The Role of Ureaplasma spp. in the Development of Nongonococcal Urethritis and Infertility among Men

Abstract

Ureaplasma spp. are a genus of bacteria for which two human-associated species exist: Ureaplasma urealyticum and Ureaplasma parvum Their definition as a pathogen in the context of nongonococcal urethritis (NGU) and infertility among males remains highly controversial, largely due to historically high rates of isolation of these bacteria from the urethra of seemingly healthy men. This review summarizes the emerging evidence suggesting a true pathogenic role of these bacteria under specific conditions, which we term risk factors. We examine the historical, clinical, and experimental studies which support a causal role for Ureaplasma spp. in the development of NGU as well as some of the proposed mechanisms behind the association of Ureaplasma spp. and the development of infertility. Finally, we discuss the potential for developing a case-by-case risk-based approach toward the management of men who present with seemingly idiopathic NGU but who are positive for Ureaplasma spp.

Keywords: Ureaplasma parvum; Ureaplasma urealyticum; infertility; nongonococcal urethritis.

FIG 1

Proposed natural history of U. urealyticum urethral infection in men following initial exposure. A hypothetical scenario in an immunologically naive male when exposed to U. urealyticum for the first time is described. The lack of prior exposure to U. urealyticum results in an increased bacterial titer and subsequent polymorphonuclear neutrophil influx (signs of infection) with accompanying symptoms. Depending on the adaptive immunological response to U. urealyticum, the infection may clear without intervention or result in persistent urethral colonization. With an increase in the number of sexual contacts, the presence of an adaptive immune response is able to keep the titer of any newly acquired U. urealyticum bacteria below the threshold which results in inflammation. In the absence of an adaptive immune response, signs and symptoms may be present again. Persistent urethral colonization may result in a commensal-like association with the host, accounting for the high prevalence among healthy individuals, or, alternatively, may result in the factors which are associated with the development of infertility.

FIG 2

Mechanisms associated with Ureaplasma species-induced infertility in men. A number of mechanisms have been proposed to account for the clinical observational studies showing decreased fertility among men who experience urethral colonization with Ureaplasma spp. These include (i) cross-reactivity of host-generated antibodies against the UreG protein of Ureaplasma spp. to the autoantigenic sperm protein; (ii) the generation of toxic compounds, such as reactive oxygen species (ROS), which contributes to lipid peroxidation, DNA fragmentation, and subsequent apoptosis; (iii) direct binding to spermatozoa, which may result in reduced motility; and (iv) reduced incorporation of P34H and hyaluronidase activity in the acrosomal cap, which may reduce the capacity of spermatozoa to penetrate the egg.