Are Ureaplasma spp a Cause of Nongonococcal Urethritis and Infertility in Men?

Emerging evidence suggests that Ureaplasma spp, and specifically Ureaplasma urealyticum, but not Ureaplasma parvum, may play a causal role in the development of nongonococcal urethritis and infertility in men, according to a paper published in Clinical Microbiology Reviews.¹

Given the inconsistencies in reporting and study design and the high prevalence of Ureaplasma spp in healthy men, Ureaplasma spp as genitourinary medicine pathogens remains controversial. As such, researchers in this review focused on risk factors that have historically been overlooked when considering Ureaplasma spp as an etiologic agent of nongonococcal urethritis. In addition, they discussed the proposed mechanisms that have been neglected as markers of infertility.

Researchers listed 3 risk factors for Ureaplasma spp that potentially play a causal role in the development of nongonococcal urethritis. The first has to do with the species of Ureaplasma present within the urethra. Up until 2002, Ureaplasma spp was not differentiated into 2 independent species: U urealyticum and U parvum. Since the recognition of 2 species, many case-control studies have identified the presence of U urealyticum more often in patients with nongonococcal urethritis than control individuals, but have lacked the confidence of associating U urealyticum with nongonococcal urethritis as a result of a low number of participants. However, a meta-analysis that included 7 case-control studies involving 1507 patients with nongonococcal urethritis and 1223 control individuals from 4 separate continents showed that U urealyticum was significantly higher in patients with nongonococcal urethritis vs in control individuals, and that U parvum was significantly higher in control individuals vs in patients with nongonococcal urethritis.² This meta-analysis provided a significant contribution to the idea that U urealyticum is the most commonly associated species of Ureaplasma in nongonococcal urethritis.

Although counterintuitive, the second risk factor for an increased risk for nongonococcal urethritis is fewer sexual partners. Findings from 2 studies showed that a greater number of sexual partners was associated with a reduced likelihood of disease.^3,4

The bacterial load of Ureaplasma spp within the male urethra was listed as the third risk factor, linking U urealyticum to the development of nongonococcal urethritis. Frølund et al reported that there was a significant association with the development of nongonococcal urethritis in the presence of U urealyticum with bacterial loads ≥1.3×10³ genome equivalents/mL of urine, corresponding to approximately 1×10³ bacteria/mL.⁴

Studies on male fertility have yielded similar results to the findings for patients with nongonococcal urethritis, suggesting an association between U urealyticum and a negative effect on fertility with little evidence for a role of U parvum. Several mechanisms have been proposed to account for infertility because of Ureaplasma spp colonization. “These include the direct binding of Ureaplasma spp. to spermatozoa, which may impede swimming motility; the production of toxic metabolites, which can damage spermatozoon membranes and result in DNA fragmentation; as well as the host generation of cross-reactive antibodies between Ureaplasma spp. and sperm surface proteins,” noted the researchers.¹

Although the role of Ureaplasma spp is beginning to be recognized in the development of infertility among men, further work is required that explores the mechanism as well as appropriate criteria for identifying patients with Ureaplasma species-induced infertility.

In terms of nongonococcal urethritis, the mounting evidence of a causal role for Ureaplasma spp brings forth the question of whether or not to treat individuals who are positive for Ureaplasma spp, with symptoms. Although the current position statement from the European Sexually Transmitted Infection Guidelines Editorial Board does not recommend routine testing or treatment of either asymptomatic or symptomatic men for any Ureaplasma spp, researchers of this review “recommend that among cases of symptomatic [nongonococcal urethritis] in which classic etiological agents have been ruled out, a risk-based approach taking into account patients with a younger age, a low number of partners, and high titers of U urealyticum should be considered for treatment.”¹

References

1. Beeton ML, Payne MS, Jones L. The role of Ureaplasma spp. in the development of nongonococcal urethritis and infertility among men. Clin Microbiol Rev. 2019;32(4):e00137-18.
2. Zhang N, Wang R, Li X, Liu X, Tang Z, Liu Y. Are Ureaplasma spp. a cause of nongonococcal urethritis? A systematic review and meta-analysis. PLoS One. 2014;9(12):e113771.
3. Wetmore CM, Manhart LE, Lowens S, et al. Ureaplasma urealyticum is associated with nongonococcal urethritis among men with fewer lifetime sexual partners: a case-control study. J Infect Dis. 2011;204(8):1274-1282.4.
4. Frølund M, Lidbrink P, Wikstrom A, Cowan S, Ahrens P, Jensen JS. Urethritis-associated pathogens in urine from men with non-gonococcal urethritis: a case-control study. Acta Derm Venereol. 2016;96(5):689-694.