72 I.3 Male Factor Fertility Problems I.3.13 Infection/Inflammation of the Accessory Sex Glands F. Comhaire, A. Mahmoud

Key Messages Infection causes inflammation characterized by the ■ Infection of the accessory sex glands is diag- classical symptoms such as pain, swelling, and im- nosed in a variable proportion of cases with paired function. The latter is responsible for deficient abnormal semen quality depending on secretion of minerals, enzymes and fluids that are regional differences. needed for optimal function and transport of the sper- ■ The influence of infection/inflammation of the matozoa. The abnormal biochemical make-up of the epididymis on semen quality and fertility is seminal plasma results in decreased seminal volume, I.3 more important than that of infection/inflam- abnormal viscosity and liquefaction, abnormal pH, mation of the prostate or seminal vesicles. and impaired functional capacity of the spermatozoa. ■ Whereas bacteria themselves have little influ- These are commonly poorly motile and may have anti- ence on the fertilizing capacity of sperma- sperm antibodies attached of the IgG and/or IgA class, tozoa, changes in the function of the affected causing immunological infertility. glands and reactive oxygen species generated In addition, infection or inflammation increase the by white blood cells damage spermatozoa. number of peroxidase-positive white blood cells (pus ■ The diagnosis of male accessory sex gland cells) generating reactive oxygen species that change infection is based on a combination of the lipid composition of the sperm membrane, reduc- elements in the patient’s history, clinical signs, ing its fluidity and fusogenic capacity with impaired and biological analysis of urine and semen. acrosome reactivity and ability to fuse with the oolem- ■ Treatment uses antibiotics and antioxidants, ma (Comhaire et al. 1999). Reactive oxygen species in- complemented with intrauterine insemination duceoxidativedamagetospermDNA,withexcessive and/or assisted reproduction, depending on production of a.o. 8-hydroxy-2-deoxyguanosin and the severity and reversibility or irreversibility mutagenesis (Chen et al. 1997). Also, inflammation in- of damage to sperm cells. creases the production of a number of cytokines such as interleukin 1 (alpha and beta), interleukin 6 and 8, and tumour necrosis factor, which further impair I.3.13.1 sperm function and fertilizing capacity (Depuydt et al. 1996; Gruschwitz et al. 1996). Definition Chronic inflammation of the epididymis may result The diagnosis of male accessory gland infection is in(partial)obstructionofthespermpassagewitholi- givenwhensemenclassificationisazoospermiaor go- or azoospermia (Dohle et al. 2003). Rupture of the abnormal spermatozoa and this is considered to result blood-testis barrier from obstruction causes anti- from present or past infection of the accessory sex sperm antibodies (Hendry 1986). glands, or inflammatory disease of the urogenital tract (Rowe et al. 2000). I.3.13.3 Clinical and Laboratory Findings I.3.13.2 History taking commonly reveals one or several epi- Aetiology and Physiopathology sodes of dysuria and/or pollakisuria, which may have Infection of the accessory sex glands includes epididy- disappeared spontaneously or after a short treatment mitis, vesiculitis and/or prostatitis, which are caused by with an antibiotic or urinary antiseptic. However, the either pathogens transmitted by sexual contact or by patient may be unaware of any acute urinary symptoms so-called trivial urological pathogens. Among the in the past. Sometimes, the patient mentions recurrent former, Chlamydia trachomatis is the most common episodes of intrascrotal pain that usually feels rather pathogen (Keck et al. 1998), but gonococcus may also dull and is exacerbated by pressure. Ejaculatory symp- occur. The urological pathogens commonly identified toms may occur such as reduced ejaculation force or are Escherichia coli, Streptococcus faecalis, Proteus volume, painful sensation during or immediately after mirabilis and pseudomonas. The role of coagulase- ejaculation, or blood staining of the ejaculate. Finally, negative staphylococcus is uncertain, while Staphylo- sexual complaints may be mentioned, including de- coccus aureus is usually a laboratory contaminant creased libido and orgasmic feeling, or even erectile (Rodin et al. 2003). dysfunction. I.3.13 Infection/Inflammation of the Accessory Sex Glands 73

Clinical examination should focus on the careful B. Abnormal urine after prostatic massage and/or de- palpation of the scrotal content, particularly the epi- tection of Chlamydia trachomatis in urine didymis and vas deferens. Any swelling or nodularity C. Ejaculate abnormalities: should be noted, as well as pain during soft pressure. – Elevated number of peroxidase-positive white Rectal examination can be performed, but transrectal blood cells or transabdominal echography may reveal more rele- – Culture with significant growth of pathogenic vant information. bacteria General blood analysis may reveal signs of infection, – Abnormal viscosity and/or abnormal biochemi- such as increased number of white blood cells, in- cal composition, and/or high levels of inflamma- creased sedimentation rate or abnormal globulin pro- tory markers or highly elevated reactive oxygen portions upon electrophoresis. Specific tests for circu- species lating antibodies against Chlamydia should be includ- ed in the routine investigation for male infertility. The The diagnosis requires either two signs from different laboratory may detect antisperm antibodies of the IgG headings, or at least two ejaculate signs in each of two class in serum. subsequent semen samples. If bacteria are detected, I.3 Urine analysis may reveal bacterial infection or an they should be identical in urine and in semen, or in the increased number of white blood cells, but the analysis two semen samples. of urine obtained after prostate massage should be Male accessory sex gland infection may be com- more relevant. However, the absence of urinary abnor- bined with other diseases such as varicocele, in which mality does not exclude male accessory gland infec- case a lower number of white blood cells may cause tion, particularly epididymitis. complementary damage (Everaert et al. 2003), or an Semenanalysisisofpivotalimportancetothediag- immunological factor, or sexual or ejaculatory dys- nosis. Semen must be collected as described in the sec- function. These diseases will require adequate manage- tion on semen analysis, in order to avoid contamina- mentandmayinterferewiththefertilityoutcomeafter tion with cells and bacteria from the skin or urethra. treatment of the infection. When semen culture is performed for the counting and identification of bacteria, preparatory dilution of the I.3.13.5 sample is required, reducing the bacteriostatic capacity of seminal plasma, prostate fluid in particular. The Treatment number of round cells must be counted, and these must Thetreatmentoftheinfectionshouldbethesameasfor be differentiated into peroxidase-negative cells, mostly urinary tract infections. However, abnormal secretion spermatogenetic cells, and peroxidase-positive white of the prostate results in an alkaline environment in blood cells (WHO 1999). Also, it is mandatory to per- this gland, by which antibiotics such as doxycycline are form biochemical analysis of the seminal plasma in or- not concentrated and are therefore inefficient. The der to measure the markers of secretion of the sex third-generation quinolones (e.g. ofloxacin and peflo- glands, including, for example, alpha-glucosidase for xacin) are concentrated in both an alkaline and acidic the epididymides, citric acid or gamma glutamyl trans- milieu, and therefore do penetrate well into the dis- ferase (or calcium or zinc) for the prostate, and, possi- eased prostate and the seminal vesicles (Comhaire bly, fructose for the seminal vesicles. 1987). In case of streptococcus infection, the quinolo- Finally, the presence of antisperm antibodies on nesarepoorlyactive,andtreatmentwithamoxicillinor spermatozoa must be traced by means of, for example, cephalosporins may be indicated. the direct MAR test for both IgG and IgA (WHO 1999). Commonly, bacterial infestation is eradicated, but it may return, sometimes with a different pathogen. It I.3.13.4 may be necessary to add a second, longer-term treat- ment with another antibiotic. Diagnosis and Differential Diagnosis The diagnosis is accepted in patients with abnormal se- I.3.13.6 men quality – oligo- and/or asteno- and/or teratozoo- spermia, or azoospermia – who combine abnormalities Results of Treatment under the following headings (Comhaire et al. 1980; Whereas bacteria can usually be eliminated from the Rowe et al. 2000): genitourinary region, white blood cells may persist for severalmonths,andfunctionalimpairmentoftheac- A. A history of urinary infection, epididymitis, sexual- cessory glands is commonly irreversible. This implies ly transmitted disease, and/or physical signs: thick- that the processes impairing the fertilizing capacity of ened or tender epididymis, thickened vas deferens, spermatozoa remain active, and that fertility is not re- abnormal rectal examination stored. Complementary treatment with food supple- 74 I.3 Male Factor Fertility Problems

ments containing antioxidants may be required, and let alone cure. Therefore, any episode of urinary com- treatment similar to that of idiopathic oligozoospermia plaints suggestive for infection in the male must be treat- can be indicated. ed adequately, in particular using quinolones, in order to In general, the success rate of antibiotic treatment of avoid pathogens being harboured in the prostate gland. male accessory gland infection in terms of spontaneous conception is poor and not significantly better than References that of placebo. Treatment aiming at the elimination of pathogens is, however, indicated for reasons of good Chen CS, Chao HT, Pan RL, Wei YH (1997) Hydroxyl radical- medical practice, and in order to reduce the risk of fu- induced decline in motility and increase in lipid peroxida- ture complications, including prostate cancer (Roberts tion and DNA modification in human sperm. Biochem Mol Biol Int 43:291–303 et al. 2004). Comhaire FH (1987) Concentration of pefloxacin in split ejac- Because oxygen damage to the sperm membrane ulates of patients with chronic male accessory gland infec- and, most of all, DNA may persist after antibiotic treat- tion. J Urol 138:828–830 ment, intrauterine insemination and in vitro fertiliza- Comhaire F, Verschraegen G, Vermeulen L (1980) Diagnosis of I.3 accessory gland infection and its possible role in male infer- tion may yield poor results, and intracytoplasmic tility. Int J Androl 3:32–45 sperm injection, though generating pre-embryos, may ComhaireFH,MahmoudAM,DepuydtCE,ZalataAA,Chri- fail in creating an ongoing pregnancy (Zorn et al. 2004). stophe AB (1999) Mechanisms and effects of male genital Therefore, careful complementary treatment and a ho- tract infection on sperm quality and fertilizing potential: the andrologist’s viewpoint. Hum Reprod Update 5:393–398 listic approach are indicated. Depuydt CE, Bosmans E, Zalata A, Schoonjans F, Comhaire FH (1996) The relation between reactive oxygen species and cy- tokines in andrological patients with or without male acces- I.3.13.7 sory gland infection. J Androl 17:699–707 Prognosis Dohle GR, van Roijen JH, Pierik FH, Vreeburg JT, Weber RF (2003) Subtotal obstruction of the male reproductive tract. Depending on the localization of the infection or in- Urol Res 31:22–24 flammation, the prognosis after treatment is variable. Everaert K, Mahmoud A, Depuydt C, Maeyaert M, Comhaire F Whereas the effects of prostatitis and vesiculitis are less (2003) Chronic prostatitis and male accessory gland infec- important, and the effect of treatment on fertility is tion–is there an impact on male infertility (diagnosis and therapy)? Andrologia 35:325–330 rather favourable, (chronic) epididymitis usually GonzalesGF,MunozG,SanchezR,HenkelR,Gallegos-AvilaG, causes substantial and irreversible damage to the quali- Diaz-Gutierrez O, Vigil P,Vasquez F, Kortebani G, Mazzolli A, ty and the fertilizing capacity of spermatozoa (Vicari Bustos-Obregon E (2004) Update on the impact of Chlamydia 2000). Also, immunological infertility, resulting from trachomatis infection on male fertility. Andrologia 36:1–23 Gruschwitz MS, Brezinschek R, Brezinschek HP (1996) Cyto- rupture of the blood–testis barrier, is irreversible. kine levels in the seminal plasma of infertile males. J Androl In view of the poor prognosis regarding the repair of 17:158–163 fertility, prevention of infectious disease is of primordi- Hendry WF (1986) Clinical significance of unilateral testicular al importance. obstruction in subfertile males. Br J Urol 58:709–714 Keck C, Gerber-Schafer C, Clad A, Wilhelm C, Breckwoldt M (1998) Seminal tract infections: impact on male fertility and I.3.13.8 treatment options. Hum Reprod Update 4:891–903 Roberts RO, Bergstralh EJ, Bass SE, Lieber MM, Jacobsen SJ Prevention (2004) Prostatitis as a risk factor for prostate cancer. Epide- On the one hand, prevention of sexually transmitted miology 15:93–99 Rodin DM, Larone D, Goldstein M (2003) Relationship be- disease, and its immediate treatment in positive cases, tween semen cultures, leukospermia, and semen analysis in will prevent infertility in a later stage. In particular, re- men undergoing fertility evaluation. Fertil Steril 79 Suppl current infections with Chlamydia were documented to 3:1555–1558 causedisastrouseffectsthatareirreversible(Gonzales Rowe PJ, Comhaire FH, Hargreave TB, Mahmoud AMA (2000) et al. 2004). WHO manual for the standardized investigation, diagnosis and management of the infertile male. Cambridge Universi- Men who smoke run a four- to fivefold higher risk of ty Press, Cambridge prostatitis and subsequent spread of infection to the oth- Vicari E (2000) Effectiveness and limits of antimicrobial treat- er accessory sex glands. In addition, tobacco smoke gen- ment on seminal leukocyte concentration and related reac- erates surplus amounts of oxygen radicals and toxic tive oxygen species production in patients with male acces- sory gland infection. Hum Reprod 15:2536–2544 damage to spermatozoa. Avoiding tobacco is, therefore, WHO (1999) WHO laboratory manual of the examination of the most important factor in the prevention of male ac- human semen and sperm-cervical mucus interaction. Cam- cessory gland infection by common urological patho- bridge University Press, Cambridge gens. In addition, relatively symptom-poor episodes of Zorn B, Virant-Klun I, Vidmar G, Sesek-Briski A, Kolbezen M, Meden-Vrtovec H (2004) Seminal elastase-inhibitor com- urinary infection, e.g. occurring after an episode of diar- plex, a marker of genital tract inflammation, and negative rhoea, may remain untreated and ultimately develop in- IVF outcome measures: role for a silent inflammation? Int J to chronic infection/inflammation that is hard to treat, Androl 27:368–374