Outcome of varicocelectomy on different degrees of total motile sperm count: A systematic review and meta-analysis

ABSTRACT

It is crucial to identify the subfertile men with varicocele who will benefit the most from varicocelectomy, and the factors which help in predicting the response to varicocelectomy. We aimed to evaluate the impact of varicocelectomy on total motile sperm count (TMSC) and spontaneous pregnancy (SP) rates. A comprehensive literature search was performed using Medline/PubMed and Google Scholar up to December 26, 2018, with no restriction on language and year of publication. Published articles reporting different degrees of TMSC before and after varicocelectomy in infertile men with varicocele (palpable and/or clinical) were extracted. In addition, SP rates as a function of TMSC after varicocelectomy were reviewed. Potential biases were analyzed to rule out skewing factors. Mean TMSC was graded as: <2 million – profound, 2–5 million – severe, 5–10 million – moderate, and >10 million – mild. Data were analyzed using Stata11. Among the total 96 articles identified through electronic and manual searches of references, nine articles fulfilling the inclusion criteria were included. All degrees of TMSC resulted in a significant postoperative improvement, with only small differences, among the profound [10.20 million (95% confidence interval [CI]: 9.11–11.30, p < 0.0001)], severe [15.77 million (95% CI: 10.65–20.89, p < 0.0001)], and moderate groups [19.18 million (95% CI: 10.40–27.96, p < 0.0001)]. However, the mild group demonstrated a highly significant improvement [49.68 million (95% CI: 38.74–60.62, p < 0.0001)]. After varicocelectomy, the SP rate was highest in the TMSC >20 million group (55.4%), followed by TMSC 5–20 million group (45.4%), and TMSC <5 million group (26.3%). In comparison, the TMSC <1.5 million group demonstrated the lowest SP rate (16.0%). Moderate evidence suggests that varicocelectomy results in a significantly improved TMSC. The improvement in TMSC and SP rates is higher in patients who present a mild or moderate decreased TMSC.

Abbreviations: TMSC: total motile sperm count; SP: spontaneous pregnancy; ART: assisted reproductive technology; IVF: in-vitro fertilization; IUI: intrauterine insemination; WMD: weighted mean difference; CI: confidence interval

KEYWORDS:

• Meta-analysis
• pregnancy
• total motile sperm count
• varicocele
• varicocelectomy

Introduction

The term varicocele is used to define an abnormally dilated tortuous veins of the pampiniform plexus. It is regarded as one of the primary causes of the male infertility, affecting nearly 15% men, and is responsible for 35–40% cases of subfertility in male gender (Greenberg 1977; Hopps et al. 2003). In some men with infertility, varicocelectomy has been found to improve sperm parameters and spontaneous pregnancy (SP) rates and further improves the outcome of assisted reproductive technology (ART) procedures (Schauer et al. 2012; Kirby et al. 2016). However, it is observed that not all men with varicocele suffer from infertility, and not all subfertile men will benefit from varicocelectomy. Thus, it is difficult to identify a subfertile man with varicocele who will benefit the most after varicocelectomy.

It is crucial to identify the factors predicting the response to varicocelectomy. Some investigators have claimed that testicular vein with higher grades of reflux and diameter >2.5 mm resulted in greater improvement in sperm parameters (Mehraban et al. 2012), while others have reported that postoperative varicocele size failed to demonstrate any statistically significant improvement in SP rates (Marks et al. 1986). Similarly, some studies have confirmed the absence of testicular atrophy as a predictor of higher postoperative SP rates (Marks et al. 1986), while others have concluded that a small-sized left testis decreases the likelihood of improvement in pregnancy (Fujisawa et al. 2002). Additionally, several studies have demonstrated that men with raised FSH levels are more likely to show non-response to varicocelectomy (Schrepferman et al. 2000; Fujisawa et al. 2002). Sperm concentration independently predicts the efficacy of varicocelectomy, and it is reported that men with sperm concentration >2 million/mL had a 56.3% improvement in sperm parameters and a 25% improvement in SP rates (Enatsu et al. 2014). While others have concluded that if sperm concentration is <5 million/mL, then couples should initially consider ART rather than varicocelectomy, because of its low SP rates (Kamal et al. 2001).

Currently, several studies have evaluated the impact of varicocelectomy using different degrees of total motile sperm count (TMSC), a sperm parameter in subfertile men with varicocele. This systematic review and meta-analysis aimed to authenticate the efficacy of varicocelectomy and summarize the available data to provide a precise estimates of the outcomes of varicocelectomy in different degrees of TMSC, with primary focus on the different degrees of change in TMSC over time and SP rates.

Results and discussion

Characteristics of individual studies

Figure 1 illustrates the studies included and excluded at various stages of analysis and the selection criteria are summarized in Table 1. After a comprehensive search, 96 articles were initially identified. On screening, seven articles were found to be duplicate, resulting in 89 articles. Among these articles, abstracts of 16 potential articles were browsed based on the outcomes in terms of sperm parameters (e.g., sperm concentration, total count, and motility) rather than TMSC. These articles were then tested extensively for compatibility in terms of methodology, selection criteria, and bias assessment resulting in nine articles, i.e., six interventional trials and three retrospective data analysis that were included in this meta-analysis. The characteristics of included studies are described in Table 2. Previous studies have illustrated that the TMSC is perhaps more powerful than the WHO grading system for distinguishing the male infertility as well as the ART outcomes (Hamilton et al. 2015; Borges 2016). TMSC is a different expression of sperm quality and is calculated by multiplying the semen volume by the percentage of progressive motile sperm by the sperm concentration divided by 100 (AYALA et al. 1996).

Table 1. Selection criteria of included studies.

	Included	Excluded
Population	Infertile men with clinical varicocele	Azoospermia Subclinical varicocele Other potential risk factors that may impair TMSC Children or adolescents Fertile men with varicocele
Intervention	Microsurgical, open, or lapro-endoscopic surgical ligation	No adjuvant medicines treatment
Comparison	The change of TMSC over time	Semen parameters that were described in terms of counts, concentration, or motility
Outcomes	TMSC before and after varicocelectomy or pregnancy	Spouse’s fertility status not described
Study type	Any type

Table 2. Characteristics of included studies.

Author (year)	Design	Patients	Varicocele grade	Surgical approach	follow-up (month)	TMSC (million)	Outcomes included
Dubin 2018	Interventional trials	Infertile patients	Any grade (I II III)	Subinguinal approach microsurgical varicocele	6	<2	TMSC before and after varicocelectomy
Masterson et al. 2018	Retrospective data analyses	Infertile patients	Any grade (I II III)	Subinguinal approach microsurgical varicocele	>6	<5	TMSC before and after varicocelectomy, SP
Samplaski et al. 2017	Interventional trials	Infertile patients	Palpable varicocele and ultrasound confirmed	Subinguinal approach microsurgical varicocele	>6	>9, 5–9, < 5	TMSC before and after varicocelectomy
Fukuda et al. 2015	Interventional trials	Infertile patients	Palpable varicocele and ultrasound confirmed	Subinguinal approach microsurgical varicocele	12	<3, 3–9,>9	TMSC before and after varicocelectomy
Jallouli et al. 2008	Retrospective data analyses	Infertile patients	Palpable varicocele and ultrasound confirmed	Ppeninguinal approach and laparoscopically	12	<1.5,1.5–5, >5	TMSC before and after varicocelectomy, SP
Gui 2006	Retrospective data analyses	Infertile patients	Clinical varicocele	High inguinal approach	12–24	<5, 5–20, >20	SP
Matkov 2001	Retrospective data analyses	Infertile patients	Clinical varicocele	Open inguinal/subinguinal approach and laparoscopically	>12	<5, 5–20, >20	SP
Takeuchi et al. 2014	Retrospective data analyses	Infertile patients	Clinical varicocele grade II or III	Microsurgical varicocelectomy	12	<5	TMSC before and after varicocelectomy, SP
Cayan 2002	Retrospective data analyses	Infertile patients	Palpable varicocele	Microsurgical varicocelectomy	>12	<1.5,1.5–5,5–20,>20	SP

TMSC: total motile sperm count; SP: spontaneous pregnancy

Figure 1. Flow diagram of literature search. Ninety-six articles were initially identified. On screening, among these articles, abstracts of 16 potential articles were browsed based on the outcomes in terms of sperm parameters, nine articles include six interventional trials and three retrospective data analysis that were included. Main reasons of exclusion were: trials were not comparison of TMSC but other sperm parameters (motility and concentration).

Impact of varicocelectomy on TMSC

Six studies examined the TMSC before and after the varicocelectomy. In these studies, varicocele repair was performed by three types of surgical techniques separately, i.e., open (inguinal/subinguinal) surgical (Matkov et al. 2001; Gui et al. 2006; Jallouli et al. 2008), microsurgical (subinguinal) (Çayan et al. 2002; Takeuchi et al. 2014; Fukuda et al. 2015; Samplaski et al. 2017; Dubin et al. 2018; Masterson et al. 2018), and laparoscopically (Matkov et al. 2001; Jallouli et al. 2008). Two studies had combined both the open surgical and laparoscopic approaches to repair varicocele (Matkov et al. 2001; Jallouli et al. 2008). Data were summarized for the four degrees of TMSCs, i.e., profound (five articles, 151 patients), severe (two articles, 115 patients), moderate (two articles, 79 patients), and mild (two articles, 248 patients). All degrees of TMSC led to a significant improvement with small differences among the profound, severe, and moderate groups. While the mild group revealed a highly significant improvement. Post-varicocelectomy, the improvement in TMSC was 10.20 million (95% CI: 9.11–11.30, p < 0.0001) in profound group, 15.77 million (95% CI: 10.65–20.89, p < 0.0001) in severe group, 19.18 million (95% CI: 10.40–27.96, p < 0.0001) in moderate group, and 49.68 million (95% CI: 38.74–60.62, p < 0.0001) in mild group (Figure 2). Similar results have been documented in previous study where men with slightly decreased sperm concentration (10–20 million/mL) were more likely to benefit from varicocelectomy than those with severely decreased sperm concentration (<5million/mL) (Fujisawa et al. 2002). Additionally, men with normal FSH or TMSC > 10 million preoperatively are more inclined to benefit from varicocelectomy. However, a preoperative TMSC of <10 million with a raised FSH level indicated a poor response to varicocelectomy (Schrepferman et al. 2000).

Figure 2. Impact of varicocelectomy on total motile sperm count. Mean TMSC classified as: <2 million – profound; 2–5 million – severe; 5–10 million – moderate; >10 million – mild. The improvement in TMSC was 10.20 million (95% CI: 9.11–11.30, p < 0.0001) in profound group, 15.77 million (95% CI: 10.65–20.89, p < 0.0001) in severe group, 19.18 million (95% CI: 10.40–27.96, p < 0.0001) in moderate group, and 49.68 million (95% CI: 38.74–60.62, p < 0.0001) in mild group post-varicocelectomy.

Pregnancy rates

Unfortunately, only four of the included studies reported the outcomes in terms of SP rates. Data were summarized for the four degrees of TMSC, i.e., the TMSC < 1.5 million group (two articles, 194 patients), the TMSC < 5 million group (four articles, 137 patients), the TMSC 5–20 million group (four articles, 238 patients), and the TMSC > 20 million group (three articles, 175 patients). After varicocelectomy, the SP rate was highest at 55.4% in the TMSC > 20 million group, followed by 45.4% in the TMSC 5–20 million group, and 26.3% in the TMSC < 5 million group. While the TMSC < 1.5 million group demonstrated the lowest SP rate of only 16.0% (Table 3). There was insufficient data to compare the effect of severity of TMSC on pregnancy rate. However, following varicocelectomy, a higher pooled improvement in SP rate was found in TMSC > 20 million group (55.4%) and TMSC 5–20 million group (45.4%) than TMSC < 5 million group (26.3%) and TMSC < 1.5 million group (16.0%). A recent study reported that the SP group had a significantly higher mean TMSC, and couples with a profound decline in TMSC (<1 million and 1–5 million) revealed a significantly lower SP rate than those with TMSC of 5–10 million, and no differences were observed between the couples with TMSC of <1 and 1–5 million (Hamilton et al. 2015). Moreover, it has been documented that a million/count increase in TMSC is associated with an approximately 1.4 times increased chances of being pregnant (Zhang et al. 2017). Considering the economic benefits, varicocelectomy is a better solution, only when pregnancy rate is greater than 14% (TMSC < 10 million at baseline) and 45% (TMSC > 10 million at baseline) after varicocelectomy (Meng et al. 2005).

Table 3. Pregnancy rates following varicocelectomy.

TMSC (million)	N/Total N SP rate (%)	Mean age ±SD (range)	Female fertility	follow-up
<1.5
Cayan 2002	21/132 (15.9)	29.5 ± 5.9	Excluded history of gynecologic surgery or ovultory abnormalities	24
Jallouli et al. 2008	10/62 (16.1)	34.7 (20–50)	No advanced female factors	12
Overall	31/194 (16.0)
<5
Matkov 2001	4/20 (20.0)	NA	No female factors referral for IVF.	12
Cayan 2002	19/62 (30.6)	29.5 ± 5.9	Excluded history of gynecologic surgery or ovulatory abnormalities	24
Jallouli et al. 2008	9/22 (40.9)	34.7 (20–50)	No advanced female factors	12
Gui 2006	4/33 (12.1)	25.6 (20–36)	Excluded history of gynecologic surgery or ovulatory abnormalities	12–24
Overall	36/137 (26.3)
5–20
Matkov 2001	7/20 (35.0)	NA	No female factors referral for IVF.	12
Cayan 2002	48/126 (38.0)	29.5 ± 5.9		24
Jallouli et al. 2008	39/59 (66.1)	34.7 (20–50)	No advanced female factors	12
Gui 2006	14/33 (42.4)	25.6 (20–36)	Excluded history of gynecologic surgery or ovulatory abnormalities	12–24
Overall	108/238 (45.4)
>20
Matkov 2001	4/18 (22.2)	NA	No female factors referral for IVF.	12
Cayan 2002	75/125 (60.0)	29.5 ± 5.9	Excluded history of gynecologic surgery or ovulatory abnormalities	24
Gui 2006	18/32 (56.3)	25.6 (20–36)	Excluded history of gynecologic surgery or ovulatory abnormalities	12–24
Overall	97/175 (55.4)

TMSC: total motile sperm count; NA: not available; SD: standard deviation; SP: spontaneous pregnancy. After varicocelectomy, the SP rate was highest at 55.4% in the TMSC > 20 million group, followed by 45.4% in the TMSC 5–20 million group, and 26.3% in the TMSC < 5 million group. While the TMSC < 1.5 million group demonstrated the lowest SP rate of only 16.0%

Varicocelectomy contributes to multiple benefits in male infertility treatment. The reported SP rates after varicocelectomy ranges from 35% to 55%, and is higher than those left untreated (Cayan et al. 2009). Prior to in-vitro fertilization (IVF) procedure, couples might benefit from varicocelectomy as a result of significant improvement in clinical pregnancy and live birth rates (Kirby et al. 2016). Even 20–50% of men with idiopathic non-obstructive azoospermia might benefit from varicocelectomy, as spermatozoa have been found in ejaculated semen (Youssef et al. 2009; Elzanaty 2014). Although men with profound or severely decreased TMSC reported a lower SP rates, these patients may also benefit from varicocelectomy, as increased TMSC could down-stage the required level of ART. Couples first started on IVF or intrauterine insemination (IUI) due to declining sperm quality and quantity, can now undergo IUI or natural conception owing to an increase in TMSC after varicocelectomy (Thirumavalavan et al. 2018). In varicocele-induced infertile male with TMSC < 2 million, varicocelectomy sequence performed with IUI was found to be more cost-effective than initial attempted to IVF (Dubin et al. 2018).

The decision to repair varicocele has always been complex and multiple factors such as patient’s age, baseline sperm parameters, cost, timing, and acceptance of ART should be considered. Some of the patients undergo varicocelectomy with an aim of achieving SP and avoiding the ART. We, therefore, suggest for consideration that men with profound or severely decreased TMSC consider IVF, rather than varicocelectomy as an initial treatment. While, irrespective of TMSC, couples requiring IVF may perhaps benefit from varicocelectomy.

This study does have some limitations, as it did not include randomized control trials. All the included studies were prospective or retrospective, and thus, signified lower quality of evidence. In addition, karyotype abnormalities are reported in 2% and Y microdeletions in 6–8% oligospermic men (Reijo et al. 1996; Pryor et al. 1997) and a negative response to varicocelectomy has been demonstrated in them (Cayan et al. 2001). In the present meta-analysis, only one study excluded these patients (Masterson et al. 2018). Moreover, the varicocelectomy was performed by different approaches, i.e., microsurgical, laparoscopic, and open varicocele ligation. Information regarding the follow-up period was not consistent across the studies, and some of the included studies had a small sample size which can amplify the bias. Thus, the results of this meta-analysis should be interpreted with caution.

Nevertheless, the present meta-analysis suggests that varicocelectomy in infertile men with varicocele results in improved TMSC and SP rates. The improvement in TMSC and SP rates were higher in patients who had a moderate and mild degree of decrease in TMSC. Infertile men with profound or severely decreased TMSC should be counseled to undergo IVF rather than varicocelectomy, as an initially preferred option.

Material and methods

This systematic review and meta-analysis was performed as per the PRISMA and AMSTAR guidelines. The study was registered at PROSPERO (registry number: CRD42019122391).

Literature search and eligibility criteria

We conducted a comprehensive literature search up to December 26, 2018, using Medline/PubMed and Google Scholar. We did not restrict ourselves to particular study design and included all types of studies. MESH terms used were ‘varicocele’, ‘varicocelectomy’ combined with a free word ‘total motile sperm count’. While searching the references of included articles and recently published abstracts, additional studies were identified and considered for inclusion. Unpublished literature or literature with incomplete data were excluded.

Data extraction and quality assessment

Based on the inclusion criteria, two authors were responsible for screening and extracting data from the retrieved full articles. Dissent was resolved by a third-party consensus. The postoperative (more than 3 months) TMSC was compared with the baseline parameters, and thus the patients acted as their own controls. Subgroup analysis was performed to distinguish the improvement between different degrees of TMSC after varicocelectomy. This meta-analysis intends to summarize published research articles. Majority of the studies included in this analysis focused on classifying the preoperative mean TMSC as <2 million, 2–5 million, 5–10 million, and >10 million. Whereas, only one study classified the mean TMSC as <5 million, 5–9 million, and >9 million. Thus, we have used a novel way to classify the mean TMSC as: Profound – <2 million; Severe – 2–5 million; Moderate – 5–10 million; and Mild – >10 million. Moreover, for assessing the spontaneous pregnancy rates, the included studies classified the mean TMSC as <1.5 million, <5 million, 5–20 million, and >20 million.

Potential biases were analyzed in accordance with Agarwal et al. (Agarwal et al. 2007). The selection/follow-up bias: focused on the study population derived and subjects recruited; and restriction against the participants with infection, previous treatment, female factor infertility, and those with >10% loss to follow-up; inclusion of studies with a maximal score of 11; and exclusion of those with a score in the range of 4–6. Confounding bias: the concerned period of follow-up and change in potential factors over time, with a maximum score of 8 and exclusion of those with a score in the range of 3–4. The information/detection bias: related to the consistency of the follow-up method, the objective measurement of outcomes, and consistency of location before and after the treatment, with a maximum score of 10 and exclusion of those with a score in the range of 3–7. Other possible biases dealt with the homogeneity of studies in the aspect of infertility duration, severity/grade of varicocele, and established guidelines for analysis, with a maximum score of 10 and exclusion of those with a score in the range of 3–7. Any other trials with biases present in two or more categories of scoring in the exclusion range were excluded.

Data analysis

The change in TMSC over time was compared after varicocelectomy. The weighted mean difference (WMD) and associated 95% confidence interval (CI) were calculated and then, a forest plot was generated. Statistical heterogeneity of the studies was assessed using I² statistics. A random-effects model was applied, if heterogeneity of the included study was >50%. Otherwise, a fixed-effects model was used (Higgins et al. 2009). Statistical significance was considered at p < 0.05. This meta-analysis was performed using Stata11 (StataCorp LP, College Station, TX, USA).

Authors’ contributions

Proposed the conception of the idea and guided the study: LW; Performed literature search and review, meta-analysis, and interpretation of results: YY; Reviewed meta-analysis results and feedback on inclusion of studies and analysis: YL; Analyzed included and excluded studies, helped summarize the collected evidence, interpretation of results, and drafted the manuscript: QW. All authors read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.