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Ureaplasma urealyticum upregulates seminal fluid leukocytes and lowers human semen quality: a systematic review and meta-analysis

Basic and Clinical Andrology volume 35, Article number: 14 (2025) Cite this article

Abstract

Background

Ureaplasma urealyticum belongs to the class Mollicutes and causes non-gonococcal urethritis, an inflammation of the urethra that is linked with impaired semen quality. However, some reports are contradictory, and the reported effect of U. urealyticum on specific sperm variables is not consistent. Thus, this study synthesized findings from published primary data and provides a robust and reliable inference on the impact and associated mechanisms of U. urealyticum on sperm quality.

Methods

A systematic search was conducted until 31st May, 2024, on Cochrane, Google Scholar, and Pubmed. The Population, Exposure, Comparator/Comparison, Outcomes, and Study Design (PECOS) model was adopted. The populations were male in their reproductive ages who were infected with Ureaplasma urealyticum and confirmed positive versus the control who were age-matched non-infected or treated, while the outcomes included conventional semen parameters, seminal fluid leucocyte count, and sperm interleukin-6 (IL-6) concentrations, and the studies were either cross-sectional or longitudinal.

Results

When compared with the control, quantitative analysis demonstrated that U. urealyticum significantly reduced ejaculate volume (SMD 0.33 [95% CI: 0.15, 0.52] p = 0.0004), sperm concentration (SMD 0.47 [95% CI: 0.31, 0.64] p < 0.00001), total sperm motility (SMD 0.73 [95% CI: 0.43, 1.02] p < 0.00001), total motile sperm count (SMD 0.21 [95% CI: 0.17, 0.26] p < 0.00001), normal sperm morphology (SMD 0.88 [95% CI: 0.42, 1.35] p = 0.0002), but increased seminal fluid leukocyte count (SMD -0.82 [95% CI: -1.61, -0.02] p = 0.04). In addition, qualitative analysis revealed that U. urealyticum-positive subjects had significantly higher levels of IL-1β, IL-6, IL-8, TNF-α, peroxidase, leukocytes, neutrophils, CD4 + T cells, and CD8 + T cells in the seminal fluid when compared with the control. Furthermore, higher sperm DNA fragmentation and apoptotic sperm cells were observed in U. urealyticum-positive subjects when compared to the control.

Conclusions

These findings revealed that U. urealyticum lowers semen quality via the upregulation of seminal fluid leukocytes, elastase, pro-inflammatory cytokines, and DNA fragmentation. However, further studies are required to elucidate the mechanisms underlying the association between U. urealyticum and semen quality decline and to develop effective therapies for this condition.

Résumé

Contexte

Ureaplasma urealyticum appartient à la classe des Mollicutes et provoque une urétrite non gonococcique, une inflammation de l’urètre, qui est liée à une altération de la qualité du sperme. Cependant, certains rapports sont contradictoires, et l’effet rapporté de U. urealyticum sur les paramètres spécifiques des spermatozoïdes n’est pas cohérent. La présente étude a synthétisé les résultats des données primaires publiées, et fournit une inférence robuste et fiable sur l’impact et les mécanismes associés d’U. urealyticum sur la qualité du sperme. Une recherche systématique a été menée jusqu’au 31 mai 2024 sur Cochrane, Google Scholar et PubMed. Le modèle PECOS (Population, Exposure, Comparator/Comparison, Outcomes, and Study Design) a été adopté. Les populations étaient des hommes en âge de procréer et infectés par U urealyticum, et dont les résultats positifs étaient confirmés par rapport aux témoins appariés selon l’âge, non infectés ou traités ; les résultats comprenaient les paramètres conventionnels du sperme, le nombre de leucocytes dans le liquide séminal et les concentrations d’interleukine-6 des spermatozoïdes (IL-6).

Résultats

Par rapport aux témoins, l’analyse quantitative a montré que U. urealyticum réduisait significativement le volume d’éjaculat (Différence de Moyenne Standardisée DMS 0,33 [IC à 95 % : 0,15, 0,52] p = 0,0004), la concentration de spermatozoïdes (DMS 0,47 [IC à 95 % : 0,31, 0,64] p< 0,00001), la motilité totale des spermatozoïdes (DMS 0,73 [IC à 95 % : 0,43, 1,02] p< 0,00001), le nombre total de spermatozoïdes mobiles (DMS 0,21 [IC à 95 % : 0,17, 0,26] p< 0,00001), les spermatozoïdes de morphologie normale (DMS 0,88 [IC à 95 % : 0,42, 1,35] p = 0,00002), mais augmentait la numération leucocytaire du liquide séminal (DMS -0,82 [IC à 95 % : -1,61, -0,02] p = 0,04). De plus, l’analyse qualitative a révélé que les sujets positifs à U. urealyticum présentaient des taux significativement plus élevés d’IL-1β, d’IL-6, d’IL-8, de TNF-α, de peroxydase, de leucocytes, de neutrophiles, de lymphocytes T CD4+ et de lymphocytes T CD8+ dans le liquide séminal par rapport aux témoins. De plus, des taux plus élevés de fragmentation de l’ADN des spermatozoïdes et de spermatozoïdes apoptotiques ont été observées chez les sujets positifs à U. urealyticum par rapport aux témoins.

Conclusions

Ces résultats ont révélé que U. urealyticum abaisse la qualité du sperme via la régulation positive des leucocytes du liquide séminal, de l’élastase, des cytokines pro-inflammatoires et de la fragmentation de l’ADN. Cependant, d’autres études sont nécessaires pour élucider les mécanismes sous-jacents à l’association entre U. urealyticum et le déclin de la qualité du sperme, ainsi que pour développer des traitements efficaces pour cette maladie.

Introduction

Infertility is the failure to achieve conception after a year of adequate unprotected sexual activity [1]. If this is due to a male factor, it is referred to as male infertility. About 30–50% infertility cases are caused by male factors, either solely or in combination with female factors [2]. Although there are emerging causes, predisposing factors of male infertility are classified as pre-testicular, testicular, and post-testicular factors. Post-testicular causes include vas deferens blockage, ejaculatory duct obstruction, retrograde ejaculation and cystic fibrosis, while testicular factors include testicular torsion/detorsion, varicocele, cryptorchidism, testicular cancer, heat stress, Orchitis, spermatocele, genetic disorders, and pre-testicular causes include endocrinopathies, smoking, use of illicit drugs, psychoemotional stress, thyroid disorders, exposure to environmental toxicants such as heavy metals, and infections [2,3,4,5,6]. These infections may be viral [7, 8], fungal [9], or bacterial [10]. One of the most prevalent bacterial causes of male infertility is Ureaplasma urealyticum [11, 12].

Ureaplasma urealyticum belongs to class Mollicutes, commonly knowns as Mycoplasma. Although commensal in the human urogenital tracts, they could be opportunistic, causing variety of reproductive diseases and disorders. Ureaplasma spp hydrolyze urea and release ammonia, they produce IgA protease, phospholipases A and C as well as hydrogen peroxide. Ureaplasma urealyticum causes non-gonococcal urethritis (NGU) [13]; an inflammation of the urethra without the presence of Neisseria gonorrhoeae. The symptoms of NGU include penile discharge, dysuria, and irritation around the urethra; these are mainly linked to a decrease in male fertility due to their effects on sperm quality [14]. Ureaplasma urealyticum spreads through several routes, such as direct sexual contact between partners, vertical transmission from mother to child, hospital-contracted infections from transplanted tissues, or unprotected anal, vaginal, or oral sex with an infected individual [15]. Ureaplasma urealyticum has been linked with central nervous system infections, bronchopulmonary dysplasia, sexually transmitted reactive arthritis (Reiter's syndrome), chronic prostatitis, epididymitis, and pregnancy complications [16].

U. urealyticum infects sperm cells by attaching and integrating itself to the head of the sperm cells, thus leading to a reduction in sperm count, concentration, viability, and motility [17, 18]. U. urealyticum also negatively impacts semen pH and sperm morphology [19]. U. urealyticum triggers inflammation [11] and enhances reactive oxygen species (ROS) generation [20], leading to damage to the sperm membrane, proteins and deoxyribonucleic acid (DNA), thus DNA fragmentation. In addition, U. urealyticum activates the immune system and promotes the production of antisperm antibodies [21] that may bind to spermatozoa and impair their motility and oocyte-penetration ability, thus reducing male fertility. U. urealyticum may also alter the chemico-biological makeup of the semen by altering the seminal fluid pH [17, 18], making the environment hostile to sperm survival and motility.

Despite several reports on the negative impact of U. urealyticum on sperm quality and male fertility, some reports are conflicting and the reported effect of U. urealyticum on specific sperm variable is not consistent. Thus, the present study synthesized findings from multiples primary data and provides a more robust and reliable conclusion on the impact and associated mechanisms of U. urealyticum on sperm quality.

Materials and methods

Protocol and inclusion criteria

The present study was registered on PROSPERO (CRD42024534950). This study adhered to the “Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)” strategy. The Population, Exposure, Comparator/Comparison, Outcomes, and Study design (PECOS) model was adopted and eligible studies published until May, 2024 were included. The studied populations were male in their reproductive ages who were infected with Ureaplasma urealyticum and confirmed positive. The outcomes included ejaculate volume, seminal fluid pH, sperm concentration, total motility, progressive motility, total motile sperm count, sperm vitality (viability), sperm morphology, and seminal fluid leucocyte count and interleukin- 6 (IL- 6) concentrations. The studies were either cross-sectional or longitudinal. Studies without appropriate control groups, studies in female, in vitro studies, review articles, commentaries, perspectives, letters to editor, editorials, preprint, conference abstract, degree thesis, and retracted papers were excluded. There was no restriction on language or country.

Search strategy, assessment of the quality of the eligible studies, and data collection.

Systematic searches were conducted on Cochrane, Google Scholar, and Pubmed using these Boolean strings ("Ureaplasma urealyticum"OR"urealyticum"OR"ureaplasma") AND ("sperm"OR"semen"OR"sperm count"OR"sperm concentration"OR"sperm motility"OR"semen volume"OR"ejaculate volume"OR"semen pH"OR"semen leucocyte"OR"semen WBC"OR"sperm viability"OR"sperm vitality").

Abstracts and full text of articles were collected by all authors, and the eligible studies were assessed for the quality of evidence (QoE), risk of bias (RoB), and certainty of evidence (CoE) by OSK, VJA, CAA, and TMA. Disputes were resolved by REA. The QoE of eligible papers was evaluated by the ErasmusAGE quality score for systematic reviews, which assigns a number between 0 and 2 to five different domains, and a possible maximum score of 10 [22], while the “Office of Health Assessment and Translation (OHAT)” methodology was used to evaluate the RoB [23] and Using the “Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group” standards as a guide, the “OHAT approach for systematic review and evidence integration for literature-based health assessment was used to assess the certainty of the evidence” [24, 25].

The data collected from the eligible studies include: last name of the principal investigator, publication date, study design, town and country of study origin, method of Ureaplasma urealyticum diagnosis, sample size, ages of patients, and measured outcomes of interest. The outcomes of interest were collected as mean and standard deviation, but when the variables were presented in other forms, the mean and standard deviation were derived from the provided data. Web Plot Digitizer was employed to derive the quantitative data in cases where graphs were used.

Quantitative and qualitative analysis.

Where sufficient data were collected, meta-analyses were conducted using Review Manager (version 5.4.1). The standardized mean difference (SMD) at 95% confidence intervals (CIs) was calculated. When p-value < 0.1 or I2 > 50% which indicates the presence of significant heterogeneity, a random-effect model was used; however, when p-value > 0.1 or I2 < 50% which suggests the absence of significant heterogeneity, a fixed-effect model was used. Subgroup analyses were performed per study design (cross-sectional studies and longitudinal studies) to evaluate the impact of Ureaplasma urealyticum infection in patients versus control, and before versus after Ureaplasma urealyticum treatment on various endpoints respectively. The controls were age-matched uninfected subjects, but in longitudinal studies, the control refers to both uninfected subjects and the treated state as indicated in the figures. Subgroup analyses were also performed based on the different diagnostic techniques [Polymerase Chain Reaction (PCR), culture or rapid diagnostic tests (RDT)]. To assess the possible sources of heterogeneity, sensitivity analysis was conducted by excluding the studies with the largest weight, low QoE (< 5), high RoB (< 4), and low CoE. Publication bias was visually determined using the funnel’s plots.

Where there were limited study and data collected were not sufficient for quantitative analysis, qualitative analyses were done.

Results

Study identification, screening, and inclusion

A total of 9202 published articles were identified from the various databases. After the exclusion of review articles, editorials, commentaries, studies in female, in vitro studies, duplicates and retracted papers, 45 articles were potentially eligible for full text evaluation. Out of this, 22 were excluded for lack of appropriate comparison, leaving 23 articles [11, 12, 17, 17, 18, 26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44] as eligible for inclusion in the study (Fig. 1).

Fig. 1
figure 1

PRISMA flowchart for the strategic identification, screening, and inclusion of eligible studies

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The eligible papers were published between 2003 and 2024, and they were from diverse geographical location. Other details of the included studies such as the diagnostic techniques, sample size, and age distribution of subjects are presented in Table 1.

Table 1 Characteristics of the eligible studies included in the meta-analysis
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Assessment of the QoE, RoB, and CoE

All the eligible studies [11, 12, 17, 18, 26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44] had QoE above 5, showing good QoE (Table 2). However, four of the studies [27, 29, 33, 39] had moderate (6/9) RoB while others [11, 12, 17, 18, 26, 28, 30,31,32, 34,35,36,37,38, 40,41,42,43,44] had low (> 6/9) RoB (Table 3). In addition, three of the eligible studies [38, 39, 43] had moderate CoE, while others [11, 12, 17, 18, 26,27,28,29,30,31,32,33,34,35,36,37, 40,41,42, 44] had high CoE (Table 4).

Table 2 Assessment of the quality of evidence of the eligible studies
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Table 3 Risk of bias assessment of the eligible studies
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Table 4 Assessment of the certainty of evidence of the eligible studies
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Quantitative analysis

Ejaculate volume

A total of 25 studies from 19 published articles consisting of 21, 111 controls and 5, 161 U. urealyticum-infected subjects were included to determine the effect of U. urealyticum on ejaculate volume. It was observed that U. urealyticum significantly reduced ejaculate volume when compared with the control (SMD 0.33 [95% CI: 0.15, 0.52] p = 0.0004). More so, there was a significant heterogeneity (I2 = 95%; X2 p < 0.00001). Publication bias was also observed (S Fig. 1). The subgroup analysis of the cross-sectional studies revealed a significant reduction in the ejaculate volume of in U. urealyticum-infected subjects when compared with U. urealyticum-negative subjects (SMD 0.43 [95% CI: 0.23, 0.64] p < 0.0001). Also, a significant heterogeneity was observed (I2 = 95%; X2 p < 0.00001). However, subgroup analysis of the longitudinal studies showed that U. urealyticum did not significantly alter ejaculate volume (SMD − 0.26 [95% CI: 0.62, 0.09] p = 0.14) and a significant heterogeneity was also observed (I2 = 81%; X2 p = 0.005). More so, the subgroup analysis of the culture-based studies showed that U. urealyticum significantly reduced ejaculate volume (SMD 1.29 [95% CI: 0.71, 1.87] p < 0.0001) but a significant heterogeneity was also observed (I2 = 97%; X2 p < 0.00001), while the subgroup analysis of the PCR-based studies showed that U. urealyticum did not alter ejaculate volume (SMD − 0.21 [95% CI: − 0.43, 0.01] p = 0.07) and a significant heterogeneity was also observed (I2 = 76%; X2 p = 0.002). The subgroup analysis of the RDT-based studies demonstrated a significant reduction in ejaculate volume in patients infected with U. urealyticum when compared with the control (SMD 0.78 [95% CI: 0.27, 1.29] p = 0.003) but a significant heterogeneity was also observed (I2 = 97%; X2 p < 0.00001). Nonetheless, the sensitivity analysis demonstrates a significant reduction in ejaculate volume in U. urealyticum-positive patients when compared with the controls (SMD 0.52 [95% CI: 0.24, 0.81] p = 0.0004) and a significant heterogeneity was also observed (I2 = 95%; X2 p < 0.00001) (Fig. 2).

Fig. 2
figure 2

Effect of ureaplasma urealyticum on human ejaculate volume. UU: Ureaplasma urealyticum, SD: Standard deviation, CI: confidence interval. Meta-analysis was performed using a random-effect model. Data are shown as standardized mean difference and Confidence interval (CI)

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Seminal fluid pH

A total of 14 studies from 10 articles, consisting of 18, 410 control and 3, 287 U. urealyticum-positive subjects, were evaluated for the impact of U. urealyticum on seminal fluid pH. It was observed that U. urealyticum did not significantly alter seminal fluid pH (SMD 0.09 [95% CI: − 0.41, 0.58] p = 0.73) when compared with the controls and a significant heterogeneity was observed (I2 = 99%; X2 p < 0.00001). Also, publication bias was observed (S Fig. 2). The subgroup analysis of the cross-sectional studies also revealed that U. urealyticum did not significantly alter seminal fluid pH (SMD − 0.08 [95% CI: − 0.64, 0.48] p = 0.78) when compared with U. urealyticum-negative controls. A significant heterogeneity was observed (I2 = 99%; X2 p < 0.00001). More so, the seminal fluid pH did not vary considerably after U. urealyticum treatment compared to before treatment (SMD 0.71 [95% CI: − 0.02, 1.44] p = 0.06) and there was a significant heterogeneity (I2 = 95%; X2 p < 0.00001). Additionally, the subgroup analysis of the culture-based studies showed that U. urealyticum significantly reduced seminal fluid pH (SMD 1.05 [95% CI: 0.57, 1.53] p < 0.0001) but a significant heterogeneity was also observed (I2 = 94%; X2 p < 0.00001), while the subgroup analysis of the PCR-based studies revealed that U. urealyticum did not alter ejaculate volume (SMD − 0.46 [95% CI: − 1.54, 0.61] p = 0.40) and a significant heterogeneity was also observed (I2 = 98%; X2 p < 0.00001). Similarly, the sensitivity analysis demonstrated no significant change in the seminal fluid pH of U. urealyticum-positive subjects when compared with the control (SMD 0.11 [95% CI: − 0.57, 0.08] p = 0.74) and a significant heterogeneity was observed (I2 = 99%; X2 p < 0.00001) (Fig. 3).

Fig. 3
figure 3

Effect of ureaplasma urealyticum on seminal fluid pH. UU: Ureaplasma urealyticum, SD: Standard deviation, CI: confidence interval. Meta-analysis was performed using a random-effect model. Data are shown as standardized mean difference and Confidence interval (CI)

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Sperm concentration

Twenty-seven (27) studies from 20 articles comprising of 21, 328 control and 5, 390 U. urealyticum-positive patients were evaluated for the impact of U. urealyticum infection on sperm concentration. It was observed that U. urealyticum led to a marked reduction in sperm concentration when compared with the control (SMD 0.47 [95% CI: 0.31, 0.64] p < 0.00001) when compared with the controls and a significant heterogeneity existed (I2 = 94%; X2 p < 0.00001). Publication bias was also observed (S Fig. 3). In addition, a subgroup analysis of the cross-sectional studies revealed that U. urealyticum-positive patients had significantly lower sperm concentration when compared with U. urealyticum-negative subjects (SMD 0.55 [95% CI: 0.36, 0.73] p < 0.00001); however, there was a significant heterogeneity (I2 = 94%; X2 p < 0.00001). The subgroup analysis of longitudinal studies showed that the sperm concentration of U. urealyticum-infected subjects did not significantly improve after treatment compared to before treatment (SMD 0.08 [95% CI: − 0.02, 0.19] p = 0.13) and there was no significant heterogeneity (I2 = 0%; X2 p = 0.82). Furthermore, the subgroup analyses of the culture-based studies (SMD 0.10 [95% CI: 0.01, 0.19] p = 0.04), PCR studies (SMD 1.55 [95% CI: 1.03, 2.08] p < 0.00001), and RDT studies (SMD 0.10 [95% CI: 0.06, 0.15] p < 0.00001) revealed that U. urealyticum significantly reduced sperm concentration when compared with the control, and there was no significant heterogeneity for the culture-based studies (I2 = 0%; X2 p = 0.82) and RDT studies (I2 = 40%; X2 p < 0.19), but there was for the PCR studies (I2 = 97%; X2 p < 0.00001). Nonetheless, sensitivity analysis demonstrated a significant reduction in sperm concentration in U. urealyticum-positive subjects when compared with the controls (SMD 0.57 [95% CI: 0.36, 0.78] p < 0.00001); but this showed a significant heterogeneity (I2 = 94%; X2 p < 0.00001) (Fig. 4).

Fig. 4
figure 4

Effect of ureaplasma urealyticum on sperm concentration. UU: Ureaplasma urealyticum, SD: Standard deviation, CI: confidence interval. Meta-analysis was performed using a random-effect model when p-value < 0.1 or I.2 > 50%; otherwise, a fixed-model effect is used. Data are shown as standardized mean difference and Confidence interval (CI)

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Sperm total motility

A total of 20 studies from 15 articles that include 18, 944 controls and 3, 136 U. urealyticum-infected patients were analyzed for the effect of U. urealyticum on sperm total motility. U. urealyticum infection significantly reduced sperm total motility when compared with the controls (SMD 0.73 [95% CI: 0.43, 1.02] p < 0.00001) and a significant heterogeneity was observed (I2 = 96%; X2 p < 0.00001). Publication bias was observed (S Fig. 4). More so, subgroup analysis of the cross-sectional studies revealed that sperm total motility was significantly lower in U. urealyticum-positive patients compared with the controls (SMD 0.77 [95% CI: 0.46, 1.08] p < 0.00001) but a significant heterogeneity was observed (I2 = 96%; X2 p < 0.00001). Additionally, the subgroup analyses of the culture-based studies (SMD 0.30 [95% CI: 0.00, 0.60] p = 0.05), PCR studies (SMD 2.82 [95% CI: 1.71, 3.94] p < 0.00001), and RDT studies (SMD 0.18 [95% CI: 0.01, 0.03] p < 0.00001) demonstrated that U. urealyticum significantly reduced sperm total motility when compared with the control, but there was significant heterogeneity (I2 = 57%; X2 p = 0.07; I2 = 98%; X2 p < 0.00001; I2 = 78%; X2 p = 0.01 respectively). Furthermore, the sensitivity analysis showed a significantly lower sperm total motility in U. urealyticum-positive patients when compared with the controls (SMD 0.98 [95% CI: 0.58, 1.38] p < 0.00001) but a significant heterogeneity was also observed (I2 = 96%; X2 p < 0.00001) (Fig. 5).

Fig. 5
figure 5

Effect of ureaplasma urealyticum on sperm total motility. UU: Ureaplasma urealyticum, SD: Standard deviation, CI: confidence interval. Meta-analysis was performed using a random-effect model. Data are shown as standardized mean difference and Confidence interval (CI)

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Sperm progressive motility

Meta-analysis of 20 studies from 14 articles that consisted of 20, 526 controls and 4, 853 U. urealyticum-positive subjects revealed that U. urealyticum did not significantly alter sperm progressive motility when compared with the controls (SMD − 0.09 [95% CI: − 0.37, 0.18] p = 0.50) and a significant heterogeneity was observed (I2 = 98%; X2 p < 0.00001). Publication bias was also observed (S Fig. 5). Moreso, the subgroup analysis of the cross-sectional studies revealed no significant difference in sperm progressive motility among U. urealyticum-positive subjects when compared with the controls (SMD − 0.21 [95% CI: − 0.52, 0.09] p = 0.17) and a significant heterogeneity was observed (I2 = 98%; X2 p < 0.00001). Similarly, sperm progressive motility did not significantly change after treatment in U. urealyticum-infected subjects when compared with before treatment (SMD 0.55 [95% CI: − 0.18, 1.28] p = 0.14) and a significant heterogeneity was observed (I2 = 95%; X2 p < 0.00001). More so, subgroup analyses of the culture-based studies (SMD − 0.74 [95% CI: − 1.92, 0.45] p = 0.22) and PCR studies (SMD 0.14 [95% CI: − 0.20, 0.47] p = 0.42) showed that U. urealyticum did not significantly affect sperm progressive motility and there was significant heterogeneity (I2 = 99%; X2 p < 0.00001; I2 = 90%; X2 p < 0.00001 respectively). However, subgroup analysis of RDT studies showed a reduction of affect sperm progressive motility in U. urealyticum-infected individuals when compared with the control (SMD 0.18 [95% CI: 0.00, 0.36] p = 0.05) (I2 = 81%; X2 p = 0.005). Additionally, sensitivity analysis also revealed that U. urealyticum did not significantly alter sperm progressive motility (SMD − 0.16 [95% CI: − 0.61, 0.29] p = 0.48) and a significant heterogeneity was observed (I2 = 98%; X2 p < 0.00001) (Fig. 6).

Fig. 6
figure 6

Effect of ureaplasma urealyticum on sperm progressive motility. UU: Ureaplasma urealyticum, SD: Standard deviation, CI: confidence interval. Meta-analysis was performed using a random-effect model. Data are shown as standardized mean difference and Confidence interval (CI)

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Total motile sperm count

Three studies from 2 articles, including 17, 118 controls and 2, 269 U. urealyticum-positive subjects, were included. U. urealyticum significantly reduced total motile sperm count when compared with the control (SMD 0.21 [95% CI: 0.17, 0.26] p < 0.00001) and there was no significant heterogeneity (I2 = 14%; X2 p = 0.31). There was also no publication bias (S Fig. 6). Sensitivity analysis also demonstrated a significantly reduced total motile sperm count in U. urealyticum-positive subjects when compared with the control (SMD 0.20 [95% CI: 0.00, 0.39] p = 0.04); however, significant heterogeneity was observed (I2 = 55%; X2 p = 0.13) (Fig. 7).

Fig. 7
figure 7

Effect of ureaplasma urealyticum on total motile sperm count. UU: Ureaplasma urealyticum, SD: Standard deviation, CI: confidence interval. Meta-analysis was performed using a random-effect model when p-value < 0.1 or I.2 > 50%; otherwise, a fixed-model effect is used. Data are shown as standardized mean difference and Confidence interval (CI)

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Sperm vitality

Ten studies from 7 articles consisting of 1, 889 controls and 632 U. urealyticum-infected subjects were adjudged eligible for inclusion. U. urealyticum infection did not significantly alter sperm vitality when compared with the controls (SMD − 0.14 [95% CI: − 0.72, 0.44] p = 0.64) and there was a significant heterogeneity (I2 = 97%; X2 p < 0.00001). Publication bias was also observed (S Fig. 7). The subgroup analyses of the culture-based studies (SMD 0.20 [95% CI: − 0.01, 0.41] p = 0.06) and PCR studies (SMD − 0.07 [95% CI: − 0.24, 0.10] p = 0.42) showed that U. urealyticum did not significantly affect sperm vitality and there was no significant heterogeneity (I2 = 0%; X2 p = 0.62; I2 = 0%; X2 p = 0.90 respectively). More so, sensitivity analysis revealed that U. urealyticum-infected subjects had a comparable sperm vitality with U. urealyticum-negative subjects SMD − 0.18 [95% CI: − 0.84, 0.49] p = 0.60) and there was a significant heterogeneity (I2 = 97%; X2 p < 0.00001) (Fig. 8).

Fig. 8
figure 8

Effect of ureaplasma urealyticum on sperm vitality. UU: Ureaplasma urealyticum, SD: Standard deviation, CI: confidence interval. Meta-analysis was performed using a random-effect model. Data are shown as standardized mean difference and Confidence interval (CI)

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Sperm normal morphology

A total of 19 studies from 15 published articles consisting of 19, 616 controls and 4, 395 U. urealyticum-infected subjects were included to determine the effect of U. urealyticum on sperm normal morphology. Subjects who were U. urealyticum-infected had a significantly lower sperm normal morphology compared with the control (SMD 0.88 [95% CI: 0.42, 1.35] p = 0.0002) and a significant heterogeneity was observed (I2 = 99%; X2 p < 0.00001). Publication bias was also observed (S Fig. 8). The subgroup analysis of the cross-sectional studies also revealed a significantly reduced sperm normal morphology in U. urealyticum-infected subjects when compared with the controls (SMD 1.00 [95% CI: 0.49, 1.51] p = 0.0001) with a significant heterogeneity (I2 = 99%; X2 p < 0.00001). However, the subgroup analysis of the longitudinal studies revealed a non-significantly reduced sperm normal morphology in U. urealyticum-infected subjects before treatment when compared with after treatment (control) (SMD 0.18 [95% CI: − 0.03, 0.39] p = 0.09) with no significant heterogeneity (I2 = 0%; X2 p = 0.86). More so, the subgroup analysis of the culture-based studies showed that U. urealyticum did not significantly alter sperm normal morphology (SMD − 0.02 [95% CI: − 0.15, 0.11] p = 0.73) and a significant heterogeneity was not observed (I2 = 0%; X2 p = 0.47), while the subgroup analysis of the PCR-based studies showed that U. urealyticum significantly reduced sperm normal morphology (SMD 2.04 [95% CI: 1.24, 2.84] p < 0.00001) but a significant heterogeneity was also observed (I2 = 98%; X2 p < 0.00001). Notwithstanding, sensitivity analysis demonstrated significantly reduced sperm normal morphology in U. urealyticum-infected subjects when compared with the controls (SMD 0.63 [95% CI: 0.26, 1.01] p = 0.0009) with a significant heterogeneity (I2 = 97%; X2 p < 0.00001) (Fig. 9).

Fig. 9
figure 9

Effect of ureaplasma urealyticum on normal sperm morphology. UU: Ureaplasma urealyticum, SD: Standard deviation, CI: confidence interval. Meta-analysis was performed using a random-effect model when p-value < 0.1 or I.2 > 50%; otherwise, a fixed-model effect is used. Data are shown as standardized mean difference and Confidence interval (CI)

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Seminal fluid leukocyte count

Meta-analysis of six studies from 5 articles consisting of 520 controls and 156 U. urealyticum-positive subjects revealed a significantly higher seminal fluid leucocyte count in U. urealyticum-positive subjects than U. urealyticum-negative controls (SMD − 0.82 [95% CI: − 1.61, − 0.02] p = 0.04) and a significant heterogeneity (I2 = 94%; X2 p < 0.00001). Publication bias was also observed (S Fig. 9). Subgroup analysis of the PCR-based studies showed that U. urealyticum did not significantly alter seminal fluid leucocyte count (SMD − 0.92 [95% CI: − 2.10, 0.26] p = 0.13) but a significant heterogeneity was also observed (I2 = 96%; X2 p < 0.00001). Sensitivity analysis revealed an insignificantly higher seminal fluid leucocyte count in U. urealyticum-positive subjects when compared with the U. urealyticum-negative controls (SMD − 1.01 [95% CI: − 2.06, 0.04] p = 0.06) and a significant heterogeneity (I2 = 95%; X2 p < 0.00001) (Fig. 10).

Fig. 10
figure 10

Effect of ureaplasma urealyticum on seminal fluid leukocyte count. UU: Ureaplasma urealyticum, SD: Standard deviation, CI: confidence interval. Meta-analysis was performed using a random-effect model. Data are shown as standardized mean difference and Confidence interval (CI)

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Seminal fluid IL- 6 levels

Two studies consisting of 75 controls and 41 U. urealyticum-positive subjects were included. U. urealyticum-positive subjects had an insignificantly higher level of seminal fluid IL- 6 when compared with the control (SMD − 2.31 [95% CI: − 5.64, 1.03] p = 0.18) and a significant heterogeneity (I2 = 97%; X2 p < 0.00001) (Fig. 11). Publication bias was also observed (S Fig. 10).

Fig. 11
figure 11

Effect of ureaplasma urealyticum on seminal fluid IL- 6. UU: Ureaplasma urealyticum, SD: Standard deviation, CI: confidence interval. Meta-analysis was performed using a random-effect model. Data are shown as standardized mean difference and Confidence interval (CI)

Full size image

Qualitative analysis

Inflammatory markers

Paira et al.[11] revealed that subjects who were U. urealyticum-positive had a significantly higher levels of IL- 8, tumor necrotic factor-alpha (TNF-α), IL- 1β, and IL- 6 when compared with U. urealyticum-negative subjects. They also observed a higher level of peroxidase, leukocytes, neutrophils, CD4 + T cells and CD8 + T cells in U. urealyticum-positive subjects when compared with their U. urealyticum-negative counterparts. In addition, Liu et al. [18] demonstrated that seminal fluid elastase was significantly higher in U. urealyticum-positive when compared with U. urealyticum-negative subjects. They also observed that seminal fluid elastase was significantly higher in U. urealyticum-infected subjects before treatment than after treatment. However, Zinzendorf et al. [44]. observed an insignificant increase in leucocyte count in U. urealyticum-positive subjects when compared with their U. urealyticum-negative counterparts.

Apoptotic markers

Qing et al. [40] revealed a higher sperm DNA fragmentation in U. urealyticum-positive subjects when compared with their U. urealyticum-negative counterparts. Also, Moretti et al. [37] observed a higher percentage of apoptotic sperm cells in U. urealyticum-positive subjects when compared with U. urealyticum-negative subjects.

Discussion

U. urealyticum is a common pathogen that is implicated in urogenital infections and may impair male fertility directly via the induction of testicular and sperm toxicity or indirectly via the induction of inflammation and oxidative stress through the upregulation of leukocytes and ROS generation respectively [10]. Despite the reported roles of direct toxicity and oxido-inflammatory injury in U. urealyticum-induced male infertility, the precise mechanism underlying the development and progression of low semen quality are yet to be fully understood, and there are ongoing studies exploring the present knowledge dearth. The present meta-analysis is the first, to the best of our knowledge and as at the time of submitting this study for publication, to evaluate the impact of U. urealyticum on semen quality and provide possible pathogenetic mechanisms of U. urealyticum. This study also performed subgroup analyses for controlled cross-sectional and longitudinal studies.

Conventional semen analysis as well as sperm DNA integrity are useful tools in the diagnosis of male infertility [45]. Notably, this study demonstrated that U. urealyticum significantly reduced ejaculate volume, sperm concentration, total sperm motility, total motile sperm count, and normal morphology. This observed decline in semen quality may be due to the direct toxicity induced by U. urealyticum on sperm cells [10], leading to alterations in the sperm form, motility, and count. This also shows that U. urealyticum may induce male infertility.

Humans have diverse immune response cells in their reproductive systems and these cells release monokines and lymphokines upon activation. These influence tissues outside of the immune system as well as modulate immunological responses locally [46]. The present study revealed that U. urealyticum may modulate reproductive immunology by enhancing sperm elastase via the upregulation of seminal fluid leucocyte. Elastase directly damage sperm by inducing phagocytosis and apoptosis by upregulating pro-inflammatory cytokines and ROS [47]. The increased leukocytes that explains the rise in elastase also upregulates ROS generation [47]; thus, U. urealyticum promotes pro-inflammatory cytokines and ROS surge in the sperm cells by activating the rise in seminal fluid leukocytes and elastase. Elastase has also been reported to indirectly cause male infertility by triggering gonadal and epididymal injury through inflammation [48].

This study also observed that U. urealyticum promoted sperm DNA fragmentation, which is likely due to its impact of seminal fluid leucocyte. ROS generation may be a cause or consequence of inflammation [49]. U. urealyticum-induced upregulation of leukocytes promotes ROS generation [47, 48], which in turn damage sperm DNA, resulting in fragmentation that is detrimental to sperm physiological function and overall male fertility. More so, U. urealyticum may disrupt the blood-testis barrier [50], compromising the protective environment for germ cells and inducing direct deleterious effect to the germ cells; thus, reducing sperm concentration, total motility, and normal morphology. Furthermore, U. urealyticum infection alters seminal fluid composition, reducing the total antioxidant capacity of the sperm cells antioxidants [12], and promoting increased sperm DNA fragmentation. Ureaplasma urealyticum fuses with the head of sperm cells, leading to impairment of the swimming movement of the cell and production of metabolites like H2O2 and OH− which are toxic to the sperm. This alters the sperm morphology and motility, and causes DNA fragmentation and deformity of the sperm cell [14].

Our pooled overall analysis revealed that U. urealyticum reduces ejaculate volume, sperm concentration, total sperm motility, and normal morphology, which was consistent with the sensitivity analysis and subgroup analysis of the controlled cross-sectional studies, but a subgroup analysis of the longitudinal study demonstrated only marginal changes in these variables. This may be due to the treatment choice and duration. Despite the convincing data presented in this study, it bears some limitations. First, publication bias was observed in most of the studies (ejaculate volume, seminal fluid pH, sperm concentration, total motility, progressive motility, vitality, normal morphology, and seminal fluid leukocytes and IL- 6 levels). This can lead to overestimation of the effect size and skewed results, making it appear as though the association between Ureaplasma urealyticum and sperm quality is stronger than it actually is. Also, the significant heterogeneity noted in some of the analyses influenced the outcome of the present study. It is likely that the different populations studied, diverse diagnostic methods, and different study design are the sources of heterogeneity. More so, prospective interventional studies were included in the meta-analysis, which may influence our findings due to the impact of the treatments. Furthermore, the different diagnostic methods of U. urealyticum (PCR, culture or rapid tests) in the primary studies and the duration of recovery after treatment may be a source of bias and influence the study outcome. Nonetheless, this is the first meta-analysis to investigate the impact of U. urealyticum on semen quality using 30 studies from 23 published articles. In addition, this study examined the possible pathogenesis of the impact of U. urealyticum on semen quality. Moreover, this study conducted a thorough assessment of the quality of evidence, risk of bias and certainty of evidence of the included study to identify the potential source of bias. Furthermore, subgroup analyses of cross-sectional, longitudinal studies (prospective studies), and different diagnostic methods of U. urealyticum (PCR, culture or rapid tests) and sensitivity analyses were performed to attenuate the influence of heterogeneity and RoB, publication bias, and strengthen the reliability of our findings.

Conclusion

There is a significant decline in semen quality, especially ejaculate volume, sperm concentration, total sperm motility, and normal morphology in U. urealyticum-infected patients as compared to the controls, which poses a threat to male fertility. The pathogenesis of U. urealyticum-induced lowered sperm quality is complex and involves the upregulation of seminal fluid leukocytes, elastase, inflammation, and DNA fragmentation. However, further studies are needed to elucidate the mechanisms underlying the association between U. urealyticum and semen quality decline, and to develop effective therapies for this condition.

Data availability

Data will be made available on request.

Abbreviations

CIs:

Confidence intervals

CoE:

Certainty of evidence

DNA:

Deoxyribonucleic acid

GRADE:

Grading of Recommendations Assessment, Development and Evaluation

IL:

Interleukin

NGU:

Non-gonococcal urethritis

OHAT:

Office of Health Assessment and Translation

PCR:

Polymerase Chain Reactionm

PECOS:

Population, Exposure, Comparator/Comparison, Outcomes, and Study design

PRISMA:

Preferred Reporting Items for Systematic Reviews and Meta-analyses

QoE:

Quality of evidence

RDT:

Rapid diagnostic Test

RoB:

Risk of bias

ROS:

Reactive oxygen species

SMD:

Standardized mean difference

TNF-α:

Tumor necrotic factor-alpha

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Acknowledgements

Not applicable.

Funding

This study was self-funded.

Author information

Authors and Affiliations

  1. Functional Microbiome Group, Uniklinik Aachen (Universitätsklinikum Aachen), Aachen, Germany

    Omotola SeunFunmi Kukoyi

  2. Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo, Osun State, Nigeria

    Omotola SeunFunmi Kukoyi, Victory Jesutoyosi Ashonibare, Cecilia Adedeji Adegbola, Tunmise Maryanne Akhigbe & Roland Eghoghosoa Akhigbe

  3. Cardiovascular Regenerative Medicine & Tissue Engineering 3D (CURE 3D) Lab, Department of Cardiovascular Surgery and Research Group for Experimental Surgery, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany

    Victory Jesutoyosi Ashonibare

  4. Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria

    Cecilia Adedeji Adegbola & Roland Eghoghosoa Akhigbe

  5. Department of Agronomy, Osun State University, Ejigbo Campus, Ejigbo, Osun State, Nigeria

    Tunmise Maryanne Akhigbe

Authors
  1. Omotola SeunFunmi Kukoyi
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  2. Victory Jesutoyosi Ashonibare
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  3. Cecilia Adedeji Adegbola
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  4. Tunmise Maryanne Akhigbe
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  5. Roland Eghoghosoa Akhigbe
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Contributions

Conceptualization and design: TMA and REA. Funding acquisition: TMA and REA. Investigation: OSK, VJA, CAA, TMA, and REA. Methodology: REA. Project administration: OSK, VJA, CAA, TMA, and REA. Supervision: REA. Validation: OSK, VJA, CAA, TMA, and REA. Writing-original draft: OSK, CAA, and REA. Writing-review and editing and final approval: OSK, VJA, CAA, TMA, and REA.

Corresponding author

Correspondence to Roland Eghoghosoa Akhigbe.

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Kukoyi, O., Ashonibare, V.J., Adegbola, C.A. et al. Ureaplasma urealyticum upregulates seminal fluid leukocytes and lowers human semen quality: a systematic review and meta-analysis. Basic Clin. Androl. 35, 14 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12610-025-00262-5

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12610-025-00262-5

Keywords

Testosterone

Basic and Clinical Andrology

ISSN: 2051-4190