Features Human Papillomavirus and
Abstract
Male infertility can have different causes, one of which may be the presence of etiologic agents that cause sexually transmitted infections. Among the most important sexually transmitted infections are human papillomavirus and Chlamydia trachomatis, which are associated with infertility in females – whether they cause infertility in men is controversial. The purpose of the chapter is to review the effect of these two pathogens on male fertility, the evidence suggests that the most important infertility effect is linked to the condition of the sperm. However, it is noteworthy that there are few studies with respect to infertility in regard to both pathogens, so it is important to further research this to elucidate the mechanisms by which these pathogens act on male infertility.
Keywords
- Human papillomavirus
- Chlamydia trachomatis
- male infertility
- sperm
- infertility
1. Introduction
Sperm production is considered a complex process that can be affected by many factors, such as infections by viruses or bacteria. These may cause changes in motility, shape and sperm function. This chapter reviews the role of human papilloma virus (HPV), the bacterium
2. Human papilloma virus
HPV belongs to the family Papillomaviridae. Members of this family are small viruses of 45–60 nm in diameter with icosahedral capsid. This family includes more than 189 genotypes, which are distributed in 29 genera [1, 2]. The main features of human papillomavirus are listed in Table 1.
|
|
|
|
Virus | Bacteria |
|
45-60 nm | 200-400 nm |
|
Icosahedral capsid | Body elemental body and reticulum |
|
189 genotypes | 15 genotypes |
|
Intracellular | Intranuclear |
|
Sexually transmitted infection Warts Nonspecific lesions Squamous intraepithelial lesions Cervical cancer and laryngeal Infertility |
Sexually transmitted infection Trachoma Pelvic inflammatory disease Lymphogranuloma venereum Infertility |
The HPV genome consists of double-stranded DNA and is divided into three regions: the long control region (LCR), the early region (E), and the late region (L). Late proteins L1 and L2 code for capsid proteins [3, 4]. Region E is involved in the formation of non-structural proteins (E1–E7). E1 and E2 genes are involved in viral replication and transcription. E5, E6 and E7 genes encode proteins involved in oncogenesis related to HPV. E6 and E7 are involved in the viral transformation process, binding cellular proteins p53 and Rb, respectively, interfering with the cell cycle and inhibiting apoptosis [5].
The infection of HPV in both women and men may be asymptomatic or manifest itself in different forms: typical is the wart. However, atypical squamous intraepithelial lesions may culminate in the development of cancer. This has been studied particularly well for cervical cancer [5], leading to an increased investigation in this area. Because infection with this virus can be initially hard to detect it can allow progress to a chronic persistent infection or can cause changes in the infected cell disrupting the normal cell cycle. HPV is generally associated with cancer [6].
It has been established that genital tract infections have an effect on fertility, however, the effect of infection with HPV remains uncertain. It is recognized that HPV is one of the most common sexually transmitted infections in the world. There have been various studies that show a wide range in prevalence (from 1.4% to 44%) in the general population [7, 8]. Specifically it is reported to cause 16% infertility in men [9]. A review indicated that prevalence may be between 1.3% and 72.9% [10].
Moreover, male infertility is multi-factorial, including etiologic agents. The human papilloma virus has been identified as a possible cause of male infertility, but not all studies confirm the mechanisms by which this happens.
There have been controversial studies on the role of HPV on fertility. A study reported that in infertile couples only 7.8% were positive for DNA from HPV genotypes, however, in this study it was reported that it does not have an effect on semen quality [11]. Other studies show that HPV is reported in infertile couples.
Different studies have linked infection with HPV in men with different clinical symptoms such as: genital warts, anal or penile intraepithelial lesions and different types of cancer in different regions – penis, anus, prostate and urethra [12, 13]. It has been found that human papillomavirus could be infecting and persisting in different areas, such as the male accessory glands, penis, exfoliated cells, semen and sperm. Some research into these effects is referred to below.
In a study, it was reported that patients with accessory gland infection and HPV have been diagnosed with infertility. It was observed that there are significant changes in sperm quality. Particularly, there is a slight lower sperm motility, despite to have normal morphology, indicating that the co-infection could be an additional risk factor for infertility [14]. Moreover, infection has been observed in epithelial cells and exfoliated cells [15].
Studies in men showing persistent HPV (penis and semen samples) indicated higher levels in the penis (22.5 months) than in semen (15.3 months). This may demonstrate that men can transmit the disease to women despite being asymptomatic [16]. Different genotypes have been found in infertile men such as HPV-45, HPV-52, HPV-18, HPV-59 and HPV-16, which have been recognized as high-risk genotypes [11, 17]. It has been observed that HPV can infect both sperm and cell desquamation [18]. However, another study showed that sperm have low motility [19, 20].
Different techniques have been used in the diagnosis of HVP:
Among the most studied area of HPV is the association with penile, larynx, head and neck cancers. It is estimated that HPV is the causative agent of 5% of human cancers [24].
In the review of Silva
3. Chlamydia trachomatis
In 1907
According to the World Health Organization (WHO), 101 million chlamydial infections are detected annually worldwide [34]. In adolescents and young adults between 12 and 24 years old the prevalence of
As a mention before,
The effects of
There are several methods available to detect
The most recent development is the real-time or quantitative PCR that detects
4. Co-infection of HPV and Chlamydia trachomatis
It has been confirmed in different studies that HPV can be part of a co-infection with
In another study, it was found that patients with
As mentioned in the above paragraphs the relationship between infection of HPV and
There are few studies showing the association of the two pathogens as co-factors with male infertility, however, there are multiple studies showing their coexistence, so it is important to know how each of these pathogens affects infertility.
5. HPV and Chlamydia trachomatis co-infection in the decrease of sperm quality
It has been written that the cause of infertility may be multifactorial and its etiology – viral and bacterial agents – is of particular interest because of its prevalence. HPV and
Infection with HPV has been identified as one of the possible causes associated with male infertility, although the mechanisms that may be using this virus are not yet clear. However, it was found that HPV can act both at conception and gestational development. Although there are different places where HPV may be infecting, as mentioned in the first section, the main concern linked to infertility is regarding the quality of sperm [18].
Other studies confirm this last statement which demonstrates a significant reduction in sperm motility while other parameters were not affected (semen volume, pH, normal morphology, viability, sperm concentration) [49] and cell desquamation. Sperm infected by HPV can go on to introduce the virus to the oocyte when being fertilized, which can have different consequences such as underdevelopment of the fetus. It has been observed that couples undergoing
Currently, molecular techniques have detected HPV in different samples (i.e. semen, scrape of the epithelium in different parts of the masculine reproductive apparatus) in heterosexual men with a maximum prevalence of 21 % [50]. Another molecular technique, fluorescent
Despite this evidence understanding has not been achieved fully regarding the role of HPV in male infertility so the study of
With respect to
It has been suggested that the cause of apoptosis of sperm is the lipopolysaccharide of the
There is little research studying the effect of these two infections as co-factors in regard to male infertility. In a study of men from Denmark it was reported that
It is proposed that co-factors such as genital tract infections could have an important role in the evolution and outcome of HVP. For example, the association of HVP with
In a study, it was found that heterosexual men, with prostatitis symptoms attributable to
Both HPV and
In conclusion, the presence of
References
- 1.
Bernard HU, Burk RD, Chen Z, et al. Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendments.Virology . 2010; 401: 70–79. DOI: 10.1016/j.virol.2010.02.002 - 2.
De Villiers EM, Fauquet C, Broker TR, et al. Classification of papillomaviruses.Virology . 2004; 324: 17–27. - 3.
Letian T, Tianyu Z. Cellular receptor binding and entry of human papillomavirus. Virology Journal . 2010; 7(2): http://www.virologyj.com/content/7/1/2. - 4.
Horvath CA, Boulet GA, Renoux VM, Delvenne PO, Bogers JP. Mechanisms of cellentry by human papillomaviruses: an overview. Virol J . 2010; 20(7): 11. DOI: 10.1186/1743-422X-7-11 - 5.
Moody CA, Laimins LA. Human papillomavirus oncoproteins: pathways to transformation. Nat Rev Cancer . 2010; 10: 550–60. - 6.
Muñoz N, Bosch FX, de Sanjosé S, Herrero R, Castellsagué X, Shah KV, Snijders PJ, Meijer CJ; International Agency for Research on Cancer Multicenter Cervical Cancer Study Group. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med . 2003; 348(6): 518-27. PubMePMID: 12571259. - 7.
Bosch FX, Lorincz A, Munoz N, et al . The causal relation between human papillomavirus and cervical cancer.J Clin Pathol . 2002; 55: 244–265. - 8.
Dursun P, Senger SS, Arslan H, et al . Human papillomavirus (HPV) prevalence and types among Turkish women at a gynecology outpatient unit.BMC Infect Dis . 2009; 9: 191. DOI: 10.1186/1471-2334-9-191 - 9.
Laprise C, Trottier H, Monnier P, et al . (2014). Prevalence of human papillomaviruses in semen: a systematic review and meta-analysis.Hum Reprod . 29; 640–651. DOI: 10.1093/humrep/det453 - 10.
Dunne EF, Nielson CM, Stone KM, Markowitz LE, Giuliano AR. Prevalence of HPV infection among men: A systematic review of the literature. J Infect Dis . 2006; 194(8): 1044–57. - 11.
Schillaci R, Capra G, Bellavia C, et al . Detection of oncogenic human papillomavirus genotypes on spermatozoa from male partners of infertile couples.Fertil Steril . 2013; 100(5): 1236–40. DOI: 10.1016/j.fertnstert.2013.06.042 - 12.
Petersen I, Klein F. HPV in non-gynecological tumors. Der Pathologe . 2008; 29(2): 118–22. DOI: 10.1007/s00292-008-1051-x - 13.
Giuliano AR, Lazcano-Ponce E, Villa LL, Flores R, Salmeron J, Lee J-H, et al . The human papillomavirus infection in men study: human papillomavirus prevalence and type distribution among men residing in Brazil, Mexico, and the United States.Cancer Epidemiol Biomarkers Prev. 2008; 17(8): 2036–43. DOI: 10.1158/1055-9965.EPI-08-0151 - 14.
La Vignera S, Vicari E, Condorelli RA, et al . Prevalence of human papilloma virus infection in patients with male accessory gland infection.Reprod Biomed Online . 2015; 30(4): 385–91. DOI: 10.1016/j.rbmo.2014.12.016 - 15.
Foresta C, Pizzol D, Moretti A, Barzon L, Palù G, Garolla A. Clinical and prognostic significance of human papillomavirus DNA in the sperm or exfoliated cells of infertile patients and subjects with risk factors. Fertil Steril . 2010; 94(5): 1723–7. DOI: 10.1016/j.fertnstert.2009.11.012 - 16.
Capra G, Nyitray AG, Lu B, et al . Analysis of persistence of human papillomavirus infection in men evaluated by sampling multiple genital sites.Eur Rev Med . 2015; 19(21): 4153–63. - 17.
Yang Y, Jia CW, Ma YM, Zhou LY, Wang SY. Correlation between HPV sperm infection and male infertility. Asian J Androl . 2013; 15: 529–32. DOI: 10.1038/aja.2013.36 - 18.
Garolla A, Pizzol D, Foresta C. The role of human papillomavirus on sperm function. Curr Opin Obstet Gynecol . 2011; 23(4): 232–7. DOI: 10.1097/GCO.0b013e328348a3a4 - 19.
Garolla A, Pizzol D, Bertoldo A, De Toni L, Barzon L, Foresta C. Association, prevalence, and clearance of human papillomavirus and antisperm antibodies in infected semen samples from infertile patients. Fertil Steril . 2013; 99(1): 125–31. DOI: 10.1016/j.fertnstert.2012.09.006 - 20.
Garolla A, Pizzol D, Bertoldo A, et al . Sperm viral infection and male infertility: focus on HBV, HCV, HIV, HPV, HSV, HCMV, and AAV.J Reprod Immunol . 2013; 100(1): 20–9. DOI: doi: 10.1016/j.jri.2013.03.004 - 21.
Cañadas MP, Lloveras B, Lorincz A, Ejarque M, Font R, Bosch FX, Silvia de Sanjosé. Evaluación de las técnicas de detección del VPH en los programas de cribado para cáncer de cuello uterino. Salud pública de méxico . 2006; 48(5): 373–378. - 22.
Concha RM. Diagnóstico y terapia del virus papiloma humano. Rev Chil Infect . 2007; 24 (3): 209–214. - 23.
Silva R, León D, Brebi P, Ili C, Roa JC, Sánchez, R. Diagnóstico de la infección por virus papiloma humano en el hombre. Rev Chilena Infectol . 2013; 30 (2): 186–192. - 24.
de Martel C, Ferlay J, Franceschi S, Vignat J, Bray F, Forman D, et al . Global burden of cancers attributable to infections in 2008: a review and synthetic analysis.Lancet Oncol . 2008; 13(6): 607–15. DOI: 10.1016/S1470-2045 - 25.
Budai I. Chlamydia trachomatis: milestones in clinical and microbiological diagnostics in the last hundred years: a review. Acta Microbiol Immunol Hung . 2007, 54: 5–22. DOI: 10.1556/AMicr.54.2007.1.2 - 26.
Resnikoff, S, et al . Global data on visual impairment in the year 2002.Bull World Health Organ , 2004. 82: 844–51. DOI: 10.1590/S0042-96862004001100009 - 27.
Ripa KT. Microbiological diagnosis of Chlamydia trachomatis infection. Infection . 1982, 10: S19–S24. DOI: 10.1007/BF01640710 - 28.
Tan M and Bauvoil P. Intracellular Pathogens I: Chlamydiales . Washington, DC, USA: ASM Press; 2012. - 29.
Torrone E, Papp J, Weinstock H. Centers for Disease Control and Prevention (CDC). Prevalence of Chlamydia trachomatis genital infection among persons aged 14-39 years--United States, 2007-2012. MMWR Morb Mortal Wkly Rep . 2014, 63: 834–838. - 30.
Hogben M, Leichliter JS. Social determinants and sexually transmitted disease disparities. Sex Transm Dis . 2008, 35: S13–S8. DOI: 10.1097/OLQ.0b013e31818d3cad - 31.
Occhionero M, Paniccia L, Pedersen D, et al . Prevalence ofChlamydia trachomatis infection and factors with the risk of acquiring sexually transmitted infections in college students.Rev Argent Microbiol . 2015, 47(1): 9–16. DOI: 10.1016/j.ram.2014.11.003 - 32.
Oakeshott P, Kerry S, Aghaizu A, et al . Randomised controlled trial of screening for Chlamydia trachomatis to prevent pelvic inflammatory disease: the POPI (prevention of pelvic infection) trial.BMJ . 2010, 340: c1642. DOI: 10.1136/bmj.c1642 - 33.
Paavonen J, Eggert-Kruse W. Chlamydia trachomatis: impact on human reproduction. Hum Reprod Update . 1999, 5: 433–47. DOI: 10.1093/humupd/5.5.433 - 34.
Geneva: World Health Organization; 2011. Global prevalence and incidence of selected curable sexually transmitted diseases: Overview and estimates. Centers for Disease Control and Prevention. Sexually transmitted disease surveillance 2011. U.S. Department of Health and Human Services, Atlanta, GA (2012) - 35.
Fieser N, Simnacher U, Tausch y, et al .Chlamydia trachomatis prevalence, genotype distribution and identification of the new Swedish variant in Southern Germany.Infection . 2013, 41: 159–66. DOI: 10.1007/s15010-012-0301-2 - 36.
Samplaski MK, Domes T, Jarvi KA. Chlamydial Infection and its role in male infertility. Advances in Andrology . 2014, 2014:1–11. DOI: 10.1155/2014/307950 - 37.
Hosseinzadeh S, Eley A, Pacey A. Semen quality of men with asymptomatic chlamydial infection. J Androl . 2004, 25: 104-109. DOI: 10.1002/j.1939-4640.2004.tb02764.x - 38.
Chernesky MA. The laboratory diagnosis of Chlamydia trachomatis infections.Can J Infect Dis Med Microbiol . 2005, 16(1): 39–44. - 39.
Harkins AL, and Munson E. Molecular diagnosis of sexually transmitted Chlamydia trachomatis in the United States. ISRN Obstet Gynecol . 2011: 2011: 279149. DOI: 10.5402/2011/279149 - 40.
Johnson AM, Horner P. A new role for Chlamydia trachomatis serology?.Sex Transm Infect . 2008, 84: 79–80. DOI: 10.1136/sti.2007.028472 - 41.
Tabora N, Zelaya A, Bakkers J, et al. Chlamydia trachomatis and genital human papillomavirus infections in female university students in Honduras.Am J Trop Med Hyg . 2005; 73: 50–53. - 42.
Colín-Ferreyra MC, Mendieta-Zerón H, Romero-Figueroa MS, Martínez-Madrigal M, Martínez-Pérez S, Domínguez-García MV. Expression of gamma interferon during HPV and Chlamydia trachomatis infection in cervical samples. Enferm Infecc Microbiol Clin . 2015; 33(2): 105–9. DOI: 10.1016/j.eimc.2014.05.014 - 43.
Tamim H, Finan RR, Sharida HE, et al. Cervicovaginal coinfections with human papillomavirus andChlamydia trachomatis .Diagn Microbiol Infect Di s. 2002; 43: 277–281. - 44.
Gopalkrishna V, Aggarwal N, Malhotra VL et al .Chlamydia trachomatis and human papillomavirus infection in Indian women with sexually transmitted diseases and cervical precancerous and cancerous lesions.Clin Microbiol Infect . 2000; 6: 88–93. - 45.
Lehtinen M, Ault KA, Lyytikainen E, et al. Chlamydia trachomatis infection and risk of cervical intraepithelial neoplasia.Sex Transm Infect . 2011; 87: 372–376. DOI: 10.1136/sti.2010.044354 - 46.
Paba P, Bonifacio D, Di BL et al . Co-expression of HSV2 andChlamydia trachomatis in HPV-positive cervical cancer and cervical intraepithelial neoplasia lesions is associated with aberrations in key intracellular pathways.Intervirology . 2008; 51: 230–234. DOI: 10.1159/000156481 - 47.
Alberts CJ, Schim van der Loeff MF, Papenfuss MR, da Silva RJ, Villa LL, Lazcano-Ponce E, Nyitray AG, Giuliano AR. Association of Chlamydia trachomatis infection and herpes simplex virus type 2 serostatus with genital human papillomavirus infection in men: the HPV in men study. Sex Transm Dis .2013; 40(6): 508–15. DOI: 10.1097/OLQ.0b013e318289c186 - 48.
Gimenes F, Medina FS, Abreu AL, et al. Sensitive simultaneous detection of seven sexually transmitted agents in semen by multiplex-PCR and of HPV by single PCR.PLoS One . 2014; 9(6): e98862. DOI: 10.1371/journal.pone.0098862 - 49.
Foresta C, Garolla A, Zuccarello D, et al . Human papillomavirus found in sperm head of young adult males affects the progressive motility.Fertil Steril . 2010; 93: 802–6. DOI: 10.1016/j.fertnstert.2008.10.050 - 50.
Vardas E, Giuliano AR, Goldstone S, et al . External genital human papillomavirus prevalence and associated factors among heterosexual men on 5 continents.J Infect Dis . 2011; 203: 58–65. DOI: 10.1093/infdis/jiq015 - 51.
Pérez-Andino J, Buck CB, Ribbeck K. Adsorption of human papillomavirus 16 to live human sperm. PLoS One . 2009; 4: e5847. DOI: 10.1371/journal.pone.0005847 - 52.
Ghosh M, Choudhuri S, Ray RG, Bhattacharya B, Bhattacharya S. Association of genital Chlamydia trachomatis infection with female infertility, study in a tertiary care hospital in Eastern India. Open Microbiol J . 2015; 9: 110–6. DOI: 10.2174/1874285801509010110 - 53.
Verweij SP, Kebbi-Beghdadi C, Land JA, Ouburg S, Morré SA, Greub G. Waddlia chondrophila and Chlamydia trachomatis antibodies in screening infertile women for tubal pathology. Microbes Infect . 2015; 17(11–12): 745–8. DOI: 10.1016/j.micinf.2015.09.019 - 54.
Steiner AZ, Diamond MP, Legro RS, et al ;. Reproductive Medicine Network. Chlamydia trachomatis immunoglobulin G3 seropositivity is a predictor of reproductive outcomes in infertile women with patent fallopian tubes.Fertil Steril . 2015; 104(6): 1522–6. DOI: 10.1016/j.fertnstert.2015.08.022 - 55.
Mazzoli S, Cai T, Addonisio P, Bechi A, Mondaini N, Bartoletti R. Chlamydia trachomatis infection is related to poor semen quality in young prostatitis patients. Eur Urol . 2010; 57(4): 708–14. DOI: 10.1016/j.eururo.2009.05.015 - 56.
Eley A, Hosseinzadeh S, Hakimi H, et al . Apoptosis of ejaculated human sperm is induced by co-incubation with Chlamydia trachomatis lipopolysaccharide.Hum Reprod . 2005a; 20: 2601–2607. - 57.
Sellami H, Znazen A, Sellami A, et al . Molecular detection of Chlamydia trachomatis and other sexually transmitted bacteria in semen of male partners of infertile couples in Tunisia: the effect on semen parameters and spermatozoa apoptosis markers.PLoS One . 2014; 9(7): e98903. DOI: 10.1371/journal.pone.0098903 - 58.
Kjaer SK, Munk C, Winther JF, Jørgensen HO, Meijer CJ, van den Brule. Acquisition and persistence of human papillomavirus infection in younger men: a prospective follow-up study among Danish soldiers. Cancer Epidemiol Biomarkers . 2005; 14(6): 1528–33. - 59.
Shigehara K, Kawaguchi S, Sasagawa T, et al . Prevalence of genital mycoplasma, ureaplasma, gardnerella, and human papillomavirus in Japanese men with urethritis, and risk factors for detection of urethral human papillomavirus infection.J Infect Chemother . 2011; 17: 487–492. DOI: 10.1007/s10156-010-0203-0 - 60.
Castle PE, Giuliano AR. Chapter 4: Genital tract infections, cervical inflammation, and antioxidant nutrients-assessing their roles as human papillomavirus cofactors. J Natl Cancer Inst Monogr . 2003; 31: 29–34. - 61.
Manavi K. A review on infection with Chlamydia trachomatis. Best Pract Res Clin Obstet Gynaecol . 2006; 20: 941–951. - 62.
Cai T, Wagenlehner F.M.E, Mondaini N, et al . Effect of human papillomavirus and Chlamydia trachomatis co-infection on sperm quality in young heterosexual men with chronic prostatitis-related symptoms.BJUI International . 2013; 113: 281–287. DOI: 10.1111/bju.12244