We designed this case-control study based on nationwide data from Taiwan NHIRD. We found that T. vaginalis infection was significantly associated with BPH and PCa in a male population. Therefore, T. vaginalis could be a pathogen that induces BPH and PCa. However, there was no significant association between trichomoniasis and BC. Furthermore, patients with both trichomoniasis and depression had 7.682 times higher risk of developing BPH, PCa, or BC. This result suggests that the joint effect of trichomoniasis and depression could increase the risk of BPH, PCa, or BC.
The mechanism of T. vaginalis inducing BPH and PCa still remains unclear. Several studies have demonstrated different possible mechanisms. In women, T. vaginalis induces pro-inflammatory cytokine production, including interleukin-6 (IL-6), interleukin-8 (IL-8), and chemokine ligand 2 (CCL2), while attaching to vaginal epithelial cells [14]. A similar inflammatory reaction was also noted in T. vaginalis-infected prostatic epithelial cells in some in vitro studies [5, 6]. Repeated cell damage and repair in chronic inflammation is likely to play an important role in inducing BPH [15]. Furthermore, the alteration in cytokine expression during chronic inflammation may have effects on cell growth and proliferation of the prostate epithelium and stroma in BPH 15. The activated mast cells stimulated by T. vaginalis-infected prostatic epithelial cells can initiate IL-8 and CCL2 expression [5]. IL-8 could be a predictive marker for BPH [16]. Some in vitro studies demonstrated that IL-8 can stimulate fibroblast growth factor 2 (FGF-2), which causes the mitosis of prostate stromal cells [17]. IL-8 could also cause cyclin D1 expression to promote stromal cells proliferation [18]. In addition, CCL2, secreted by the prostatic stroma fibroblast, could promote both BPH and PCa progression [5].
T. vaginalis possibly induces carcinogenesis of the prostate. The infected prostatic epithelial cells produce IL-6 in chronic inflammation [19]. In early studies, an elevated serum IL-6 level was noted in patients with advanced PCa [20]. The positive correlation between IL-6 receptor expression and cell proliferation has been reported [21]. IL-6 also induces epithelial-mesenchymal transition (EMT) in breast cancer growth and metastasis [22], and the same reaction may also occur in prostatic epithelial cells [23]. In addition, more than one study has demonstrated that IL-6 could enhance androgen receptor (AR) activity and AR gene expression [24], which is also related to prostate cancer growth. Twu et al. demonstrated that T. vaginalis macrophage migration inhibitory factor (TvMIF) plays an important role in inducing PCa [7]. There are already studies that have proven that higher human macrophage migration inhibitory factor (HuMIF) levels are present in several cancers, including PCa [25]. The structure of TvMIF is similar to that of HuMIF, which might explain why TvMIF also has the ability to promote cell proliferation, sustain inflammation, and stimulate the growth of prostate cancer cells [7].
There were still a lack of studies to prove that trichomoniasis is associated with BC. We still included BC patients in our study because the inflammatory cytokinesfound in trichomoniasis, including IL-6 and IL-8, are also associated with a higher risk of developing BC [26, 27] and some parasites, such as Schistosoma haematobium, can induce BC. However, our study shows no significant association between T. vaginalis infection and BC probably because of limited sample.
Our results demonstrate that except for depression, no comorbidities had a significant association with BPH, PCa, or BC. The joint effect of trichomoniasis and depression increased the risk by 7.682 times that of the control group. A recent study showed that depression is associated with decreased immunity [28]. Moreover, depression can also cause cytokine dysregulation and increased serum IL-6 concentration [28], which might enhance carcinogenesis after T. vaginalis infection.
Although this study was a large-scale population-based nationwide design with long-term monitoring from 2000 to 2015, there are still several limitations. First, the NHIRD does not contain detailed information regarding the histological and TNM classification of PCa and BC, serum sex hormone concentrations, family history, or personal history such as physical activity, alcohol consumption or tobacco smoking. Second, we did not include body mass index (BMI) as one of our variables. Obesity is one of the risk factors for BPH and PCa [29], which might affect their association with trichomoniasis. Third, our study might underestimate the exact number of patients with trichomoniasis. Most male patients would not seek treatment due to being asymptomatic, and ineffective screening protocols because of the lack of public health awareness could also lead to possible T. vaginalis infection being neglected [30]. Fourth, the number of cases of BC might be too small to be significant and the tracking time might not be sufficient for disease monitoring.