Epidemiology, Natural History, Diagnosis, and Treatment of Trichomonas vaginalis in Men

Abstract

Trichomonas vaginalis infections in men are traditionally considered to be benign and consequently have been overlooked. However, men with this common sexually transmitted infection can experience urethritis, prostatitis, reduced fertility, and amplified human immunodeficiency virus risk. In addition, men are often asymptomatic and can unknowingly spread the infection to their female sexual partners. With advances in T. vaginalis diagnostics, more men are being diagnosed, yet the optimal method of treatment in men remains unknown. The purpose of this review is to discuss the epidemiology, natural history, diagnosis, and treatment of T. vaginalis among men.

In this review of trichomoniasis in men, we discuss what is currently known regarding the epidemiology and natural history of Trichomonas vaginalis in men as well as provide an overview of current diagnostics and treatment studies in men.

Trichomonas vaginalis is estimated to be the most common nonviral sexually transmitted infection (STI) among women worldwide [1]. Infection in men is traditionally thought to be benign and self-limited [2]. Trichomonas vaginalis is, however, known to be associated with nongonococcal urethritis (NGU) [3, 4], prostatitis [5, 6], and impaired sperm function [7–9]. Trichomonas vaginalis also increases shedding of human immunodeficiency virus (HIV) in seminal fluid of HIV-positive men [10]. Along with these impacts of infection on men, transmission to female sexual partners can have important consequences. In women, trichomoniasis has been associated with significant reproductive morbidity (eg, vaginitis, cervicitis, pelvic inflammatory disease, increased cervical cancer risk) [11–14], adverse birth outcomes (eg, premature rupture of membranes, low birth weight, preterm birth) [15, 16], and increased HIV acquisition risk [17, 18]. Since up to 72% of male sexual partners of infected women can also be infected [19], diagnosis and treatment of T. vaginalis in men is essential to decrease the negative outcomes associated with this infection in both sexes. Despite this important public health consideration, routine screening of both women and men for T. vaginalis is not currently recommended by the Centers for Disease Control and Prevention (CDC) [20]. To date, most trichomoniasis research has been conducted in women. With recent advances in T. vaginalis diagnostics, more men are being diagnosed, yet the optimal treatment method in men remains unknown. We discuss what is currently known regarding the epidemiology and natural history of T. vaginalis in men as well as provide an overview of current diagnostics and treatment studies in men.

EPIDEMIOLOGY

Trichomonas vaginalis is not a reportable infection; thus, estimates of prevalence generally come from modeling or ad hoc population-based studies. In 2016, the World Health Organization estimated the global prevalence of T. vaginalis to be 5.0% in women and 0.6% in men [1]. These data demonstrate a geographically variable burden of trichomoniasis among men, with prevalence ranging from 0.2% to 1.3%, with the highest rates occurring in Africa and the Americas [1]. In the United States, T. vaginalis incidence among men was estimated to be 4.1 million infections in 2018 [21]. Data from the 2013–2014 cycle of the National Health and Nutrition Examination Survey (NHANES) estimated the US T. vaginalis prevalence in men ages 18–59 years to be 0.5% compared with 1.8% among women [22]. This study was the first to provide national prevalence data for T. vaginalis in US men. In addition, it was the first time NHANES utilized the highly sensitive and specific Hologic Gen-Probe Aptima T. vaginalis nucleic acid amplification test (NAAT) on urine specimens for diagnosis in both women and men [23]. Given the sexually transmitted nature of T. vaginalis, the prevalence in men and women should be approximately equivalent. However, the discrepancy in prevalence between women and men in the NHANES could be biological as spontaneous resolution of T. vaginalis among men is described in several small studies [24, 25]. Diagnostic difficulties in men could also contribute to this difference [26].

There are striking racial and socioeconomic disparities related to T. vaginalis in the United States. One study demonstrated that Black men are 7 times more likely than White men to be infected [27]. In addition to racial inequity, other factors noted to be associated with high rates of T. vaginalis are low educational attainment, poverty, being unmarried, and more than 5 lifetime sexual partners [22]. Importantly, these disparities are complex and impacted by broad structural factors ingrained within social and healthcare constructs, such as systemic racism and stigma surrounding sexual health [28–31].

Trichomonas vaginalis is a rare cause of urethral and/or rectal infection among men who have sex with men (MSM). One study of 678 MSM attending a Dutch sexually transmitted disease clinic [32] and another longitudinal study of 600 MSM found no cases of T. vaginalis infection using highly sensitive NAAT tests [33]. This low prevalence is thought to be due to limited, if any, exposure to women with infected vaginal fluid [34]. Thus, routine screening of T. vaginalis among MSM is not recommended.

While the existing epidemiologic data imply that men are impacted less frequently than women, the degree to which men are affected is more complicated. There is a notable difference in prevalence between symptomatic and asymptomatic men with T. vaginalis. Recent estimates of T. vaginalis prevalence for men range from 6% of asymptomatic men [35] to 20% of men with urethritis in Africa [3] and from 4% to 17% of men, with and without symptoms, attending US STI clinics [36–38]. The higher prevalence among symptomatic men may be related to less detection among asymptomatic men due to lack of screening recommendations.

NATURAL HISTORY

Investigation of the natural history of T. vaginalis in men has been limited. Because men with T. vaginalis are often asymptomatic, natural history studies are difficult to conduct [39]. Partner studies in the 1960s described sexual transmission of T. vaginalis to men through vaginal intercourse with women with chronic trichomoniasis. One study found a higher prevalence of trichomoniasis among male partners of 30 women with chronic trichomoniasis (60%) compared with a control group (8%), suggesting that repeated sexual contact in the absence of treatment played a role in transmission [40].

Trichomonas vaginalis is frequently asymptomatic among infected men given their lower parasite burden compared with women [2]. In 1 US study, 177 men with trichomoniasis-infected female sexual partners were assessed and 136 (76.8%) were infected but asymptomatic. Among the minority of symptomatic men in this study, penile discharge was most commonly reported [19]. Another study evaluated 30 men with female sexual partners undergoing therapy for trichomoniasis. Of these men, 18 (60%) had urine cultures positive for T. vaginalis but 11 (61%) had no clinical abnormalities or symptoms [41s in the Supplementary References]. Given that men are frequently asymptomatic when compared with women, it is possible that they serve as a reservoir for infection with T. vaginalis. In the absence of treatment or spontaneous resolution, they could continue to reinfect female sexual partner(s) unknowingly [42s]. This theory provides another explanation for the difference in T. vaginalis prevalence between men and women; perhaps asymptomatic infections among men with low parasitic burden are simply undetected [2].

Symptomatic men experience symptoms of urethritis (ie, dysuria, clear or mucopurulent urethral discharge) [43s]. Early natural history studies estimate an incubation period of 3–9 days for men with T. vaginalis urethritis [44s]. While most men experience mild symptoms, serious sequelae of T. vaginalis in men also occur. If untreated, T. vaginalis can ascend the urethra and affect the prostate, leading to prostatitis [45s]. Several studies have also described an association between persistent T. vaginalis infection and the development of prostate cancer [46s–48s]. It is unclear, however, whether this infection is related to a higher risk of advanced or fatal disease in patients who develop prostate cancer given the multifactorial nature of these studies [45s, 49s]. Other reported sequelae of persistent T. vaginalis include balanoposthisis, epididymitis, and infertility [8, 50s, 51s].

As previously mentioned, some men who acquire T. vaginalis can experience spontaneous resolution of infection without treatment [24, 25]. The exact frequency at which spontaneous resolution occurs is unknown. One small longitudinal study of 14 men observed prolonged asymptomatic carriage (ie, over 4 months) among participants [39]. However, 5 (36%) of the men experienced spontaneous resolution of infection at an average of 16 ± 12 days after diagnosis. In addition, investigators were able to culture T. vaginalis from semen of 4 patients when concomitant cultures from other sites (ie, external genitalia, urethra, first-void urine sediment) were negative [39]. An additional study incidentally found a 69% rate of spontaneous resolution of T. vaginalis in 11 of 16 men without treatment after initial diagnosis [24]. Of these men, 8 spontaneously resolved their infection 15–19 days after their initial T. vaginalis diagnosis while another 3 spontaneously resolved their infection at 35–45 days. However, this study was not adequately powered to assess this finding and additional natural history studies are needed in larger populations of men.

DIAGNOSIS

Since men with trichomoniasis are often asymptomatic and have a lower parasite burden than infected women, diagnosis can be challenging [26]. Table 1 summarizes T. vaginalis diagnostic tests currently available for men. Trichomonas vaginalis testing with NAATs is recommended in men when they are a known sexual contact to a female partner with T. vaginalis or are presenting with symptoms of NGU, since routine screening is not currently recommended by the CDC [20].

Table 1.

Diagnostic Tests for Trichomonas vaginalis in Men

Test [Supplementary Reference]	Sensitivity, %	Specificity, %	Specimen Types	Comments
Xpert TV Assay (Cepheid) [61s]	97.2a	99.9a	Urine	Results in 60 minutes. Can use the same sample as used for CT/NG testing
Cobas TV/MG Assay (Roche) [62s]	100	98.4	Urine	Simultaneous diagnosis of MG. Can also order simultaneous CT/NG.
BDMax CTGCTV2 Assay (BD) [63s]	97.9	99.7	…	Simultaneous diagnosis of CT/NG.
InPouch culture (Biomed Diagnostics) [53s, 54s]	40–56%	100	Urine, urethral swabs, semen	Requires urethral swab or spun urine sediment.
Wet-mount microscopy [73s]	25–40%	100	Urine, urethral swabs, semen	Not recommended for use in men.

Abbreviations: CT, Chlamydia trachomatis; NG, Neisseria gonorrhoeae; TV, Trichomonas vaginalis; MG, Mycoplasma genitalium.

^aRelative to patient infected status as determined by results from both broth culture for T. vaginalis and bidirectional gene sequencing of amplicons.

The 2 most common T. vaginalis diagnostic tests used for men are culture and NAATs. Prior to the development of highly sensitive and specific NAATs, culture was the gold standard for the diagnosis of T. vaginalis in men and women. Traditionally, culture is performed by isolating T. vaginalis in Diamond’s medium [52s], but culture systems such as the InPouch system (BioMed Diagnostics, White City, OR) are now commonly used to limit contamination with commensal bacteria and yeast [53s, 54s]. Trichomonas vaginalis culture is time consuming and requires incubation at 37°C. It is also categorized by the Clinical Laboratory Improvement Amendments (CLIA) as a moderately complex diagnostic test [55s]. Culture can be performed on urethral, urine, or semen specimens from men, with sensitivity ranging from 40% to 56% compared with NAAT [56s–58s]. Cultures of male urine sediment specimens are more sensitive than urethral swab specimens [58s]. Multiple studies have demonstrated that pooling multiple specimen types increases T. vaginalis culture sensitivity in men [59s, 60s]. This pooling technique is more applicable to research settings as it is time consuming and impractical for clinical use. As opposed to T. vaginalis cultures from women, which frequently become positive within the first 3 days of incubation, cultures from men should be read for 5 days over a 7-day time period (or longer) before they are considered negative, given the lower sensitivity [58s].

NAATs are now the gold standard for T. vaginalis diagnosis in both men and women. Currently, 3 NAATs are commercially available for diagnosing T. vaginalis in men [61s–63s]. The GeneXpert TV Assay (Cepheid, Sunnyvale, CA) was Food and Drug Administration (FDA)–approved in 2018 for T. vaginalis diagnosis using male urine specimens, demonstrating 97.2% sensitivity and 99.9% specificity compared with culture [61s]. This test allows for on-demand diagnosis and treatment since it yields results in 40–60 minutes after a specimen is collected and placed on the testing platform [61s, 64s]. The Cobas TV/MG assay (Roche, Basel, Switzerland) was also recently FDA-approved for T. vaginalis diagnosis in men using urine samples, demonstrating 100% sensitivity and 98.4% specificity compared with the patient infected status (PIS). In order to determine the PIS, urine samples were assayed in 3 different NAAT assays and if the participant has 2 or more positive results, they are classified as “infected.” The Cobas TV/MG assay is performed on the Cobas 6800/8800 platform and can also reliably detect Mycoplasma genitalium in male urine [62s]. The BD CTGCTV2 assay for the BD MAX system (Becton, Dickinson and Company, Sparks, MD) is also approved for T. vaginalis diagnosis in men using urine samples, demonstrating 97.9% sensitivity and 99.7% specificity while also reliably detecting chlamydia or gonorrhea coinfection simultaneously [63s]. The PIS is the reference standard for this test. While not FDA-approved in men in the United States, the APTIMA T. vaginalis assay (Hologic Gen-Probe, San Diego, CA) can be used on male urine or urethral specimens in laboratories with internal validation of the test [57s].

While urine is the most convenient and frequently used specimen for T. vaginalis diagnosis in men, other specimen types have demonstrated enhanced sensitivity. Neither urethral swabs nor penile meatal swabs are currently an FDA-approved specimen type for any of the NAATs mentioned above. One study, however, found that, when collected simultaneously using the APTIMA T. vaginalis assay, self-collected penile meatal swabs yielded a 4.7 times higher positivity rate than first-catch urine [65s]. Another study using the same assay in self-collected home testing found that penile meatal swabs had a sensitivity of 80.4% in men, much higher than that of urine specimens, which was 39.3% [66s]. NAAT testing with penile meatal swab specimens is not only more sensitive and easier to transport than urine specimens but also less invasive than the often-uncomfortable urethral swab [67s]. When compared with clinician-collected urethral swabs, self-collected penile meatal swabs have demonstrated a sensitivity of 85% and specificity of 96.7% and accuracy similar to urethral swabs [68]. There is evidence that most men (86% in 1 study) prefer self-collected penile swabs over clinician-collected urethral swabs [68s]. Because of their accuracy, rapid results, and preference among patients, penile meatal swabs warrant further exploration as an FDA-approved specimen type for T. vaginalis testing as they may expedite diagnosis and treatment in clinical settings [69s]. NAAT testing on penile meatal swabs can be used for T. vaginalis diagnosis in the clinical setting if the laboratory internally validates the process [70s].

Since women are symptomatic more frequently than men, a clinical diagnosis of trichomoniasis is possible through wet-mount microscopy of vaginal fluid, which can quickly visualize motile trichomonads. However, this commonly used point-of-care (POC) test is only 44–68% sensitive compared with culture [43s, 57s] and 25–40% compared with NAATs for female specimens [71s, 72s]. Wet-mount microscopy has very low sensitivity for male genital specimens (eg, urethra, urine sediment, semen; <51%) and is not commonly used in men [73s]. Other rapid, POC tests have been developed recently (eg, OSOM Trichomonas Rapid Test by Sekisui Diagnostics, CA, Framingham, MA, USA), but they are not approved for use in men due to inadequate sensitivity [74s]. Supporting this decision is a recent study that found that the sensitivity and specificity of the OSOM Rapid Trichomonas Test on male urine specimens was 37.5% (95% confidence interval [CI]: 8.5–75.5%) and 82.9% (95% CI: 75.6–88.7%), respectively, compared with the APTIMA T. vaginalis NAAT assay [75s]. Trichomonas vaginalis can also be incidentally detected in urine cytology specimens from men; however, this finding is rare (seen in <0.1% of specimens in one 30-year, retrospective study) and not clinically useful [76s].

TREATMENT

While the natural history of T. vaginalis in men is poorly understood, the CDC recommends treating men diagnosed with trichomoniasis or who have been sexually exposed to this infection due to the possibility that they may have contracted it unknowingly and, thus, could potentially spread it to other female sexual partners [20]. The 5-nitroimidazoles (metronidazole [MTZ], tinidazole [TDZ], secnidazole [SEC]) are the only class of antimicrobials effective against T. vaginalis. MTZ and TDZ have been FDA-approved for T. vaginalis treatment for decades. FDA approval for SEC is in progress for the treatment of women [77s]. Oral MTZ (2 g) or oral TDZ has long been the treatment of choice for persons with T. vaginalis, with multidose oral MTZ (500 mg twice daily for 7 days) as an alternative [20]. Recent data from 2 trials [78s, 79s] and a meta-analysis [80s] have demonstrated that, among women, 2 g MTZ is not as effective as multidose MTZ. As a result of these findings, the 2021 CDC STI Treatment Guidelines will no longer recommend 2 g MTZ for T. vaginalis–infected women but will continue to recommend 2 g MTZ for men, citing lack of data to support changing the regimen for men (Kimberly Workowski, Chair, 2021 CDC STI Treatment Guidelines, personal communication, 2021). Trichomoniasis treatment studies in men are summarized in Table 2.

Table 2.

Treatment Studies for Men Infected With Trichomonas vaginalis

Authors (Year Published) [Supplementary Reference]	Study Objective	Study Design	Clinical Efficacy	Microbiological Efficacy
Sena et al (2012) [84s]	Assess predictors of persistence of STIs associated with NGU (including TV) following treatment among men in multiple STI clinics in the United States	RCT (13 men with T. vaginalis received doxycycline and TDZ)	NR	TDZ: 92.3%a
Khrianin and Reshetnikov (2006) [81s]	Compare efficacy of single-dose MTZ and ornidazole in treatment of urogenital trichomoniasis in men in Russia	RCT (210 men received MTZ, 217 received ornidazole)b	MTZ: 57.6%; ornidazole: 94.5%	MTZ: 77.1%; ornidazole: 98.2%
Ozbilgin et al (1994) [87s]	Assess efficacy of 5-nitroimidazoles (ornidazole, MTZ, SEC) in treating trichomoniasis in men in Egypt	RCT (85 men with trichomoniasis were treated with ornidazole [n = 26], MTZ [n = 29], or SEC [n = 30])	100% in all groups	100% in all groups
Latif et al (1987) [82s]	Ascertain the prevalence of confirmed trichomoniasis among men attending STD clinics in Zimbabwe	Prospective cohort (218 men enrolled with positive T. vaginalis culture, 38 received single-dose MTZ and 15 received MTZ 400 mg × 5 days)	Single-dose MTZ: 57.1% asymptomatic after treatment; 5 days MTZ: 100% asymptomatic after treatment	NRc
Kawamura (1978) [83s]	Compare efficacy of single-dose TDZ 1 g versus MTZ 1.5 g in men with trichomoniasis attending urology clinic in Japan	RCT (39 men received TDZ, 34 men received MTZ)	NR	TDZ: 100%d MTZ: 100%d

Abbreviations: MTZ, metronidazole; NGU, nongonococcal urethritis; NR, not reported; PCR, polymerase chain reaction; RCT, randomized controlled trial; SEC, secnidazole; STD, sexually transmitted disease; STI, sexually transmitted infection; TDZ, tinidazole; TV, Trichomonas vaginalis.

^aNegative PCR 3–4 weeks after treatment.

^bSide effects more common in MTZ group compared with ornidazole group (59.0% vs 3.7%).

^cNo follow-up microbiologic testing performed.

^dNegative T. vaginalis culture at 14 and 30 days after treatment.

There are data, however, that 2 g MTZ has suboptimal cure rates in men. In 1 Russian study of 210 men given 2 g MTZ, cure rates were only 57.6% [81s]. In 1 Zimbabwean study of 38 men with T. vaginalis who were given 2 g MTZ, only 42.9% cleared the infection, whereas of the 287 men given 400 mg MTZ 3 times daily for 5 days, all cleared infection [82s]. While these data suggest that 2 g MTZ is insufficient for T. vaginalis treatment in men, and since the current treatment recommendations in men have largely been extrapolated from studies conducted in women [20], an adequately powered head-to-head comparison of 2 g MTZ versus multidose MTZ is needed.

The use of TDZ in men is poorly studied. In 1 Japanese study of 39 men given 1 g TDZ and 34 men given 1.5 g MTZ, all had a negative T. vaginalis culture 14 and 30 days post-treatment [83s]. In a study of men with NGU randomized to azithromycin versus doxycycline ± TDZ, 1 of 13 had persistence per polymerase chain reaction testing 3–4 weeks post-treatment with TDZ [84s]. One benefit of TDZ in men is better absorption of TDZ compared with MTZ in the prostate and other male genital tissues [85s, 86s].

SEC is even less well studied in men than TDZ, but some data support it as an effective treatment option. One Egyptian study enrolled 415 men, 85 of whom tested positive for T. vaginalis. Men were either treated with ornidazole (n = 26), MTZ (n = 29), or SEC (n = 30) for 5 days. All 85 men tested negative for T. vaginalis and were asymptomatic at follow-up [87s]. There are other studies examining the efficacy of SEC for treatment of T. vaginalis in men, but they also included women; cure rates were 92–98% [88s–90s].

Patients reporting allergies to MTZ and other 5-nitroimidazoles can be challenging to treat. Given the lack of efficacious and safe alternative treatments for T. vaginalis, men with a confirmed hypersensitivity reaction to 5-nitroimidazoles should be referred to an allergist for consideration for desensitization. Some alternative agents such as intravaginal boric acid and intravaginal paromomycin have been reported as effective in case reports including women, but these regimens would not be able to be used in men [91s–93s].

MTZ resistance is a well-documented explanation for T. vaginalis treatment failure among women; however, no data exist in men [94s]. One CDC study tested 175 T. vaginalis isolates of women with treatment-refractory infections (ie, those who had failed at least 2 courses of standard T. vaginalis treatment) and found that 115 of them (66%) had some level of MTZ resistance [95s]. Presumably, since T. vaginalis is exclusively sexually transmitted, men may also experience infections with resistant parasites. Given the low sensitivity of T. vaginalis culture in men and the lack of drug-resistance studies with this population, there are currently no data describing the frequency of MTZ-resistant T. vaginalis infection among men. Along these lines, the optimal treatment of MTZ-resistant T. vaginalis infections in men is unknown.

CONCLUSIONS

Trichomonas vaginalis can lead to reproductive morbidity among infected men. It is an imperative public health issue given the impact that asymptomatic, untreated men have on female sexual partners. In order to combat this common STI and its associated sequelae for both men and women, a better understanding of the natural history of T. vaginalis and how to treat it is essential.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Acknowledgments. The authors thank Barbara Van Der Pol, PhD, at the University of Alabama at Birmingham, Division of Infectious Diseases, for advising us on the most up-to-date T. vaginalis diagnostics available for use in men.

Disclaimer. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Financial support. This work was supported by the Agency of Healthcare Research and Quality (grant number T32HS013852 to O. T. V. G.). A. F. C. reports that research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number TL1TR003106.

Potential conflicts of interest. C. A. M. has received research grant support from the National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID; K23 Award, R01 Award from NIAID), the CDC (consultant on 2021 CDC STI Treatment Guidelines), and Lupin Pharmaceuticals, Inc; serves as a consultant for Abbott Molecular, Lupin Pharmaceuticals, Inc, PhagoMed, Cepheid, and BioFire Diagnostics; and receives honoraria from Elsevier, Abbott Molecular, Cepheid, Becton Dickinson, Roche Diagnostics, Jesperson & Associates, DynaMed, and Lupin Pharmaceuticals, Inc. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.