II.2.4 Urethritis, Sexually Transmitted Diseases (STD), Acquired Immunodeficiency Syndrome (AIDS) 327

tween chronic prostatitis syndrome and pelvic venous dis- Wilson M, Seymour R, Henderson B (1998) Bacterial pertur- ease: a survey of 2,554 urological outpatients. Eur Urol bation of cytokine networks. Infect Immun 66:2401–2409 37:400–403 Witkin SS (1988) Mechanisms of active suppression of the im- Purvis K, Christiansen E (1993) Infection in the male repro- mune response to spermatozoa. Am J Reprod Immunol Mic- ductive tract. Impact, diagnosis and treatment in relation to robiol 17:61–64 male . Int J Androl 16:1–13 Witkin SS, Kligman I, Bongiovanni AM (1995) Relationship Rajasekaran M, Hellstrom WJ, Naz RK, Sikka SC (1995) Oxida- between asymptomatic male genital tract exposure to Chla- tive stress and interleukins in seminal plasma during leuko- mydia trachomatis and an autoimmune response to sperma- cytospermia. Fertil Steril 64:166–171 tozoa. Hum Reprod 10:2952–2955 Rowe PJ, Comhaire FH, Hargreave TB, Mahmoud AM (2000) Wolff H (1995) The biological significance of white blood cells World Health Organization manual for the standardized in- in semen. Fertil Steril 63:1143–1157 vestigation, diagnosis and management of the infertile Wolff H (1998) Methods for the determination of male genital male, 1st edn. Cambridge University Press, Cambridge tract inflammation. Andrologia 30:35–39 Shimoya K, Matsuzaki N, Ida N, Okada T, Taniguchi T, Sawai K, WolffH,PolitchJA,MartinezA,HaimoviciF,HillJA,Anderson Itoh S, Ohashi K, Saji F, Tanizawa O (1995) Detection of DJ (1990) Leucocytospermia is associated with poor semen monocyte chemotactic and activating factor (MCAF) and quality. Fertil Steril 53:528–536 interleukin (IL)-6 in human seminal plasma and effect of Yamauchi-TakiharaK,IharaY,OgataA,YoshizakiK,AzumaJ, leukospermia on these cytokine levels. Am J Reprod Immu- Kishimoto T (1995) Hypoxic stress induces cardiac myocy- nol 34:311–316 te-derived interleukin-6. Circulation 91:1520–1524 Shoskes DA, Albakri Q, Thomas K, Cook D (2002) Cytokine Yanushpolsky EH, Politch JA, Hill JA, Anderson DJ (1995) An- polymorphisms in men with chronic prostatitis/chronic tibiotic therapy and leucocytospermia: a prospective, ran- syndrome: association with diagnosis and treat- domised, controlled study. Fertil Steril 63:142–147 ment response. J Urol 168:331–335 Yoshimura T, Matsushima K, Oppenheim JJ, Leonard JJ (1987) Tomlinson MJ, Barratt CLR, Cooke ID (1993) Prospective Neutrophil chemotactic factor produced by lipopolysaccha- study of leukocytes and leukocyte subpopulations in semen ride (LPS)- stimulated human blood mononuclear leuko- suggests they are not a cause of male infertility. Fertil Steril cytes: partial characterization and separation from interleu- 60:1069–1075 kin 1 (IL 1). J Immunol 139:788–793 WeidnerW,KrauseW,LudwigM(1999)Relevanceofmaleac- Zalata AA, Christophe A, Depuydt CE, Schoonjans F, Comhaire cessory gland infection for subsequent fertility with special FH (1998) White blood cells cause oxidative damage to the focus on prostatitis. Hum Reprod 5:421–432 fatty acid composition of phospholipids of human sperma- Westendorp RG, Langermans JA, Huizinga TW, Verweij CL, tozoa. Int J Androl 21:154–162 Sturk A (1997) Genetic influence on cytokine production in Zalata AA, Ahmed AH, Allamaneni SS, Comhaire FH, Agarwal meningococcal disease. Lancet 28; 349(9069):1912–1913 A (2004) Relationship between acrosin activity of human WHO (1987) Towards more objectivity in diagnosis and man- spermatozoa and oxidative stress. Asian J Androl 6:313–318 agement of male infertility. Int J Androl [Suppl 7] 19–33

II.2.4 Urethritis, Sexually Transmitted Diseases (STD), Acquired Immunodeficiency Syndrome (AIDS) F. R. Ochsend orf

Summary According to the present data, urethritis poses no paired with progression of the acquired immuno- problem for male fertility. In chronic infections, for deficiency. Reproduction in HIV-serodiscordant example gonorrhoea, urethral strictures and epidi- couples is possible by special sperm washing pro- dymo-orchitis are possible. Chlamydia trachomatis cedures and testing of the samples prior to assisted and Neisseria gonorrhoeae can lead to pelvic in- reproductive techniques. flammatory disease of the female partner and tubal obstruction. Depending on the local prevalence some sexually transmitted disease (STD) agents can II.2.4.1 impair male fertility if not adequately treated. Any Introduction II.2 STD increases the chance of transmission of human immunodeficiency virus (HIV). HIV infection is as- A common feature shared by STD is that the causative sociated with infectious semen and the risk of trans- microorganisms are labile in inanimate environments. mission of the virus. Men who are seropositive only Therefore, they are only transmitted via intimate con- and do not have full-blown AIDS often present with tact. They are summarized in Table II.2.4 and normal semen parameters. Their endocrine and Chap. I.6.1. Due to their shared mode of transmission, exocrine testicular functions are, however, im- several of these agents may be transferred together, so the diagnosis of one STD prompts the search for others. 328 II.2 Mechanisms of Dysfunction and Pathology

Table II.2.4. The most common microorganisms causing urethritis, their diagnoses and treatment. The percentages are taken from the literature; in case of strong variance, the maximal and minimal numbers are given in parentheses (from Gall et al. 1999; Elsner et al. 1987; Heise 2001; Kohl 2001) Microorganism and Frequency (%) Detection method Therapy incubation time Neisseria gonorrhoea [0] 0.4 – 9– [18] Culture (Thayer-Martin Once: spectinomycin 2 g or ceftriaxone 1–6 (–14) days selective medium; fast trans- 0.25 g i.m. alternatively (p.o.): cefixim port!); DNA hybridization 400 mg or ciprofloxacin 500 mg or ofloxacin (first-void urine) 400 mg or azithromycin 1 g C. trachomatis [6] 15–26 Ag-detection (direct immu- Once: azithromycin 1 × 1000 mg or 7 days: 7–21 days nofluorescence, EIA), DNA doxycycline2×100mg;alternative:(7days amplification (PCR; LCR) p.o.): tetracyclines 4 × 500 mg or erythro- mycin 4 × 500 mg or ofloxacin 2 × 300 mg Mycoplasma 10–21 Culture (special medium) As Chlamydia Ureaplasma urealyticum 15–17 Mycoplasma hominis 4–6 Mycoplasma genitalium 18–45 Special culture (no routine 7 days doxycycline 2 × 100 mg/day; alterna- (Deguchi and Maeda 2002) method available) tive: macrolides, new chinolone Pathogenic bacteria (Entero- [4] – 20–31 Culture According to antibiogram coccus, beta-haemolysing streptococci, E. coli, Staphylo- coccus aureus) Trichomonas vaginalis 0.4–1 Urine sediment of first-void Once metronidazole 2 g p.o. or tinidazole 4daysto3weeks urine 2gp.o. Herpes simplex Single cases Only if no therapeutic effect: Aciclovir5×200mgp.o.5–7days culture, antigen detection or PCR Candida Single cases 3 Only if no therapeutic effect: Topical imidazole derivative; alternative: culture p.o.: fluconazole 1 × 150 mg p.o. or keto- conazole 2 × 200 mg 5 days No agent demonstrable –26 Possible causes: False-negative test Repetition of microbiologic Functional irritation tests, history Traumatic urethritis Tumours of the urethra Urologic diagnostics HPV infection (urethroscopy) General disease History

STDs can lead to pelvic inflammatory disease (Ankum is likely that the prevalence of STDs, the availability of et al. 1996), ectopic pregnancy, infertility, chronic pel- health services, and the time and mode of STD treat- vic pain, genital lesions, genital neoplasms, adverse ment in a given population are all factors influencing pregnancy outcomes, immune system dysfunction, liv- the role of these infections in male infertility (Cates et er disease, gonococcal sepsis and even death; so, they al. 1985; De Schryver and Meheus 1990; Bambra 1999; have a considerable impact on the health of men and Jansen et al. 2003; Orroth et al. 2003; Bayasgalan et al. women. Even if the disease does not cause definite im- 2004). There are several reviews addressing these ques- pairment of sperm parameters, for example Chlamydia tions in more detail (Keck et al. 1998; Comhaire et al. trachomatis infections in men, it may be transferred to 1999; Paavonen and Eggert-Kruse 1999; Sulak 2003). the female partner and so has considerable impact in II.2 women, such as pelvic inflammatory disease resulting in tubal occlusion (Sulak 2003). II.2.4.2 There are studies reporting a positive history con- Urethritis cerning STDs in 45% of infertile patients (Schulenburg II.2.4.2.1 et al. 1993), while others did not find associations be- Pathogens tween prior urethral discharge or dysuria and subse- quent semen quality (Oldereid et al. 1992). A higher Urethritis can be caused by several pathogens (Ta- percentage of STD agents was reported in infertile men ble II.2.4; Elsner et al. 1987; Gall et al. 1999; Heise 2001; and women than in controls (Rodriguez et al. 2001). It Kohl 2001; Deguchi and Maeda 2002). The most rele- II.2.4 Urethritis, Sexually Transmitted Diseases (STD), Acquired Immunodeficiency Syndrome (AIDS) 329 vant are gonorrhoea, Chlamydia trachomatis, Urea- Especially in Africa infertility due to tubal obstruc- plasma urealyticum, Mycoplasma genitalium, Tricho- tionappearstobearelevantissue(Meheusetal.1986). monas vaginalis (Table II.2.4). Urethritis caused by me- In men urethral strictures may occur (Osoba 1981; Fie- chanical trauma is unrelated to infertility. Ascension of vet et al. 1987). Most strictures are seen in the posterior gonococci is estimated to occur in about 1% of infected urethra, where fibrosis and narrowing may extend patients. from a short length of under 5 mm to well over 10 cm. A wide variety of initial complaints and complications occurs. When the patient presents in acute retention or II.2.4.2.2 with a history of difficult micturition, the diagnosis is Clinical Presentation easy. However, when stricture is the underlying cause The symptoms are variable. In acute urethritis, the pa- of perianal abscess, gangrene of the scrotum caused by tient notices a urethral discharge and dysuria. Others extravasation, uraemia or hypertension, hernia or rec- have no symptoms or are symptom-free throughout tal prolapse, urinary infection, or elephantiasis of scro- the day and only notice a drop of pus in the morning tum with multiple fistulae, diagnosis may be difficult. A prior to the first voiding of urine. Sometimes the glans careful history is helpful, particularly if previous go- or meatus urethrae may present with some redness as a norrhoea is involved. The definite diagnosis is made be sign of inflammation. urethrography and urethroscopy (Bewes 1973). In Western countries such as Scotland, however, gonorr- hoea is not a relevant cause of urethral strictures II.2.4.2.3 (McMillan et al. 1994). It was proposed that a decline in Diagnosis subfertility in Sweden could be attributed to the eradi- The demonstration of >15 granulocytes in the sedi- cation of gonorrhoea (Akre et al. 1999), a view not ment of the first 3 ml of urine (400× magnification) is shared by others (Jensen et al. 2000). regarded as pathognomonic for an acute inflammation In men with asymptomatic gonorrhoea no differ- of the urethra (Schiefer 1998). The definite diagnosis is ences in spermatogram parameters were found before made by demonstration of the pathogenic agent [cul- and after treatment in comparison to a control group, ture, direct immunofluorescence, enzyme immunoas- with the exception of lowered citrate concentrations say (EIA) and nowadays molecular methods such as (Perez-Plaza et al. 1982). However, a follow-up investi- polymerase chain reaction (PCR) or ligase chain reac- gationofmenwithprovenfertilityafterhavinghadgo- tion (LCR); see Table II.2.4]. These tests have different norrhoeal urethritis and unilateral epididymo-orchitis sensitivities and specificities (Watson et al. 2002). showed that 2 years later only 21% produced semen considered adequate for conception. Although the le- sions were clinically confined to one testis, testicular II.2.4.2.4 biopsy samples showed damage in both testes. So go- Relevance norrhoea can lead to oligo- and azoospermia (Osegbe The question of whether urethritis leads to male infer- 1991). Others reported an increased incidence of anti- tility is discussed controversially. It is biologically plau- sperm antibodies after gonococcal urethritis (Shahma- sible that gonorrhoea and/or Chlamydia could cause neshetal.1986).Gonococcisurvivecryopreservation male infertility. There is clinical and pathologic evi- in liquid nitrogen, which has to be taken into account dence linking these pathogens to urethritis, linking for the screening of sperm donors (Sherman and Ro- urethritis to epididymo-orchitis, and linking epididy- senfeld 1975; Glander et al. 1986). mo-orchitistoinfertility.Aretrospectiveanalysesof During routine semen analyses of asymptomatic the literature, however, could not substantiate whether males no screening for gonococci routinely takes place these pathogens alter sperm characteristics. Methodo- in a low prevalence setting. It was reported that dilution logical problems were thought to be responsible (Ness of semen (1:2 with saline) enhances the detection rates et al. 1997). As yet there are no prospective controlled of N. gonorrhoeae (undiluted: 0 positive; diluted: 9/68 studies definitely proving this association. Urethral positive;Vicarietal.1986).Thesameauthorsreported stricture is another possible complication of urethritis, positive gonorrhoea cultures in 111/785 (14%) men in II.2 mainly due to gonococci (Bewes 1973). an andrologic outpatient clinic (Vicari et al. 1991). So the screening apparently has to be adjusted to local prevalence of the disease. Gonorrhoea The relevance of N. gonorrhoeae lies in its capacity The seroprevalence of N. gonorrhoeae ranged from 3% to lead to urethral strictures and testicular damage as a to 31% in different risk groups (study in Mexico; Cravi- consequence of epididymo-orchitis in the male as well oto Mdel et al. 2003). These rates are different in other as ductal inflammation and obstruction in the female. countries (Dougan et al. 2004). 330 II.2 Mechanisms of Dysfunction and Pathology

(Vigil et al. 2002). So sperm apparently act as vehicles Chlamydia trachomatis to transport the pathogen to the female. TheroleofChlamydia trachomatis as a cause of male Thereisnoquestionthatmalegenitalchlamydialin- infertility is discussed controversially (Krause and fections are a threat to female genital organs, because Bohring 2003; Gonzales et al. 2004). There is no doubt C. trachomatis infection of the female genital organs that Chlamydia trachomatis is a frequent pathogen in may be deleterious to female fertility mainly due to male genital inflammation and that this organism is tubal occlusion. This has been repeatedly demonstrat- rarely present in healthy men. Chlamydia trachomatis ed (Eggert-Kruse et al. 1990, 1996; Paavonen and Eg- causes inflammation of the male urethra and the epi- gert-Kruse 1999; Krause and Bohring 2003; Mardh didymis. However, it remains unresolved and unclear 2004). So C. trachomatis primarily has to be regarded as whether it causes prostatitis and infections of the semi- a threat to . nal vesicles (Weidner et al. 1999, 2002). Chlamydia trachomatis antigen or DNA is easily de- Mycoplasmas monstrable in urethral swabs and the urine. The sensi- tivities of DNA amplification techniques (LCR, PCR, Mycoplasmas include Mycoplasma hominis, Ureaplas- gene probe) in first-void urine were higher (85–96%) ma urealyticum and Mycoplasma genitalium. While the than in cervical swabs (84–88%; the same will hold first two germs can colonize the urethra without caus- true for urethral swabs) and yielded better results than ingsymptoms,thelatterwassuspectedtobeamajor an EIA (urine 38%, swab 65%). Especially in low prev- cause of urethritis and possibly (Uuskula and alence populations the molecular methods are more ef- Kohl 2002). It was suggested that female partners fective at detecting asymptomatic chlamydial infec- should be screened for these microorganisms in order tions than conventional tests (Watson et al. 2002). Chla- to detect them in the male genital tract (Trum et al. mydia trachomatis,however,cannotbereproducibly 2000). The incidence of U. urealyticum in the semen of demonstrated in secretions of the male accessory fertile and infertile men was reported to range between glands, including semen. 7 and 42% (Reichart et al. 2000). A higher incidence Serologic studies can be useful in epidemiologic in- wasreportedinthesemenofinfertilemen(38%to9% vestigations. In these studies an association was found in controls) (dXu et al. 1997). U. urealyticum was sus- between the detection of immunotype-specific C. tra- pected to cause chronic prostatitis (Badalyan et al. chomatis antibodies and subfertility both in men and 2003). U. urealyticum and M. genitalium can attach to women. So a previous C. trachomatis infection appears spermatozoa, be transported in the female genital tract to be associated with subfertility in male or female and can cause female genital disease (Taylor-Robinson partners of a given couple (Karinen et al. 2004). 2002; Svenstrup et al. 2003). TheroleofChlamydia serology as a marker of re- In in vitro fertilization (IVF) programmes M. homi- cent infection is a matter of debate. Former investiga- nis was found in 2–12% and U. urealyticum in 17–29% tions used tests that could not discriminate between C. in semen (Hill 1990; Witkin et al. 1995b). The demon- trachomatis and C. pneumoniae. Different test systems stration of a mycoplasma infection was not related to a yielded conflicting results. Thus determination of change in sperm parameters (Soffer et al. 1990) or chlamydial antibodies in serum or semen does not poorer IVF outcome if prior treatment with tetracy- conclusively indicate a current infection with C. tra- clines had been performed (Witkin et al. 1995a, b). It chomatis. The profile of these antibodies after treat- was suggested, however, that this infection can cause ment is unknown. Some authors found higher anti- embryo loss without necessarily affecting semen quali- body prevalences of Chlamydia trachomatis anti- ty. One possible mechanism is unstable chromatin. In bodies in infertile men and associations with heat- vitro incubation resulted in time- and dose-dependent shock proteins (Schuppe et al. 2003), others with in- chromatindecondensationandDNAdamageofsperm flammatory markers (Wolff et al. 1991; Ochsendorf cells. In vivo these effects could be reduced by doxycy- et al. 1999). cline therapy (Reichart et al. 2000). Observations are available indicating that Chlamyd- Thus U. urealyticum maycauseinfertilityviadelete- II.2 ia can enter human spermatozoa (Erbengi 1993), that rious effects on sperm chromatin and DNA, leading to they may induce antibody production (Shahmanesh et impairment of embryo development. The exact role of al. 1986; Soffer et al. 1990; Witkin et al. 1995a, b) and these microorganisms, however, has still to be eluci- may be associated with oxidative stress (Segnini et al. dated. 2003) and inflammation (Hosseinzadeh et al. 2004). However, there are no conclusive studies showing that Trichomonas vaginalis men infected with C. trachomatis are less fertile than uninfected men (literature in Krause and Bohring Protozoan infections of the male genital tract are rare 2003). Furthermore, sperm functions are not impaired and only a few species of parasites are involved (Marti- II.2.4 Urethritis, Sexually Transmitted Diseases (STD), Acquired Immunodeficiency Syndrome (AIDS) 331 nez-Garcia et al. 1996). T. vaginalis is the most common HIV epidemic and a current rise in incidence (Dougan agent (~120 million new cases worldwide; Crosignani et al. 2004). et al. 1992). Recently it was shown that the incidence in Abouttwo-thirdsofSTDsaffectindividualsyounger men may be underestimated if only one specimen was than 25 (Braverman 2000). This sexually active popula- used to screen for this agent. Compared to first-void tion may have long-term negative sequelae, such as in- urine and urethral swabs, semen proved to be the most fertility, chronic pelvic pain and cancer; so, educational sensitive single specimen (in 25% only semen positive) strategies are needed for their prevention (Wilken and for the detection of T. vaginalis (Kaydos-Daniels et al. Rosler 1985; Stone 1990; Workowski et al. 2002). This is 2004). In areas with a high prevalence of trichomonia- sometimes hampered by fragmented responsibilities sis, the addition of metronidazole to the syndromic for STD and infertility services (Hardon 2003). management of male urethritis is recommended (Price Human papilloma virus was demonstrated on the etal.2003).Inwomennodifferencesinthedetection skin of about 13% of men attending an infertility clinic rates of T. vaginalis between fertile and infertile women as well as in the semen of men with and without genital were reported (Okonofua et al. 1995). However, it was warts (Green et al. 1991; Pakendorf et al. 1998). Trans- stressedthattrichomoniasismayplayaroleinthede- missionfromthewomantothemanappearstoberath- velopment of cervical neoplasia, postoperative infec- er inefficient. HPV type 16 DNA and RNA (25% and tions and adverse pregnancy outcomes, and as a factor 8% of randomly selected patients) as well as type 18 in atypical pelvic inflammatory disease and infertility DNA and RNA (46% and 21%) were detected in sperm (Soper 2004). cells (literature in Dejucq and J´egou 2001). The inci- A higher seminal contamination with Trichomonas dence of asthenozoospermia was reported to be signifi- was found in infertile men compared to fertile men cantly higher in patients with HPV in their semen (Lai (47% to 30%) as well as a higher viscosity and sperm et al. 1997). agglutination. A significant improvement in semen Syphilis incidence in an andrological outpatient de- characteristics was found in 50% of patients 1 month partmentwasreportedtobe3–8%inSouthAfrica after treatment with metronidazole (Bornman et al. (Bornman et al. 1992a). This is important from an epi- 1992b). Others could not confirm detrimental effects of demiological point of view: even if Treponema palli- T. vaginalis onspermmotility(Dalyetal.1989).No dum does not directly impair male infertility it demon- detrimental effects on sperm–mucus interaction were stratesthatpatientsareatriskforotherSTDs,especial- found (Eggert-Kruse et al. 1987). T. vaginalis does not ly HIV infection. survive cryopreservation of spermatozoa (Glander et Today one main impact of STDs is their potential to al. 1986). increasetherateofHIVtransmission.Thishasbeen Trichomoniasis might cause reversible infertility in clearly proven and reviewed. Therefore, the treatment men, although the actual role of T. vaginalis infection of STDs is not only relevant to the prevention of long- in infertility has not yet been clearly defined (Martinez- term negative consequences for fertility but also to the Garcia et al. 1996; Soper 2004). prevention of HIV spread (Passey 1996; Ping et al. 2000; Aral 2001; Pilcher et al. 2004). II.2.4.3 Finally, STD agents have to be taken into account during assisted reproductive techniques (Diani 1999) STD and in sperm donor programmes. Again the regional Agents that are sexually transmitted are summarized in variation of STDs explains the large variations in re- Chap. I.6.1, Table II.2.4. Some agents are not listed there ported incidences (Craig et al. 1997; Olatunbosun et al. as they are not associated with male infertility such as 1998; Wortley et al. 1998). scabies or human papilloma virus infections. STDs are reviewed in several publications (Moskowitz and Mel- II.2.4.4 linger 1992; Radcliffe 2001; Center of Disease Control and Prevention 2002; Sulak 2003). It was concluded that HIV STDs are less important for men than for women with The first reports about unusual deaths in homosexual regard to fertility (Westrom 1994). Studies on large co- men were published in 1981. Within months an ac- II.2 horts of men showed that there is no increased rate of quired immunodeficiency was identified. In 1983 a vi- antisperm antibody production in men attending STD rusastheprobablecauseofthisacquiredimmunodefi- clinics (Hargreave et al. 1984). So this mechanism ap- ciency syndrome (AIDS) was isolated and in the follow- pears not to be relevant. ing years the causal link was proven (literature in: Hoff- TheprevalenceofSTDsdiffersworldwidewithhigh- mann and Kamps 2004 or www.HIV.net,www.hivmedi- er incidences in developing countries (De Schryver and cine.com). One main goal is the prevention of further Meheus 1990). Furthermore the pattern changes from spread of the disease. At present, intravaginal topical year to year, with a decrease in the 1990s during the formulations of anti-HIV agents or microbicides to 332 II.2 Mechanisms of Dysfunction and Pathology

prevent the mucosal and perinatal HIV transmission tach to the surface of spermatozoa and enter these cells are being developed. These agents should be capable of through the intact plasma membrane (Bagasra et al. attacking HIV from different routes: directly inactivat- 1994) probably by an alternative receptor (the GalAAG) ing HIV, preventing HIV from attaching to, entering or (Piomboni and Baccetti 2000) or a 160-kDa sperm pro- replicating in susceptible target cells as well as preven- tein (Bandivdekar et al. 2003). Others could not con- tion of dissemination from target cells present in se- firm this (Pudney et al. 1998). It is possible to generate men or the host cells that line the vaginal wall (D’Cruz HIV-free spermatozoa fractions by washing proce- and Uckun 2004). dures, which is an argument against infection of motile InthefirstyearsoftheHIVepidemicproblemsoth- spermatozoa by this virus (Semprini and Fiore 2004). er than reproduction had to be addressed. The wish for In prostate and testis tissues T lymphocytes were the an own child was opposed by concerns about possible predominant cells infected with HIV-1. So it was con- infections of the partner as well as the prognosis of the cluded that HIV-1 in seminal plasma is derived from disease. Today, HIV infection is a chronic disease, so the prostate, while HIV-1-infected cells in semen origi- couples will be seen in greater numbers for preconcep- nate mostly from the rete testis and epididymis (Paran- tion counselling. This involves a multidisciplinary ap- jpe et al. 2002). proach to ensure that a couple is fully informed. The Several endocrine and testicular dysfunctions have criteria to offer treatment or not should be based on the been reported in men infected with HIV, depending, in same criteria that are applied to couples who are affect- part, on the stage of the disease. Hypogonadism was ed by other chronic diseases. Medical treatment is de- showntobecommoninHIVdisease.Itwassuggested pendent on the unique circumstances of each couple that the weight loss observed in full-blown AIDS may be (Williams et al. 2003). a result of lowered testosterone levels (Dobs et al. 1988; It is possible to help couples by using different meth- Villette et al. 1990; Schurmeyer et al. 1997). A significant ods of assisted reproduction. Until the middle of 2003 association was observed between testicular atrophy more than 1800 couples were treated in about 4500 cy- and body mass index (BMI) (P = 0.0496). Thus, under- cles and about 500 children were born in Europe (Son- weight patients with HIV infection were 3.52 times nenberg-Schwan 2004). more likely to have testicular atrophy than those with Infection with HIV has different influences on re- acceptable body weight (Mhawech et al. 2001). productive medicine: the function of the reproductive Studies showing that testosterone replacement in organs, ethical issues, prevention of spread to the child HIV-infected patients with weight loss and low testos- and safety issues for the laboratory personnel (Ethics terone levels can improve muscle mass, effort-depen- Committee of the American Society for Reproductive dent strength, lean body mass and other symptoms of Medicine 2004). hypogonadism are in favour of this argument (Bhasin et al. 1998; Bhasin and Javanbakht 1999). If reproduction is planned, however, it has to be taken into account that II.2.4.4.1 reversible azoospermia may result from testosterone EffectsofHIVontheFunctionofMaleReproductiveOrgans therapy (Pena et al. 2003). Furthermore it was shown that about one-third of HIV-infected men attending Testis gyms used anabolic steroids (Bolding et al. 2002). The most relevant sources of HIV in the male reproduc- In AIDS patients orchitis, hypogonadism, oligozoo- tive tract are infected leukocytes (lymphocytes, mono- spermia or azoospermia have been reported (Dobs et cytes, macrophages) (Dulioust et al. 1998). Vasectomy al. 1988; Pudney and Anderson 1991; Poretsky et al. does not influence the amount of free virus in seminal 1995). Furthermore in some cases testicular germ cell plasma (Krieger et al. 1998). Controversy surrounds tumours or lymphoma were found. The incidence of whether the virus also infects spermatozoa (Dejucq testis tumours was 57 times higher than the average US and J´egou 2001). incidence (0.2% in 3015 HIV-positive men to 0.0035% It was shown that testicular macrophages express in the normal population; Tessler and Catanese 1987). CD4, CCR5 and CXCR4 thus allowing entry of HIV into Discussed mechanisms for the mode of action of II.2 these cells and providing a reservoir (Habasque et al. HIV on the testis include unspecific accompanying de- 2002). terioration of functions due to the chronic debilitating Proviral DNA was detected in the nuclei of germ illness and cachexia of the patients or synergistic ef- cells at all stages of differentiation in the testes of HIV- fects of opportunistic infections such as cytomegalovi- positive men by in situ PCR hybridization. The pres- rus (CMV), Mycobacterium avium-intracellulare or ence of provirus was not associated with germ cell Toxoplasma gondii in the testis. As only every third pa- damage, spermatogenesis was normal and a very mild tient had such infections but demonstrable testis local immune response was observed (Muciaccia et al. changes, these infections were probably not the main 1998b). According to electron microscopy, HIV can at- cause(DePaepeetal.1990).Achangeinthehypotha- II.2.4 Urethritis, Sexually Transmitted Diseases (STD), Acquired Immunodeficiency Syndrome (AIDS) 333 lamic-pituitary axis, initially discussed (Dobs et al. counts (<200 mm3)wereassociatedwithsignificantly 1988), could not be confirmed in later studies (Schlien- lower motility, lower than normal sperm morphology ger and Lang 1989; Poretsky et al. 1995). Elevated lu- by strict criteria, more spermatids in semen, and high- teinizing hormone (LH) and follicle-stimulating hor- er percentages of teratozoospermia, oligoasthenotera- mone (FSH) levels, found in some patients, suggest a tozoospermia and leukocytospermia. Healthier men, primary testicular failure (Croxson et al. 1989). based on clinical categories, had significantly more Autopsy studies reported testicular atrophy in AIDS normal-shaped spermatozoa and fewer had azoosper- patients (Chabon et al. 1987). The hypogonadism prob- mia, oligoasthenoteratozoospermia or leukocytosper- ably results from a decrease in Leydig cell number and mia. In AIDS patients, grossly abnormal sperm and py- a lymphocyte infiltration and fibrosis of the interstitial ospermia was reported (Muller et al. 1998; Nicopoullos testicular tissue (Dalton and Harcourt-Webster 1991; et al. 2004). There were no differences in any parame- Pudney and Anderson 1991). In the testis several ters in those taking antiretroviral medication (Nicopo- changes were described and a classification system for ullos et al. 2004). them was proposed (De Paepe and Waxman 1989; Yos- Others reported reduced semen volume, lower per- hikawa et al. 1989). The authors found Sertoli cell only centages of rapidly progressive motility, total sperm syndrome (42%), germ cell generation (27%), peritu- count and increased concentrations of non-spermatic bular fibrosis associated with tubular hyalinization cells (Dulioust et al. 2002). (15%), maturation arrest (12 5) and normal appear- In one sperm donor semen was analysed before and ance (3%). In addition, spermatogenic arrest at various after HIV infection. Semen volume, sperm motility and points, degenerating germ cells and block in the epi- the percentage of sperm with normal morphology were didymis were described by others (Shevchuk et al. reduced after HIV positivity. A disturbed function of 1998). Prolonging the survival by antiretroviral drug seminal vesicles and prostate gland could explain the therapy was associated with a shift in the histologic decreasedvolumeaswellasthemoreviscoussemen findings toward more pronounced loss of germ cells found in HIV-infected subjects (Dondero et al. 1996; (Shevchuk et al. 1999). Van Leeuwen et al. 2004). Sperm alterations found to- Thus it appears that direct local action may be re- day are attributed to effects of antiretroviral therapy sponsible for this observed damage within the gonads. (Dulioust et al. 2002; Barboza et al. 2004). There are several lines of evidence for this statement: Da Silva et al. 1990 detected the HIV p17 protein in the II.2.4.4.2 testis by immunohistochemistry. Later, HIV-infected Ethical Issues cells of the lymphocytic/monocytic type were found in the seminiferous tubules and interstitium of the testis A recent update on the ethical issues associated with re- as well as semen (Pudney and Anderson 1991). With production in HIV-positive patients concluded that PCR HIV-1 DNA was found within testicular germ cells HIV infection is not yet curable, but treatable. It has to in spermatogonia, spermatocytes and some sperma- be classified as a chronic disease due to the significant tids (Nuovo et al. 1994). Others demonstrated the pres- advances in HIV treatment, which delay the onset of ence of HIV DNA in the nuclei of spermatogonia and AIDS in many, but not all, infected persons. The poten- germ cells at all stages of differentiation (Muciaccia et tial for HIV-positive persons to have uninfected chil- al.1998a,b).Themerepresenceoftheproviruswasnot dren and not transmit the virus to their partners has associated with impaired spermatogenesis in asymp- been substantially enhanced. So both HIV-infected tomatic HIV-positive men. In AIDS patients, however, persons and health-care providers share responsibility spermatogenesis was arrested and only few infected for the safety of the uninfected partner and the poten- spermatogonia and spermatocytes were found (Muci- tial offspring. It was recommended that couples re- accia et al. 1998a). In about 25–33% of the residual questing assistance should have their own genetically germ cells in the testes of AIDS patients, HIV DNA related child seek care at institutions with the facilities couldbefoundbutnotinthetestesofadolescentboys that can provide the most effective evaluation, treat- who had acquired HIV in utero (Shevchuk et al. 1998). mentandfollow-up.Asanalternative,donorsemen, So the HIV infection impairs exocrine and endocrine adoption or not having children have to be considered II.2 testicular functions with progression of the disease. (Ethics Committee of the American Society for Repro- ductive Medicine 2004). Ejaculate II.2.4.4.3 In symptomless HIV-positive men semen parameters Reproduction in Discordant Couples within the normal range are found. With progress of the disease more defects are found, particularly in In a serodiscordant couple the female partner has a strict criteria of sperm morphology. Lower CD4+ cell 0.1–0.2% risk of acquiring HIV per act of unprotected 334 II.2 Mechanisms of Dysfunction and Pathology

intercourse (Mastro et al. 1997). This is dependent on dure is repeated twice more. Then a swim-up proce- the viral load in semen: it was calculated that the proba- dure is done. An aliquot of washed spermatozoa is sub- bility of HIV-1 transmission is 1/100 when semen con- sequently tested for detectable HIV RNA [for example, tains 100,000 copies of HIV RNA and 3/10,000 with a nucleic acid-based sequence amplification (NASBA) 1000 copies of HIV RNA in semen (Chakraborty et al. assay such as Biom´erieux]. In one study about 5% of 2001). So attempts to conceive naturally carry a serious NASBA tests were positive after this procedure (Nico- risk for the uninfected woman or child (Mandelbrot et poullos et al. 2004). al. 1997). The problems and unresolved questions of as- sisted reproduction in this situation are reviewed else- HIV Infection of the Woman where (Englert et al. 2004). During the initial consultation both partners should Here a self-insemination could be tried at the optimum be counselled. This should include: information con- time point of the cycle. An inverted spermicide-free cerning diagnostics, therapy options, information on condom, a cervical cap, a vaginal applicator or a sy- the psychosocial and economic situation and future ringe may be used. perspectives of the couple, the family, and support If assisted reproduction is necessary the experience through families and friends. It has to be stressed that to date points to a limited success rate (Ohl et al. 2003). the chances of HIV transmission are extremely im- probable, but not impossible, and that a successful re- II.2.4.4.4 sult of therapy, i.e. birth of a healthy child, cannot be Safety Issues of the Laboratory Personnel guaranteed.Alsothealternatives,i.e.thedecisionsof not having children, adoption or donor semen, have to Only a few occupational transmissions of HIV have be discussed. been reported. If standard precautions to prevent infec- If the couple opts for reproductive measures, an in- tious disease transmission are taken, the risk of virus terdisciplinary approach is recommended (general transmission to lab personnel is very small. In most medical diagnostics including infectiology, gynaecolo- cases nurses and laboratory technicians accidentally gic and andrologic workup). Contact with an experi- inoculated themselves with a patient’s blood by a nee- enced centre with facilities for sperm preparation and dlestick or were contaminated with bloody fluid and HIV testing has to be established. The costs and insur- had significant mucocutaneous exposure (http://www. ance coverage of the planned procedures, which are dif- cdc.gov/niosh/topics/bbp/emergnedl.html, http://www. ferent everywhere, have to be considered. cdc.gov/ncidod/hip/Needle/needle.htm). Psychosocial counselling is very important. Up to one-third then decide against children. If not discussed properlyfrustrationscouldleadtounprotectedinter- References course. In addition, comorbidities, such as drug abuse, can be detected (Sonnenberg-Schwan 2004). Akre O, Cnattingius S, Bergstrom R, Kvist U, Trichopoulos D, Ekbom A (1999) Human fertility does not decline: evidence from Sweden. 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II.2.5 Disorders of Blood Flow: Arterial and Venous/ and Varicocele G. M. Colpi, M. Mancini, G. Piediferro, F. I. Scroppo

Summary ■ Endothelial damage is the key disorder in ■ In cases of testicular torsion there is reduced vasculogenic organic erectile dysfunction (ED). blood flow in the contralateral side due to a ■ Middle-aged men with ED should be screened sympathetic reflex arising from the testicular for vasculogenic risk factors. artery under distress. II.2 ■ Our improved understanding of endothelial ■ Anomalies of testicular circulation are six damage will facilitate the development of a times more frequent in men who have had marker of endothelial damage, which, if devel- orchiopexy for testicular maldescent compared oped, could have a significant impact on the with normal men. Although some of this may diagnosis of men’s vascular disorders. be intrinsic some of this vascular damage is ■ Varicocele alters the dynamics of testicular iatrogenic. circulation and this, in turn, damages spermato- genesis and endocrine function of the testis.