72 I.3 Male Factor Fertility Problems I.3.13 Infection/Inflammation of the Accessory Sex Glands F. Comhaire, A. Mahmoud Key Messages ■ ■ I.3 ■ ■ ■ Infection of the accessory sex glands is diagnosed in a variable proportion of cases with abnormal semen quality depending on regional differences. The influence of infection/inflammation of the epididymis on semen quality and fertility is more important than that of infection/inflammation of the prostate or seminal vesicles. Whereas bacteria themselves have little influence on the fertilizing capacity of spermatozoa, changes in the function of the affected glands and reactive oxygen species generated by white blood cells damage spermatozoa. The diagnosis of male accessory sex gland infection is based on a combination of elements in the patient’s history, clinical signs, and biological analysis of urine and semen. Treatment uses antibiotics and antioxidants, complemented with intrauterine insemination and/or assisted reproduction, depending on the severity and reversibility or irreversibility of damage to sperm cells. I.3.13.1 Definition The diagnosis of male accessory gland infection is given when semen classification is azoospermia or abnormal spermatozoa and this is considered to result from present or past infection of the accessory sex glands, or inflammatory disease of the urogenital tract (Rowe et al. 2000). I.3.13.2 Aetiology and Physiopathology Infection of the accessory sex glands includes epididymitis, vesiculitis and/or prostatitis, which are caused by either pathogens transmitted by sexual contact or by so-called trivial urological pathogens. Among the former, Chlamydia trachomatis is the most common pathogen (Keck et al. 1998), but gonococcus may also occur. The urological pathogens commonly identified are Escherichia coli, Streptococcus faecalis, Proteus mirabilis and pseudomonas. The role of coagulasenegative staphylococcus is uncertain, while Staphylococcus aureus is usually a laboratory contaminant (Rodin et al. 2003). Infection causes inflammation characterized by the classical symptoms such as pain, swelling, and impaired function. The latter is responsible for deficient secretion of minerals, enzymes and fluids that are needed for optimal function and transport of the spermatozoa. The abnormal biochemical make-up of the seminal plasma results in decreased seminal volume, abnormal viscosity and liquefaction, abnormal pH, and impaired functional capacity of the spermatozoa. These are commonly poorly motile and may have antisperm antibodies attached of the IgG and/or IgA class, causing immunological infertility. In addition, infection or inflammation increase the number of peroxidase-positive white blood cells (pus cells) generating reactive oxygen species that change the lipid composition of the sperm membrane, reducing its fluidity and fusogenic capacity with impaired acrosome reactivity and ability to fuse with the oolemma (Comhaire et al. 1999). Reactive oxygen species induce oxidative damage to sperm DNA, with excessive production of a.o. 8-hydroxy-2-deoxyguanosin and mutagenesis (Chen et al. 1997). Also, inflammation increases 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 sperm function and fertilizing capacity (Depuydt et al. 1996; Gruschwitz et al. 1996). Chronic inflammation of the epididymis may result in (partial) obstruction of the sperm passage with oligo- or azoospermia (Dohle et al. 2003). Rupture of the blood-testis barrier from obstruction causes antisperm antibodies (Hendry 1986). I.3.13.3 Clinical and Laboratory Findings History taking commonly reveals one or several episodes of dysuria and/or pollakisuria, which may have disappeared spontaneously or after a short treatment with an antibiotic or urinary antiseptic. However, the patient may be unaware of any acute urinary symptoms in the past. Sometimes, the patient mentions recurrent episodes of intrascrotal pain that usually feels rather dull and is exacerbated by pressure. Ejaculatory symptoms may occur such as reduced ejaculation force or volume, painful sensation during or immediately after ejaculation, or blood staining of the ejaculate. Finally, sexual complaints may be mentioned, including decreased libido and orgasmic feeling, or even erectile dysfunction. I.3.13 Infection/Inflammation of the Accessory Sex Glands Clinical examination should focus on the careful palpation of the scrotal content, particularly the epididymis and vas deferens. Any swelling or nodularity should be noted, as well as pain during soft pressure. Rectal examination can be performed, but transrectal or transabdominal echography may reveal more relevant information. General blood analysis may reveal signs of infection, such as increased number of white blood cells, increased sedimentation rate or abnormal globulin proportions upon electrophoresis. Specific tests for circulating antibodies against Chlamydia should be included in the routine investigation for male infertility. The laboratory may detect antisperm antibodies of the IgG class in serum. Urine analysis may reveal bacterial infection or an increased number of white blood cells, but the analysis of urine obtained after prostate massage should be more relevant. However, the absence of urinary abnormality does not exclude male accessory gland infection, particularly epididymitis. Semen analysis is of pivotal importance to the diagnosis. Semen must be collected as described in the section on semen analysis, in order to avoid contamination with cells and bacteria from the skin or urethra. When semen culture is performed for the counting and identification of bacteria, preparatory dilution of the sample is required, reducing the bacteriostatic capacity of seminal plasma, prostate fluid in particular. The number of round cells must be counted, and these must be differentiated into peroxidase-negative cells, mostly spermatogenetic cells, and peroxidase-positive white blood cells (WHO 1999). Also, it is mandatory to perform biochemical analysis of the seminal plasma in order to measure the markers of secretion of the sex glands, including, for example, alpha-glucosidase for the epididymides, citric acid or gamma glutamyl transferase (or calcium or zinc) for the prostate, and, possibly, fructose for the seminal vesicles. Finally, the presence of antisperm antibodies on spermatozoa must be traced by means of, for example, the direct MAR test for both IgG and IgA (WHO 1999). I.3.13.4 Diagnosis and Differential Diagnosis The diagnosis is accepted in patients with abnormal semen quality – oligo- and/or asteno- and/or teratozoospermia, or azoospermia – who combine abnormalities under the following headings (Comhaire et al. 1980; Rowe et al. 2000): A. A history of urinary infection, epididymitis, sexually transmitted disease, and/or physical signs: thickened or tender epididymis, thickened vas deferens, abnormal rectal examination 73 B. Abnormal urine after prostatic massage and/or detection of Chlamydia trachomatis in urine C. Ejaculate abnormalities: – Elevated number of peroxidase-positive white blood cells – Culture with significant growth of pathogenic bacteria – Abnormal viscosity and/or abnormal biochemical composition, and/or high levels of inflammatory markers or highly elevated reactive oxygen species The diagnosis requires either two signs from different headings, or at least two ejaculate signs in each of two subsequent semen samples. If bacteria are detected, they should be identical in urine and in semen, or in the two semen samples. Male accessory sex gland infection may be combined with other diseases such as varicocele, in which case a lower number of white blood cells may cause complementary damage (Everaert et al. 2003), or an immunological factor, or sexual or ejaculatory dysfunction. These diseases will require adequate management and may interfere with the fertility outcome after treatment of the infection. I.3.13.5 Treatment The treatment of the infection should be the same as for urinary tract infections. However, abnormal secretion of the prostate results in an alkaline environment in this gland, by which antibiotics such as doxycycline are not concentrated and are therefore inefficient. The third-generation quinolones (e.g. ofloxacin and pefloxacin) are concentrated in both an alkaline and acidic milieu, and therefore do penetrate well into the diseased prostate and the seminal vesicles (Comhaire 1987). In case of streptococcus infection, the quinolones are poorly active, and treatment with amoxicillin or cephalosporins may be indicated. Commonly, bacterial infestation is eradicated, but it may return, sometimes with a different pathogen. It may be necessary to add a second, longer-term treatment with another antibiotic. I.3.13.6 Results of Treatment Whereas bacteria can usually be eliminated from the genitourinary region, white blood cells may persist for several months, and functional impairment of the accessory glands is commonly irreversible. This implies that the processes impairing the fertilizing capacity of spermatozoa remain active, and that fertility is not restored. Complementary treatment with food supple- I.3 74 I.3 I.3 Male Factor Fertility Problems ments containing antioxidants may be required, and treatment similar to that of idiopathic oligozoospermia can be indicated. In general, the success rate of antibiotic treatment of male accessory gland infection in terms of spontaneous conception is poor and not significantly better than that of placebo. Treatment aiming at the elimination of pathogens is, however, indicated for reasons of good medical practice, and in order to reduce the risk of future complications, including prostate cancer (Roberts et al. 2004). Because oxygen damage to the sperm membrane and, most of all, DNA may persist after antibiotic treatment, intrauterine insemination and in vitro fertilization may yield poor results, and intracytoplasmic sperm injection, though generating pre-embryos, may fail in creating an ongoing pregnancy (Zorn et al. 2004). Therefore, careful complementary treatment and a holistic approach are indicated. I.3.13.7 Prognosis Depending on the localization of the infection or inflammation, the prognosis after treatment is variable. Whereas the effects of prostatitis and vesiculitis are less important, and the effect of treatment on fertility is rather favourable, (chronic) epididymitis usually causes substantial and irreversible damage to the quality and the fertilizing capacity of spermatozoa (Vicari 2000). Also, immunological infertility, resulting from rupture of the blood–testis barrier, is irreversible. In view of the poor prognosis regarding the repair of fertility, prevention of infectious disease is of primordial importance. I.3.13.8 Prevention On the one hand, prevention of sexually transmitted disease, and its immediate treatment in positive cases, will prevent infertility in a later stage. In particular, recurrent infections with Chlamydia were documented to cause disastrous effects that are irreversible (Gonzales et al. 2004). Men who smoke run a four- to fivefold higher risk of prostatitis and subsequent spread of infection to the other accessory sex glands. In addition, tobacco smoke generates surplus amounts of oxygen radicals and toxic damage to spermatozoa. Avoiding tobacco is, therefore, the most important factor in the prevention of male accessory gland infection by common urological pathogens. In addition, relatively symptom-poor episodes of urinary infection, e.g. occurring after an episode of diarrhoea, may remain untreated and ultimately develop into chronic infection/inflammation that is hard to treat, let alone cure. Therefore, any episode of urinary complaints suggestive for infection in the male must be treated adequately, in particular using quinolones, in order to avoid pathogens being harboured in the prostate gland. References Chen CS, Chao HT, Pan RL, Wei YH (1997) Hydroxyl radicalinduced decline in motility and increase in lipid peroxidation and DNA modification in human sperm. Biochem Mol Biol Int 43:291 – 303 Comhaire FH (1987) Concentration of pefloxacin in split ejaculates of patients with chronic male accessory gland infection. J Urol 138:828 – 830 Comhaire F, Verschraegen G, Vermeulen L (1980) Diagnosis of accessory gland infection and its possible role in male infertility. 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