	<0.01	NA	8	Low
					Sperm motility	3	151/145	0.16	0.05–0.28	Random	92	<0.01	NA	8	Low
Vitamins plus CXJC	Wang et al.17	2020	RCT	Infertility	Sperm concentration	3	110/99	0.07	−0.07–0.20	Random	99	<0.01	NA	8	Low
					Sperm motility	2	86/72	0.81	0.65–0.96	Fixed	25	0.247	NA	8	Low
Vitamins plus SJC	Wang et al.17	2020	RCT	Infertility	Sperm motility	2	101/97	0.37	0.23–0.51	Random	97	<0.01	NA	8	Low
Adjuvant drug therapy for 3 months after varicocelectomy	Chen et al.18	2018	RCT	Clinical varicocele-associated infertility	Sperm concentration	6	251/221	0.16	0.07–0.25	Random	96	<0.01	NA	7	Moderate
					Sperm motility	6	251/221	0.54	0.45–0.63	Fixed	49	0.06	NA	7	Moderate
Adjuvant drug therapy for 6–9 months after varicocelectomy	Chen et al.18	2018	RCT	Clinical varicocele-associated infertility	Sperm concentration	4	180/113	0.08	−0.04–0.19	Random	96	<0.01	NA	7	Moderate
					Sperm motility	3	136/697	0.07	0.01–0.14	Fixed	12	0.34	NA	7	Moderate

*Supplements included zinc sulfate, CoQ10, carnitine, L-carnitine, fish oil, and profertil. AMSTAR: a measurement tool to assess systematic reviews; GRADE: Grading of Recommendations, Assessment, Development, and Evaluation; SMD: standard mean difference; CI: confidence interval; NA: not available; HSC: Huanshao capsule; CXJC: compound Xuanju capsule; SJC: Shengjing capsule; FSH: follicle-stimulating hormone; rhFSH: recombinant-human FSH; hpFSH: human pituitary FSH; RCT: randomized controlled trial; AIs: aromatase inhibitors; SERMs: selective estrogen receptor modulators; VR: varicocele repair; NAC: N-acetyl-cysteine; TCM: traditional Chinese medicine

Methodological quality and quality of evidence

Of these included meta-analyses, approximately 70% were randomized controlled trials. The methodological quality of 18 meta-analyses was evaluated by AMASTAR, with a score ranging from 6 to 9 (median=8; interquartile range: 7–9) points (Supplementary Table 2). The detailed AMASTAR scores of each meta-analysis are shown in Supplementary Table 3. According to the 11 items of AMASTAR, no studies were rated as low quality, whereas 12 (66.7%) and 6 (33.3%) were rated as high- and moderate-quality studies, respectively.

Supplementary Table 3.

Assessments of a measurement tool to assess systematic reviews scores for the included studies

Treatments	Author	Year	A priori design provided	Duplicate study selection and data extraction	At least two electronic databases searched	Status of publication used as an inclusion criterion	List of included and excluded studies provided	Characteristics of included studies provided	Scientific quality of included studies assessed	Scientific quality of the included studies used appropriately to form conclusions	Appropriate methods to combine studies	Publication bias assessed	Conflict of interest included	Total AMSTAR score
Wuzi Yanzong Pill	Ming Peng Zhao	2018	1	1	1	0	1	1	1	0	1	0	1	8
Acupuncture	Wen Jia	2021	1	1	1	0	1	1	1	0	1	1	0	8
Qilin Pill	Xin Jin	2017	0	1	1	0	1	1	1	0	1	1	0	7
Vitamins combined with TCM	Ming Wang	2020	0	1	1	0	1	1	1	0	1	1	1	8
Antioxidant therapy	Ashok Agarwal	2023	1	1	1	0	1	1	1	0	1	1	1	9
AIs	Bin Guo	2022	1	1	1	0	1	1	1	0	1	1	1	9
Clomiphene citrate	Manou Huijben	2023	1	1	1	0	1	1	1	0	1	0	1	8
FSH therapy hpFSH, rhFSH	Rossella Cannarella	2020	0	1	1	0	1	1	0	1	1	0	1	7
Alpha-lipoic acid	Liang Dong	2022	1	1	1	0	1	1	1	0	1	1	1	9
Selenium	Aditya P Sharma	2021	1	1	1	0	1	1	0	0	1	1	1	8
Phosphodiesterase-5 inhibitors	Liang Dong	2021	1	1	1	0	1	1	1	0	1	1	1	9
VR	Ashok Agarwal	2023	1	1	1	0	1	1	1	0	1	1	1	9
Redo varicocelectomy	Mohamed Mahdi	2022	0	1	1	0	1	1	1	0	1	0	1	7
Adjuvant drug therapy after varicocelectomy	Yin-Wei Chen	2018	1	1	1	0	1	1	1	0	1	0	0	7
Subclinical varicocelectomy	Jae Hung Jung	2016	0	1	1	0	1	1	1	0	1	0	0	6
L-carnitine/L-acetyl-carnitine NAC	Guangzhu Wei	2021	0	1	1	0	1	1	1	0	1	0	1	7
Withania somnifera (Indian ginseng)	Sharanbasappa Durg	2018	0	1	1	1	1	1	1	0	1	0	1	8
SERMs: hormones, vitamins, supplements, Tamoxifen, clomiphene, zinc sulfate, CoQ10, FSH, testosterone	Muhammad Nabeel Shahid	2021	1	1	1	1	1	1	1	0	1	0	1	9

FSH: follicle-stimulating hormone; rhFSH: recombinant-human FSH; hpFSH: human pituitary FSH; AMSTAR: a measurement tool to assess systematic reviews; NAC: N-acetyl-cysteine; AIs: aromatase inhibitors; SERMs: selective estrogen receptor modulators; VR: varicocele repair; TCM: traditional Chinese medicine

Detailed information on the quality of evidence for the 90 estimated summary effects evaluated by GRADE is provided in Supplementary Table 4. Of the 90 estimated summary effects, no studies were rated as having high-evidence quality, whereas 53.3% (n = 48), 25.6% (n = 23and 21.1% (n = 19) were rated moderate, low, and very low, respectively (Supplementary Table 2).

Supplementary Table 4.

Grading of recommendations-assessment-development-and evaluation classification of quality of evidence for the effectiveness of treatments on sperm parameters

Intervention	Sperm parameter	Author	Year	Number of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Publication bias	Plausible confounding	Magnitude of effect	Dose-response gradient	Quality
Phosphodiesterase-5 inhibitors	Sperm concentration	Dong et al.	2021	3	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Moderate
NAC	Sperm concentration	Wei et al.	2021	3	RCT and non-RCT	Very serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Very low
Antioxidant therapy	Sperm concentration	Agarwal et al.	2023	36	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Strongly suspected	Could reduce effect	No	No	Moderate
Antioxidant therapy for 3 months or less	Sperm concentration	Agarwal et al.	2023	36	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Would be spurious effect	No	Yes	Moderate
Antioxidant therapy for 6 months	Sperm concentration	Agarwal et al.	2023	22	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	Yes	Moderate
Antioxidant therapy for 9 months or more	Sperm concentration	Agarwal et al.	2023	8	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Would be spurious effect	No	Yes	Moderate
AIs	Sperm concentration	Guo et al.	2022	8	RCT and non-RCT	Very serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Very low
Clomiphene citrate	Sperm concentration	Huijiben et al.	2023	15	RCT and non-RCT	Very serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Very low
Hormones	Sperm concentration	Shahid et al.	2021	15	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	No	Moderate
SERMs	Sperm concentration	Shahid et al.	2021	9	RCT	Serious risk	No serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Low
Tamoxifen	Sperm concentration	Shahid et al.	2021	7	RCT	Serious risk	No serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Low
FSH therapy	Sperm concentration	Cannaralle et al.	2020	9	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	No	Moderate
Low dose of FSH therapy	Sperm concentration	Cannaralle et al.	2020	3	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	Yes	Moderate
Interediate dose of FSH therapy	Sperm concentration	Cannaralle et al.	2020	4	RCT	Serious risk	No serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Would be Spurious effect	No	Yes	Moderate
High dose of FSH therapy	Sperm concentration	Cannaralle et al.	2020	2	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	Yes	Yes	Moderate
rhFSH	Sperm concentration	Cannaralle et al.	2020	4	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Low
hpFSH	Sperm concentration	Cannaralle et al.	2020	5	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Low
Qilin Pill	Sperm concentration	Jin et al.	2017	8	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Low
Wuzi Yanzong Pill	Sperm concentration	Zhao et al.	2018	5	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Low
Indian ginseng	Sperm concentration	Durg et al.	2018	3	RCT and non-RCT	Very serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	Yes	No	Very low
VR	Sperm concentration	Agarwal et al.	2023	14	RCT and non-RCT	Very serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Very low
Redo varicocelectomy	Sperm concentration	Mahdi et al.	2022	5	RCT and non-RCT	Very serious risk	No serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	Yes	No	Very low
Subclinical varicocelectomy	Sperm concentration	Kim et al.	2016	7	RCT	Serious risk	No serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Moderate
Acupuncture	Sperm concentration	Jia et al.	2021	2	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	No	Moderate
Supplements	Sperm concentration	Shahid et al.	2021	13	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Low
Vitamins	Sperm concentration	Shahid et al.	2021	4	RCT	Serious risk	No serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Moderate
Alpha-lipoic acid	Sperm concentration	Dong et al.	2022	3	RCT	Serious risk	No serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Moderate
CoQ10	Sperm concentration	Shahid et al.	2021	4	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Would be spurious effect	No	No	Moderate
Selenium	Sperm concentration	Sharma et al.	2021	3	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	No	Moderate
L-carnitine	Sperm concentration	Wei et al.	2021	4	RCT and non-RCT	Very serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Very low
Zinc sulfate	Sperm concentration	Shahid et al.	2021	4	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	Yes	No	Moderate
Vitamins plus TCM	Sperm concentration	Wang et al.	2020	12	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	No	Low
Vitamins plus HSC	Sperm concentration	Wang et al.	2020	3	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Would be spurious effect	No	No	Low
Vitamins plus CXJC	Sperm concentration	Wang et al.	2020	3	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	Yes	No	Low
Adjuvant drug therapy for 3 months after varicocelectomy	Sperm concentration	Chen et al.	2018	6	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	Yes	No	Moderate
Adjuvant drug therapy for 6–9 months after varicocelectomy	Sperm concentration	Chen et al.	2018	4	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	No	Moderate
Phosphodiesterase-5 inhibitors	Sperm morphology	Dong et al.	2021	3	RCT	Serious risk	No serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Moderate
NAC	Sperm morphology	Wei et al.	2021	3	RCT and non-RCT	Very serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Would be spurious effect	No	No	Moderate
Antioxidant therapy	Sperm morphology	Agarwal et al.	2023	18	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	Yes	Low
Antioxidant therapy for 3 months or less	Sperm morphology	Agarwal et al.	2023	18	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	Yes	Moderate
Antioxidant therapy for 6 months	Sperm morphology	Agarwal et al.	2023	7	RCT	Serious risk	No serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	Yes	Moderate
AIs	Sperm morphology	Guo et al.	2022	6	RCT and non-RCT	Very serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Very low
Clomiphene citrate	Sperm morphology	Huijiben et al.	2023	6	RCT and non-RCT	Very serious risk	No serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Would be spurious effect	No	No	Very low
SERMs	Sperm morphology	Shahid et al.	2021	9	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	No	Moderate
Hormones	Sperm morphology	Shahid et al.	2021	15	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Low
FSH therapy	Sperm morphology	Cannaralle et al.	2020	8	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	No	Moderate
Low dose of FSH therapy	Sperm morphology	Cannaralle et al.	2020	3	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	Yes	Moderate
Interediate dose of FSH therapy	Sperm morphology	Cannaralle et al.	2020	3	RCT	Serious risk	No serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Would be spurious effect	No	Yes	Moderate
High dose of FSH therapy	Sperm morphology	Cannaralle et al.	2020	2	RCT	Serious risk	No serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	Yes	Moderate
hpFSH	Sperm morphology	Cannaralle et al.	2020	5	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Low
rhFSH	Sperm morphology	Cannaralle et al.	2020	3	RCT	Serious risk	No serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Low
Testosterone	Sperm morphology	Shahid et al.	2021	2	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Would be spurious effect	Yes	No	Moderate
Wuzi Yanzong Pill	Sperm morphology	Zhao et al.	2018	2	RCT	Serious risk	No serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Low
VR	Sperm morphology	Agarwal et al.	2023	11	RCT and non-RCT	Very serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Very low
Redo varicocelectomy	Sperm morphology	Mahdi et al.	2022	3	RCT and non-RCT	Very serious risk	No serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Very low
Subclinical varicocelectomy	Sperm morphology	Kim et al.	2016	7	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	No	Moderate
Supplements	Sperm morphology	Shahid et al.	2021	13	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	No	Moderate
Vitamins	Sperm morphology	Shahid et al.	2021	4	RCT	Serious risk	No serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Moderate
Alpha-lipoic acid	Sperm morphology	Dong et al.	2022	2	RCT	Serious risk	No serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Moderate
CoQ10	Sperm morphology	Shahid et al.	2021	4	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	No	Moderate
L-carnitine	Sperm morphology	Wei et al.	2021	2	RCT and non-RCT	Very serious risk	Serious inconsistency	No serious indirectness	No serious Imprecision	Not detected	Could reduce effect	No	No	Very low
Zinc sulfate	Sperm morphology	Shahid et al.	2021	4	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	No	Moderate
NAC	Sperm motility	Wei et al.	2021	3	RCT and non-RCT	Very serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Would be spurious effect	No	No	Very low
Antioxidant therapy	Sperm motility	Agarwal et al.	2023	36	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	No	Moderate
Antioxidant therapy for 3 months or less	Sperm motility	Agarwal et al.	2023	24	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	Yes	Moderate
Antioxidant therapy for 6 months	Sperm motility	Agarwal et al.	2023	14	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	Yes	Moderate
Antioxidant therapy for 9 months or more	Sperm motility	Agarwal et al.	2023	4	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Would be spurious effect	Yes	Yes	Moderate
AIs	Sperm motility	Guo et al.	2022	10	RCT and non-RCT	Very serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Very low
Hormones	Sperm motility	Shahid et al.	2021	15	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Low
SERMs	Sperm motility	Shahid et al.	2021	9	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	No	Moderate
Tamoxifen	Sperm motility	Shahid et al.	2021	7	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	No	Moderate
Clomiphene citrate	Sperm motility	Huijiben et al.	2023	13	RCT and non-RCT	Very serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Very low
Qilin Pill	Sperm motility	Jin et al.	2017	4	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Low
Wuzi Yanzong Pill	Sperm motility	Zhao et al.	2018	5	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Low
VR	Sperm motility	Agarwal et al.	2023	7	RCT and non-RCT	Very serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	No	Very low
Redo varicocelectomy	Sperm motility	Mahdi et al.	2022	5	RCT and non-RCT	Very serious risk	No serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	No	Very low
Subclinical varicocelectomy	Sperm motility	Kim et al.	2016	4	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	No	Moderate
Acupuncture	Sperm motility	Jia et al.	2021	2	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	No	Moderate
Supplements	Sperm motility	Shahid et al.	2021	13	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	No	Moderate
Vitamins	Sperm motility	Shahid et al.	2021	4	RCT	Serious risk	No serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Low
Alpha-lipoic acid	Sperm motility	Dong et al.	2022	3	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Would be spurious effect	No	No	Moderate
CoQ10	Sperm motility	Shahid et al.	2021	4	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	No	Moderate
L-carnitine	Sperm motility	Wei et al.	2021	4	RCT and non-RCT	Very serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	Could reduce effect	No	No	Very low
Zinc sulfate	Sperm motility	Shahid et al.	2021	4	RCT	Serious risk	No serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	Yes	No	Moderate
Vitamins plus TCM	Sperm motility	Wang et al.	2020	13	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	Yes	No	Low
Vitamins plus HSC	Sperm motility	Wang et al.	2020	3	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	Yes	No	Low
Vitamins plus CXJC	Sperm motility	Wang et al.	2020	2	RCT	Serious risk	No serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Low
Vitamins plus SJC	Sperm motility	Wang et al.	2020	2	RCT	Serious risk	Serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	No	Low
Adjuvant drug therapy for 3 months after varicocelectomy	Sperm motility	Chen et al.	2018	5	RCT	Serious risk	No serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	Yes	Moderate
Adjuvant drug therapy for 6–9 months after varicocelectomy	Sperm motility	Chen et al.	2018	5	RCT	Serious risk	No serious inconsistency	No serious indirectness	No serious imprecision	Not detected	None	No	Yes	Moderate

HSC: huanshao capsule; CXJC: compound Xuanju capsule; SJC: shengjing capsule; FSH: follicle-stimulating hormone; rhFSH: recombinant-human FSH; hpFSH: human pituitary FSH; RCT: randomized controlled trial; NAC: N-acetyl-cysteine; AIs: aromatase inhibitors; SERMs: selective estrogen receptor modulators; VR: varicocele repair; TCM: traditional Chinese medicine

Effectiveness of treatments on sperm concentration

A total of 36 estimated summary effects of 25 interventions on sperm concentration were extracted from 18 published studies and are graphically illustrated in Figure 2.

Figure 2.

Summary estimates for effectiveness of treatments on sperm concentration. HSC: Huanshao capsule; CXJC: compound Xuanju capsule; SJC: Shengjing capsule; FSH: follicle-stimulating hormone; rhFSH: recombinant human FSH; hpFSH: highly purified FSH; CoQ10: coenzyme Q10; CI: confidence interval; GRADE: Grading of Recommendations, Assessment, Development, and Evaluation; AMSTAR: Assessment of Multiple Systematic Reviews.

Twelve meta-analyses assessed the effectiveness of 21 pharmacological interventions on sperm concentration, and 27 estimated summary effects were reported. Compared with placebo and vitamin control, a significantly higher increment of sperm concentration was found in all pharmacological intervention groups, except for low-dose FSH therapy, vitamins, L-carnitine, and zinc sulfate. Time-related effectiveness was only explored on antioxidant therapy, and antioxidant therapy cycles of up to 6 months (SMD: 0.14; 95% CI: 0.09–0.18) achieved the best results of sperm concentration improvement, with moderate quality of evidence. Moreover, dose-related effectiveness was only explored on FSH therapy, and the best results of sperm concentration improvement were achieved with high doses of FSH therapy (SMD: 0.48; 95% CI: 0.31–0.64) with a moderate quality of evidence.

Four previous meta-analyses have assessed the effectiveness of four nonpharmacological interventions on sperm concentration, and four estimated summary effects were reported. Regarding surgical interventions, a statistically significant role was found only in VR (SMD: 0.12; 95% CI: 0.08–0.16) and redo varicocelectomy (SMD: 0.29; 95% CI: 0.14–0.44), whereas the quality of evidence was very low. However, no clear effectiveness was observed with subclinical varicocelectomy or acupuncture.

Only two combined interventions, namely, vitamins plus TCM and adjuvant drug therapy after varicocelectomy, were evaluated for sperm concentration with five estimated summary effects. Significantly positive effects were found in vitamins plus TCM (SMD: 0.11; 95% CI: 0.05–0.16; grade: low) and its subgroup (vitamins plus Huanshao capsule; SMD: 0.17; 95% CI: 0.06–0.28; grade: low) as well as adjuvant drug therapy for 3 months after varicocelectomy (SMD: 0.16; 95% CI: 0.07–0.25; grade: moderate). However, no clear effectiveness was observed with the aspect of vitamins plus compound Xuanju capsule and adjuvant drug therapy for 6–9 months after varicocelectomy.

Effectiveness of treatments on sperm morphology

A total of 26 estimated summary effects of 19 interventions on sperm morphology were extracted from 12 published studies and are graphically illustrated in Figure 3.

Figure 3.

Summary estimates for effectiveness of treatments on sperm morphology. FSH: follicle-stimulating hormone; rhFSH: recombinant human FSH; hpFSH: highly purified follicle-stimulating hormone; CoQ10: coenzyme Q10; CI: confidence interval; GRADE: Grading of Recommendations, Assessment, Development, and Evaluation; AMSTAR: Assessment of Multiple Systematic Reviews.

Nine meta-analyses have assessed the effectiveness of 17 pharmacological interventions on sperm morphology, and 23 estimated summary effects have been reported. Compared with the placebo or vitamin control, a significantly higher increment of sperm morphology was found with phosphodiesterase-5 inhibitors, NAC, antioxidant therapy, AIs, SERMs, hormones, testosterone, FSH therapy, supplements, alpha-lipoic acid, and L-carnitine. Time-related effectiveness was only explored on antioxidant therapy, and antioxidant therapy cycles of up to 6 months (SMD: 0.20; 95% CI: 0.16–0.25) achieved the best results of sperm morphology improvement, with moderate quality of evidence. Moreover, dose-related effectiveness was only explored for FSH therapy, and significant improvements were observed in intermediate-dose FSH therapy (SMD: 0.17; 95% CI: 0.04–0.30) but not in low-dose or high-dose FSH therapy.

Three meta-analyses have assessed the effectiveness of three surgical interventions on sperm morphology, and three estimated summary effects were reported. In terms of surgical interventions, VR (SMD: 0.11; 95% CI: 0.06–0.16) and redo varicocelectomy (SMD: 0.42; 95% CI: 0.22–0.63) played statistically significant roles, whereas the quality of evidence was very low. However, no clear effectiveness was observed about subclinical varicocelectomy.

Effectiveness of treatments on sperm motility

A total of 28 estimated summary effects of 25 interventions on sperm motility were extracted from 13 published studies and are graphically illustrated in Figure 4.

Figure 4.

Summary estimates for effectiveness of treatments on sperm motility. HSC: Huanshao capsule; CXJC: compound Xuanju capsule; SJC: Shengjing capsule; CoQ10: coenzyme Q10; CI: confidence interval; GRADE: Grading of Recommendations, Assessment, Development, and Evaluation; AMSTAR: Assessment of Multiple Systematic Reviews.

Eleven meta-analyses assessed the effectiveness of 15 pharmacological interventions on sperm motility, and 18 estimated summary effects were reported. Compared with that of the placebo or vitamin control, a significantly higher increment of sperm motility was found in all pharmacological intervention groups, except for vitamin and antioxidant therapy for ≥9 months. Time-related effectiveness was only explored with antioxidant therapy, and antioxidant treatment cycles of up to 6 months achieved the best results of sperm morphology improvement, with moderate quality of evidence.

Four meta-analyses have assessed the effectiveness of four nonpharmacological interventions on sperm motility, and four estimated summary effects were reported. All surgical interventions, including VR (SMD: 0.06; 95% CI: 0.01–0.12), redo varicocelectomy (SMD: 0.24; 95% CI: 0.09–0.39), and subclinical varicocelectomy (SMD: 0.15; 95% CI: 0.05–0.25), played statistically significant roles. However, no clear effectiveness was observed in acupuncture.

Only two combined interventions, vitamins plus CTM and adjuvant drug therapy after varicocelectomy, were evaluated for sperm motility with six estimated summary effects. Significantly positive effects were observed in all the combined interventions.

Pooled results of the endpoints

The pooled results for sperm concentration, morphology, and motility are shown in Table 1. Significant improvements in sperm concentration, morphology, and motility were observed with pharmacological interventions (NAC, antioxidant therapy, AIs, SERMs, hormones, supplements, and alpha-lipoic acid) and nonpharmacological interventions (VR and redo varicocelectomy). However, vitamin supplementation did not significantly positively affect sperm concentration, motility, or morphology.

Table 1.

The pooled results of sperm concentration, morphology, and motility

Intervention	Sperm concentration	Sperm morphology	Sperm motility
Pharmacological intervention
NAC	Yes	Yes	Yes
Antioxidant therapy	Yes	Yes	Yes
Antioxidant therapy for 3 months or less	Yes	Yes	Yes
Antioxidant therapy for 6 months	Yes	Yes	Yes
AIs	Yes	Yes	Yes
SERMs	Yes	Yes	Yes
Hormones	Yes	Yes	Yes
Supplementsa	Yes	Yes	Yes
Alpha-lipoic acid	Yes	Yes	Yes
Phosphodiesterase-5 inhibitors	Yes	Yes	NA
FSH therapy	Yes	Yes	NA
Intermediate-dose of FSH therapy	Yes	Yes	NA
Qilin Pill	Yes	NA	Yes
Wuzi Yanzong Pill	Yes	No	Yes
Clomiphene citrate	Yes	No	Yes
CoQ10	Yes	No	Yes
L-carnitine	No	Yes	Yes
Tamoxifen	Yes	NA	Yes
High dose of FSH therapy	Yes	No	NA
rhFSH	Yes	No	NA
hpFSH	Yes	No	NA
Indian ginseng	Yes	NA	NA
Testosterone	Yes	NA	NA
Selenium	Yes	NA	NA
Zinc sulfate	No	No	Yes
Antioxidant therapy for 9 months or more	Yes	NA	No
Vitamins	No	No	No
Low dose of FSH therapy	No	No	NA
Nonpharmacological intervention
VR	Yes	Yes	Yes
Redo varicocelectomy	Yes	Yes	Yes
Subclinical varicocelectomy	No	No	Yes
Acupuncture	No	NA	No
Combined intervention
Vitamins plus TCM	Yes	NA	Yes
Vitamins plus HSC	Yes	NA	Yes
Adjuvant drug therapy for 3 months after varicocelectomy	Yes	NA	Yes
Vitamins plus CXJC	No	NA	Yes
Vitamins plus SJC	NA	NA	Yes
Adjuvant drug therapy for 6–9 months after varicocelectomy	No	NA	Yes

^aSupplements included zinc sulfate, CoQ10, carnitine, L-carnitine, fish oil, and profertil. Yes: P<0.05; No: P≥0.05. HSC: Huanshao capsule; CXJC: compound Xuanju capsule; SJC: Shengjing capsule; FSH: follicle-stimulating hormone; rhFSH: recombinant-human FSH; hpFSH: human pituitary FSH; NA: not available; AIs: aromatase inhibitors; SERMs: selective estrogen receptor modulators; VR: varicocele repair; NAC: N-acetyl-cysteine; TCM: traditional Chinese medicine ; FSH: follicle-stimulating hormone; rhFSH: recombinant human FSH; hpFSH: highly purified FSH; CoQ10: coenzyme Q10

Heterogeneity and publication bias of the included studies

The I² statistic was reported in all meta-analyses (n = 18) and all estimated summary effects (n = 90). Cochran’s Q test was also employed in all meta-analyses (n = 18) and 96.7% estimated summary effects (n = 87). Among these estimated summary effects, 73.3% (n = 66) were reported with high-level heterogeneity (I² ≥ 50%), and 70.0% (n = 63) were reported with a Q test P < 0.10.

Egger’s regression was only applied in 22.2% (n = 4) of the meta-analyses and 11.1% (n = 10) of the estimated summary effects, of which 50.0% (n = 5) were reported to have significant publication bias.

DISCUSSION

This umbrella review provides a broad overview of existing evidence regarding the effectiveness of pharmacological, nonpharmacological, and combined interventions on male infertility and evaluates the methodological quality of the included meta-analyses and the quality of evidence for extracted associations.

A total of 18 published meta-analyses were included in this umbrella review, with 90 estimated summary effects for 28 interventions on male infertility. The methodological quality was high for two-thirds of the included meta-analyses, and none of them were rated as low quality. None of the estimated summary effects of interventions were rated high in terms of the quality of evidence, and moderate, low, and very low quality of evidence accounted for approximately 53.3%, 25.6%, and 21.1%, respectively. A significant positive effect of pharmacological interventions (NAC, antioxidant therapy, AIs, SERMs, hormones, supplements, and alpha-lipoic acid) and nonpharmacological interventions (VR and redo varicocelectomy) was found on sperm concentration, morphology, and motility, suggesting that these interventions are potentially effective treatments for male infertility. However, vitamins, including vitamins A, D, and E, and folic acid, may not be an appropriate choice for men with infertility because no significant improvement was observed in sperm concentration, motility, or morphology. Moreover, phosphodiesterase-5 inhibitors, FSH therapy, Qilin Pill, Indian ginseng, testosterone, selenium supplements, vitamins plus TCM, and adjuvant drug therapy for 3 months after varicocelectomy may be promising choices for males with infertility; however, further investigation is required.

Pharmacological interventions cover hormone-related and nonhormone-related choices, with the latter mainly including antioxidant compounds, prokinetic compounds, and TCM, supported by variable levels of evidence of clinical efficacy. This umbrella review supported a significantly optimistic effect of antioxidant interventions on primary sperm parameters, possibly because semen oxidative stress (OS) has been identified as a potential factor for various causes of infertility.20,21 Seminal reactive OS, the by-products of metabolic pathways, is necessary for normal sperm function,21 whereas OS, the result of an imbalance between reactive OS and antioxidants, hinders fertilization by interfering with capacitation, destroying sperm DNA integrity, and damaging the sperm membrane.19,22,23 The property of being susceptible to high concentrations of reactive OS might be attributed to the multiple polyunsaturated fatty acids in their plasma membrane and insufficient enzymes in the cytoplasm, with poor ability to neutralize reactive OS.24 Interestingly, owing to a deepened understanding of this field, a new phrase, named male OS infertility), was specifically coined by Agarwal et al.25 in 2019 to refer to male infertility because of high OS.

Consequently, the application of antioxidant therapy in male infertility is mainly based on several reasonable mechanisms, including neutralizing free radicals, preserving sperm DNA integrity, and guaranteeing mitochondrial transport.26 In a previous review, Agarwal et al.27 systematically identified 97 studies on single or combined antioxidant therapy in men with infertility and finally recommended the use of antioxidant therapy in patients with abnormal sperm quality (Grade C), varicocele (Grade B), and idiopathic and unexplained infertility (Grade B). The subsequent addition of antioxidant therapy after varicocelectomy demonstrated a significant increase in sperm concentration, total motility, progressive motility, and morphology.28

According to the presence or absence of enzyme factors, antioxidant treatment can be roughly divided into two categories, of which the former mainly includes glutathione peroxidase and glutathione reductase, and the latter includes AC, carotenoids, vitamin C, vitamin E, CoQ10, selenium, zinc, and folate.20,29 This umbrella review summarizes the evidence for NAC, vitamins, CoQ10, selenium, and zinc, whereas only NAC achieved significant improvement in sperm concentration, morphology, and motility. As a derivative of L-cysteine, NAC was reported to possess the ability to scavenge free radicals in vivo and in vitro and play an important role in reducing reactive OS and sperm DNA oxidation.30,31,32 However, no obvious differences in improving serum hormone levels, including testosterone, luteinizing hormone, FSH, and prolactin, were observed in patients receiving NAC.33 In addition, CoQ10 supplementation failed to confirm the significant benefit of sperm morphology, and no significant increase in sperm concentration or morphology was found with zinc sulfate. Although the vitamins in this article contain three antioxidants (folic acid, vitamin C, and vitamin E) and vitamin D, no significant positive effects on sperm concentration, motility, or morphology were found; this finding was consistent with the results of network meta-analyses.11 Although antioxidant treatment as an umbrella term for a choice of therapies has great benefits, the evidence for a specific type of antioxidant therapy remains unclear, which might pose great confusion to clinicians in clinical practice. Moreover, because of the great heterogeneity among studies, antioxidant therapy is not recommended as a routine treatment by the European Association of Urology.34 Therefore, future studies are required for further investigation.

Hormone-related interventions, which refer to SERMs, AIs, and FSH, are another major component of pharmacological interventions. The findings showed a significant improvement in sperm concentration, morphology, and motility in hormones (umbrella term), SERMs, and AIs. SERMs were used to play a role in patients with decreased sperm number by acting as estrogen agonists or antagonists in a tissue-specific manner.35,36 The main mechanisms included increasing gonadotropin secretion, improving Leydig cell sensitivity to luteinizing hormone, interfering with xenoestrogens, and enhancing sex hormone-binding globulin secretion. In addition, Guo et al.37 found increased total antioxidant capacity and decreased reactive OS in patients who received tamoxifen therapy for 3 months and suggested that antioxidant properties might also account for the effect of SERMs. In this study, the findings on SERMs were roughly consistent with those of Cannarella et al.38 who further investigated the effect of SERMs on FSH and finally attributed the positive effect of SREMs on sperm parameters to the increase in serum FSH levels.

In this umbrella review, FSH therapy greatly improved sperm concentration and morphology; however, no evidence for sperm motility was noted.39 The rational basis for prescribing FSH in men with infertility is to induce the secretion of glial cell-derived neurotrophic factor) and fibroblast growth factor 2, thereby promoting the self-renewal of stem cell niches and reducing the production of inhibin A.40,41 In addition, the dose-dependent analysis demonstrated that moderate-dose FSH therapy (350–525 IU per week) had significant positive effects on sperm concentration and morphology, high-dose FSH therapy (700–1050 IU per week) had no significant effect on sperm morphology, and low-dose FSH therapy (175–262.5 IU per week) had no significant effect on sperm concentration or morphology. This result indicated medium-dose FSH therapy was preferred when considering the effect on sperm concentration and morphology. However, Cannarella et al.39 provided evidence in favor of high-dose FSH therapy by considering sperm concentration and total sperm count as the primary endpoints. High- and low-dose FSH therapies were reported effective in increasing progressive sperm motility; however, the intermediate-dose was not, and the reasons for this remain unclear. Despite the lack of severe side effects of high-dose FSH therapy in men, the prescription of FSH should be clinically individualized, such as giving priority to moderate FSH doses where sperm morphology is a major problem.

As new antiestrogen treatments, AIs were first used to treat oligozoospermia in 1981 and showed promising results.42 In this study, AI intervention showed a higher increment of sperm concentration, morphology, and motility than placebo or vitamin control, which was statistically significant. Moreover, AI intervention was found to be associated with superior total functional sperm fraction and total sperm count and increased serum FSH and LH levels.43 Promising effectiveness may be achieved by a modest increase in the androgen–estrogen ratio. However, it is worth mentioning that the most representative side effect was decreased libido, which was not life-threatening but greatly impaired quality of life.44

In recent years, the treatment of male infertility with TCM has received extensive attention. In this study, TCM, including the Qilin Pill, Wuzi Yanzong Pill, and vitamin plus TCM, achieved satisfactory results in terms of sperm concentration and motility.45,46,47 but with high statistically significant heterogeneity. While the effectiveness of TCM is easily susceptible to drug preparation, route of administration, dose, duration, and frequency, more high-quality studies are urgently needed to verify the current unstable conclusion about the effect of TCM on male infertility.

Varicoceles is a relatively common disease that is present in approximately one in six healthy men,48 accounting for 35%–44% of primary infertility and 45%–81% of secondary infertility.49 Deterioration of sperm quality is the most prominent problem and the main cause of infertility in men with varicoceles. Therefore, VR was recommended, with moderate recommendation and moderate evidence level, to men with infertility by the American Urological Association and the American Society for Reproductive Medicine,50 which was confirmed by the results of pooled analysis of previous studies in the present umbrella review.51 The incidence of recurrent varicocele varies from 0 to 35% depending on the initial surgical technique,52 and the recurrence might be related to the lack of ligation of all veins that can develop varicocele. Interestingly, this study found that redo varicocelectomy also plays a beneficial role in male infertility and could be a potential choice for men with infertility and recurrent varicocele.53 However, subclinical varicocelectomy for men with infertility and subclinical varicocele only improves the quality of sperm motility,54 and the management of subclinical varicocele requires further investigation.

Strengths and limitations

Notably, this is a comprehensive evaluation and overview of the evidence from meta-analyses about the effect of variable treatments on male infertility, providing additional evidence for existing guidelines in several aspects and a reference for future studies.

However, several limitations must be noted. First, limitations are inherent to the limited number of included studies and sample size in each meta-analysis. The undetected bias, including publication and sperm analysis biases, and great heterogeneity among studies made the results unreliable. More well-designed studies are required to compensate for this deficiency. Second, the endpoints of interest in this study were limited to only sperm concentration, morphology, and motility, whereas sperm volume, sperm count, acrosomal enzyme activity, sperm DNA fragmentation, pregnancy rate, or progressive sperm motility were not included because of the limited number of studies. It will yield discordant results with existing studies and pose great difficulties in comparison among interventions. However, this study aimed to provide a broad overview of existing evidence regarding interventions on male infertility rather than to rank the interventions, which was the strength of network meta-analysis. The three endpoints in this study were the most commonly used to describe the effectiveness of interventions on sperm quality; therefore, the results of this study are still of clinical significance and scientific value. Third, most studies included patients with infertility as a condition restriction and did not place specific restrictions on the sperm quality of men with infertility, which may have skewed the interpretation of the results. In addition, detailed information on the World Health Organization (WHO) reference ranges for sperm normality was only given in 5 (5/18, 27.8%) meta-analyses, and only 2 meta-analyses reported specific restrictions on the edition of the WHO criteria, posing great heterogeneity to the study results. Future similar meta-analyses could reduce the heterogeneity and improve the reliability of the results by limiting the edition of the WHO criteria. Moreover, this study still failed to explain the mechanisms by which each intervention affects each outcome, which might be of great concern to individualized therapy.

In conclusion, this comprehensive review of the literature provided a general overview of the current status of treatments for male infertility. We propose that treatments for male infertility are increasingly diverse; however, further well-designed studies on single treatment and high-quality meta-analyses of intertreatment comparisons are still needed.

AUTHOR CONTRIBUTIONS

JJY, ZYC, and YGB collected and analyzed the data and wrote the manuscript. LRL, QW, and YGB designed the study, supervised the project, and revised the manuscript. JJY, QHW, and ZYC assisted with detailed statistical analysis. JJY, XYL, CCZ, and XYW helped with data extraction. All authors read and approved the final manuscript.

COMPETING INTERESTS

All authors declare no competing interests.