Impact of human papillomavirus infection in semen on sperm progressive motility in infertile men: a systematic review and meta-analysis

Abstract

Introduction

Infertility is defined as the inability of a couple to conceive after 1 year of unprotected sexual intercourse, which affects approximately one-fifth of couples at the reproductive age [1]. Among them, male infertility contributes to roughly 50% of overall infertility cases [2]. Seminal infections are significant etiologic factors in male infertility and often associated with impaired semen quality [3, 4]. Chronic viral infection of the urogenital tract, especially human immunodeficiency virus (HIV) infection, may result in urethral inflammation and decreased fertility [5, 6]. Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in semen can also adversely alter seminal parameters [7, 8]. Human papillomavirus (HPV) is one of the most common sexually transmitted viruses in both males and females worldwide [9]. Some studies have reported that HPV can bind to the head of sperm and result in decreasing male fertility or even causing infertility [10]. A significant association between seminal HPV infection and male fertility abnormality has been reported [11, 12]. Also, recent researches suggested that HPV infection of semen represented a significant risk factor for infertility in men [13, 14].

The possible mechanisms underlying correlation between HPV seminal infection and infertility remain unclear [15] and one possibility is that HPV infection significantly lowered the key sperm parameters [14]. Sperm progressive motility has conventionally been considered as a good indicator of motility and a key functional parameter essential for fertilization. The effects of HPV infection on sperm progressive motility in infertile men have been investigated, but the results are controversial [16]. Several researches indicated that HPV infection was closely related to male infertility with decreased sperm progressive motility [17–25], while Zheng et al. revealed that there was no significant difference of sperm progressive motility rate between infected and non-infected infertile subjects [26]. In this research, we performed a systematic review and meta-analysis to investigate the possible impact of HPV infection in semen on sperm progressive motility in infertile individuals.

Methods

Results

Study characteristics

The initial literature search yielded 291 potentially relevant studies. Most ineligible studies were excluded based on information in the title or abstract and the remaining 32 eligible studies were reviewed in detail. The selection process was shown in Fig. ​Fig.1.1. As a result, ten articles were included in the final meta-analysis, providing data on 616 HPV DNA positive men among 2645 participants from 3 countries. The main characteristics of the studies included in our meta-analysis were described in Table 1.

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Fig. 1

Flow diagram of the studies identified in the systematic review and meta-analysis

Table 1

Basic characteristics of the eligible studies included in the present meta-analysis

Study	Country	Age /Sample size (n)		HPV genotype	Study Design
		HPV+patients	HPV−patients
Moghimi 2019 [20]	Iran	NA (n = 8)	NA (n = 62)	16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59	Case-control
Yang 2016 [24]	China	NA (n = 64)	NA (n = 289)	18 HPV genotypes including 16,45,52,59,18,33,68,81	Cross-sectional
Garolla 2016 [21]	Italy	NA (n = 54)	NA (n = 172)	NA	Cross-sectional
Foresta 2015 [22]	Italy	37.1 ± 7.4 (n = 179)	38.2 ± 8.1 (n = 440)	6, 11, 16, 18, 26, 31, 33, 35, 39, 40,42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 69, 71, 70, 73, 74,	Cohort
Yang 2015 [25]	China	NA (n = 86)	NA (n = 41)	6,11,16,18,31,33,45,52,56,58	Cross-sectional
Zheng 2014 [26]	China	NA (n = 30)	NA (n = 300)	6,16,18,31,33,52,58	Cross-sectional
Foresta 2013 [23]	Italy	38.8 ± 9.8 (n = 16)	37.5 ± 5.9 (n = 16)	HPV-16	Cross-sectional
Yang 2013 [19]	China	NA (n = 107)	NA (n = 508)	At least 20 HPV genotypes, including 6, 11,16, 18, 31, 33,39, 40, 42, 43,45, 51, 52, 53,54, 59, 66, 68,70, 81	Cross-sectional
Garolla 2013 [17]	Italy	35.3 ± 4.7 (n = 61)	34.2 ± 3.8 (n = 104)	6, 11, 16, 18, 26, 31, 33, 35, 39, 40, 42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 69/71, 70, 73, 74, 82.	Cross-sectional
Foresta 2010 [18]	Italy	NA (n = 11)	NA (n = 97)	6,16,18,52,53,56,61,66,70,84,90	Cross-sectional

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Meta analysis

To assess the effect of HPV seminal infection on sperm progressive motility, ten eligible studies including 616 infertile patients with HPV-infected in semen and 2029 non-infected infertile subjects were analyzed. According to the results of the heterogeneity test, the random effect model was chosen to estimate the SMD. A significant reduction of sperm progressive motility was found in semen samples of HPV-infected infertile patients compared with non-infected groups (SMD:-0.88, 95% CI:-1.17 ~ − 0.59) (Fig. 2).

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Fig. 2

Primary outcome in overall analysis

A subgroup analysis was performed to differentiate the effect size based on study region. The pooled SMD was highest in China (− 0.59, 95% CI: − 0.73 ~ − 0.45), followed by Italy (− 1.10, 95% CI: − 1.54 ~ − 0.67) and Iran (− 1.26, 95% CI: − 2.02 ~ − 0.49) (Fig. 3). There was no statistical heterogeneity in the subgroup of China.

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Fig. 3

Subgroup analysis by study region

Sensitivity analysis

None of an individual study significantly altered the overall significance of the combined SMD in the analyses relating to the impact of HPV seminal infection on sperm progressive motility in infertile individuals (Fig. 4).

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Fig. 4

Sensitivity analysis of the association between human papillomavirus seminal infection and sperm progressive motility

Discussion

HPV has been considered as an infectious factor that might be linked to unexplained infertility in men. Previous meta analyses have reported the prevalence of HPV in semen [28] and the risk for male infertility [13, 14]. Laprise et al. [28] exhibited that the pooled HPV prevalence in semen was estimated at 16% for men seeking fertility evaluation/treatment and at 10% in general populations. Xiong et al. [14] and Lyu et al. [13] demonstrated that HPV semen infection was a risk factor for male fertility abnormality with an OR of 3.02 (95% CI: 2.11–4.32) and 2.93 (95% CI: 2.03–4.24) respectively. The issue whether HPV seminal infection has significance and consequence for sperm progressive motility in infertile men is controversial. The current study conducted a meta-analysis to evaluate the impact of HPV semen infection on sperm progressive motility in infertile subjects. The results showed that the prevalence of HPV detection in semen in infertile men ranged from 9.1% by Zheng et al. [26] to 67.7% by Yang et al. [25]. Sperm progressive motility reduced significantly in seminal HPV infected patients compared with non-infected groups. In the aspect of HPV genotypes distribution, the results showed that HPV-16, HPV-18/52, HPV-33, in decreasing order, were the most prevalent genotypes in semen of infertile group. Previous studies have shown that in semen the HPV were detected both in exfoliated cells [29] and in sperm surface, especially in the sperm head [17]. In an in vitro study, Carlo et al. [30] reported that HPV could infect human sperm and it localized at the equatorial region of sperm head through interaction between the HPV capsid protein L1 and syndecan-1. Moreover, HPV binding to sperm was tenacious [10, 31] and conventional methods of sperm washing could not clear HPV DNA from sperm surface [32].

The pathogenic mechanism explicating the reduction of sperm progressive motility related to seminal HPV infection might be associated with anti-sperm antibodies (ASAs), glandular dysfunction and sperm DNA fragmentation. Firstly, several studies have shown that infertile patients with HPV semen infection had a high percentage of ASAs on sperm surface and the presence of HPV in semen was frequently related with ASAs of IgA and IgG classes, which suggested that the presence of HPV DNA on the sperm surface might represent an antigenic stimulus for ASA formation [17, 33]. Although the role of ASAs is controversial, some mechanisms have been proposed affecting sperm quality: sperm agglutination and complement mediated sperm cytotoxicity occurring within the male genital tract [34]. Secondly, HPV seminal infection in infertility men may have altered proportions of secretory products mainly from prostate and seminal vesicles, which could have a negative impact on sperm motility [35]. Thirdly, HPV infection might result in the increased rate of sperm DNA fragmentation and apoptosis. In vitro study by Connelly et al. [36] indicated that sperm cells transfected with exogenous HPV E6/E7 DNA had higher percentages of breakages characteristic of apoptosis compared to the uninfected controls. In contrary, in vivo study by Cortes et al. [37] failed to find any association between HPV positive and sperm DNA fragmentation. Further evidence gathered through well-designed trials to confirm whether HPV-infected sperm is more susceptible to DNA damage is warranted.

In fact, HPV-infected sperm maintained their ability to fertilize the oocyte, interfered with implantation and embryo development, thus affecting the outcome and safety of assisted reproduction techniques (ARTs) [38]. Henneberg et al. [39] demonstrated embryo stage-specific disruption effects of HPV on early development. Perino et al. [40] reported the lower pregnancy rate and increased percentage of abortions in ARTs with HPV positive in semen. In a cross-sectional clinical study [21], cumulative pregnancy rates recorded in noninfected and infected couples undergoing ART were, respectively, 38.4 and 14.2%. During the follow-up of these pregnancies, a significantly higher miscarriage rate (62.5% vs. 16.7% of noninfected) was observed in HPV-infected subjects. In particular, all pregnancy losses of the infected group took place very early (three at 5th and two at 6th gestational week).

The results showed that I²-value was greater than 50%, which suggested that there was potential heterogeneity between studies. The heterogeneity might be attributed to differences in study region, sample size, the definition of male infertility and the number of HPV types detected. The inclusion criterion of the infertile group was at least 1 year or 2 years of unprotected sexual intercourse without conception. The study by Foresta et al. [23] included the infertile patients of case group only affected by HPV-16 semen infection and HPV-genotypes other than HPV-16 were all excluded. Multiple HPV-genotypes were detected in most of articles included in the present study and the genotype was not mentioned in one study [21]. The results of subgroup analysis showed that I²-value was equal to zero in the subgroup of China, which suggested that study region might be the causes of heterogeneity.

In addition, some limitations of the present meta-analysis should be considered when interpreting the results. Firstly, though we performed an extensive literature search, potential selection bias could not be completely avoided because only articles published in Chinese and English were included. Secondly, some important confounding factors, such as male age and environmental exposures were not always noted. These factors might have confounding effects on the correlation between HPV semen infection and reduced sperm progressive motility. Thirdly, most articles were not prospective study and might therefore decrease the reliability of our results.

Conclusions

In summary, the current evidences suggest that HPV semen infection could significantly reduce sperm progressive motility in infertile individuals compared with non-infected infertile group. This information could make recommendations for reproduction diagnosis and treatment and could affect public health. However, this evidence is far from conclusive because of the small sample sizes and existing confounding factors of the currently available studies. Future studies with large sample size and rigorous design are necessary to elucidate the impact of HPV semen infection on sperm quality.

Supplementary information

Acknowledgements

Abbreviations

Authors’ contributions

XC and RW conceived and designed the study. XZ and JZ performed the systematic literature review. XC and JL conducted the statistical analysis. XC and YC drafted the manuscript. All authors reviewed and approved the final version of the manuscript.

Funding

This study was supported by Natural Science Foundation of Ningbo (2018A610330; 2019A610357).

Availability of data and materials

The current study was based on results of relevant published studies.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Footnotes

References