internationaliournal of andrology,l6:1- 13(1993)

1

Review Infection in the male reproductive tract. Impact, diagnosis and treatment in relation to male infertility

K. PURVIS and E. CHRISTIANSEN Andrology Laboratory, Institute of Pathology, The National Hospital, Oslo, Norway

Summary The following are the conclusions that can be derived from a review of the literature regarding the role of infection in the aetiology of male infertility. (i) Temporary inflammatory episodes in the male reproductive tract which are selflimiting are probably common. (ii) Caution should be exercised in the use of leukospermia or bacteriospermia as parameters for glandular infection. (iii) There is a need for alternative techniques for detecting non-symptomatic deep pelvic infections in the male; one technique of great promise is rectal ultrasound. (iv) Rectal ultrasound indicates that a large number of men with poor sperm quality have a non-symptomatic, chronic prostatovesiculitis. (v) Increasing evidence implicates Chlamydia tvachomatis as being a major cause of chronic non-bacterial prostatitis. (vi) An important aspect of chlamydia1 infections in men may be that the male accessory sex glands may function as reservoirs for the organism, increasing the probability of infection in the female. (vii) Ureaplasma uvealyticum may also play an important aetiological role in male infertility but its significance is confounded by its acknowledged function as a commensal in the reproductive tract. (viii) One of the manifestations of male reproductive tract infectiw is the induction of sperm autoantibodies. (ix) There is a need for more systematic controlled studies of the effects of antibiotic treatment on sperm quality with different preparations for extended periods using patient groups in which a glandular infection has been verified, e. g. by rectal ultrasonography. Keywords: Chlamydia tvachomatis, infection,

leukospermia, male infertility,

rectal ultrasound, Ureuplarma uvealyticum. Conclusions regarding the incidence and consequences of infection in the male reproductive tract have been made uncertain by the lack of suitable diagnostic criteria for demonstrating its presence and the possibility that a large Correspondence: Dr Kenneth Purvis, Andrologisk laboratorium, Institutt for patologi, Rikshospitalet, 0027 Oslo 1, Norway.

number of cases are symptomless. When these conditions can progress unregistered by the patient or undetected by the physician, the possibility of damage to the reproductive tract and its function is increased. The purpose of the present review is to explore what is known of the impact of infection in the male reproductive tract, in particular its consequences for male fertility.

2 K. Punir and E. Christiansen

Temporary inflammatory episodes It is likely that in the majority of sexually active men,

immune mechanisms in the reproductive tract are activated relatively often in response to local and transitory inflammatory episodes precipitated by pathological organisms. In most cases, these are apparently not registered by the host. Figure 1 shows the proportion of symptom-free men undergoing fertility investigation who exhibited elevated levels of secretory IgA in their seminal plasma. No relationship could be demonstrated between

this immune response and sperm quality (data not shown). Similarly, Fig. 2 shows the transitory rise and fall in the concentration of seminal leucocytes in a sperm donor without any symptoms, without any effects on sperm quality and without any form of therapy. The relevance of this spontaneous regression of glandular infection in infertile men has been discussed previously (Comhaire et al., 1986). The factors governing why such transitory 'silent' inflammatory episodes should in some individuals progress into acute symptomatic or chronic conditions is unknown.

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Figure 1. Seminal plasma concentrations of secretory IgA in 100 consecutive non-symptomatic men under fertility investigation. The subjects could be allocated to three groups according to their IgA level. No association could be demonstrated between IgA secretion, which indicates an active, local infection, and sperm quality or the seminal concentration of leucocytes.

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The significance of leukospermia There is a wide variation in the white cell levels in prostatic secretions obtained by prostatic massage from normal non-symptomatic men (Jameson, 1967) and leucocytes are often present in the ejaculates of fertile controls in studies on male infertility (e.g. El-Demiry et al., 1986). However, it is generally accepted that an increase in the concentration of leucocytes to greater than 1 x 10' ml-' ejaculate can be considered a sign of glandular infection (Comhaire et al., 1980). Indeed, elevated numbers of leucocytes in prostatic secretions are typical of acute and chronic bacterial and non-bacterial prostatitis (Drach, 1975; Meares, 1989) and are associated often with symptoms from the urino-genital tract in infertile men (Colpi et al., 1988). O n the other hand, the absence of leukospermia does not exclude infection, especially when there are focal inflammatory lesions and occlusion of the excretory ducts. Studies on the prostates of male accident victims indicate that areas of inflammation in the gland are increasingly common with advancing age, are often focal

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Comhaire et al. (1980) have recommended several criteria for demonstrating an infection in the male sex glands, including: (a) a history of urogenital infection and/or abnormal rectal palpation, (b) alterations (in the numbers of leucocytes or bacteria) in expressed prostatic secretion (EPS) and/or urinary sediment after prostatic massage, (c) uniform growth of > 1000 pathogenic bacteria per ml or >10000 non-pathogenic bacteria in seminal plasma diluted 1:2 per ml, (d) > 1 million leucocytes per ml ejaculate and, (e) disturbed secretory function of the accessory sex glands. The presence of two of these criteria in any combination makes the diagnosis of an accessory gland infection likely. However, there are reservations associated with each of these criteria, which must be considered before an infection in the male acccssory sex glands is dismissed. This is particularly important when one considers the confusion and contradictory results which have been reported in this field especially with regard to the aetiology of male infertility.

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Time (weeks) Figure 2. Sperm motility and the concentration of leucocytes in ejaculates obtained regularly from the same individual over a period of several months. A transient period of leukospermia, which corresponded to a change in sexual partner, was not associated with any symptoms from the genital tract or with any deterioration in sperm quality.

Infection In the male rsproducHvetract 3

and involve one or more excretory ducts which become occluded. Because of its focal nature, the authors concluded that transrectal biopsies may fail to confirm a diagnosis of prostatitis and that it may be difficult to obtain representative samplings during prostatic massage or after normal ejaculations (cited by Colleen & Mirdh, 1982). The presence of a chronic symptomatic prostatovesiculitis verified by ultrasound is not always associated with an increase in leucocytes (Christiansen et al., 1992). Moreover, there is no clear association between the presence of leucocytes and bacteria in semen (Comhaire, 1978; El-Demiry et a f . , 1986). Significantly, Ureaplarrna urealyticiim was found to be present with a similar frequency in men with and without pyospermia (Bennet et of., 1982) and some organisms, i.e. Chlamydia trachomatis may not constitute such a strong antigenic stimulus in men that they mobilize leucocyte migration (Treharne, 1983). In direct contrast, Close et al. (1990) indicated that local inflammatory changes in the reproductive tract associated with cigarette smoking or heavy alcohol consumption can also increase the appearance of leucocytes in the ejaculate. These findings and the observation that men may have coincidental, transitory leukospermia of no pathological significance, suggests that caution should be exercised when interpreting leucocyte numbers in the ejaculate.

The significance of bacteriospermia The male reproductive tract, with the exception of the urethra, is normally free of aerobic bacteria (see review by Fowler & Kessler, 1983, p. 283). Traditionally, the existence of pathogenic bacteria in seminal plasma (e.g. Dahlberg, 1976) or elevated numbers of bacteria ml-' (e.g. Eneroth et al., 1978) have been taken as signs of an active infection in the male reproductive tract. This is certainly true in cases of acute and chronic bacterial prostatitis (Meares, 1989), although these conditions are encountered more seldomly. More specifically, the uniform growth of > 1000 pathogenic bacteria ml-' or > 10 000 non-pathogenic bacteria in seminal plasma diluted 1:2 has been taken as indicative of bacterial inflammation (Comhaire et al., 1980). However, certain facts complicate the use of this parameter: (a) seminal fluid exhibits antibacterial activity (Mirdh & Colleen, 1975) which can serve to differentially inhibit the culture of certain pathogenic bacteria. Some have suggested diluting the seminal plasma prior to cultivation to reduce this inhibitory influence (Comhaire et al., 1980); (b) the male urethra is colonized by a variety of micro-organisms (see review by Fowler & Kessler, 1983, p. 285) and it is extremely difficult, if not impossible, to avoid contamination of the ejaculate with urethral and post-urethral bacteria when the sample is provided by masturbation; (c) it is still not clear to what extent bacteria normally regarded as commensals in the male reproductive tract, can contribute to an inflammatory process in the

male pelvic organs, either as secondary opportunists or as a main cause; and (d) the existence of focal infection combined with obstruction of excurrent ducts will not be associated with bacteriospermia. In view of the probability of urethral contamination, it is therefore not surprising that bacterial cultures are positive in more than 50% of semen samples from nonsymptomatic men (Grossebauer & Kaden, 1970). In cofitrast, chronic symptomatic inflammation of the accessory sex glands can occur often without any clear indications of bacteriospermia. This is true especially of non-bacterial prostatitis which constitutes 80% of the cases of symptomatic prostatitis. In this condition, in spite of leukospermia, no clear pathogenic organism can be isolated (Meares, 1989). In view of these findings and the above reservations, several authors have concluded that routine cultures of semen, especially during fertility investigation, are unlikely to be rewarding (e.g. Nahoum, 1982). To circumvent the problem of urethral contamination of the ejaculate, Meares & Stamey (1968) developed the Four Glass technique consisting of (a) the first 5-10 ml of voided urine, (b) a mid-stream urine sample prior to prostatic massage, (c) a sample of expressed prostatic secretion (EPS) under massage, and (d) a post-massage urine sample. In this way the bacteria or leucocytes associated only with prostatic secretion can be identified. However, there are certain drawbacks linked with this technique: (a) the area of the gland massaged by the physician may not be appropriate, (b) the infection may be encapsulated within the gland, (c) the high concentration of substances with potential antibacterial activity (e.g. zinc, spermine) in the prostatic fluids may distort the culture findings, and, more importantly, (d) the infection may not be localized primarily to the prostate, but in the seminal vesicles or epididymides. This may explain why EPS does not correlate always with identification of a bacterial pathogen in cultures (Meares, 1973).

The use of rectal ultrasound In recent years, the application of rectal ultrasound to the investigation of deep pelvic organ infections in the male have offered new insights into the aetiology of male infertility and the symptomatology associated with chronic inflammatory conditions of the sex organs. Various ultrasonographic criteria have been considered indicative of chronic inflammation in the prostate and the seminal vesicles (Di Trapani et al., 1988; Christiansen & Purvis, 1991) including: (a) glandular assymetry, (b) hypoechogenicity associated with oedema, (c) hyperechogenicity associated with areas of calcification, and (d) dilation of the periprostatic venous plexus in the case of prostatitis (Fig. 3) and (a) enlargement and assymetry (b) thickening and calcification of the glandular epithelium, and (c) areas

4 K. Purvis and E. Christiansen

Figure 3. Rectal ultrasound photographs (transverse plane) of the prostate gland from a control subject (a) and a man with

a symptomatic chronic abacterial prostatitis (b). Note the presence of calcifications, oedema and asymmetry in the inflamed gland.

of encapsulation, in the case of vesiculitis (Fig. 4). Studies in a group of men with symptomatic, non-bacterial prostatovesiculitis indicated that (a) the extent of ultrasonographic findings could not be related to the severity of the symptoms and that extensive pathological changes in the sex glands could often bc present without clear symptoms, (b) that invariably both the prostate gland and scminal vesicles showed evidence of inflammatory changes a t the same time, (c) symptoms from the sex organs were associated with ultrasonographic changes on the ipsilateral side, and (d) these inflammatory changes were not associated necessarily with leukospermia (Christiansen & Purvis, 1991). The large number of men with ultrasonographic changes in their prostate glands without symptoms, prompted one author to conclude that ‘chronic prostatitis may be an occult disease that is present in more patients than indicated by current clinical investigations’ (Doble & Carter, 1989). Indeed, when a non-symptomatic

Figure 4. Rectal ultrasound photographs (transverse plane)

of the left seminal vesicle from a control subject (a) and a man with a symptomatic chronic prostatovesiculitis (b). Note the enlargement of the affected gland and the presence of thickened septa and multiple encapsulated areas.

group of men under fertility investigation were examined by rectal ultrasound with no prior knowledge of the sperm quality, a clear association could be demonstrated between ultrasonographic evidence for a vesiculitis and the extent of sperm pathology (Purvis & Christiansen, 1992). In men with severe oligozoospermia almost 40% had indications of a ‘silent’ vesiculitis (Fig. 5 ) . It is also significant in this respect, that a large number of men developing acute epididymitis had ultrasonographic evidence of a chronic prostatic infection (Doble et al., 1988), implying that the infection had been non-symptomatic and latent in the sex glands before its intracanalicular spread and activation in the epididymis. Using rectal ultrasound, postinflammatory stenosis of the ejaculatory ducts can often be seen in men with oligozoospermia as a pre-stenotic dilation of the duct in the prostate gland (Fig. 6). Such alterations are seldom manifested by symptoms. Thus, rectal ultrasound adds a new dimension to the

Infection in the male reproductivetract 5

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Figure 5. Incidence of vesiculitis verified by rectal ultrasonography (m), varicocele ( 0 )and a tender prostate gland (m) (after rectal palpation) in 100 consecutive subjects under fertility investigation, grouped according to various grades of

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sperm quality. In general, sperm quality decreased with clinical or ultrasonographic evidence of pelvic organ inflammation (Purvis & Christionsen, 1992).

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Figure 6. Rectal ultrasound photographs from a subject with oligoasthenoteratozoospermia and a pre-stenotic dilatation of the right ejaculatory duct shown in transverse (a) and sagittal (b) planes and in diagrammatic form (c).

battery of tests which have been proposed to demonstrate an infection in the male accessory sex glands and may clarify some of the inconsistencies which have made this area of andrology so controversial for such a long time.

Infection and sperm quality Infection, especially tuba1 pathology, is acknowledged to be a major cause of infertility in women, and although it is probable that it also has a major role to play in the male, the evidence is Controversial and conflicting. One problem is that the infection may no longer be active and another, discussed above, is that the diagnostic criteria for a deep

6 K. Purvir and E. Christianson

pelvic infection may not be adequate. In 1966, Eliasson et reported that from cytological and/or bacteriological evidence, inflammation of the male accessory sex glands was common in infertile men. Indeed, some have made the general observation that the ejaculates of infertile men contain more leucocytes than fertile controls (Ulstein et al., 1976) and that sperm quality is decreased in the presence of elevated concentrations of leucocytes (Caldamone & Crockett, 1981). The number of leucocytes in semen was the most important predictive factor for an abnormal score in the sperm penetration of zona-free hamster oocytes and after doxycycline treatment there were fewer in the semen samples of the improved group (Berger et al., 1983). This association between infection and depressed sperm quality was also supported in some studies by the finding that there were fewer bacteria in the seminal fluid of fertile than infertile men (Toth & Lesser, 1981; McGowan et al., 1981). In a review of seven authors published between 1981 and 1983, Megory et al. (1987) reported that, on average, twice as many positive bacterial cultures can be obtained from the ejaculates of infertile than fertile men. In contrast, Comhaire et al. (1986) found only 1.6% of their couples had a glandular infection which could be related to abnormal sperm quality and El-Demiry et al. (1986) found no correlation between leucocyte counts, sperm quality and the growth of micro-organisms. There were also reports of no difference between the semen parameters of men with and those without bacteriospermia (Comhaire et al., 1980; McGowan et a l . , 1981; Gregoriou et al., 1989a). The possible reasons for these discrepancies have been discussed earlier. Chronic prostatitis is assumed generally to be caused by a pathogenic organism which in the majority of cases is associated with leukospermia (Meares, 1973). The difference between the bacterial and non-bacterial forms of the condition is that in the former the presumptive aetiological agent has been isolated. Whether the sperm quality of men with chronic prostatitis is depressed compared to healthy controls is still a matter of controversy. Several studies ,have indicated an association between chronic prostatovesiculitis and poor sperm quality (Eliasson et al., 1966; Von Szenohradszky et al., 1978; Gallo et al., 1986) and impairment of prostatic secretory function (Eliasson, 1968). Scarselli et al. (1978) showed that 54% of infertile men had evidence of chronic prostatovesiculitis, often linked with asthenozoospermia. Giamerellou et al. (1984) has shown that chronic prostatitis is often associated with oligoasthenoteratozoospermia (OAT) and that long-term antibiotic treatment not only cured the prostatitis but also normalized or improved the spermatograms in 70% of the patients. This contrasts with the recent findings of Weidner et al. (1991) that failed to demonstrate any impairment of sperm quality in a group of men with chronic prostatitis defined using conventional criteria. Our own study of 50 men, in whom the prostatitis was verified by rectal ultraal.

sonography, indicated that a large number had disturbances in sperm quality including azoospermia (Fig. 7; Christiansen et al., 1992). The reasons for the controversy is unknown. However, it is likely that the presence of a chronic bacterial infection, over an extended period, predisposes the host for intracanicular spread to the rest of the reproductive tract with negative consequences for sperm quality, resulting from ductal stenosis (Schoysman, 1981) and subclinical orchitis (Nilsson et al., 1968).

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Figure 7. Incidence of normospermia, azoospermia and borderline and poor sperm qualities in men with symptomatic non-bacterial prostatovesiculitis(CPV, n = 50) compared with non-symptomatic,age-matched controls ( n = 33; Christionsen et ol., 1992).

The role of specific organisms Aerobic gram-negative bacilli are believed to play major roles in non-gonoccal bacterial infections of the male genital tract. In 20-30% of cases of acute epididymitis (e.g. Mittemeyer et al., 1966) and many of the cases of chronic bacterial prostatovesicultis (Meares, 1973) the organism responsible is a gram negative bacillus, often E . coli. However, these conditions are encountered less frequently than chronic non-bacterial prostatovesiculitis (Meares, 1973) and therefore, are presumably more seldom a cause of infertility. Gram-positive aerobic bacteria frequently colonize the male urethra but are rarely a causative factor in non-gonococcal urethritis (Holmes et al., 1975) or acute epididymitis (Berger et al., 1979) and is rarely reported as a cause of prostatitis. Moreover, infection with these agents ‘constitutes an extremely uncommon causative factor in male infertility’ (Fowler & Kessler, 1983). ‘Over almost two decades, two organisms in particular have been discussed as having key roles in both symptomatic and non-symptomatic infections in the male reproductive tract: (a) the ureaplasmas, in particular,

Infedon Inthe male reproductive had 7

Ureaplasma urealyticum and (b) Chlamydia trachomatis. However, many of the studies indicating an involvement of these bacteria have been closely followed by results refuting their relevance. Confusion about their involvement may stem from the wide variety of methods used to establish the presence of the organisms (Chlamydia trachomatis) and the fact that the ureaplasmas under normal conditions are commensals in the reproductive tract, and their pathological significance is therefore more dificult to demonstrate.

Ureaplasma urealyticum Four different species of mycoplasmas are known to colonize the male reproductive tract, M . hominis, reaplasma urealyticum, M . fermentans and M . genitalium (TaylorRobinson & McCormack, 1980), but it is Ureaplasrna urealyticum which is considered a facultative pathogen in male urogenital tract infections, associated with nonspecific urethritis (Weidner et al., 1982) and prostatitis (Weidner et al., 1980). In general, in cases of non-bacterial prostatitis, Ureaplasma urealyticum can be implicated as a cause of the inflammation in 11-15% of the cases (Meseguer et al., 1984; Weidner et al., 1985). In most of these studies, larger numbers of the bacteria could be detected in the urethral discharge and prostatic secretions of affected men than in healthy controls. Treatment with tetracycline reduced the number of leucocytes and bacteria in the secretions. The role of Ureaplasma urealyticum as an aetiological agent in male infertility has been discussed since the early observation that these organisms can attach firmly to spermatozoa (Fowlkes et al., 1975). Indeed, when Ureaplasma urealyticum has been implicated as a causative factor, it has often been associated with reduced sperm motility and poor sperm morphology (Swenson et al., 1979; Aparicio et al., 1980; Toth & Lesser, 1982). Mycoplasma infections also appear to be associated with an increase in the percentage of coiled sperm tails (Busolo et al., 1984) and infected sperm exhibit reduced oocyte penetration (Busolo & Zanchetta, 1985). In many of the cases in which tetracycline therapy was initiated, varying grades of improvement in sperm quality were recorded. The incidence of ureaplasma infection has also been reported to be higher amongst couples with idiopathic infertility (Toth et al., 1983). In a survey of 10 authors, Megory et al. (1987) noted an average incidence of mycoplasma infection of approximately 40% of infertile men, compared to an average of 28% in fertile controls. In contrast, other groups have been unable to confirm any association between ureaplasma infections and infertility or sperm quality (Desai et al., 1980; Weidner et at., 1985). With regard to the controversy surrounding the role of the mycoplasmas, an important question is whether an organism such as Ureaplasma urealyticum, which is so wide-

spread in the normal male reproductive tract, can increase in numbers simply because the local immune system is attenuated by a primary infection. If so, much of its aetiological significance is weakened.

Ch/amydia frachomafis Chlamydia1 infections are now reported to be the most prevalent and among the most damaging of sexually transmitted diseases (Smith & Winship, 1987). Its manifestations are well acknowledged in women in whom it is responsible for the majority of cases of salpingitis (Mirdh et al., 1977) and pelvic inflammatory disease (Westrom, 1975) and thus accounts for a large number of cases of female factor infertility (Paavonen et al., 1979). More than 70% of women with signs of tuba1 damage have circulating antibodies to Chlamydia trachomatis compared to none in a group of controls with normal fallopian tubes (Moore et al., 1982). Similarly, Gump et al. (1983) reported a 64% incidence of chlamydial antibodies in women with residual inflammatory adnexal lesions, compared to 28% in women with normal adnexae. The implication is that the organism has a predilection for inducing inflammatory changes of the deep pelvic organs in the female which, as will be seen later, may also have relevance to its pathological significance in the male.

Association with epididymitis and urethritis Chlamydia trachomatis has been documented to be one of the main aetiological agents in urethritis (Handsfield, 1981) and acute epididymitis (Krieger, 1984) in men less than 35 years of age. Retrograde ascent of pathogens via the ejaculatory duct into the vas deferens is the usual route of epididymal infection (Schmidt & Hinman, 1950; Berger et al., 1979). Doble et al. (1988) showed that of 20 men with clinically diagnosed acute epididymo-orchitis, 85% had abnormal prostatic ultrasound, 65% with ejaculatory duct calcification. This suggests that the route of spread of the organism is intracanalicular, possibly secondary to urinary reflux into the vasa caused by the structural changes in the ejaculatory ducts. It also implies that non-symptomatic chlamydial prostatitis may precede acute epididymal infection. As in the female, such chlamydial infections in the vas deferens or epididymis may cause partial or complete stenosis in these organs, resulting in dramatic changes in sperm quality. Non-bacterial prostatitis The most common form of prostatitis is non-bacterial prostatitis, characterized by elevated numbers of leucocytes in the ejaculate or EPS without any clear indications as to which pathogenic organism is responsible (Meares, 1973). In recent years, there has been a growing indication that Chlamydia trachomatis may be at least one candidate. Non-gonococcal urethritis is reportedly accompanied by

8 K. Purvis and E. Christianoen

prostatitis in 30-100% of cases (Kaufman & Wiesner, 1974; Oates, 1976). As early as 1972, using a complement fixation test, Mirdh et al. demonstrated the presence of Chlamydia trachomatis in 33% of 79 men with chronic nonbacterial prostatitis, compared to 3% in 72 age-matched controls. Recently, Weidner et al. (1991) found that Chlamydia trachomatis could be cultured from the urethral swabs of 28% of men with non-bacterial prostatitis after prostatic massage. This confirmed an earlier report, using tissue culture and immunofluorescence, of the presence of the organism in the prostatic fluid from six men with chronic prostatitis (Bruce & Reid, 1989). Di Trapani et al. (1988) isolated Chlamydia trachomatis either alone or with other bacterial agents from 34% of men with chronic prostatitis verified by rectal ultrasonography. In our own studies, close to 45% of men with symptomatic, nonbacterial prostatitis and leukospermia had elevated levels of IgA specific for Chlamydia trachomatis in their ejaculates (Brandtzaeg et al., 1992). Similar findings of an increase in Chlamydia-specific IgA have also been reported in the prostatic fluid of japanese men with chronic prostatitis (Tsunekawa et al., 1991), and Suominen et al. (1983) showed that over half of the infertile men presenting with a history of infection (non-symptomatic chronic prostatitis) had elevated seminal plasma levels of Chlamydia-specific IgA, compared to 23.5% of fertile men and 27% of men without any signs of infection. Poletti et al. (1985) reported the isolation of Chlamydia trachomatis from prostatic cells in patients affected by non-acute, non-bacterial prostatitis. Furthermore, using colorimetric, in-situ DNA hybridization for detection of Chlamydia trachomatis, Abdelatif et al. (1991) have demonstrated the intracellular presence of the organism in 30% of prostatic specimens obtained by transurethral resection. This is in contrast to the findings of Doble et al. (1989) using transperineal biopsies from 50 men with chronic non-bacterial prostatovesiculitis. They failed to find any evidence of Chlamydia trachomatis in prostatic tissue after culture and immunofluoresence or after serological investigations. The reason for this discrepancy is as yet unknown. Moreover, Berger et al. (1989) failed to demonstrate the presence of Chlamydia trachomatis in the prostatic fluid of 34 men with chronic prostatitis using cultures. O n the other hand, negative cultures of Chlamydia trachomatis from prostatic fluid or semen should not be taken as definitive proof that the bacteria is not present, because of its intracellular nature and the fact that male reproductive fluids can exert an inhibitory influence on the culture cells used to demonstrate the organism (Mlrdh et al., 1980). Relationship to disturbances in sperm quality and male fertility There is a great variability in the reported incidence of Chlamydia trachomatis in infertile men, which appears to be related to the methods used. When seminal fluid or

urethral smears are cultured (in McCoy cells combined with detection of Chlamydia inclusion bodies), the incidence is around 5% (Busulo et a/., 1984; Hellstrom et al., 1987; Megory et al., 1987; Ruijs et al., 1990). When urethral smears were cultured from 175 infertile men with a poor post-coital test, the number of positives increased to 15% (Soffer et a/., 1990), which is similar to the 14% registered by Nagy et al. (1989) in 184 asymptomatic men participating in an IVF programme. The latter figure is not surprisingly high as the female partners of the majority of men in this group had a history of tuba1 occlusion or ectopic pregnancies which in all probability were linked to a Chlamydial infection. More recently, authors have measured Chlamydiaspecific immunoglobulins either in serum or seminal plasma. Similar studies by two authors, when Chlamydiaspecific serum IgG was measured, indicated that: (a) both fertile and subfertile men without a history of a previous genito-urinary infection exhibit a similar incidence (about 28%) of Chlamydial infection, and (b) in the subfertile group this is increased to 50% in men with a previous genital infection (Auroux et a/., 1987; Gregoriou et al., 1989b). Other authors, also measuring serum IgA describe incidences in infertile men of 57% (21 men; Nikkanen et al., 1980) and 71% (37 men; Hellstrom et al., 1987). Unlike IgG, IgA is an immunoglobulin which is secreted locally in response to a relatively more recent infection (Treharne, 1983). In an early study, Suominen et al. (1983) reported that 51% of infertile men with a history of genital infection had elevated levels of Chlamydia IgA in their seminal plasma, compared to 27% in the rest of the subfertile group. Our own studies showed an incidence of 35% in a group of 28 oligozoospermic men (Bjerke & Purvis, 1992). A common feature of the majority of the above reports, is that no relationship could be established between sperm quality and a Chlamydial infection, previous or present, using culture or serology. Several facts should be considered in this respect. (i) In contrast to the female, Chlamydia trachomatis constitutes a weak antigenic stimulus to the immune system, resulting in only modest antibody responses (Treharne, 1983). Indeed, an immunological response cannot be detected in approximately 20% of infected males. (ii) There is a growing awareness of a crossreaction between non-genital species of Chlamydia (Scheibel & Ibsen, 1985) which could account for a large number of false positives when serum IgG is measured. Seminal IgA would be more appropriate. (iii) Chlamydia trarhomatis is associated with deep pelvic organ infections both in the male and female (see earlier) and urethral sampling may not be appropriate in the majority of cases. One of our own studies indicated that a high degree of transmission of Chlamydia trachomatis occurs between infertile partners without either of them registering symptoms (Bjerke & Purvis, 1992). Indeed, Nikkanen et al. (1980) had noted earlier that 76% of the male partners of

Infection in the male reproductivetract 9

Chlamydia-positive females exhibited evidence of infection. As the pathological significance of Chlamydia trachomatis in the female is well documented, it may be that the significance of the organism in men may lie in their capacity to retain a reservoir of bacteria in their sex glands which can innoculate the female partner repeatedly. Over time such a chronic infection in the female may cause tubal or endometrial pathology. This presumably explains the higher incidence of active Chlamydial infection in the male partners of women with tubal pathology (Nagy et al., 1989; Eggert-Kruse et al., 1990). Significantly, Chlamydia trachoniatis is capable of attaching to sperm (WolnerHanssen & Mirdh, 1984). A similar conclusion about a bacterial reservoir function for the male was reached by other authors (Toth et a/., 1984) who noted that the incidence of vaginitis, salpingitis, herpes and urinary tract infection in 1350 infertile couples was generally higher in women whose husbands had reported a previous history of genito-urinary infection. Another possibility is that Chlamydia trachomatis may influence infertility by inducing sperm autoantibodies (Soffer et al., 1990, see below) or by impairing more subtle aspects of sperm quality not registered by conventional techniques. It may be significant in this respect that a special form of ‘jerking movement’ has been registered by automatic motility analysis of sperm from men infected with Chlamydia trachomatis, which is normalized after treatment with tetracycline (Diquelou et al., 1989). Furthermore, increased incidence of Chlamydia trachoniatis has been found in men with obstructive azoospermia (Gerris et a / ., 1985) which supports its acknowledged role in the aetiology of epididymitis (Berger et al., 1978), a common sequela of which is epididymal stenosis (Krieger, 1984). Clearly, more studies should be carried out to clarify the importance of this bacteria in male infertility.

Infection and the production of sperm autoantibodies Several early reports have suggested a relationship between a genital infection and the production of sperm autoantibodies. Fjallbrant & Obrant (1968) and Quesada et al. (1968) showed that the frequency of prostatovesiculitis was significantly higher in men with antibodies against spermatozoa than in those without antibodies. Furthermore, a sexually transmitted disease also appears to predispose men to the development of sperm antibodies (Shahmanesh et al., 1986). Witkin & Toth (1983) showed that in non-symptomatic men under fertility investigation, a previous history of prostatitis or urethritis was associated with a marked increase in the incidence of sperm antibodies (47 vs so/,). Moreover, in men with mycoplasmal or Chlamydial infections there was a highly significant increase (14 vs 1.2%) in the number with sperm antibodies in their seminal plasma compared to the non-infected

controls (Soffer et al., 1990). A history of exposure to Chlamydia trachomatis, as determined by serum antibody, could be related to the presence of sperm agglutinating antibodies (Close et a/. , 1987). The mechanism responsible for this induction of antibodies is still unknown. Inflammation may lead to the migration of immune cells into the genital tract which then react to spermatozoa, which may be trapped in excurrent ducts. Alternatively, antibodies may be formed to common antigens between the bacteria and spermatozoa.

The effects of antibiotic therapy on sperm quality and/or fertility There has been a large number of studies on the effects of antibiotic therapy on sperm quality and the pregnancy rate, many of which have been contradictory. Although some authors have obtained an improvement in semen quality and/or fertility in men with infected semen after antibiotic therapy (Boccon Gibod, 1977; Scarselli et al., 1978; Aparicio et al., 1980; Berger et al., 1983; Giamerellou et al., 1984), others have failed to corroborate these findings (Harrison et al., 1975; Moberg et al., 1980; Baker, 1984). Comhaire et al. (1986), in a double-blind trial treated both partners of 33 infertile couples, with evidencc of an accessory sex gland infection in the male, with doxycycline. No difference was recorded between antibiotic treatment and placebo with regard to pregnancy rate, although both groups showed an improvement in certain aspects of sperm quality. The general conclusion was that glandular infections can regress spontaneously and that any resulting improvement in sperm quality does not improve the chances of conception. There may be several reasons for difficulties in showing an antibiotic effect on male infertility: (a) the therapy may not have been appropriate for the organism responsible or it may not have been of inadequate dose or duration. This is particularly pertinent with regard to prostatovesiculitis in which the infections have a tendency to be encapsulated, and (b) the pathological changes in the reproductive tract responsible for the poor sperm quality may be permanent (e.g. epididymal stenosis causing a delay in transit time or seminiferous tubule failure caused by orchitis). Figure 8 indicates the relatively dramatic effects of treatment with erythromycin for 4 weeks on the sperm count in two men exhibiting a progressive decline in sperm quality associated with prostatovesiculitis verified by rectal ultrasonography. This type of response implies that glandular or epididymal infection can reduce the sperm count, presumably by causing a reversible stenosis of the excurrent ducts. In less frequent cases, restoration of a normal sperm count could only be obtained after extended treatment with clindamycin, suggesting the presence of an anaerobic infection (Purvis, unpublished data). In conclusion, the impact of bacterial infection on male

10 K. Punir and E. Chridianren

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Figure 8. Progressive decline in sperm concentration over two to three years in two subjects with a chronic prostatovesiculitis verfied by rectal ultrasonography. Antibiotic therapy with erythromycin (black boxes) resulted in a

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fertility is still uncertain. Circumstantial evidence favours a role for chronic inflammatory conditions in the male reproductive tract as a major cause of disturbances in sperm quality. However, a greater acknowledgement of its importance may have to await the more widespread application of techniques such as rectal ultrasound, and the development of genetic probes or specific antibodies for the more efficient detection of the bacterial organisms involved. In addition, better indices of sperm quality

should be utilized in addition to the conventional laboratory techniques (e.g. hamster egg penetration tests) to register more subtle aspects of biochemical function. Indirect consequences of glandular infection such as the induction of sperm antibodies, alterations in seminal fluid viscosity by virtue of disturbances in secretory function and the role of the male sex glands as reservoirs for repeated infections of the female partner should also be explored more fully.

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Infectionin the male reproductivetract 13

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