ZKKL Academic Sharing | Recent Advances in Research on the Pathogenicity of Mycoplasma genitalium

This article is reprinted from: Chinese Journal of Dermatology and Venereology.

Author: Li Binglei, Zhan Cheng

[Abstract] In recent years, Mycoplasma genitalium infection has attracted increasing attention due to its steadily rising proportion among sexually transmitted infections. Its pathogenicity has been increasingly recognized by researchers as related studies have deepened. Currently, in addition to being closely associated with nongonococcal urethritis and cervicitis, M. genitalium–related conditions also include pelvic inflammatory disease, obstetric complications, prostatitis, and epididymitis. Furthermore, studies have indicated that M. genitalium infection is linked to the development and progression of malignancies and immunodeficiency syndromes, with infection rates showing a year‑by‑year upward trend. However, limitations in diagnostic techniques continue to impede the timely identification of etiologic factors and the implementation of etiological therapies for these clinical conditions.

[Keywords] Mycoplasma genitalium; urethritis; cervicitis

Mycoplasma genitalium (Mg) belongs to the class Mollicutes, order Mycoplasmatales, and is a prokaryotic organism situated between bacteria and viruses. It is the twelfth mycoplasma species identified in humans. In 2009, the European guidelines for the treatment of non‑gonococcal urethritis (NGU) explicitly recognized Mg as one of the causative agents of NGU, and in 2010, the U.S. Centers for Disease Control and Prevention (CDC) likewise emphasized its pathogenic role in its clinical practice guidelines for cervicitis. Additionally, Mg has been implicated in a range of other conditions, including pelvic inflammatory disease (PID), obstetric complications, prostatitis, epididymitis, and balanoposthitis. Recent studies have further suggested that Mg infection may be associated with tumorigenesis and the progression of HIV infection. Since Tully et al. first isolated and cultured two strains of Mg from urethral secretions of male patients with NGU in 1981, its pathogenicity remained uncertain for several decades due to the challenges of isolation and cultivation—only with the maturation of PCR technology was it finally established. Subsequently, numerous researchers conducted extensive investigations into Mg’s growth characteristics, immunological properties, molecular biological features, and its relationships with various diseases. At the 20th World Congress of Dermatology, the pathogenic significance of Mg was elevated to a new level. To better understand Mg, investigators have developed multiple diagnostic methods; among these, quantitative fluorescent PCR is widely employed in experimental settings, offering high sensitivity and specificity. Edwards proposed using loop‑mediated isothermal amplification (LAMP) for Mg detection, which exhibits comparable sensitivity and specificity to quantitative fluorescent PCR while being more cost‑effective. Despite the growing array of available assays, considering both technical maturity and experimental costs, no single method yet meets the criteria for widespread adoption in clinical diagnostics. This review summarizes the diseases associated with Mycoplasma genitalium and discusses its role in the pathogenesis of these conditions.

1 Epidemiology of Mg

In recent years, owing to the increasing prevalence of Mycoplasma genitalium (Mg) infections and advances in diagnostic techniques, reported infection rates have shown a steady annual rise, ranging from 0% to 47.5% across different population samples. Such substantial variability can be attributed, first, to differences in specimen types selected in various studies; second, to variations in study populations, with inconsistent inclusion criteria even within the same demographic; and third, to significant disparities in the diagnostic methods employed. McGowin et al., by reviewing 48 published studies, estimated an overall infection rate of 2.0% in low-risk groups and 7.3% in high-risk groups, suggesting that Mg infections may be more widespread than previously thought. These data underscore that Mg has emerged as a significant pathogen among sexually transmitted infections.

2 Diseases caused by magnesium

2.1Mg and Urethritis In 2001, Taylor‑Robinson and colleagues established the role of Mycoplasma genitalium (Mg) in the pathogenesis of urethritis; subsequently, it has been widely accepted that Mg is a major causative agent of non‑gonococcal urethritis (NGU). Among the pathogens implicated in NGU, Chlamydia trachomatis is well‑defined and was officially classified in 2006 as Chlamydia trachomatis infection of the genitourinary tract. Nevertheless, the etiology remains unclear in 20%–50% of NGU cases. Prenitice proposed designating such urethritis as non‑Chlamydial, non‑gonococcal urethritis (NCNGU), with Mg accounting for the largest proportion among its various causative agents. Among individuals with sexually transmitted infections, Mg infection more frequently manifests as urethral discharge than infections caused by other pathogens, with up to 90% of symptomatic men exhibiting signs of urethritis; quantitative PCR further confirms higher bacterial loads in symptomatic males. In vitro studies have also demonstrated Mg’s pathogenicity: chimpanzees inoculated with Mg developed symptoms of urethritis, characterized primarily by an acute inflammatory response featuring polymorphonuclear leukocytes (PMNL), followed by the development of specific antibody responses. These animal experiments extend Koch’s postulates and provide robust evidence that Mg is a causative agent of NGU. Moreover, following acute infection, Mg tends to precipitate persistent or recurrent urethritis; clinicians often treat such cases with azithromycin; however, some patients initially testing negative may readily convert to positive after macrolide therapy. Falk et al. conducted a prospective study to identify an optimal timing for detecting Mg in NGU patients who are initially Mg‑negative, recommending Mg testing 3–4 weeks after macrolide treatment to assess for seroconversion. While numerous studies have confirmed Mg as one of the causative agents of urethritis, both diagnostic methods and therapeutic strategies require further investigation.

2.2 Mg and Cervicitis Recently, the U.S. CDC updated its guidelines on the diagnosis and treatment of cervical inflammation with only minor revisions, placing greater emphasis on the pathogenic role of Mycoplasma genitalium (Mg). The establishment of Mg infection as an independent causative factor in cervicitis was demonstrated by Manhart et al., who, after excluding interference from Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) and adjusting for confounding factors, employed multivariate logistic regression analysis. They found that among women with cervicitis, the attributable risk of Mg infection was 70%. In China, Chen Fangru and colleagues also supported the notion that Mg acts independently of CT; their study focused on patients with non‑gonococcal, non‑chlamydial cervicitis (NGNCC), and the results showed that the Mg infection rate in the NGNCC group (10.13%) was significantly higher than in the non‑NGNCC group (3.06%) and the healthy control group. Lis et al. conducted a meta‑analysis of Mycoplasma genitalium and female reproductive tract infections, reporting an attributable risk of 1.66 for Mg‑associated cervicitis—consistent with findings from previous similar analyses and most experimental studies. Overall, the majority of studies underscore the close association between cervicitis and Mg infection, and emphasize that early, timely, and standardized treatment is crucial for preventing pelvic inflammatory disease caused by this pathogen. Therefore, clinicians should give due consideration to Mg when managing cervicitis.

2.3Mg and Pelvic Inflammatory Disease Pelvic inflammatory disease (PID) refers to a group of infectious conditions affecting the upper female reproductive tract, with hysteroscopy serving as the “gold standard” for its diagnosis. Chlamydia trachomatis and Neisseria gonorrhoeae are well‑known causative agents of PID; however, in a substantial proportion of cases, the etiology remains unknown. Since the isolation of Mycoplasma genitalium (Mg), numerous studies have highlighted its critical role in the pathogenesis and progression of PID. In 2015, the U.S. National Institutes of Health emphasized the need to determine whether mycoplasmas play a significant role in the development and outcomes of pelvic inflammatory disease. Compared with Chlamydia trachomatis and Neisseria gonorrhoeae, Mg‑induced symptoms tend to be milder and often go unnoticed by patients due to their subtlety; yet, if left untreated, such infections can lead to serious complications. The pathogenic mechanism of PID involves ascending infection from the lower genital tract. Gowin et al. demonstrated that, following vaginal inoculation of mice treated with progesterone or estradiol, Mg persisted in the lower genital tract for up to 77 days and, within a few weeks post‑inoculation, could disseminate to the upper reproductive tract and even the knee joint. Additionally, studies have shown a significant association between Mg infection and the subsequent onset of pelvic inflammatory disease after abortion. Therefore, Mg infection should be given due consideration in the management of PID.

2.4Mg and Infertility One of the consensus statements reached at the 2015 American Society for Reproductive Medicine (ASRM) Congress regarding the diagnosis and treatment of female infertility is that tubal obstruction is a major cause of female infertility. Furthermore, Baczynski et al., by co-culturing Mg with human fallopian tube tissue, demonstrated that Mg can infect the fallopian tubes and elicit an inflammatory response; salpingitis, in turn, is a significant contributor to tubal obstruction. However, due to the limited number of experimental studies, current literature does not yet permit definitive conclusions. Whether Mg infection leads to male infertility remains unresolved; only a few studies have suggested an association between male infertility and Mg infection, but these studies often lack robustness because they do not include a fertile male control group. Reports indicate that 15% of cases of male infertility are linked to reproductive tract infections, though the extent to which Mg contributes to this subset still requires further investigation and exploration.

2.5 mg and obstetric complications Peuchant et al. concluded in a prospective study that women with a history of miscarriage are more susceptible to Mycoplasma genitalium (Mg) infection, though this association is not linked to preterm birth; moreover, the prevalence of Mg infection among pregnant women varies geographically. Ma Limin’s research suggests a close association between Mycoplasma genitalium infection and stillbirth, miscarriage, and low‑birth‑weight infants. Tian Yan et al., examining 72 patients with premature rupture of membranes (PROM), found that Mg infection may serve as an contributing factor to PROM, and that PROM patients exhibited significantly higher rates of pregnancy complications—including preterm labor, puerperal infections, neonatal infections, and pathological jaundice—compared with the control group. Therefore, screening for and treating Mg infection should be prioritized in pregnant women who are suspected of being infected, and it is recommended that vaginal and cervical secretions be routinely collected early on for Mg testing.

2.6 mg and prostatitis There are relatively few reports on the relationship between chronic prostatitis and Mycoplasma infection, and opinions remain inconsistent. Mandar et al. used PCR to detect Mycoplasma in semen from 60 male patients with chronic prostatitis (meeting the U.S. NIH Class IIIa criteria), finding a positive rate of 18%, which supports the hypothesis that Mycoplasma may contribute to chronic prostatitis. In contrast, another study examined prostate tissue obtained under ultrasound guidance from 50 patients with chronic nonbacterial prostatitis; PCR testing for Mycoplasma yielded negative results. In China, relevant research is limited. Liu Qi et al. reported that among patients with chronic nonbacterial prostatitis following sexually transmitted urethritis, the detection rate of Mycoplasma in prostatic fluid was 6.4%, with no significant difference compared to the group without prostatitis, suggesting insufficient evidence to link Mycoplasma to this condition.

2.7Mg and Other Diseases Magnesium may also play a role in the development of prostate cancer, ovarian cancer, and lymphoma. Some researchers have used in vitro cell culture and ELISA assays to demonstrate a potential association between magnesium and the onset of certain tumors; however, several experimental studies with small sample sizes have concluded that no such association exists. To date, there is still insufficient epidemiological evidence to establish magnesium’s specific role in carcinogenesis, and its underlying pathogenic mechanisms remain to be further investigated. Horner et al. suggest that Mg infection could be one of the causes of asymptomatic proctitis. Other conditions, such as acute epididymitis, may also be linked to Mg‑related pathogenesis.

2.8 mg and the human immunodeficiency virus (HIV) HIV is the pathogen responsible for acquired immunodeficiency syndrome (AIDS), and HIV/AIDS has now become a global epidemic. Two perspectives exist regarding the association between Mycoplasma genitalium (Mg) infection and HIV infection: one posits that, because the two share similar transmission routes, high-risk individuals engaging in sexual activity may simultaneously be infected with both Mg and HIV; the other suggests that Mg constitutes a risk factor for HIV acquisition and transmission, or that HIV infection increases the host’s susceptibility to Mg colonization. In 1990, Montagnier et al. first identified and reported that Mg might play a role in HIV infection and transmission, and since then, numerous researchers have investigated the relationship between the two. In 2012, Mavedzenge et al., from the standpoint of the biological plausibility of Mg facilitating HIV acquisition and transmission, demonstrated that, among HIV-infected women, cells harboring Mg were more likely to shed HIV‑DNA compared with those lacking Mg. By 2014, in vitro studies had already shown that Mg infection can enhance HIV infection. By 2015, Mg was confirmed to be independently associated with HIV‑1 RNA in the genital tract; however, the precise causal relationship and underlying mechanisms linking Mg and HIV remain under active investigation. If Mg infection indeed promotes HIV acquisition and transmission, then screening for and treating Mg could reduce the risk of HIV transmission. Therefore, it is imperative to elucidate Mg’s role in HIV transmission as soon as possible, a task of critical importance for AIDS prevention and control.

3 Summary

To date, the pathogenic role of magnesium has been established only in a limited number of diseases. Among the conditions discussed above, most are associated with magnesium deficiency, yet definitive laboratory evidence and large‑scale epidemiological data remain lacking. This underscores the need for more in‑depth research, while clinicians urgently require a simple, rapid, and accurate diagnostic assay that can be employed when patients present relevant clinical symptoms to facilitate definitive diagnosis and guide subsequent treatment. Such a test would also be of great importance in curbing the rising incidence of magnesium‑related infections and preventing the emergence of drug‑resistant strains resulting from inappropriate antimicrobial use.

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