Andrology Centre, Department of Internal Medicine, University of Catania, Via A.Diaz 15, 95125 Catania, Italy
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Abstract |
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Key words: antimicrobial treatment/male accessory gland infections/ROS production/seminal white blood cells/sperm parameters
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Introduction |
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Recently, a strong association has been demonstrated between sexual gland post-inflammation damage found by an abnormal ultrasound and increased WBC concentration and ROS production, particularly in patients affected by PVE compared with values seen in patients with prostatitis (PR) or prostatovesiculitis (PV) (Vicari, 1999). Thus, a prospective, randomized, controlled trial was carried out on 122 asymptomatic, infertile males with a high bacterial count [>105 colony-forming units (CFU)/ml] and ultrasound evidence of MAGI limited to the prostate (n = 52), extended to seminal vesicles (n = 32), or also to the epididymis (n = 38), to evaluate whether bacteriological cure, sperm outcome, spontaneous pregnancy rate and WBC-related ROS production were related to the extent of the infection and to an intermittent and repetitive treatment with two different antibiotics, ofloxacin and doxycycline. These antibiotics were chosen because they possess certain general characteristics (broad antibacterial spectrum against relevant Gram-negative, Gram-positive pathogens as well as Chlamydia trachomatis or Ureaplasma urealyticum; excretion primarily by the kidneys with minimal metabolism; sufficient drug penetration into the inflamed sexual glands; low rate of adverse sperm effects following short-term treatment) and specific in-vitro susceptibility. Doxycycline was proven to penetrate into the normal prostate due to acidity of the secretions and ionic trapping, but does not penetrate well into the diseased prostate because of the alkaline pH of the gland's secretions (Schramm, 1986
; Cunha and Garabedian-Ruffalo, 1990
; Naber et al., 1993
).
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Materials and methods |
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Rather, a male infertility factor might be postulated since: (i) both the results of the post-coital test and in-vitro bovine cervical mucus sperm penetration capacity were repeatedly negative. The former was true in 68.0% of cases [83/122 patients exhibiting <10 spermatozoa/high-power field (HPF) with directional motility in the endocervical specimen], and the latter in 73.8% of cases (90/122 samples exhibiting penetration <16 mm); and (ii) all patients had to exhibit oligo-, astheno- or teratozoospermia, as suggested by conventional criteria (WHO, 1993).
Clinical characteristics of infected categories
All infertile patients were affected by presumptive MAGI, suspected upon the basis of oligozoospermia (sperm concentration <20x106/ml), asthenozoospermia (<50% spermatozoa with forward progression, categories a and b), or teratozoospermia (<30% spermatozoa with normal oval form), and fulfilled conventional criteria (WHO, 1993). Eligibility criteria (clinical, laboratory and ultrasound examination) and exclusion criteria (i.e. history of smoking, alcoholic consumption, occupational chemical exposure) were as previously reported (Vicari, 1999). In particular, all patients had one or two consecutive cultures with significant bacteriospermia (>105 CFU/ml), C. trachomatis or U. urealyticum detected in cultures of urethral swabs obtained after prostatic massage. A cut-off value of >105 CFU/ml was used; this was much higher than the value cited earlier (WHO, 1992) because it was based on the strong association with ultrasound abnormalities, as reported recently (Vicari, 1999
).
The clinical diagnosis of epididymitis was suspected when, at the physical examination of the epididymis, there were painful palpation, swelling and/or microcysts or micronodularity in the caput or caudal region from one or both sides. These clinical findings suggested that the ultrasound investigation to be second mandatory additional proof, even in order to distinguish accurately the site (PR, PV and PVE) of MAGI. To this end, ultrasound findings considered indicative of chronic inflammation were used, as reported recently (Vicari, 1999).
Study design and treatments
Before initiating antibiotic treatment, sperm and microbial assessments were performed on the three major categories (PR, PV, PVE) of the overall infected population (n = 122). Patients of each category were allocated at random into three subsets which were assigned either to antimicrobial therapy (ofloxacin or doxycycline) or to no therapy (controls). Randomization was achieved using a computer program. The first random set of numbers was assigned to treatment with ofloxacin, the second set to treatment with doxycycline, and the third set to controls. In particular, the first two random sets of numbers, including together 40 PR, 20 PV and 25 PVE, received ofloxacin (200 mg orally every 12 h; Flobacin®, SigmaTau, Italy) or doxycycline (100 mg orally once daily; Bassado®, Poli, Italy) intermittently for 14 days each month over a 3-month period. The third random set (12 PR, 12 PV and 13 PVE patients) received no treatment. All patients provided written informed consent; they completed the entire trial, including treatment and follow-up examinations.
In order to eradicate infection from each couple, the female partner was treated for 8 days/cycle (days 5 to 12) with the same antibiotic as used in the male partner. During this time, sexual intercourse using condoms was recommended until bacteria were eradicated in both partners.
The duration of treatment for each group was 14 consecutive days per month, with a subsequent 2-week washout period for a 3-month period. This treatment course was chosen arbitrarily on the basis of two considerations: (i) modern fluoroquinolones are recommended to be administered for a minimum of 24 weeks (Weidner, 1992; Bjerklund Johansen et al., 1998
); and (ii) it was reported previously that, in some normozoospermic and most oligoasthenoteratozoospermic (OAT) infected patients, prolonged treatment with antimicrobials (>2 weeks) was accompanied by an antibiotic-independent `stress tubular pattern' (STP), characterized by reduced sperm concentration and increased percentages of both spermatozoa with abnormal morphology and sperm precursors (Vicari and Sidoti, 1991
). This pattern was reversible between 39 months after discontinuation of therapy. Since in our experience the potential risk of STP was greater in patients with OAT, most patients in the present study might incur this adverse side effect and thus misrepresent the usefulness of antimicrobials, which in MAGI have a rational application.
Pre-treatment microbial and sperm characteristics of the different MAGI categories
The microbiological results of the three major clinical categories of MAGI are reported in Table I.
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Isolated bacterial strains exhibited a high susceptibility to both ofloxacin and doxycycline in the present study. In terms of MIC (minimum inhibitory concentration) values of the isolates, the random antibiotic (ofloxacin or doxycycline) chosen had lower MIC values (<1 mg/l) than any of the other antimicrobials tested in vitro.
Results of conventional semen analyses in the patients with PR and PV showed median values significantly (P < 0.01) higher than those found in patients with PVE. The values were not significantly different between the PR and PV patients (Table I). Seminal WBC concentrations in the PVE group were significantly (P < 0.01) higher than those found in PR patients, but not higher than those of PVE patients (Table I
).
Sampling management
In the overall population, sperm and bacteriological effectiveness was assessed by semen analysis and culture tests based on CFU/ml measurements in baseline or pre-treatment condition (T0) or tests for Chlamydia and Mycoplasma in cultures of urethral swabs obtained following a prostate massage. Two semen specimens were collected by masturbation into a sterile polystyrene jar, after 35 days of sexual abstinence, spaced 510 days apart. Patients were requested to wash their hands and genital region carefully with bactericidal and antifungal soap, and to rinse the soap away with isotonic solution. All patients agreed to the above control analyses either during treatment, and two observations obtained 7 and 11 days after temporary withdrawal of the therapy at month 1 (T1) and month 3 (T3), and 90 days (range 90103 days) after completion of therapy (T6).
After liquefaction, semen samples were analysed for sperm concentration (C; x106/ml), total sperm number (TSN; x106/ejaculate), forward motility percentage (M; % grade a+b, after 1 h), sperm morphology [percentages of both normal oval forms (Ov) and pathological coiled tails (Ct)] and seminal leukocyte concentration (WBC; x106/ml) according to WHO guidelines (WHO, 1992). In particular, conventional immunocytochemical staining (WHO, 1992) was used to assess seminal WBC concentration, according to previously published methods (Vicari, 1999). Furthermore, sperm preparation by a two-step Percoll 45/90% discontinuous gradient separation technique as well as determination of WBC-specific ROS production were performed using methods and WBC chemoattractant peptide fMPL (formyl-leucyl-phenylalanine; Sigma Chemical Co., St Louis, MO, USA) dissolved in dimethyl sulphoxide to measure the maximal WBC-specific ROS production, as reported previously (Vicari, 1999
). The ROS measurements were made on 400 µl aliquots of cell suspension. ROS measurements were reported to a standard concentration of 2.5x106 spermatozoa/ml to reduce the number of WBC in the aliquots and consequently the number of `overflow', particularly in patients with PVE. The same sample was measured three times when overflow (>1000x1000 c.p.m.) values were detected the first time: in the presence of 2/3 counts >1000 (x 1000 c.p.m.), the final value assigned to the subject was arbitrarily 1000 (x 1000 c.p.m.).
An aliquot from all samples was also cultured aerobically and anaerobically after 1:2 dilution in saline solution. Standard bacteriological methods were used to quantify and identify all organisms according to previously published methods (Vicari et al., 1986). Primary infection agents were considered to be bacteria isolated in a concentration >105 CFU/ml from semen specimens.
In addition, all spermiograms were performed by the same investigator in a blinded fashion, thus minimizing methodological error.
Assessment of efficacy
The bacteriological response of all major MAGI categories to antimicrobial (ofloxacin or doxycycline) treatment was rated as a cure if a negative (0103 CFU/ml) culture was present at the time when treatment was discontinued (TI or T3), or after completion of therapy (T6). Relapse (same species) or re-infection (different species) were assumed if significant bacteriospermia was present at any time point during treatment or follow-up.
Assessment of safety
The safety assessment included a medical history, a physical examination, haematology and serum chemistry profile at all visits, and monitoring for drug-related adverse events by indirect questioning and patient diaries.
Statistical analysis
In every phase of the trial (pre-treatment, treatment and follow-up examinations) sperm results were the mean of two consecutive semen specimens, collected 35 days apart and registered in each patient. Sperm results are reported as median, with the 10th and 90th percentile in parentheses. Within each subset, one-way variance analysis (ANOVA) followed by Duncan's multiple range test was employed to evaluate differences between assessment intervals and pre-treatment conditions for each parameter, throughout the study. A 2 test and Fisher's exact test were used throughout the study to compare: (i) the pre-treatment percentages of microorganisms isolated of each MAGI category; (ii) the change in the proportion of patients who tested negative for seminal culture at T1, T3 or T6 within three subsets for each major infected category as well as between varying groups at T1, T3 or T6 respectively; and (iii) pregnancy rates (and pregnancy rate per cycle) in treated versus untreated cases. Comparisons between treated subsets and matched control groups were carried out using the non-parametric, MannWhitney U-test for unpaired data.
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Results |
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Bacteriological effects
In all control groups (no treatment), seminal cultures always remained positive with a bacteriological cure rate of 0% over time, which was significantly different compared with patients who became negative throughout the study (Table II). There was no significant difference between treatment groups in all categories (data not shown). Bacteriological cure rates were significantly different among the different MAGI groups (PR > PV > PVE) in a time-dependent manner (Table II
). Indeed, at T1 and T3, bacteriological cure rates were 75.0% and 92.5% for PR patients, 40.9% and 70.4% for PV patients, and 16.0% and 52.0% for PVE patients. At T6, the bacteriological cure rates remained significantly different among infected categories, being 87.5%, 50.0% and 36.0% in PR, PV and PVE respectively. The decrease in the bacteriological cure observed at T6 was explained by a negligible relapse with the same bacterial species (growth of >105 E. coli or Proteus spp.) which occurred both in the treated PR subset on the one hand, and a significant percentage of antibiotic-independent re-infection with a different bacterial species which occurred in PV and PVE patients on the other hand. It is noteworthy that only Gram-positive bacteria caused re-infection (growth of >105 Enterococcus spp. or Staphylococcus aureus) that was resistant to both drugs (MIC 816 mg/l).
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When the bacteriological cure was obtained, 24/85 (28.2%) patients treated with antimicrobials (17/40 with PR, 7/20 with PV, but 0/25 patients with PVE) and 2/37 (5.4%) patients not treated (both affected by PR) achieved a spontaneous pregnancy. The difference between the pregnancy rate in treated versus untreated cases was significant (2 test, P = 0.0097). It is noteworthy that while most patients (20/24; 76.9%) impregnated their partners following the third course of treatment, the remaining four patients (all with PR) became fertile following the first course of treatment, while the two patients with untreated PR fathered after the third month of follow-up. Thus, the pregnancy rate per cycle was also significantly different between treated versus untreated patients with PR or PV, particularly after one and three courses of treatment. In the former group, the pregnancy rate was respectively 10% (4/40) and 12% (13/108) versus 0% and 6% (2/36), while in the latter group it was 0% and 12% (7/60) versus 0% in both follow-up examinations. Finally, the pregnancy rate per cycle was not significantly different between treated versus untreated patients with PVE, being always 0% in both subsets.
Sperm outcome
Sperm outcomes, exhibiting significant changes throughout the trial, are reported in Tables III and IV. No statistical significant difference was found in the three subsets after randomization at T0. Sperm outcome did not vary in MAGI patients without treatment. However, following antibiotic treatment, only some sperm parameters showed significant changes in the three treated subsets throughout the trial (P < 0.01, ANOVA). The significant differences were always registered at T3 and/or at T6 versus T0 and T1 (P < 0.05, Duncan's multiple range test) within each category. Particularly, in comparison with pre-treatment sperm values, the percentages of forward motility showed a significant (P < 0.05) change in both the PR and PV treated subsets; total sperm number showed a significant (P < 0.05) response in the PV treated subset, while the percentages of pathological coiled tails were significantly (P < 0.05) lowered in all patient groups (Table III
). The percentage of normal oval forms also remained unaffected during antibiotic treatment in all patient groups.
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Although in all patient groups the 45% Percoll fraction WBC-specific ROS overproduction registered in the pre-treatment was significantly (P < 0.05) reduced in time-dependent manner, at T3 and T6 the chemiluminescent ROS signals were also significantly (P < 0.01) different among treated subsets (group P < PV < PVE). In particular, baseline (non-fMLP-stimulated) ROS counts in the PVE group remained significantly (P < 0.01) and markedly higher than those found in both the PR and PV groups (Table IV).
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Discussion |
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Our data demonstrated that patients with bacterial MAGI are a heterogeneous composition of different clinical entities (PR, PV and PVE), with varying expression on the sperm output. Because of the well-defined homogeneity of the three patient groups, the efficacy of the antimicrobial treatment can be proven without a placebo-controlled trial. Indeed, an important reason for performing a placebo-controlled study is the clinical heterogeneity of patients under treatment (O'Donovan et al., 1993; Schill, 1995
).
In comparison with matched (untreated) control groups, although occasional pregnancy occurred after the third month of follow-up in two patients who had untreated PR and showed both bacteriospermia and leukocytospermia that remained elevated and unmodified throughout the trial, only antibiotic therapy (ofloxacin or doxycycline) was efficacious in eradicating microorganisms and reducing the WBC concentration in sperm specimens. In contrast, antimicrobial treatment was also required because patients were selected suffering from andrological infection (>105 CFU/ml) and persistent leukocytospermia (Fedder, 1996), and not bland colonization (<104 CFU/ml) (Andreeßen et al., 1993
).
Following antimicrobial treatment, although the bacteriological results were related to two factorsnamely, the extent of infection (bacteriological cure in the PR group > PV group > PVE group) and duration of therapy (better at T3 than at T1)sperm outcome (including WBC concentrations and ROS analysis) and the spontaneous pregnancy rate reflected both the above factors and the varying antibiotic-related antioxidant balance. During the trial, the sperm analysis was characterized by significant changes in three parameters (total sperm number, forward motility and coiled forms) in PV patients and by two parameters (forward motility and coiled forms) in PR patients, but by only one parameter (coiled forms) in PVE patients. During follow-up, these differences in sperm results were maintained at the same statistical significance among groups and compared with the pre-treatment period. The pre-treatment sperm parameters, as well as the post-antimicrobial sperm outcome detected in the three MAGI groups, could not be explained clearly. However, they could in part reflect varying pathogenically effective mechanisms, especially involving the complicated MAGI (PV and PVE) and the degree of their reversibility following antimicrobial treatment: direct effects of the microorganisms on spermatozoa (Gnarpe and Friberg, 1973; Swenson et al., 1979
), ductal stenosis (Schoysman, 1981
) or subclinical orchitis (Nilsson et al., 1968
), secretory malfunction of the epididymis or/and the accessory sex glands (Cooper et al., 1990
; Wolff et al., 1991
; Gonzales et al., 1992
), induction of sperm phagocytosis (Berger et al., 1982
) or immunological processes, WBC response in terms of cytokines (Bar-Chama and Fisch, 1993
) and ROS overproduction (Wang et al., 1997
; Vicari, 1999
). ROS produced during infections of the testis and epididymis are especially harmful to spermatozoa due to the longer contact time and the lack of antioxidant protection (Ochsendorf, 1999
).
Our sperm findings are in agreement with the suggestion that the function of the seminal vesicles (Gonzales et al., 1992) or epididymis is important to prevent a deleterious effect of WBC on semen output or semen quality, through the above pathogenic mechanisms. Indeed, in agreement with other experimental models (Depuydt et al., 1996
; Wang et al., 1997
), we found varying changes of WBC and WBC response, in terms of ROS production, which was markedly enhanced in the presence of infectious (and probably cytokine-stimulating) factors in the three major MAGI groups. Following antibiotic treatment, although seminal WBC concentrations as well as ROS production (basal and not fMLP-stimulated) were lowered in patients with PR or PV, a clear juxta-sperm (basal and not fMLP-stimulated ROS hyperproduction) oxidative stress was persistent in patients with PVE. The varying antioxidative seminal balance registered among the three (treated or untreated) infected categories was directly associated with the spontaneous pregnancy rate that occurred in these patients, being 42.5%, 35% and 0% in treated patients with PR, PV or PVE respectively. On the other hand, among untreated (matched control) infected patients, only two (16.6%) with untreated PR impregnated their partners, while no patients with untreated PV or PVE were able to impregnate.
Thus, in patients with PVE a quantitatively persistent dyspermia and infertility could be secondary to a hostile epididymal microenvironment due to the residual presence of pro-oxidant factors (microorganisms, expression of some cytokines) (Omu et al., 1998) and/or inadequate antioxidant activity (epididymal secretory dysfunction) (Ochsendorf, 1999
).
The present results are in agreement with those previously reported by our group, i.e. in patients with treated epididymitis, an unmodified dyspermia was associated with juxta-sperm ROS overproduction in the 90% Percoll fraction and in the seminal plasma, and this persisted, even following antimicrobial treatment (Vicari et al., 1997).
We believe that our study raises some important issues with respect to MAGI and infertility. In particular, in order to point out some important inflammatory damages from acting directly on semen and accessory sex glands, we included two types of patient: (i) those with >105/ml bacteria in their semen cultures, approximating to the study of spermatozoa infected experimentally with E. coli (106 CFU/ml) in which a reduction in sperm motility was demonstrated (Auroux et al., 1991); and (ii) those with abnormal ultrasound signs to reinforce the hypothesis suggested by some authors (Purvis and Christiansen, 1993
; Vicari, 1999
) that MAGI may contribute indirectly to infertility through combined abnormal structural echopattern and biochemical inflammatory damage (Vicari, 1999
), and not simply through inflammatory biochemical damage, with decrease of the specific markers of the epididymis and/or the accessory sex glands, as reported in the literature (Cooper et al., 1990
; Wolff et al., 1991
; Gonzales et al., 1992
).
In the present study, a comprehensive microbiological ejaculate analysis, including Chlamydia and U. urealyticum in cultures of urethral swabs obtained after prostatic massage, allowed us to detect significant aerobic bacterial growth in 58.2% of semen specimens, with Chlamydia (mainly in PVE patients) in 20.5% and U. urealyticum in 10.7%, while anaerobic growth was seen in the remaining 10.7%. It is worth noting that proof of PVE or PR and not just urethritis was two-fold: these patients were asymptomatic and had had no presence of Chlamydia or U. urealyticum in cultures of urethral swabs obtained without prostatic massage.
In comparison with the higher (42%) anaerobic colonization rate reported earlier (Eggert-Kruse et al., 1995), our low anaerobic colonization might in part be related to methodology used (our seminal plasma samples were cultured after diluting 1:2 in saline; Comhaire et al., 1980) and to different selection criteria of patients, since others (Eggert-Kruse et al., 1995
) identified an asymptomatic infertile group without `clinical signs' of genital tract infections.
From the therapeutic point of view, several points may be underlined about bacteriological outcome. First, that bacteriological outcome reflected a significantly different positive balance between the percentage of cured patients among categories, and the percentage of failure (with relapse or re-infection). Since these results are time- and infected gland-dependent (PR group > PV group > PVE group), we propose at least two possible explanations. First, some microorganisms could require a long-term therapy because of their strong adhesion to the mucous glandular membrane, e.g. Gram-positive microorganisms have a tendency to be encapsulated, protected either by a glycocalix matrix formed by themselves (Nickel and Costerton, 1993) and by an inflamed, hyperviscous vesicular microenvironment. Thus, these mechanisms predispose the host for intracanicular spread to the rest of the reproductive tract. Furthermore, the bacterial re-infections in patients with PV or PVE might in part be explained through a stratified bacterial infection, in which the bacterial glycocalix exhibiting a strong adhesion on one side directly to the glandular mucous membrane could enhance a weaker adhesion to the fimbrias of the Gram-negative organisms on the opposite side. This weak adhesion could be more easily removed by antibiotic treatment, masking the re-infection due to Gram-positive organisms, as seen in our patients. The second point is that, under these especially expressed conditions of MAGI, it is important to emphasize that in all control groups seminal cultures always remained positive with a bacteriological cure (defined as CFU 0103/ml) of 0%, as if a natural history towards spontaneous resolution of bacteriospermia in these patients was not present. A spontaneous resolution of bacteriospermia described in some patients with MAGI (Comhaire et al., 1986
) could be due to temporary inflammatory episodes or to a low number of sexual gland abnormalities detected by ultrasound (Vicari, 1999
), probably through a low degree of bacterial adhesion to infected glands. The third point is that, although twice-daily ofloxacin or once-daily doxycycline, when given orally for 14 days each month over three consecutive months, seem equipotent in the treatment of PR, PV and PVE, and covering the range of causative organisms, antimicrobial treatment showed limited bacteriological cure in patients suffering from PV, and was even less effective in those patients with PVE.
Data reported about the effects of fluoroquinolones on sperm output in infertile MAGI patients with complicated (PV or PVE) infections are difficult to compare because not all investigators used the same diagnostic criteria, and there was a considerable range in the dosage, duration of treatment and follow-up (Schramm, 1986; Weidner et al., 1987
; Malinverni and Glauser, 1988
; Naber, 1991
; Andreeßen et al., 1993
; Stamm and Hoton, 1993
; Vicari and Mongioì, 1993
, 1994
; Vicari et al., 1997
). However, integrating our results with bacteriological rates reported with one of the newer oral fluoroquinolones (ciprofloxacin, enoxacin, fluoroxacin, lomefloxacin, norfloxacin, ofloxacin or pefloxacin) in the treatment of cystitis (9499%) (Del Rio et al., 1996
) and uncomplicated prostatitis (7092%) (Weidner et al, 1987
; Andriole, 1991
), one can postulate that in MAGI categories, bacteriological rate is related to the extent of the infectious process, being highest in the PR group receiving antibiotics (92.5%), followed by the PV group (70.4%), and lowest in the PVE group (52.0%). Thus, the proposed rationale would be to further treat PVE patients with antimicrobials alone, or in combination with antiphlogistic and/or antioxidant drugs. However, the incomplete bacteriological efficacy of even repetitive courses of antimicrobials in PVE patients might have an additional explanation. Indeed, in this group the prolonged pre-ejaculatory spermatozoaWBC interaction could also progressively reduce the antioxidative properties of the epididymis, through low and non-antibiotic-reversible seminal levels of some functional seminal markers (e.g. carnitine, alpha-glucosidase) as was detected preliminarily in some of our patients (data not shown) following antimicrobial treatment.
Since the pro- and antioxidative properties of therapeutic drugs as part of anti-infectious therapies (Ochsendorf, 1999) are a promising strategy to improve human reproductive function, so that a re-equilibrium between leukocytes and/or sperm ROS production and anti/pro-oxidant scavenger efficacy in seminal plasma can be reached (for reviews, see Ford and Whittington, 1998; Geva et al., 1998; Lenzi et al., 1998; Tarín et al., 1998), patients affected by PVE may represent a valid clinical model for the rational use of antioxidant scavengers, since they showed persistent infertility as well as a juxta-sperm oxidative stress even following antimicrobial treatment, which may play a causative role in their infertility (Sikka et al., 1995
).
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Acknowledgments |
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References |
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Submitted on February 24, 2000; accepted on September 8, 2000.