Male Genital Infection and Infertility

1. Male Genital Infection and Infertility Du Geon Moon, MD, Ph.D. Department of Urology Korea University College of Medicine

2. Contents • Text & Controversy • Pyospermia • Microbiology • Chlamydia • Mycoplasmataceae • Male accessory gland infection & Infertility • Urethritis, Prostatitis, Epididymitis, Orchitis* * Male accessory gland infection by the WHO [1993]

3. EAU Guidelines on Male Infertility • One of the potentially correctable causes of male infertility is symptomatic and asymptomatic infection of the male urogenital tract. European Urology 48 (2005) 703-711

4. Components of the History in the Evaluation of Infertile Male Past Medical History Urinary infections  STD  Viral orchitis Epididymitis   Tuberculosis Classification of Male Infertility by Criteria of Semen Analysis Azoospermia Spermatogenic abnormalities : Viral orchitis Asthenospermia Genital tract infection What’s on Text? Campbell-Walsh Urology 9th edition

5. Controversy • Evident infertility • Male accessory organ destruction • Seminal tract obstruction • Lack of evidence for negative influence on sperm quality • Basic ejaculate analysis does not reveal a link between accessory gland infection and impaired sperm characteristics • Antibiotic treatment • symptomatic relief, eradicates micro-organisms • no positive effect on inflammatory alterations • cannot reverse functional deficits and anatomical dysfunctions • may provide improvement in sperm quality • not always enhancethe probability of conception Campbell-Walsh Urology 9th edition

6. Do you think Male genital infections are related to Infertility?

7. Pyospermia, Infection and Fertility • POSITIVE • Infertile couples tend to have greater concentrations of WBCs than fertile populations (Wolff & Anderson, 1988) • Infection and infertility have been associated with pyospermia (Caldamone, 1980; Maruyama, 1985) • NEGATIVE • Presence of bacteria in semen has not always correlated with the presence of pyospermia (Rodin, 2003) • Many patients of pyospermia do not have genital tract infections • Not all studies of patients with increased leukocytes in the semen report decreased fertility rates (Tomlinson, 1993) Campbell-Walsh Urology 9th edition

8. Pyospermia • S/A reports that list numbers or conc. of WBCs • should be viewed with skepticism • Immature germ cells (spermatocytes) and leukocytes • appear similar under wet mount microscopy • known as round cells • cannot usually be differentiated without special stain • Increased numbers of round cells • should list as round cells unless special stains • true pyospermia: 1/3, spermatocytes: 2/3(Sigman & Lopes, 1993) • WBC staining of semen • not generally used during semen analysis • more than 10 to 15 round cells/HPF or 1 million round cells/mL Campbell-Walsh Urology 9th edition

9. Management of Pyospermia • If the majority are WBCs and  1 million cells/mL • considered abnormal • possible genital tract infection or inflammation • should be evaluated for a genital tract infection • Absence of infection • anti-inflammatory medication • empirical antibiotic therapy • frequent ejaculations • prostatic massage Lack of proven efficacy (Yanushpolsky, 1995) • Semen processing to remove the WBCs • combined with IUI or IVF Campbell-Walsh Urology 9th edition

10. Microbiology (semen culture) • Human semen culture • Many aerobic and anaerobics (Upadhyaya, 1984) • Mycoplasma (Naessens, 1986) • Effects of seminal bacteria on fertility • may be spermicidal (Paulson, 1977) • no consistent effect on fertility (Berger, 1982) • Routine genital tract cultures are not indicated • clinical symptoms (-) or documented pyospermia(-) • Culture(+) genital infection with clinical symptoms • appropriate treatment Campbell-Walsh Urology 9th edition

11. I. Chlamydia trachomatis • Obligate intracellular bacterium • One of the most common STD • Up to 50% of infected may be asymptomatic • Cause of nongonococcal urethritis & epididymitis • Those with symptom, urethritis is most common • Can C. trachomatis directly damage sperm? • The effect on male infertility is unclear and controversial. • Cultured from semen, prostatic secretions, urine (Thompson & Washington, 1983)

12. Past infection in men, in-vivo Correlation of serological markers with infertility status or semen quality Semen quality is not different from uninfected controls (Ness RB, 1997) not seem to affect semen parameters in the absence of epididymal obstruction Independent association between infertility and chlamydial IgG antibodies (Idahl A, 2004) Lancet Infect Dis 2005;5:53-57

13. Ongoing infection in men, in-vivo Obvious ethical and technical difficulties Unaffected by the bacterium Semen quality (Hosseinzadeh S, 2004) Key aspects of sperm function (Vigil P, 2002) Chlamydia (+) men significant reduction in sperm acrosomal reaction (Jungwirth A, 2003) Lancet Infect Dis 2005;5:53-57

14. Bacterial adherence to spermatozoa Bacterial hitch hikers (Eley A, 2001) Explanation of disease spread C. trachomatis elementary bodies decline in sperm mortility (Hosseinzadeh S, 2001) Premature sperm death Attachment of green fluorescent C. trachomatis elementary bodies to humen sperm C. trachomatis infection,in-vitro Most in-vitro studies concentrated on the effect of the bacterium on sperm function directly Lancet Infect Dis 2005;5:53-57

15. C trachomatis lipopolysaccharide Lancet Infect Dis 2005;5:53-57 • Primary cause of spermatozoa death • premature sperm death (Hosseinzadeh S, 2003) • same as female genital tract • Most spermicidal in human beings • 65% mortality in spermatozoa (0.1ug/mL, 1hr) • 500 times more active than E. coli

16. Proposed hypothesis on Future research • CD14 lipopolysaccharide interacts with cells via CD14 in seminal plasma & on spermatozoa • Reactive oxygen species (ROS) • decrease sperm mortility • disrupt sperm function by peroxidation • Apoptosis • ROS, act as molecular mediators of apoptosis Lancet Infect Dis 2005;5:53-57

17. II. Mycoplasmataceae • Include Mycoplasma and Ureaplasma : Gram's stain (-) • Mycoplasma hominisandUreaplasma urealyticum • Ass.with nongonococcal urethritis in humans • U. urealyticum attacks spermatozoa directly • Attachment on head, midpiece of sperm by EM (Gnarpe, 1972) • Attachment on sperm decrease sperm quality (Grossgebauer, 1984) • U. urealyticum • elevated levels of leukocyte-derived ROS  damage sperm by lipid peroxidation (Potts, 2000)

18. Recent Evidence of Mycoplasmataceae • M. hominis and U. urealyticum in semen culture (+) • represents colonization and not infection • no evidence of inflammatory reactions (Pannekoek, 2000) • U. urealyticum • decrease motility and membrane changes (Nunez, 1998) • no differences in semen parameters between culture (+) and (-) (Busolo, 1984; Soffer, 1990; Andrade-Rocha, 2003) • M. genitalium • clearly pathogenic, a common cause of urethritis (Jensen, 2004) • Lack of studies regarding the role on male infertility

19. Test for M. genitalium & C. trachomatis • Clinical evidence of inflammatory or infectious process • Urine culture • should be in patients with evidence of cystitis or urethritis • Semen culture • frequently yield low concentrations of multiple organisms for distal urethral contamination. • Antibacterial skin preparation and voiding before ejaculation • decreases the incidence of false (+) (Kim & Goldstein, 1999) • First-void urine PCR • higher sensitivity than culture • less uncomfortable than urethral swabs (Maeda, 2004)

20. Urethritis - Impact on infertility Sexually acquired urethritis Neisseria gonorrhoeae Chlamydia trachomatis Ureaplasma urealyticum Negative influence is under debate Past infection with N. gonorrhoeae associated with leukocytospermia (Trum, 1998) Impair fertility Urethral stricture & ejaculatory disturbance (WHO 1993) Urethral obstruction & ejaculatory disturbance (Purvis and Christiansen, 1995)

21. “Prostatitis is associated with Infertility” • 5-12% of infertile man • history of past infection (Dohle, 2003) • 12% of abnormal semen quality • male genital infection (Everaert, 2003) • Bacteria itself can produce IL-8 • deleterious effect on fertility (Depuydt, 1996) • Chlamydia, E. coli • decrease acrosomal reaction (Kohn, 1998)

22. “Prostatitis is not associated with Infertility” Krieger et al, 1999, Campbell’s Urology 9th edition • Nonbacterial prostatitis/prostatodynia vs normal control • No difference in density, motility, morphology (Weidner, 1999) • Nonbacterial prostatitis (Ludwig, 2003) • leukocytospermia(+) • no effect on density, motility, morphology

23. Chronic pelvic pain syndrome affect the acrosomal reaction in human spermatozoa • Sperm membrane for normal sperm function • Genital tract infection, reactive oxygen species: • responsible for damage of sperm via sperm membrane function • resulting in loss of sperm motility, compromised fertility World J Urol (2006) 24: 39-44

24. Impact of Prostatitis IIIB (Prostatodynia) on Ejaculate Parameters • The first age-matched controlled study European Urology 44 (2003) 546-548

25. Summary of Prostatitis • Fertility and prostatitis relations remain obscure • Limitations of current studies on semen quality • exact classification criteria, control groups, complete spermiogram data • Reduced fructose conc. in prostatitis NIH IIIB • impaired secretion of the seminal vesicles, somatic factor • reduction of motility, indirectly linked to forward sperm motility through prostasome function • Acrosomal function in chronic prostatitis • Balance between ROS and antioxidant capacity in semen plays critical role in the pathophysiology of genital tract inflammations and their impact on sperm functions and fertilization

26. Epididymitis Sexually active men <35 yrs : C. trachomatis or N. gonorrhoeae Men > 35 yrs : Gram-negative enteric organism Pathophysiology of epididymal duct stenosis, obstruction Wall thickening and altered contractility (Pelliccione, 2004) replacement of spindle-shaped myoid cells in normal contractile tubules by large smooth muscle cells (SMCs) Increased mechanical forces from the obstruction activate the differentiation of myoid cells into SMCs Reduction of sperm count, eventual azoospermia Rare azoospermia after initial 14-day epididymitis (Weidner, 1990) Initial antibiotic therapy prevent worse effect on sperm transportation (Purvis & Christiansen, 1995)

27. Ejaculate analysis & Impact on fertility Transient decrease of sperm count and forward motility

28. Tb epididymitis Ko et al. Korea J Urol 1994 • Vasal infection in 20-41% • Asymtomatic inflammation of epididymis and vas deference • eventual epididymal & vasal obstruction • Semen analysis • decrease semen volume : 33% • oligospermia : 11%

29. Orchitis - Ejaculate analysis • Leukocytic exudate inside and outside the seminiferous tubules resulting in tubular sclerosis • Acute epididymo-orchitis, • transient decrease of sperm count and forward motility (Diemer & Desjardins, 1999) • Acute obstructive azoospermia is rare complication • Chronic inflammation of seminiferous tubules • disrupt normal spermatogenesis, alterations in sperm number and quality (Purvis & Christiansen, 1995) • spermatogenic arrest (Weidner & Krause, 1999) • testicular atrophy and azoospermia in mumps-orchitis

30. Take Home Messages • Unlike female sterility, the significance of genital infections for male infertility is still debating. • Male accessory glands are reservoirs for organisms(C. trachomatis and M. genitalium) hence increase transmission to the partners. • Cautious use of leukospermia or bacteriospermia as parameters for glandular infection. Instead of classical parameters, e.g. the determination of microorganisms and/or counting leukocytes, functional parameters such as cytokines, ROS or other indicators of inflammation should be estimated if available. • Proper antibiotic treatment and empirical treatment are important for eradicating microorganism, symptom improvement, prevention of transmission to others and decrease of potential complications, e.g. stricture, obstruction or atrophy.

31. Now, do you think Male genital infections are related to Infertility? Thank You for Attention !!