Infection

DOI 10.1007/s15010-015-0860-0

REVIEW

Trichomonas vaginalis: pathogenicity and potential role in human

reproductive failure
Ewelina Mielczarek1 · Joanna Blaszkowska2 

Received: 27 September 2015 / Accepted: 27 October 2015

© Springer-Verlag Berlin Heidelberg 2015

Abstract  Keywords  Trichomoniasis · Trichomonas vaginalis ·

Purpose  Trichomonas vaginalis, which colonizes the Infertility · Pathogenesis
genitourinary tract of men and women, is a sexually trans-
mitted parasite causing symptomatic or asymptomatic Abbreviations
trichomoniasis. The host–parasite relationship is very com- AP Adhesion proteins
plex, and clinical symptoms cannot likely be attributed to a CDC Centers for Disease Control and Prevention
single pathogenic effect. Among the many factors respon- CDF Cell-detaching factor
sible for interactions between T. vaginalis and host tissues, CN Cervical neoplasia
contact-dependent and contact-independent mechanisms CP Cysteine peptidases
are important in pathogenicity, as is the immune response. FDA Food and Drug Administration
Methods  This review focuses on the potential virulence prop- GFB Transforming growth factor beta
erties of T. vaginalis and its role in female and male infertility. HIV Human immunodeficiency virus
Results  It highlights the association between T. vaginalis HPV Human papillomavirus
infection and serious adverse health consequences experi- HSV Herpes simplex virus
enced by women, including infertility, preterm birth and IgA Immunoglobulin A
low-birth-weight infants. Long-term clinical observations IgG Immunoglobulin G
and results of in vitro experimental studies indicate that in IL Interleukin
men, trichomoniasis has been also associated with infertil- ITS Internal transcribed spacer
ity through inflammatory damage to the genitourinary tract NAATs Nucleic acid amplification tests
or interference with sperm function. LPG Lipophosphoglycan
Conclusion  These results contribute significantly to PID Pelvic inflammatory disease
improving our knowledge of the role of parasitic viru- PCR Polymerase chain reaction
lence factors in the development of infection and its role in STD Sexually transmitted disease
human infertility. STI Sexually transmitted infection
TVVs  Trichomonas vaginalis viruses
* Joanna Blaszkowska VECs Vaginal epithelial cells
joanna.blaszkowska@umed.lodz.pl
Ewelina Mielczarek
ewelina_mielczarek@outlook.com Introduction
1
Department of Obstetrics and Gynaecology, The Ludwig
The flagellated protozoan parasite Trichomonas vaginalis,
Rydygier Medical Center in Lodz, 13 Sterlinga Street,
90‑217 Lodz, Poland occurring in the human urogenital tract, is the etiological
2 agent of trichomoniasis, the most common worldwide non-
Department of Diagnostics and Treatment of Parasitic
Diseases and Mycoses, Medical University of Lodz, Pl. viral sexually transmitted infection (STD) [1]. Trichomonal
Hallera 1, 90‑647 Lodz, Poland infection has been noted in every continent and climate [1,

13

2] and with no seasonal variability. The outcome of infec-
tion with T. vaginalis varies depending on many factors,
such as the genetic variability of the isolates and the host
immune response [3, 4]. The incidence of trichomoniasis
rate depends on many factors including age, sexual activ-
ity, number of sexual partners, the presence of other STDs,
sexual customs, phase of the menstrual cycle, techniques of
examination, specimen collection and laboratory technique.
Together with Chagas disease, cysticercosis, toxocariasis
and toxoplasmosis, trichomoniasis belongs to the group of
neglected parasitic infections (NPIs), which has been tar-
geted by the CDC as a priority for public health action [5].
The public health importance of the problem is under-
lined by the fact that T. vaginalis infection is prevalent in
women of reproductive age, and is associated with serious
adverse reproductive outcomes [6, 7]. This infection may
also increase the risk of human immunodeficiency virus
(HIV) transmission and other STD infections which are
observed significantly more frequently in women [8, 9].
Infection may cause chronic inflammation of the genitouri-
nary tract, which may even lead to infertility. Several stud-
ies report that patients with T. vaginalis infection display
deleterious outcomes in reproduction. Additionally, the
incidence and severity of cervical dysplasia and prostate
cancer is also associated with trichomoniasis [10, 11].
Very probably, the true prevalence of T. vaginalis is
much higher due to its frequent asymptomatic course. This
parasite is not routinely screened in asymptomatic patients
and the infection can persist for 3–12 months in the geni-
tal tract [4]. Moreover, the detectability of trichomonads in
examined biological material substantially depends on the
choice of applied diagnostic method [12, 13].
Brief characteristics of T. vaginalis
Trichomonas vaginalis is an amitochondrial, microaero-
tolerant flagellate which has various shapes and sizes, but
on average measures about 9 × 7 µm. It has five flagella;
four are present anteriorly and the other flagellum is incor-
porated within the undulating membrane. It has unique
energy-producing double membrane organelles known as
hydrogenosomes. It reproduces every 8–12 h by longitu-
dinal binary fission. T. vaginalis is a obligate parasite that
phagocytoses bacteria, vaginal epithelial cells (VECs),
spermatozoids and erythrocytes [3, 14–16]. This unicellular
parasite (strain G3) has a genome of over 176 megabases
with 60,000 genes, the largest number of genes ever identi-
fied in protozoans. It also has a massive proteome, express-
ing ∼4000 genes. Until now, 411 proteins have been identi-
fied, many of which are known to be membrane proteins
with possible roles in the pathogenesis of T. vaginalis or
which may help parasite to adapt and survive in diverse
13
E. Mielczarek, J. Blaszkowska
environments [17, 18]. Outside the host, the parasite can
survive for 6–24 h in urine, semen and swimming pool
water [19], but only up to 30 min when exposed to air. T.
vaginalis can grow over a wide range of pH values with an
optimum level between pH 6 and 6.3 [20].
Trichomonas vaginalis exists as a trophozoite with-
out the true cystic stages. The two described forms of
trophozoite are characterized by different morphologies:
free-swimming, flagellated or amoeboid cells. It has been
recently shown that T. vaginalis occurs in another cellular
form: a pseudocyst described as a non-motile stage, which
is rounded without a true cyst wall, and an external fla-
gella [21]. It has been suggested that this form is created
in response to unfavorable culture conditions [20]. Addi-
tionally, T. vaginalis pseudocysts have been isolated from
cervical neoplasia (CN) patients. The study conducted
by Afzan and Suresh [11] confirms that the pseudocystic
stage from CN has unique biochemical, surface, and ultra-
structural properties compared to the other forms. Moreo-
ver, Hussein and Atwa [22] report that the pseudocysts
were able to cause infection in mice, with trophozoites of
T. vaginalis being detected in the urine of experimentally
infected animals on day 4 after inoculation. They postulate
that pseudocysts play a significant role in the life cycle of
T. vaginalis and the pathophysiology of the infection.
Epidemiology and modes of transmission
The available WHO estimates suggest that the global inci-
dence of T. vaginalis infection increased between 1995 and
2008 (Table 1) [1, 2]. Its prevalence has increased from
152.9 million (22.2 %) since 2005 to 187.1 million concur-
rent infections at any point in 2008. However, these esti-
mates may be low, since they are based on wet mounts that
are not as sensitive as new molecular diagnostic techniques
[13].
Trichomonas vaginalis is a sexually transmitted patho-
gen with the highest annual incidence of all curable and
non-viral STIs. At the 2008, the prevalence of T. vaginalis
was higher than Chlamydia trachomatis (100.4 million),
Neisseria gonorrhoeae (36.4) and Treponema pallidum
(36.4) infections combined [2]. In addition, trichomoniasis
is the most common parasitic infection in the US, affect-
ing an estimated 3.7 million persons nationwide, including
2.3 million women and 1.4 million men [5]. There are large
differences in the prevalence of Trichomonas infections
between different WHO regions populations (Table 2).
Additionally, epidemiological studies of this protozoan in
local communities have revealed a wide range of preva-
lence. In the US, the prevalence among women ranges from
2.8 % in adolescents nationwide to up 50 % among Afri-
can–American women in urban communities [23].
Trichomonas vaginalis: pathogenicity and potential role in human reproductive failure

Table 1  Estimates of the global Year Incidencea [millions] Prevalenceb [millions]

incidence and prevalence of
T. vaginalis infection among Female Male Total Female Male Total
adults aged 15–49-year
1995 84.57 82.55 167.12 Not reported
1999 87.68 85.78 173.46 Not reported
2005 105.63 142.85 248.48 135.52 17.38 152.90
2008 132.20 144.20 276.40 169.50 17.60 187.10

Estimates from the World Health Organization [1, 2]

a
  The number of new cases of T. vaginalis infection occurring per year
b
  The number of cases of T. vaginalis infection at any point in time of year

Table 2  Regional prevalence estimates for T. vaginalis infection for and respiratory tracts have been reported in newborns of
2008 infected mothers [28].
WHO region Prevalence [millions] Non-sexual transmission is rare, but has been observed
Female Male Total
in cases involving contaminated showers, moist wash-
clothes, toilet seats, or specula [29–31]. Crucitti et al. [32]
African Region 38.9 3.9 42.8 found a high prevalence of trichomoniasis in adolescent
Region of the Americas 52.7 5.2 57.9 girls attending school in Ndola, Zambia following non-sex-
South-East Asia Region 25.7 3.0 28.7 ual transmission of trichomoniasis via shared bathing water
European Region 13.0 1.3 14.3 and inconsistent use of soap. Adu-Sarkodie [30] reports
Eastern Mediterranean Region 12.0 1.3 13.3 the transmission of T. vaginalis from mother to children
Western Pacific Region 27.2 2.9 30.1 through the sharing of bathing implements in Ghana. Addi-
Global total 169.5 17.6 187.1 tionally, Charles [29] describes an epidemic of trichomo-
niasis in young girls in a rural area in India spread through
Estimates from the World Health Organization [1]
contaminated water.

Biological differences between the sexes contribute to

these striking differences in the incidence and prevalence
of T. vaginalis infection between men and women [4]. For
men it was calculated as one tenth of the prevalence in
women [1, 2]. An individual with no symptoms of tricho-
moniasis is classified as a chronic asymptomatic carrier,
and these constitute 70–100 % of male population and in
35–85 % of the female population with confirmed T. vagi-
nalis infection [3].
Trichomonas vaginalis is commonly spread through
sexual contact with the vaginal or urethral discharges of
infected persons [20]. Urethral infection by T. vaginalis is
present in at least 80 % of infected women and over 73 %
of male partners of women diagnosed with vaginal tricho-
moniasis [24]. Additionally, transmission of protozoa is
also possible via artificial insemination of infected cry-
obanked semen [25, 26]. However, in some rare cases, the
presence of T. vaginalis has also been documented outside
the genitourinary tract: in the pharynx and lower respira-
tory tract of adults. The occurrence of this protozoan in the
respiratory tract has been linked to orogenital sexual activ-
ity [27]. Although T. vaginalis commonly affects adults,
documented cases of T. vaginalis infections have also been
seen in neonates who acquired the infection vertically
from the maternal genitourinary tract. Some rare cases of
infections with T. vaginalis of the vaginal, urinary, nasal
Virulence factors of T. vaginalis
The host–parasite relationship is very complex [33, 34]. A
successful invasion of T. vaginalis requires the existence of
several virulence mechanisms such as the transformation
of the trophozoite into an ameboid form, cell-to-cell adhe-
sions [20, 35–37] hemolytic activity [20], trichomonad pro-
teinase activity [38], contact-independent mechanisms and
cell-detaching factor [36, 39] phagocytosis [3, 36] and host
immune system evasion [3, 20, 36, 40].
The morphological change of the trophozoite
One of the determinants of pathogenicity of T. vaginalis
is the ability of the trophozoite from a flagellated free-
swimming cell to an amoeboid-adherent stage. Scanning
electron microscope studies by Figueroa-Angulo et al. [36]
suggest that the amoeboid form is the key player of patho-
genesis, as this morphological transition occurs when the
parasite attaches itself to cervical and prostatic cells. Mor-
phological transformations are associated with cytoskel-
eton protein rearrangement and an increased expression of
genes encoding cytoskeletal proteins. Upon contact with
vaginal epithelial cells, the diffuse localization of actin and
fimbrin 1 (Tv Fim1) changes dramatically [36]. Live cell

13

imaging demonstrates that trichomonal amoeboid stages do
not just adhere to host tissue, but actively migrate across
human epithelial cells in a concerted manner, with an aver-
age speed of 20 µm per minute [37].
Cytoadherence
Several proteomic analyses have also provided an insight
into the surface, soluble and secreted proteins that may be
involved in T. vaginalis pathogenesis [17, 33, 34]. The con-
tact-dependent mechanisms described above play an impor-
tant role in cell destruction of host. Adhesion of T. vagi-
nalis to red blood cells or the urogenital epithelium triggers
the degradation of the skeleton of the host cell membrane,
which can lead to cytolysis [34]. All 26 strains of T. vagi-
nalis examined by Lustig et al. [35], with various degrees
of virulence and isolated from various geographic loca-
tions, required contact with host cells to induce cytolysis.
The lipophosphoglycan (LPG) is a major adherence
factor in T. vaginalis, although molecular studies have
revealed that the expression of several other genes coding
adhesion proteins (AP), fibronectin (FN)-binding protein,
laminin-binding protein, actinin, enolase, phosphogluco-
mutase, and conserved GTP-binding protein (GTP-BP) are
up-regulated [36]. The human cell receptor of T. vaginalis,
galectin-1, has been identified on cervical epithelial cells
and has been shown to bind to Trichomonas LPG [36].
The adhesion of the parasite to the epithelial cells is
mediated by numerous adhesins, including AP120, AP65,
AP51, AP33, AP23, GAPDH, and several hypothetical
proteins [18, 36] which act in a specific receptor-ligand
fashion, dependent on time, temperature, and pH. Gene
expression of these APs is coordinately upregulated at the
transcriptional level by iron. The parasite AP65-1 gene
encodes a 65-kDa protein, which is believed to be one of
the surface adhesins upon iron repletion. Iron-inducible
transcription of the AP65-1 gene in T. vaginalis involves
at least three Myb-like transcriptional factors (tvMyb1,
tvMyb2 and tvMyb3) that differentially bind to two
closely spaced promoter sites, MRE-1/MRE-2r and MRE-
2f [41].
Twu et al. [42] report that T. vaginalis secretes small
vesicles called exosomes that are capable of fusing with,
and delivering their contents to, host cells. A total of 215
proteins including surface proteins (Tvag_240680, BspA
family) and proteases (Tvag_224980, metallopeptidase)
have been detected in exosomes isolated from T. vaginalis
strain B7RC2. Hence, proteins that may have a role in T.
vaginalis pathogenesis are also present in the exosome
proteome. These parasite-secreted vesicles were found to
induce changes in the host cell and to mediate the interac-
tion of T. vaginalis with host by increasing the adherence
of the parasite to host cells. T. vaginalis exosomes were
13
E. Mielczarek, J. Blaszkowska
also shown to modulate host cell cytokine/interleukins 6
(IL-6) and 8 (IL-8)/production [42].
Hydrolases and cytotoxic molecules
A wide range of hydrolases (20–110 kDa) have been iso-
lated from T. vaginalis, including cysteine proteinases
which appear to be strongly correlated with virulence [38].
Currently, this parasite is estimated to contain 156 cysteine
peptidases (CPs) [18], most of which are necessary for effi-
cient AP-mediated adhesion of T. vaginalis to target cells.
These hydrolases have trypsin-like activity and function as
cell-detaching factors by degrading host cell proteins such
as laminin, fibronectin, and other components.
Trichomonas vaginalis produces several cytotoxic mole-
cules and mediates cytotoxicity by damaging the target cell
plasma membrane. Since T. vaginalis lacks the ability to
synthesize lipids, the parasite obtains essential fatty acids
by hemolytic activity [36]. The identification of parasite
60-kDa CP, which is capable of degrading hemoglobin into
heme and globin, supports the supposition that this parasite
may use hemoglobin as a source of iron [43]. The lysis of
erythrocytes appears to be mediated by protein receptors on
the surfaces of erythrocytes and parasites. Some molecules
have a perforin-like activity and create pores in erythrocyte
membranes [36]. Twelve genes (TVSaplip1 to TVSaplip
12) containing pore-forming domains have been identified.
T. vaginalis also secretes various lytic factors with phos-
pholipase A2 activity to destroy nucleated cells, erythro-
cytes and specifically degrade phosphatidylcholine [44].
Pindak et al. [39] showed that apoptosis of the host cells
may occur without the contact-dependent mechanisms of T.
vaginalis, but also through the production of acidic metab-
olites and other factors by the living parasite. One of these
factors is known as cell-detaching factor (CDF), which is
released by the parasite and is known to have trypsin-like
activity. CDF, a 200-kDa glycoprotein that causes detach-
ment of monolayer cells in vitro, analogous to the vaginal
epithelial cell sloughing seen in trichomoniasis [20]. CDF
activity is pH dependent. Further, the production of CDF
has been shown to decrease in the presence of estrogen.
Phagocytosis
The cytopathogenic action of T. vaginalis may be divided
into four stages: adhesion, cytolysis following contact,
phagocytosis and intracellular digestion [14, 15]. The
phagocytosis of various cell types by T. vaginalis has
been described: this parasite is able to efficiently ingest
and degrade lactobacilli, yeast cells, vaginal and cervical
epithelial cells, leukocytes, erythrocytes, prostatic cells
and spermatozoids [14–16]. T. vaginalis phagocytosis is
thought to be both an efficient means of obtaining nutrients
Trichomonas vaginalis: pathogenicity and potential role in human reproductive failure
for the parasite and an important factor in the pathogenesis
of trichomonal infections of the human genitourinary tract.
Two types of yeast cell phagocytosis have been observed
by virulent strains of T. vaginalis [15]. The first involves
a ‘sinking’ process, without any apparent participation of
plasma membrane extensions, while the second resem-
bles the classical phagocytosis described for professional
phagocytes, where pseudopodia are extended toward the
target cell, which is subsequently engulfed. Although these
two phagocytic processes were detected in both strains of
T. vaginalis investigated by Pereira-Neves and Benchimol
[15], the first mechanism was found to occur more com-
monly with the more virulent T016 strain.
The in vitro adherence and phagocytosis of sperm cells
by T. vaginalis was demonstrated by Benchimol et al. [16]
using transmission and scanning electron microscopy. The
adhesion between trichomonads to the sperm cell occurred
either by the flagella or sperm head. The parasites were
able to attach to the sperm cells by their cell surface, before
commencing phagocytosis. This process began with a tight
membrane–membrane adhesion and the incorporation
of the sperm cell within an intracellular vacuole. After-
wards, the sperm cell was gradually digested in lysosomes.
Another study conducted by Midlej and Benchimol [14]
reports that the cytopathic effect of T. vaginalis occurs due
to mechanical stress and subsequent phagocytosis of the
necrotic cells.
Host response to T. vaginalis infections
LPG plays a major pathogenic and immunoregulatory role
in adherence with VECs [36]. LPG triggers leukocytes to
secrete IL-8, parasite-specific immunoglobulin G (IgG)
and A (IgA), Th1 cytokines, leukotrienes, reactive nitro-
gen intermediates and macrophage inflammatory protein-
3a [40, 45]. Reighard et al. [46] report increased numbers
of polymorphonuclear leukocytes (PMNs), T cells, B cells,
and plasma cells in the endometrial tissue of the lower gen-
ital tract of women with T. vaginalis infection. Although
the endometrial mucosa is home to immune responses
capable of eradicating pathogens, the increased inflamma-
tory infiltrate associated with this infection may increase
the likelihood for immunopathological upper genital tract
damage.
The mechanisms of pregnancy complications linked to
T. vaginalis infection remain unexplained. Asymptomatic
trichomoniasis in pregnancy is accompanied by a state of
neutrophil activation. Additionally, women with asympto-
matic trichomoniasis have been reported to have detectable
vaginal fluid neutrophil defensins and cervical IL-8 concen-
trations [40]. The presence of increased C-reactive protein
levels in the sera of pregnant women infected with T. vagi-
nalis suggests that the impact of the immunoinflammatory
reaction to the parasite exceeds the boundaries of the repro-
ductive tract mucosa [7].
Immune evasion strategy of T. vaginalis
Trichomonas vaginalis has numerous ways of evading the
immune system, which include evasion of complement-
mediated destruction, molecular mimicry, and the ability to
coat itself with host plasma proteins [33, 36, 40, 47].
Provenzano and Alderete [48] report that numerous CPs
secreted by T. vaginalis degrade different types of immu-
noglobulins which allows the parasite to survive the anti-
body response. Degradation of IgG and IgA was observed
following incubation with lysates and culture supernatants
of T. vaginalis. Among the CPs, TVCP39 is one of the
papain-like proteinases that degrades both several extracel-
lular matrix proteins, including fibronectin, various types
of collagen, IgG, IgA and hemoglobin. In addition, the T.
vaginalis cysteine proteases, including CP30, induce apop-
tosis in vaginal epithelial cells and in multiple mucosal
immune cell types. T. vaginalis produces immuno-sup-
pressive cytokines (IL-10, TGFB) and causes caspase-
mediated apoptosis in T-cells, macrophages and dendritic
cells [40].
A recent study by Ibáñez-Escribano et al. [47] describes
a novel strategy by T. vaginalis to evade the lytic action of
the complement based on its procurement of host protein.
Trichomonads with surface-bound host-CD59 were pro-
tected from lysis.
Upon T. vaginalis infection, cervical and vaginal epithe-
lial cells release galectin-1 and galectin-3. These modulate
the inflammatory responses, with galectin-1 suppressing
and galectin-3 enhancing the leucocyte response to inflam-
mation [40]. In addition, galectin-1 acts as a soluble adhe-
sion molecule by facilitating the attachment of HIV-1 to the
cell surface, thereby augmenting the efficiency of the viral
infection process [8].
The presence of dsRNA viral infection of T. vaginalis
Trichomonas vaginalis can be infected with four dsRNA
viruses (TVVs), which are members of the Totiviridae. The
genome of each TVVs is a single dsRNA molecule, approx-
imately 4300–5500 bp in length [49]. It is suggested that
the presence of TVV in T. vaginalis may have an impact
on its virulence. This infection causes the up-regulation of
synthesis and surface expression of highly immunogenic
proteins, especially P270, and significant differences in
the total protein composition of the parasite. The presence
of TVV is also associated with differential qualitative and
quantitative expression of cysteine proteinases, which are
linked with cytoadherence, cytotoxicity, and degradation of
basement membrane components.
13

A study investigating the genetic diversity and popula-
tion structure of T. vaginalis identified two major genotypes
for the parasite (type 1 and type 2) with distinct properties
[3, 50]. T. vaginalis isolates type 1 are more sensitive to
metronidazole, and are also significantly more likely to be
infected with TVV than T. vaginalis type 2, in a ratio ∼3:1.
Type 2 isolates are notable for having a higher prevalence
of metronidazole resistance [51].
Consequence of T. vaginalis infections in man
Trichomonas vaginalis has been detected in up to 77 % of
the male partners of infected women, and of those men,
about 70 % were asymptomatic [24]. This high prevalence
of T. vaginalis among sexual partners confirms its easy
transmission. Male trichomoniasis is most often associated
with urethritis, but infection may occur in other areas of
the urogenital system [20]. In rare cases, T. vaginalis also
infects the epididymis and prostate gland and occasionally,
the testis [3, 4, 52].
Although T. vaginalis has been identified in urethral
discharge, urine, semen and prostatic fluid, its presence in
these fluids does not confirm infection of either the prostate
or seminal vesicles, since fluid can be contaminated when
it passes through the urethra. Although some authors regard
the prostate as an ecological niche for T. vaginalis, others
consider it to be an etiologic agent of chronic prostatitis.
Gardner et al. [53] reported 5 well-documented cases of
T. vaginalis detection in prostates obtained through autop-
sies, with clinical evidence of the parasite in the urine of
patients. Microscopic examination of all specimens dem-
onstrated multiple foci of nonspecific acute and chronic
prostatitis characterized by intraluminal macrophages and
a mixed chronic inflammatory infiltrate in the adjacent
stroma. Other studies have shown the presence of T. vagi-
nalis in the prostate gland: trophozoites have been identi-
fied in the prostatic urethra, glandular lumina, submucosa,
and stroma, in benign hyperplastic prostatic tissue [42, 54].
Mitteregger et al. [54] detected T. vaginalis DNA in 34 %
of investigated samples from 86 patients suffering from
benign prostatic hyperplasia (BPH), with chronic inflam-
matory tissue infiltration of unknown etiology. They also
observed foci with nonspecific acute and chronic inflam-
mation, as well as intraepithelial vacuolization near trich-
omonads which may lead to prostate carcinogenesis. Twu
et al. [42] demonstrated that a secreted T. vaginalis protein
(TvMIF—T. vaginalis macrophage migration inhibitory
factor) homologous to human macrophage migration inhib-
itory factor (HuMIF) elicits antibodies in infected individu-
als, increases prostate cell proliferation and invasiveness,
and induces cellular pathways linked to inflammation that
contribute to the promotion and progression of prostate
13
E. Mielczarek, J. Blaszkowska
cancer. Sutcliffe et al. [55] describe two possible molecular
mechanisms for T. vaginalis-mediated prostate carcinogen-
esis: the first occurring via the inflammation process, and
the second proceeding through initiation of the cell-sign-
aling cascade using proto-oncogenes PIM1, c-MYC, and
HMGA1.
Role of T. vaginalis in male infertility
Several studies report that men with T. vaginalis infection
display deleterious outcomes in reproduction [24, 52, 56,
57]. This has been associated with urethritis, prostatitis,
epididymitis, and infertility through inflammatory damage
or interference with sperm function.
Sexual transmission of T. vaginalis is well established,
either via urethral discharge of men with urethritis or
through the semen. In men, trichomoniasis has been most
frequently related to infertility by deficit of sperm cell
quality and function due to physical damage. Significantly
higher levels of seminal contamination with the parasite
have been found in infertile men compared to fertile con-
trols [56]. The semen characteristics of males affected by
T. vaginalis have been described in several studies [24, 58].
Gopalkrishnan et al. [58] note differences to the semen
from asymptomatic men, and showed that spermatozoan
motility, viability and morphologically normal forms were
decreased significantly during infection. Additionally,
seminal fluid viscosity has been reported to be increased in
asymptomatic men with trichomoniasis, without significant
change in pH.
In vitro studies have shown that proteins secreted by T.
vaginalis rapidly immobilize or kill sperm. Sperm agglu-
tination has also been described after exposure of human
semen to high concentrations of live trophozoites ranging
from 104 to 107 parasites per ml [59]. Benchimol et al. [16]
report that, after 1 h of interaction between trichomonads
and sperm cells under incubation conditions, 75 % of the
sperm cells were immotile or dead. Under scanning elec-
tron microscopy, the interaction of T. vaginalis and sperm
cells results in high agglutination, membrane protrusions,
or the formation of channels between the sperm plasma
membrane and parasite surface. Additionally, Mali et al.
[57] reported a case of phagocytic interaction and agglu-
tinated human spermatozoa by T. vaginalis, observed after
a Papanicolaou-stained cervical smear under light micros-
copy. Recently, experimental studies found that the secre-
tory products of trichomonads decrease fertilizing capacity
of mice sperm [60]. The incubation of sperm with extra-
cellular polymeric substances (EPS) from T. vaginalis, sig-
nificantly decreased sperm motility, viability and functional
integrity in a concentration and time-dependent manner.
These effects on sperm quality also resulted in a decreased
fertilization rate in vitro.
Trichomonas vaginalis: pathogenicity and potential role in human reproductive failure
A strong association between inflammation of the male
reproductive system and infertility has been reported [52,
61, 62]. The role of chronic infection by T. vaginalis on
male infertility via the inflammatory process is not com-
pletely understood. However, rare cases of sterile men with
trichomoniasis suggest the significant role played by these
protozoa in fertility disorder. One such difficult diagnosis
of T. vaginalis orchitis was detected in men with severe
oligoasthenoteratospermia [63]. Semen analysis showed
a sperm concentration of less than 100,000/ml with 0 %
motility and 0 % morphological normal forms. Pathologi-
cal analysis confirmed the diagnosis of right orchitis caused
by T. vaginalis. Janssenswillen et al. [64] report a case
of non-obstructive azoospermia in a 34-year-old patient
resulting from maturation arrest associated with Tricho-
monas infection at the level of the epididymis. The flag-
ellated T. vaginalis cells were observed in the epididymal
aspiration, while spermatozoa were not present and a wet
preparation of multiple testicular biopsies failed to demon-
strate any spermatozoon.
In HIV-positive men, adverse effects on sperm qual-
ity have been noted and semen quality has been found to
deteriorate with the progression of immunodeficiency [65].
Hobbs et al. [66] report that the HIV RNA concentration
observed in the seminal plasma of HIV-positive Malawian
men with symptomatic urethritis was significantly higher in
those also infected with T. vaginalis. The role of co-infec-
tions of T. vaginalis with HIV in the impairment of sperm
quality and motility still needs further investigation.
Consequence of T. vaginalis infections in women
In females, 50 % of cases of T. vaginalis infections are
asymptomatic and parasites can persist for long periods
of time in the urogenital tract of women. Between 25 and
50 % are asymptomatic for the first 6 months of infec-
tion, and organisms can survive indefinitely in the lower
urogenital tract if left untreated [4, 20]. The parasite is
normally isolated from the vagina, cervix, bladder, Bartho-
lin’s, Skene’s, and periurethral glands [4]. Clinical forms
of trichomoniasis in women ranges from an asymptomatic
carrier state to symptomatic vaginitis [3, 4]. Rarer compli-
cations may result in pyosalpinx endometritis, adnexitis,
and can trigger inflammatory responses in the mucosal gen-
ital tract, increasing the risk of pelvic inflammatory disease
(PID) by microhemorrhages [4, 20].
Some authors suggested that in women, trichomonia-
sis increases the predisposition to cervical neoplasia (CN)
[11]. The epidemiological data suggest that the aetiological
agents of CN are genital pathogens, mainly human papil-
lomavirus (HPV), herpes simplex virus (HSV) type-2, and
C. trachomatis. Moreover, concomitant STDs, including
trichomoniasis may promote HPV infection and further
increase the risk of CN [67, 68]. A study of rural Tanza-
nian patients found that those with T. vaginalis infection
were 6.5 times more likely to have HPV type 16 than those
without [69]. The proposed mechanism for increased risk
of cervical dysplasia in the case of Trichomonas invasion
is that the parasite produces mediators of inflammatory
response which cause cervical inflammation. The cervical
epithelium, as a protective barrier, is disrupted by inflam-
mation, allowing for penetrance of HPV to the basement
membrane [69, 70]. As co-infections of T. vaginalis with
viral and bacterial pathogens are known to occur, Chigbu
et al. [71] suggest that the detection of T. vaginalis from the
lower genital tract can serve as an indicator for other more
serious STIs caused by N. gonorrhoeae, Gardnerella vagi-
nalis and C. trachomatis, as well as HIV and HPV.
Trichomonas vaginalis infections have been associated
with 1.5–2.7 times greater risks of HIV acquisition and
transmission [9, 72, 73]. According to Coleman et al. [72]
T. vaginalis has emerged as a cofactor for HIV transmis-
sion and potential mechanisms for increased susceptibility
include various complex processes: (1) recruitment of HIV
target cells (CD4+ T cells) to the genital tract as a result
of the host immune response to T. vaginalis, (2) degrada-
tion of HIV-protective factors such as secretory leukocyte
protease inhibitor, and (3) the direct and indirect cyto-
toxic effects of the parasite itself. Additionally, this pro-
tozoan secretes a CDF that releases epithelial cells from
the tissue, thus thinning the protective barrier against HIV
invasion. T. vaginalis also elicits minor extravasation in
mucosal genital tract tissue, which may facilitate transmis-
sion for HIV [8].
The factors that influence the host inflammatory
response to T. vaginalis remain not fully understood, how-
ever, hormonal levels, iron resource and the coexisting
vaginal flora in the vagina have an important influence on
the severity of trichomoniasis in female patients [36]. The
rise of vaginal pH during infection may therefore be cru-
cial in the pathogenesis of the disease. This phenomenon
is accompanied by a concomitant reduction of protective
lactobacilli that facilitates colonization of the reproductive
tract with opportunistic pathogens [4]. The roles played by
pH and hormones in trichomoniasis may explain the obser-
vation that the symptoms of the disease are often worse
during menstruation [20].
Role of T. vaginalis in female infertility
The presence of pathogens in the reproductive tract can
result in fertility disorders, and similarly, the presence
of T. vaginalis in semen samples affects the quality of
sperm cells and impedes their ability to achieve oocyte
fertilization.
13

The clinical data show that the prevalence of T. vagi-
nalis is significantly higher among infertile women than
fertile controls [74]. El-Sharkawy et al. [75] showed that
infertile women with T. vaginalis have decreased C3 and
C4, increased IgA level in vaginal discharge and increased
serum prolactin.
More than 20 % of women with trichomoniasis have a
chronic inflammatory process in the reproductive tract. The
protozoan attaches to vaginal epithelial cells and secretes
various proteases and a CDF, leading to an intense host
inflammatory response, inducing local cytotoxic effects,
genital tract damage, and reproductive effects [20, 39, 72].
This parasite has been isolated from fallopian tubes, peri-
toneal fluid, and the pouch Douglas, suggesting that motile
trophozoites may be able to invade the whole genital tract
[6, 71]. By virtue of their mobility, T. vaginalis not only
infect the cervical canal, but simultaneous endometrial
infection is also present, affecting the development of the
uterine lining [46].
While roles for C. trachomatis and N. gonorrhoeae
infections in pelvic inflammatory disease (PID) pathogen-
esis are well delineated [76], the etiologic contributions
of T. vaginalis have been not clarified. Some authors sug-
gest that in rare cases, untreated trichomoniasis in HIV-
positive patients or during co-infection of T. vaginalis with
other genital pathogens can lead even to PID [4, 77, 78].
Cherpes [78] notes that T. vaginalis infection and positive
HSV-2 serology are associated with endometritis. Accord-
ing to Moodley [77], T. vaginalis infection of the lower
genital tract is associated with a clinical diagnosis of PID
in HIV-1–infected women. Unfortunately, no data exist
regarding the mechanism for such an association. Theo-
retically, the proteinases produced by T. vaginalis have
the potential to disrupt the protective cervical mucus plug,
allowing the protozoan to pass from the lower to the upper
genital tract [38]. Reighard et al. [46] demonstrated an
increase in endometrial leukocyte subpopulations among
women with lower genital tract T. vaginalis infections,
which suggests that the protozoan may play a role in upper
genital tract inflammatory processes. Additionally, motile
trichomonads have been isolated from samples of perito-
neal fluid from women with vaginal trichomoniasis [79].
Although some evidence links T. vaginalis infection to
upper genital tract infection, no conclusive proof of causal-
ity exists. Further studies will be needed to determine the
potential roles this parasite may play in PID pathogenesis.
T. vaginalis infection and its effects on pregnancy
outcomes
During pregnancy, T. vaginalis infection has been asso-
ciated with such adverse outcomes as preterm rupture
of membranes, preterm delivery, and low-birth-weight
13
E. Mielczarek, J. Blaszkowska
neonates [80–83]. For recent decades, the prevalence of
newborn infection with T. vaginalis is unknown, but liter-
ature data indicate rare cases of vertical transmission [28,
84–89]. However, 40 years ago, al-Salihi et al. [90] esti-
mated that transmission to newborns occurred in 2–17 %
of female neonates of infected women. The mode of trans-
mission is proposed to occur through direct contact with
the maternal genital tract during birth or contact between
the neonate and infected maternal fluids after delivery. It
has been hypothesized that the premature rupture of fetal
membranes promotes the transmission of T. vaginalis,
because prolonged exposure to the vaginal flora enhances
the chance of neonatal colonization and infection by these
organisms [91]. A few reports have shown the presence of
T. vaginalis in the respiratory tract of neonates [87–89].
Most documented cases of neonatal trichomoniasis include
vaginal or urinary tract infections and parasitosis were
diagnosed in the newborn from 5 to 28 days after birth [28,
81–85]. A high risk of developing urinary tract or vaginal
T. vaginalis infections exists in newborns due to the influ-
ence of maternal estrogen, which remains at a high level in
the neonate for four to 6 weeks after birth [90]. Under the
influence of high maternal estrogen, the vaginal milieu of
newborn females has more glycogen deposits and a thicker
epithelium than found in older children, which increases
the susceptibility to infection with T. vaginalis during the
neonatal period [89]. According to Jenny et al. [92], the
identification of sexually transmissible agents, including T.
vaginalis in children beyond the neonatal period strongly
suggests sexual abuse, and every such case requires spe-
cial attention. It is also important to note that perinatally
acquired rectal or vaginal C. trachomatis infection may
persist for 2–3 years after birth while T. vaginalis neonatal
infections may continue for several months [93].
Genitourinary tract infections are one cause of preterm
delivery. Approximately 40 % of spontaneous premature
births are thought to be caused by infection. Many authors
have confirmed the relationship of T. vaginalis with preterm
labor. An analysis of the 178 articles published before May
2013 concerning perinatal outcomes in women infected
with T. vaginalis provides strong evidence that trichomo-
niasis in pregnancy is associated with an increased risk of
preterm birth [6]. Uterine contractions may be induced by
cytokines (IL-1β), IL-6), and prostaglandins (PGE2 and
PGE2a), which are released following T. vaginalis infec-
tion [82].
Diagnostic tests
Microscopic examination of a wet mount preparation of
genital secretions is still the most common method for
T. vaginalis detection because of convenience and low
Trichomonas vaginalis: pathogenicity and potential role in human reproductive failure
cost. However, the sensitivity of this traditional method is
60–70 %, and decreases by as much as 35 % within half
hour after collection [13, 94, 95]. Culture has a sensitiv-
ity of 75–96 % and a specificity of up to 100 % [96], but
is rarely used in routine laboratory tests [20]. Culture was
considered the gold standard method for diagnosing T. vag-
inalis infection before molecular detection methods became
available [97]. The newly designed NAATs (e.g., APTIMA
T. vaginalis FDA-approved assay) are the most sensitive
tool for identifying Trichomonas asymptomatic infection
in both women and men [12, 13], but their high cost and
required infrastructure prevent their widespread use in lab-
oratories. Additionally, point-of-care tests that detect pro-
tozoan antigens (e.g., OSOM® Trichomonas Rapid Test) or
unamplified RNA (e.g., Affirm VP III) has also been devel-
oped [13, 97]. Unfortunately, these commercially kits have
limited availability. Additionally none of these tests has
been evaluated for screening asymptomatic women or for
diagnosis of trichomoniasis in men. Current recommenda-
tions for T. vaginalis testing and screening, can be found
in CDC’s STD Treatment Guidelines, available online at:
http://www.cdc.gov/std/treatment [97].
Treatment
Most strains of T. vaginalis are sensitive to nitroimidazoles.
Currently FDA-cleared metronidazole and tinidazole are
the standard drugs for therapy of trichomoniasis [97, 98].
According to CDC guidelines, a single 2 g dose of metro-
nidazole or 2 g dose of tinidazole is sufficient to cure more
than 90 % of women with trichomoniasis, while metroni-
dazole 500 mg orally twice a day for 7 days can be used as
an alternative [97]. Both drugs are recommended treatment
regimens in infected men. Metronidazole (FDA pregnancy
category B) is recommended for pregnant women which
can be treated with 2 g metronidazole in a single dose at
any stage of pregnancy [98]. Because tinidazole is qualified
to pregnancy category C the manufacturers advise against
its use during the first trimester. Detailed guidelines regard-
ing therapy of trichomoniasis, including cases of nitroimi-
dazole-resistant infections, are available in the 2015 Sexu-
ally Transmitted Disease Treatment Guidelines published
by the Centers for Disease Control and Prevention [97].
Conclusions
Despite the fact that trichomoniasis is the most common
curable sexually transmitted infection worldwide, the medi-
cal community still considers T. vaginalis a harmless inhab-
itant of the human reproductive tract. In the meantime,
serious adverse reproductive health outcomes, including
pregnancy complications, infertility and an increased risk
of HIV acquisition, as well as cervical and prostate cancer,
have been linked to T. vaginalis infection. This infection
has a cosmopolitan distribution and has been identified in
all racial groups and socioeconomic strata. For this reason,
trichomoniasis is one of CDC’s neglected parasitic infec-
tions, which are a group of five parasitic diseases that have
been targeted as priorities for public health action.
Thanks to its wide clinical spectrum, control of this
infection must be based on the screening of symptomatic
women and their partners and the appropriate treatment
of infected individuals to prevent the continued spread of
the disease. In addition, screening might be advisable for
asymptomatic women at high risk of infection (e.g., with a
history of any STD or multiple sex partners).
Compliance with ethical standards 
Conflict of interest  The authors declare that they have no conflict of
interest to disclose. On behalf of all authors, the corresponding author
states that there is no conflict of interest.
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