EAU Guidelines on Male Infertility$ W

Home , Azoospermia, Epididymitis, Orchitis, Seminal tract

European Urology European Urology 42 (2002) 313±322

EAU Guidelines on Male Infertility$ W. Weidnera,*, G.M. Colpib, T.B. Hargreavec, G.K. Pappd, J.M. Pomerole, The EAU Working Group on Male Infertility aKlinik und Poliklinik fuÈr Urologie und Kinderurologie, Giessen, Germany bOspedale San Paolo, Polo Universitario, Milan, Italy cWestern General Hospital, Edinburgh, Scotland, UK dSemmelweis University Budapest, Budapest, Hungary eFundacioÂ Puigvert, Barcelona, Spain Accepted 3 July 2002

Keywords: Male infertility; Azoospermia; Oligozoospermia; Vasectomy; Refertilisation; Varicocele; Hypogo- nadism; Urogenital infections; Genetic disorders

1. Andrological investigations and 2.1. Treatment spermatology A wide variety of empiric drug approaches have been tried (Table 1). Assisted reproductive techniques, Ejaculate analysis and the assessment of andrological such as intrauterine insemination, in vitro fertilisation status have been standardised by the World Health (IVF) and intracytoplasmic sperm injection (ICSI) are Organisation (WHO). Advanced diagnostic spermato- also used. However, the effect of any infertility treat- logical tests (computer-assisted sperm analysis (CASA), ment must be weighed against the likelihood of spon- acrosome reaction tests, zona-free hamster egg penetra- taneous conception. In untreated infertile couples, the tion tests, sperm-zona pellucida bindings tests) may be prediction scores for live births are 62% to 76%. necessary in certain diagnostic situations [1,2]. Furthermore, the scienti®c evidence for empirical approaches is low. Criteria for the analysis of all therapeutic trials have been re-evaluated. There is 2. Idiopathic oligoasthenoteratozoospermia consensus that only randomised controlled trials, with `pregnancy' as the outcome parameter, can accepted Most men presenting with infertility are found to for ef®cacy analysis. have idiopathic oligoasthenoteratozoospermia (OAT). It is diagnosed according to WHO criteria. However, other factors, such as duration of the couple's inferti- 3. Genetic disorders1 lity, previous pregnancy history and the age of the female partner are better predictors of pregnancy than Chromosomal abnormalities are more common in sperm quality [3,4]. infertile men than in fertile men. Standard karyotype analysis should be offered to all men with damaged $ Regarding each section, selected references are offered for further spermatogenesis who are seeking fertility treatment by reading. The complete list of references used to establish these guidelines IVF or ICSI. Fluorescent in situ hybridisation (FISH) is found in the full-length version of the ``EAU Guidelines on Male analysis of spermatozoa is a research investigation Infertility'' presented at the XVIth EAU Annual Congress, Geneva, [5±7]. Switzerland (ISBN 90-806179-3-9), or the EAU website www. uroweb.org. * Corresponding author. Tel. 49-641-99-44501; Fax: 49-641-99-44509. E-mail address: [email protected] (W. Weidner). 1 Co-author: C. Ghosh, Edinburgh, UK.

Ta bl e 1 Empiric therapy of idiopathic oligoasthenoteratozoospermia (OAT)a

Therapeutic approaches EAU recommendations

Hormonal GnRH Contradictory results. Not controlled trials. Not recommended. hCG/hMG Lack of ef®cacy. Not recommended. FSH Lack of ef®cacy. Further trials needed. Androgens Lack of ef®cacy. Not recommended. Antioestrogens (clomiphene citrate, tamoxifen) Possible small effect. Use must be counterbalanced by potential side-effects. Non-hormonal Kinin-enhancing drugs Unproven ef®cacy. Use in clinical trials only. Bromocriptine Lack of ef®cacy. Not recommended. Antioxidants May bene®t selected patients. Use in clinical trials only. Mast cell blockers Some ef®cacy shown. Further evaluation needed. Use in clinical trials only. a-Blockers Lack of ef®cacy. Not recommended. Systemic corticosteroids Lack of ef®cacy. Patients with high levels of antisperm antibodies should enter an ICSI protocol. Assisted reproductive techniques Intrauterine insemination IVF/ICSI

FSH: follicle-stimulating hormone; GnRH: gonadotrophin-releasing hormone; hCG: human chorionic gonadotrophin; hMG: human menopausal gonadotrophin; ICSI: intracytoplasmic sperm injection; IVF: in vitro fertilisation. a Also based in parts on the recommendations of the ``Infertility Guidelines Group'' of the Royal College of Obstetricians and Gynaecologists, London, 1998.

3.1. Sex chromosomal abnormalities is desirable in men with severely damaged spermato- 3.1.1. Klinefelter's syndrome (47XXY) and variants genesis, who are seeking IVF/ICSI. The techniques are (46XY or 47XXY mosaicism) becoming widespread in IVF/ICSI units, but have not This is the most common sex chromosome abnorm- been standardised. If a man is found to have micro- ality. These men have an increased risk of producing deletions and the couple wishes to proceed with ICSI, 47XXY spermatozoa. Pre-implantation diagnosis or they can be advised that microdeletions will be passed amniocentesis and karyotyping should be done in to sons but not daughters. Patients who have autosomal IVF/ICSI, and embryos with Klinefelter's karyotype defects resulting in severe phenotypic abnormalities should not be implanted. and infertility will already be under medical care. Any fertility problem should be managed within that con- 3.2. Autosomal abnormalities text. Where an autosomal karyotypic abnormality is already known, or found to be present, in the male 3.4. Cystic ®brosis mutations and male infertility partner, all couples requesting fertility treatment Cystic ®brosis (CF) is a fatal autosomal recessive should be offered genetic counselling (see Section 3.5). disorder. It is the most common genetic disease of Caucasians; 1 in 25 are carriers of gene mutations 3.3. Genetic defects involving the CF transmembrane conductance regula- 3.3.1. X-linked genetic disorders and male fertility tor gene (CFTR). X-linked recessive disorders manifest in males and are carried by daughters. X-linked disorders associated 3.4.1. Men with congenital bilateral absence of vas with infertility include Kallman's syndrome and Rei- deferens (CBAVD) fenstein's syndrome (androgen insensitivity). Many Carrier status in men of the CFTR gene is associated X-linked disorders have phenotypic abnormalities, with CBAVD. Thus, if a male has CBAVD,both he, and e.g. retinitis pigmentosa, Menkes' syndrome, but do his partner, must be tested for CF mutations. If the not affect fertility. Couples should receive appropriate female partner is also found to be a carrier, the couple genetic counselling (see Section 3.5). must be carefully counselled about the risks of proceed- ing with ICSI using the husband's sperm (see Section 3.3.2. Y genes and male infertility 3.5). Although unilateral absence of the vas deferens Defects in the Y gene are associated with impaired or probably has a different genetic cause, there have been absent spermatogenesis. If fertility is possible, the reports of some men having CF mutations and these defect will be passed to sons. Y microdeletion analysis men should be tested as for men with CBAVD. W. Weidner et al. / European Urology 42 (2002) 313±322 315

3.5. Genetic counselling and ICSI Testicular biopsy is indicated in patients without The main dif®culties will occur if there is a con¯ict obvious factors, i.e. they have a normal FSH and of interest between the wishes of the couple and the normal testicular volume, to differentiate between interests of a future child. The best initial management obstructive and non-obstructive azoospermia. Some is to give full information to the couple, who should azoospermic patients may present with both obstruc- then decide whether to proceed or not. However, there tive and spermatogenic pathologies and increased is often a greatly increased likelihood of a future child serum FSH levels. Testicular biopsy may also be inheriting a genetic disorder. If the decision is taken to indicated in patients with clinical evidence of non- proceed, it is important for the couple to appreciate obstructive azoospermia, who request ICSI. Testicular fully what may be in store for them and their child. Pre- biopsy is a simple, outpatient procedure performed implantation diagnosis with replacement only of nor- under local anaesthesia, as an open or percutaneous mal embryos, or if not available, amniocentesis and the biopsy or by testicular ®ne-needle aspiration. Several possibility of termination, should also be considered. testicular samples should be taken because of regional differences. There is a good correlation between diagnostic biopsy histology and the likelihood of ®nding 4. Primary spermatogenic failure mature sperm cells. Any type of testicular biopsy should provide suf®cient material to cryopreserve Primary spermatogenic failure (Table 2) is de®ned as sperm for future ICSI cycles. any spermatogenic alteration caused by reasons other than hypothalamic±pituitary diseases. Severe forms of 4.2. Testicular morphology primary spermatogenic failure present clinically as Severe forms of altered spermatogenesis are com- non-obstructive azoospermia [8,9]. plete sclerosis; complete aplasia of germ cells (Sertoli cell-only syndrome [SCOS] or Del Castillo syndrome) 4.1. Diagnosis and complete spermatogenic arrest at the spermatocyte In non-obstructive azoospermia, semen analysis level. Infrequently, spermatogenic arrest is seen at the shows normal ejaculate volume and azoospermia after spermatogonia or round spermatid level. Less severe several centrifugations. The serum level of FSH is forms include hypospermatogenesis, partial spermato- mainly correlated with the number of spermatogonia. genic arrest, focal SCOS and mixed patterns. In focal There is no correlation between FSH levels and the spermatogenesis, mature cells are produced by loca- presence of sperm in testicles with non-obstructive lised seminiferous tubules. About 50±60% of men azoospermia. The measurement of luteinising hormone with non-obstructive azoospermia have some semini- (LH) and testosterone should be considered in patients ferous tubules with spermatozoa that can be used for with clinical signs of hypogonadism. For genetic ICSI. studies see Section 3. 4.3. Treatment The only treatment for patients with non-obstructive Ta bl e 2 azoospermia is testicular sperm retrieval, to be used Causes of primary spermatogenic failure and underlying clinical entities either fresh or cryopreserved in ICSI. Karotyping and Y microdeletion analysis are necessary to identify the Aetiology implications for a future child. If genetic anomalies are Congenital detected, the couple will need genetic counselling (see Maldescended testes Other chromosomic alterations Section 3). Complete and focal germ cell aplasia (either congenital or acquired: maldescended testes, irradiation, cytostatic drugs, etc.) 4.3.1. Testicular sperm extraction (TESE) techniques Post-in¯ammatory (orchitis) Open biopsy including microsurgical techniques and Systemic diseases (liver cirrhosis, renal failure) Varicocele ®ne-needle aspiration are the two main techniques for Idiopathic sperm retrieval from the testicle. In non-obstructive Acquired (trauma, testicular torsion, tumour, surgery) azoospermia, multiple TESE or testicular punctions Klinefelter's syndrome have been associated with focal in¯ammation and Germ cell aplasia Spermatogenic arrest haematoma, as well as impaired testicular blood ¯ow. Exogenous factors (medications, toxics, irradiation, heat, etc.) In small testes, an intermittent decrease in serum Testicular tumour testosterone levels is debated. Of 616 TESE reported Surgeries that can damage vascularisation of the testes procedures, 373 (60.6%) yielded sperm for ICSI. The 316 W. Weidner et al. / European Urology 42 (2002) 313±322 mean fertilisation rate was 52.5% (38.6±69%) and the 5.3. Investigations mean pregnancy rate was 29.2% (11.3±31%). In most The history and examination should follow the series, successful testicular sperm retrieval and ICSI investigation of infertile men (see Section 1). A semen was not associated with the patient's age, aetiology of volume of less than 1.5 ml, acid pH and low fructose infertility, testicular volume, serum FSH levels and levels suggest an ejaculatory duct obstruction or histopathology, or whether sperm was fresh or cryo- CBAVD. When semen volume is low, spermatozoa preserved. in urine after ejaculation must always be searched for to rule out an ejaculatory disorder. Serum FSH levels may be normal, but this does not exclude a 5. Obstructive azoospermia testicular cause of azoospermia, e.g. spermatogenic arrest. Transrectal ultrasonography (TRUS) must be Obstructive azoospermia is the absence of both performed, especially when the semen volume is spermatozoa and spermatogenetic cells in semen and 1.5 ml. Seminal vesicle enlargement (anterior±pos- post-ejaculate urine (see Section 1) because of a com- terior diameter 15 mm), roundish, anechoic areas plete obstruction of seminal ducts. Total obstruction of in the seminal vesicles and median intraprostatic cysts the seminal ducts is often accompanied by gonadal are typical. Distal seminal tract evaluation has to secretory dysfunction. Permanent absence of sperma- consider the anatomical permeability of the seminal tozoa in the semen results in male infertility [10±13]. ducts below the proximal vas deferens. Each vas deferens may be microsurgically cannulated with con- 5.1. Proximal obstruction secutive saline injection; if the saline solution passes Intratesticular obstruction occurs in 15% of obstruc- through, vasography is not needed. The injected solu- tive azoospermia. Congenital obstruction is less com- tion passed into the bladder is recovered through a mon than acquired obstruction (post-in¯ammatory or Foley catheter, and spermatozoa are searched for and post-traumatic). Epididymal obstruction is the most counted (seminal tract washout). Testicular biopsy can common cause of obstructive azoospermia. It usually be added when concomitant pathology is suspected. In manifests as bilateral corpus and/or CBAVD, which is addition, the procedure may be used to extract testi- associated with CF gene mutation (see Section 3). In cular spermatozoa (TESE) for cryopreservation and Young's syndrome, a mechanical blockage is caused by subsequent ICSI (see Section 4). debris within the proximal epididymal lumen. Acquired epididymal obstruction occurs most often 5.4. Management following acute (gonococcal) and subclinical (e.g. 5.4.1. Intratesticular obstruction chlamydial) epididymitis (see Section 10). Proximal TESE or ®ne-needle aspiration should be used to vas deferens obstruction is the most frequent cause of retrieve spermatozoa for immediate use in ICSI or acquired obstruction following vasectomy for sterilisa- cryopreservation (see Section 4). tion (see Section 6). Herniotomy may also result in vasal obstruction. 5.4.2. Epididymal obstruction Microsurgical epididymal sperm aspiration (MESA) 5.2. Distal obstruction or TESE are mandatory in CBAVD. Retrieved sperma- Ejaculatory duct obstruction occurs in about 1±3% tozoa are generally used for ICSI, with one MESA of obstructive azoospermia, and is either cystic or post- procedure usually providing material for several ICSI in¯ammatory. Cystic obstructions are usually conge- cycles. In patients with azoospermia due to acquired nital cysts that occur in the prostate between the epididymal obstruction, end-to-side microsurgical epi- ejaculatory ducts. Post-in¯ammatory obstructions of didymovasostomy must be performed. Reconstruction the ejaculatory duct are rare and usually secondary to may be done uni- or bilaterally, with higher patency urethroprostatitis. Congenital or acquired complete and pregnancy rates associated with bilateral surgery. obstructions of the ejaculatory ducts are associated Before performing microsurgery, the epididymis must with low semen volume, decreased or absent seminal be checked for full patency downstream. It may take 3± fructose and acid pH. Seminal vesicles are usually 18 months for anatomical recanalisation to occur fol- dilated (anterior±posterior diameter >15 mm). Func- lowing surgery. Before performing microsurgery, epi- tional obstruction of the distal seminal ducts may didymal spermatozoa should be aspirated and be associated with local neuropathy urodynamic cryopreserved for ICSI in case of surgical failure. dysfunction, juvenile diabetes and polycystic kidney Patency rates of 60±87% and cumulative pregnancy disease. rates of 10±43% have been obtained. Late failure W. Weidner et al. / European Urology 42 (2002) 313±322 317 occurs in 10±21% of recanalisations, due to abnormal 6.1. Complications testicular histology, absence of sperm in the epididy- Local complications include haematoma (1% of mal ¯uid, ®brosis of the epididymis and abnormalities cases), wound infection and epididymitis. Chronic in the prostate. testicular pain may develop. Vasectomy does not signi®cantly alter spermatogenesis and Leydig cell func- 5.4.3. Vas obstruction tion. Epididymal tubular damage (`blow-out') is Vas obstruction after vasectomy requires microsur- common, leading to sperm granuloma. Antisperm anti- gical vasectomy reversal (see Section 6). Proximal vas bodies are typical in the follow-up. Ejaculate volume is deferens sperm aspiration or TESE/MESA may be unchanged. All available data indicate vasectomy is possible in cases of concomitant epididymal obstruc- safe and not associated with any serious, long-term tion. The routinely use of sperm reservoirs is not side-effects. recommended. 6.2. Vasectomy failure 5.4.4. Ejaculatory duct obstruction Vasectomy has a failure rate of less than 1%. Pater- Transurethral resection of the ejaculatory ducts nity as a result of recanalisation (including very rarely (TURED) is recommended in post-in¯ammatory long-term recanalisation) can occur at any time after obstruction, when one or both ejaculatory ducts empty vasectomy and does not depend on the surgical pro- into an intraprostatic midline cyst. Complications asso- cedure. No motile spermatozoa should be detected 6±8 ciated with TURED include retrograde ejaculation due weeks after vasectomy. If azoospermia fails to occur, to bladder neck injury, and also urine re¯ux into the repeat vasectomy. seminal pathways (causing poor sperm motility, acid semen pH and epididymitis). Alternatives to TURED 6.3. Preoperative patient counselling are MESA, TESE, proximal vas deferens sperm aspira- Patients must be aware that vasectomy is not irre- tion, seminal vesicle aspiration and direct ultrasoni- versible and of its complications and failure rate. cally-guided cyst aspiration. In functional obstruction Normal contraceptive methods must be used post- of the distal seminal ducts, antegrade seminal tract surgery until there is evidence of azoospermia. washout should be used to retrieve spermatozoa. Sper- matozoa retrieved by any of the aforementioned sur- 6.4. Vasectomy reversal gical techniques should always be cryopreserved for There are no standardised criteria for the results of assisted reproductive procedures. vasectomy reversal. A wide range of surgical success rates have been published up to 90%. Personal experi- 5.5. Conclusions ence with a particular technique is an important factor Results of reconstructive microsurgery depend on in success. Although there are no randomised, con- the cause and location of the obstruction and the trolled trials, reports from case series indicate better expertise of the surgeon. Standardised procedures results with microsurgery compared with loop surgery. include vasovasostomy, epididymovasostomy and It is therefore strongly recommended that microsurgi- TURED. In addition, sperm retrieval techniques can cal vasectomy reversal is the standard method used. be used (MESA, TESE, testicular ®ne-needle aspira- Reported vasovasostomy results have shown patency tion). However, the consensus is that these methods rates (up to 90%) superior to pregnancy rates. The should only be used if cryopreservation is available. reason for this discrepancy is unclear. However, the longer the interval from vasectomy to reversal, the lower the pregnancy rates. The necessity for epididy- 6. Vasectomy and vasectomy reversal movasostomy in some cases after vasectomy has been discussed previously (see Section 5). Vasectomy is the most effective method of permanent surgical sterilisation. A man undergoing vasect- 6.5. Treatment of post-vasectomy infertility omy should be interested in permanent surgical Microsurgical vasectomy reversal was compared contraception. Initial discussion should include both with epididymal or testicular sperm retrieval and ICSI. the failure rate and the possibility of vasectomy rever- Compared with a calculated 29% delivery rate for sal. The most appropriate technique should be chosen. MESA and ICSI, the data provide strong evidence One standard technique is cauterisation and ligation of for the better outcome of simple vasectomy reversal the vasal lumina. Fascial interposition between the compared to sperm retrieval and ICSI. In addition, in vasal ends is recommended [14±16]. contrast to ICSI, conception follows normal inter- 318 W. Weidner et al. / European Urology 42 (2002) 313±322 course without intervention and its associated risks for men with Klinefelter's syndrome, who are already at the female partner. MESA/TESE and ICSI should be risk for spontaneous hypogonadism with ageing. reserved for failed surgery or cases not amenable to Laboratory diagnosis of hypergonadotrophic hypogo- surgical reconstruction. nadism is based on decreased serum testosterone and increased LH levels. Additional prolactin measurement is suggested. 7. Special problems (1): hypogonadism 7.3. Treatment Men with hypogonadism usually present with symp- There is general agreement that patients with primary toms of androgen de®ciency. Hypogonadotrophic hypo- or secondary hypogonadism should receive testosterone gonadism may sometimes result in infertility. Disorders substitution therapy. Testosterone supplementation is with male hypogonadism are given in Table 3 [17,18]. only indicated in men with levels consistently lower than normal (<12 nmol/l 300 ng/dl). Injectable, oral 7.1. Hypogonadotrophic hypogonadism and transdermal testosterone preparations are avail- Hypogonadotrophic hypogonadism is caused by able. The best preparation is the one that maintains hypothalamic or pituitary diseases. Endocrine de®- serum testosterone levels as close to physiological ciency leads to a lack of spermatogenesis and testos- concentrations as possible. terone secretion due to decreased secretion patterns of LH and FSH. Drug therapy is effective in achieving fertility. The therapy of choice is hCG treatment; hMG 8. Special problems (2): varicocele may be added later, depending on initial testicular volume. For hypogonadotrophic hypogonadism that Varicocele is a common condition (Table 4). Diag- is hypothalamic in origin, treatment with pulsatile nosis is by clinical examination. A doubtful diagnosis GnRH for one year is as effective as gonadotrophins may be con®rmed by colour Doppler ultrasound or, in in stimulating spermatogenesis. Once pregnancy has some centres, radiography [19,20]. been achieved, patients return to testosterone substitu- Varicocele has been associated with the following tion therapy (see Section 7.3). andrological problems: failure of ipsilateral testicular growth and development, infertility, reduced testoster- 7.2. Hypergonadotrophic hypogonadism one in older men and symptoms of pain and discomfort. In younger men, common conditions associated with In some men, the presence of a varicocele is thought to hypergonadotrophic hypogonadism are testicular dis- be associated with progressive testicular damage from orders (Table 3). Hypertrophic hypogonadism may also adolescence onwards, resulting in reduced male ferti- occur after extensive testicular biopsy to recover sperm lity. However, the man's reduced fertility will only for IVF/ICSI; the risk is almost certainly increased in manifest as an infertile couple if the female partner's fertility is also reduced.

Ta bl e 3 a 8.1. Treatment Disorders with male hypogonadism The treatment modalities are: sclerotherapy (ante- Disorder grade, retrograde), embolisation, and open surgery, Hypothalamic hypogonadism (pituitary origin) including microsurgical dissection. Choice of therapy Idiopathic hypogonadotrophic hypogonadism, including Kallman's is mainly in¯uenced by the therapist's experience. syndrome (hypogonadotrophic secondary hypogonadism) Although laparoscopic varicocelectomy is also feasible, Delay of puberty Hyperprolactinaemia it still needs to be justi®ed in terms of cost-effectiveness. Hypergonadotrophic syndromes (primary hypogonadism of testicular origin) Ta bl e 4 Anorchia (acquired) Clinical classi®cation of varicocele Klinefelter's syndrome Grading Feature Leydig cell tumours General diseases (e.g. liver cirrhosis) Subclinical Not palpable or visible either at rest or during Valsalva Target organ resistance to androgens manoeuvre, but can be demonstrated by special tests Testicular feminisation (re¯ux on Doppler examination) Reifenstein's syndrome (androgen insensitivity) Grade 1 Palpable during a Valsalva manoeuvre but not otherwise Grade 2 Palpable at rest but not visible a Adapted from [18]. Grade 3 Visible and palpable at rest W. Weidner et al. / European Urology 42 (2002) 313±322 319

8.1.1. Indications for treatment not completely understood, the following alterations Treatment is recommended in adolescents if serial have been discussed aetiologically: decreased number clinical examination shows progressive failure of tes- of tubules containing spermatogonia, decreased num- ticular development. Treatment is probably recom- ber of spermatogonia per tubule, mild concomitant mended in adolescents with ipsilateral testicular hypogonadotrophic hypogonadal situation, damaging atrophy. Treatment may be indicated in adolescents effects on the contralateral testis, induction of sperm in whom varicocele is associated with an exaggerated antibodies, epididymal malformations. response to gonadotrophin-releasing hormone (GnRH). Although no real consensus exists, it seems logical to There is no evidence to indicate that varicocele treat- suggest orchiectomy as the treatment of choice for ment bene®ts adolescents in the absence of either most infertile men presenting with unilateral cryp- ipsilateral testicular atrophy or endocrine abnormal- torchidism. This is in accordance with accepted think- ities. It is general clinical urological practice to recom- ing that the malignant potential of abnormally located mend varicocele treatment for adolescents and adults testis increases with age. with symptoms. In the era of ICSI, TESE may be considered during According to meta-analysis of randomised clinical operation for sperm retrieval in azoospermic men. In trials, varicocele ligation for infertility does not patients with bilateral cryptorchidism, it is very dif®- improve fertility. However, there are case reports cult to decide between conservative orchiectomy (plus showing restoration of fertility. Thus, varicocele liga- testosterone replacement) and orchidopexy (after tion for infertility should only be carried out after biopsy has excluded carcinoma in situ). There is no discussing fully the uncertain bene®ts of treatment. consensus, neither in the literature nor in the EAU It may be worth selecting subgroups of men with Working Group on infertility. infertile marriages, according to endocrine measure- ments. New methods of endocrine measurement, e.g. inhibin Bmeasurement, may be helpful. Observational 10. Special problems (4): urogenital evidence suggests that older men with varicocele may infections3 have lower testosterone levels than those without varicocele. However, there are no clinical trials to address Infections of the male urogenital tract are potentially whether varicocele ligation helps restore testosterone correctable causes of male infertility. A generalised levels. By the time, these changes become manifest, in¯ammatory disease has been de®ned as male acces- damage is almost certainly irreversible. In the absence sory gland infection by WHO. Male urogenital infec- of local symptoms of pain and discomfort, treatment of tions include urethritis, prostatitis, orchitis and varicocele in older men with low testosterone levels is epididymitis [23±25]. not recommended. 10.1. Urethritis In urethritis, the anterior urethra is full of infectious 9. Special problems (3): cryptorchidism2 and in¯ammatory material. Due to contamination of the ejaculate with this in¯ammatory material, the The association between testicular maldescent and impact of urethritis on semen quality and fertility is infertility has been well known for a long time [21,22]. not really proven. A negative in¯uence of sexually transmitted microorganisms on sperm function is a 9.1. Impact on fertility matter of debate. Obstruction has been claimed to Among men who have untreated unilateral cryp- impair fertility, either as a normal urethral stricture torchidism (and still cryptorchid on semen analysis), or as a lesion in the posterior urethra in the area of the between 50 and 70% are azoospermic or oligozoos- veromontanum, both of which can lead to ejaculatory permic. In contrast, almost all men with untreated disturbances. Treatment is standardised by the guide- bilateral cryptorchidism are infertile. Although the lines of the Centers of Disease Control and Prevention. mechanisms for impaired fertility in these cases are The impact upon fertility is unknown.

2 As cryptorchidism is discussed in the EAU Guidelines on paediatric 3 As male genital infections are discussed in the UIT Guidelines, only urology, Chapter 2, p. 7±10, only the impact on fertility disorders will be the impact on fertility disorders will be reviewed here (EAU Guidelines for reviewed here (EAU Guidelines published at the time of the XVIth EAU the management of urinary and male genital tract infections. Eur Urol Annual Congress in Geneva, ISBN 90-806179-3-8). 2000;40:576±88). 320 W. Weidner et al. / European Urology 42 (2002) 313±322

Ta bl e 5 Classi®cation of the prostatitis syndrome from the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK)

Category Comment

I Acute bacterial prostatitis (ABP) Acute infection of the prostate gland II Chronic bacterial prostatitis (CBP) Recurrent infection of the prostate III Chronic abacterial prostatitis/chronic pelvic pain No demonstrable infection syndrome (CPPS) IIIA In¯ammatory chronic pelvic pain syndrome White cells in semen, expressed prostatic secretions or post-prostatic massage urine IIIBNon-in¯ammatory chronic pelvic pain syndrome No white cells in semen, expressed prostatic secretions or post-prostatic massage urine V Asymptomatic in¯ammatory prostatitis No subjective symptoms. In¯ammation detected either by prostate biopsy or by the presence of white cells in expressed prostatic secretions or semen during evaluation for other disorders

10.2. Prostatitis function. Sex gland infections can impair their excre- Prostatitis is the most common urological diagnosis tory function. Decreased quantities of citric acid, in men aged under 50 years. A new classi®cation phosphatase, fructose, zinc and a-glutamyltransferase system including semen analysis is given in Table 5. activity in seminal plasma have been evaluated as disturbed prostatic secretory parameters and reduced 10.2.1. Ejaculate analysis fructose concentration as an indicator of impaired Ejaculate analysis is part of the new classi®cation vesicular function. (Table 5) and helps to clarify whether the prostate is part of a generalised infection of the accessory sex 10.2.6. Sperm antibodies glands and also gives the semen quality. Leukocyte Post-in¯ammatory seminal plasma antibodies to analysis allows differentiation between in¯ammatory sperm antigens do not play a decisive role in immune and non-in¯ammatory CPPS. infertility.

10.2.2. White blood cells 10.2.7. Reactive oxygen species According to WHO classi®cation, >1Â106 white Levels may be increased in chronic urogenital infec- blood cells per ml are de®ned as leukocytospermia. tions associated with increased leukocyte numbers. The great majority of leukocytes are neutrophilic However, their biological signi®cance in prostatitis granulocytes. The clinical signi®cance of an increased remains unclear. concentration of white blood cells in the ejaculate is highly controversial. This debate re¯ects earlier ®nd- 10.3. Treatment ings that elevated leukocyte numbers are not a natural Treatment of chronic prostatitis is normally targeted cause of male infertility. at relieving symptoms. Therapy for altered semen composition in male adnexitis is aimed at reduction 10.2.3. Microbiological ®ndings or eradication of microorganisms in prostatic secre- In evidence of 106 peroxidase-positive white blood tions and semen, normalisation of in¯ammatory para- cells per ml ejaculate (see above), a culture for com- meters, possible improvement of sperm parameters to mon urinary tract pathogens should be performed. A counteract fertility impairment. Although antibiotic concentration of 103 cfu/ml of urinary tract patho- procedures may improve sperm quality, therapy does gens in the ejaculate is signi®cant bacteriospermia. not always enhance the probability of conception.

10.2.4. Semen quality Deteriorative effects of chronic prostatitis on sperm 11. Special problems (5): orchitis and density, motility and morphology are debated contra- epididymitis dictory, recent data do not con®rm a decisive role of chronic prostatitis for male infertility. 11.1. Orchitis Orchitis is an in¯ammatory lesion of the testicle, 10.2.5. Seminal plasma alterations associated with a predominantly leukocytic exsudate, Seminal plasma elastase is a biochemical indicator inside and outside the seminiferous tubules, resulting of granulocyte activity in the ejaculate. Various cyto- in tubular sclerosis. Chronic in¯ammatory changes kines, involved in in¯ammation, may in¯uence sperm alter both sperm number and quality. Orchitis is an W. Weidner et al. / European Urology 42 (2002) 313±322 321

Ta bl e 6 Ta bl e 7 Classi®cation of epididymo-orchitis Treatment of epididymo-orchitis

Acute bacterial Non-speci®c chronic Condition Therapy epididymo-orchitis epididymo-orchitis Acute bacterial epididymo-orchitis N. gonorrhoeae Granulomatous (idiopathic) orchitis N. gonorrhoeae Tetracyclines C. trachomatis Pneumococcus spp. C. trachomatis Tetracyclines E. coli (and other Salmonella spp. E. coli, Enterobacteriaceae Fluoroquinolones Enterobacteriaceae) Mumps orchitis Inteferon a-2b Klebsiella spp. Haemophilus in¯uenzae Non-speci®c chronic Steroidal and non-steroidal epididymo-orchitis antiphlogistic substances Speci®c disorders Viral disorders Gonadotrophin-releasing hormone Speci®c granulomatous orchitis Mumps orchitis Granulomatous (idiopathic) orchitis Semicastration Tuberculosis Coxsackie B Lues Specific orchitis According to therapy of Brucellosis underlying diseases important cause of spermatogenetic arrest, which may is involved in the in¯ammatory process known as be reversible, and of testicular atrophy. Orchitis is epididymo-orchitis (Table 6). classi®ed according to aetiology (Table 6). 11.2.1. Diagnosis 11.1.1. Diagnosis Ejaculate analysis, including leukocyte analysis, 11.2.1.1. Ejaculate analysis. In acute epididymo- indicates persistent in¯ammatory activity. Especially orchitis semen analysis is not recommended. In in acute epididymo-orchitis, there is transiently chronic epididymitis, ejaculate analysis, including decreased sperm counts and reduced forward motility. leukocyte count, may indicate persistent inflammatory Obstructive azoospermia due to complete bilateral activity. In many cases, transiently decreased sperm epididymal obstruction is a rare complication. Mumps counts and forward motility are observed. Ipsilateral orchitis may result in bilateral testicular atrophy and low-grade orchitis has been discussed as the cause of testicular azoospermia. When granulomatous orchitis this slight impairment in sperm quality. Development is suspected, sperm-bound autoantibodies occur. of stenosis in the epididymal duct, reduction of sperm count and azoospermia are important in the follow-up 11.1.2. Treatment of bilateral epididymitis (see Section 5). The true Only the antibiotic therapy of acute bacterial epidi- prevalence of azoospermia after unilateral epididymo-orchitis and of speci®c granulomatous orchitis is dymitis is unclear. standardised (Table 7). Several regimens are thought to improve the in¯ammatory lesion and to be bene®cial 11.2.2. Treatment for the risks of infertility. Unfortunately, corticoster- Antibiotic therapy is indicated before culture oids and non-steroidal antiphlogistic substances, i.e. results are available (Table 7). Treatment should resul- diclofenac, indomethacin and acetylsalicylic acid, have tin a microbiological cure of infection, improvement not been evaluated as to their andrological outcome. of signs and symptoms, prevention of transmission gonadotrophin-releasing hormone has been used with to others and a decrease in potential complications, the aim of prevention of spermatogenesis. e.g. in¯ammatory obstructive lesion. Patients with epididymitis, known or suspected to be caused 11.2. Epididymitis by N. gonorrhoeae or C. trachomatis, should be In¯ammation of the epididymis is almost unilateral instructed to refer sex partners for evaluation and and relatively acute in onset. In many cases, the testicle treatment.

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