Male Genital Infection and Infertility

Du Geon Moon, MD, Ph.D.

Department of Urology

Korea University College of Medicine

Contents

Text & Controversy

Pyospermia

Microbiology

Chlamydia

Mycoplasmataceae

Male accessory gland infection & Infertility

Urethritis, Prostatitis, Epididymitis, Orchitis*

* Male accessory gland infection by the WHO [1993]

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

What’s on Text?

Components of the History in th

e 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

Campbell-Walsh Urology 9th edition

ControversyEvident 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 enhance the probability of conception

Campbell-Walsh Urology 9th edition

Do you think Male genital infections are related to Infertility?

Pyospermia, Infection and FertilityPOSITIVE Infertile couples tend to have greater concentrations of WBCs t

han 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 t

he 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 sem

en report decreased fertility rates (Tomlinson, 1993)

Campbell-Walsh Urology 9th edition

PyospermiaS/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

Management of PyospermiaIf 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

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

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)

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 epidid

ymal obstruction

Independent association between infertility and chlamydial IgG antibodies (Idahl A, 2004)

Lancet Infect Dis 2005;5:53-57

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

C. trachomatis infection, in-vitro

Bacterial adherence to spermatozoa Bacterial hitch hikers (Eley A, 2001) Explanation of disease spread

C. trachomatis elementary bodies decline in sperm mortility (Hosseinz

adeh S, 2001) Premature sperm death

Attachment of green fluorescent C. trachomatis elementary bodies to humen sperm

Lancet Infect Dis 2005;5:53-57

Most in-vitro studies concentrated on the effect of the bacterium on sperm function directly

C trachomatis lipopolysaccharide

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

Lancet Infect Dis 2005;5:53-57

Proposed hypothesis on Future research

CD14 lipopolysaccharide interacts with c

ells via CD14 in seminal plasma & on spermatozoa

Reactive oxygen species (ROS) decrease sperm mortility disrupt sperm function by peroxida

tion

Apoptosis ROS, act as molecular mediators o

f apoptosis

Lancet Infect Dis 2005;5:53-57

II. Mycoplasmataceae

Include Mycoplasma and Ureaplasma : Gram's stain (-)

Mycoplasma hominis and Ureaplasma urealyticumAss.with nongonococcal urethritis in humans

U. urealyticum attacks spermatozoa directlyAttachment on head, midpiece of sperm by EM (Gnarpe, 1972)Attachment on sperm decrease sperm quality (Grossgebauer, 19

84)

U. urealyticum elevated levels of leukocyte-derived ROS

damage sperm by lipid peroxidation (Potts, 2000)

Recent Evidence of MycoplasmataceaeM. 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, 200

4) Lack of studies regarding the role on male infertility

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 di

stal 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)

Urethritis - Impact on infertilitySexually acquired urethritis Neisseria gonorrhoeae Chlamydia trachomatis Ureaplasma urealyticum

Negative influence is under debatePast infection with N. gonorrhoeae associated with leukocytospermia (Trum, 1998)

Impair fertility Urethral stricture & ejaculatory disturbance (WHO 1993) Urethral obstruction & ejaculatory disturbance (Purv

is and Christiansen, 1995)

“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)

“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

Chronic pelvic pain syndrome affect the acrosomal reaction in human spermatozoa

Sperm membrane for normal sperm functionGenital 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

Impact of Prostatitis IIIB (Prostatodynia) on Ejaculate Parameters

The first age-matched controlled study

European Urology 44 (2003) 546-548

Summary of Prostatitis

Fertility and prostatitis relations remain obscure

Limitations of current studies on semen quality exact classification criteria, control groups, complete spermiogra

m 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 thr

ough prostasome function

Acrosomal function in chronic prostatitis Balance between ROS and antioxidant capacity in semen plays c

ritical role in the pathophysiology of genital tract inflammations and their impact on sperm functions and fertilization

EpididymitisSexually 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 tub

ules by large smooth muscle cells (SMCs) Increased mechanical forces from the obstruction activate the differ

entiation 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 transportatio

n (Purvis & Christiansen, 1995)

Ejaculate analysis & Impact on fertility

Transient decrease of sperm count and forward motility

Tb epididymitis

Vasal infection in 20-41%

Asymtomatic inflammation of epididymis and vas deference eventual epididymal & vasal obstruction

Semen analysis decrease semen volume : 33% oligospermia : 11%

Ko et al. Korea J Urol 1994

Orchitis - Ejaculate analysisLeukocytic exudate inside and outside the seminiferous tubules resulting in tubular sclerosis

Acute epididymo-orchitis, transient decrease of sperm count and forward motility (Dieme

r & 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

Take Home MessagesUnlike 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.

Now, do you think Male genital infections are related to Infertility?

Thank You for Attention !!