The symptoms of a patient with MAGI can be investigated by collecting the clinical history. Recently, we developed a questionnaire with specific questions to investigate the presence of symptoms [23]. The questionnaire is composed of 30 questions with four possible answers, subdivided in four symptom domains:

Infertile patients with prostate-vesiculitis or prostate-vesiculo-epididymitis have higher questionnaire scores compared to patients with prostatitis alone. In addition, patients with prostate-vesiculo-epididymitis show high scores in domains number 2 and 3 compared to patients with prosto-vesiculitis, confirming that the greater extent of inflammation correlates with symptoms [23]. Potential complications of MAGI are [9, 12, 22, 36]:

These complications can result in sexual dysfunction [9, 12] and male subfertility [24, 28].

According to the extension, MAGI can be classified in uncomplicated and complicated forms. The former include prostatitis, whereas the latter comprehend prostate-vesiculitis, prostate-vesiculo-epididymitis, and epididymo-orchitis. Moreover, according to the presence/absence of microorganisms, MAGI can be divided into microbial, characterized by the presence of bacteria, fungi, and virus, and inflammatory forms, characterized by leukocytospermia and/or overproduction of reactive oxygen species (ROS).

MAGI microbial forms show the growth of more than 10³ pathogenic bacteria or more than 10⁴ nonpathogenic bacteria per ml, in culture of diluted seminal plasma. The most common microorganisms are Enterobacteriaceae (such as Escherichia coli and Klebsiella), Neisseria gonorrhoeae, and Chlamydia trachomatis [22]. A recent study has shown that patients with MAGI who have lower serum levels of total testosterone tend to have a more complicated form of MAGI, involving more than one site, than those with normal levels [9, 12].

According to the National Institutes of Health classification (category II), some Gram-negative bacteria (Enterobacteriaceae such as Escherichia coli, Klebsiella species, Proteus, Serratia, Pseudomonas species, etc.) and etiological agents of sexually transmitted diseases (Chlamydia trachomatis, Ureaplasma urealyticum, Treponema pallidum, Neisseria gonorrhoeae, etc.) are acknowledged as “certain pathogens” of the prostate.

Gram-positive germs (Enterococcus spp., Staphylococcus aureus, and obligate anaerobes) or coagulase-negative germs (Staphylococcus haemolyticus, Staphylococcus epidermidis, and mycoplasmas) are occasionally detectable in the urogenital tract and are considered by some authors to be “nonpathogenic” [27].

A viral form emerging seems to be the HPV infection [29] that, therefore, cannot rely on antibiotic treatment.

Antibiotics are prescribed when a urogenital infection is identified. Negative culture may occur for various reasons: low sample volume, antibiotic treatment prior to collection of the prostate secretions, and presence of undetectable microorganisms. These patients, with clinical evidence of chronic prostatitis, may also benefit from antibiotic treatment to improve the symptomatology.

The antibiotic must have a higher dissociation constant to allow its diffusion into the prostate because of the epithelial lining and pH gradient that inhibit this transition. A meta-analysis of randomized, controlled trials on the pharmacologic treatment of chronic prostatitis and chronic pelvic pain syndrome showed that α-blockers and antibiotics, as well as combinations of these drugs, appear to achieve the greatest improvement in clinical symptom scores, compared with placebo [2]. Anti-inflammatory drugs had a lower, but measurable, benefit on selected outcomes [18].

The most used antibiotics in the clinical practice are quinolones (ciprofloxacin, levofloxacin, etc.), tetracyclines, macrolides, trimethoprim, and β-lactam antibiotics (penicillin derivatives, cephalosporins, monobactams, carbapenems) [34, 39]. The addition of anti-inflammatory drugs and α-blockers (terazosin, doxazosin) improves symptoms. The α-blockers can help to decrease recurrences by diminishing urinary obstruction due to prostate enlargement or congestion secondary to inflammation.

Complicated MAGI are characterized by a chronic inflammatory response and oxidative stress-related alterations. In these cases, a better sperm response is obtained from the sequential treatment strategy: antibiotics (if needed) followed by anti-inflammatory drugs and subsequent antioxidant prescription [44, 45].

The inflammatory forms are characterized by leukocytospermia (seminal fluid leukocyte concentration >10⁶/ml) and/or overproduction of ROS.

An increased number of leukocytes in the seminal fluid may persist even after antibiotic treatment for a microbial form in some patients with complicated MAGI, such as prostate-vesiculo-epididymitis. In addition to leukocytospermia [49], these patients have often abnormal conventional sperm parameters (concentration, motility, and morphology) [50] and other signs of inflammation. Anti-inflammatory drugs should be given when leukocytospermia and/or inflammatory sign and/or symptoms are present. The main anti-inflammatory drugs include nonsteroidal anti-inflammatory drugs (salicylates, fenamic acids, profens, Cox-2 inhibitors, arylacetics, sulfonanilides, oxicams), steroidal anti-inflammatory drugs, and fibrinolytic treatment (serratiopeptidase, bromelain, escin).

MAGI can cause infertility with multiple pathogenetic mechanisms that act at different levels to damage spermatozoa. The infectious/inflammatory process can damage spermatozoa directly or in an indirect manner by altering their microenvironment or determining a sub-obstruction of the excretory proximal and/or distal seminal tract where they transit toward the outside.

The conventional sperm parameters (concentration, motility, and morphology) are frequently altered. MAGI may also affect negatively the so-called biofunctional sperm parameters increasing the percentage of spermatozoa with fragmented DNA, with low mitochondrial membrane potential and apoptosis, and decreasing the number of viable spermatozoa [25].

Most of the studies seem to confirm that MAGI are an important risk factor for male infertility [25]. MAGI are also frequently associated with pH changes, increased seminal fluid liquefaction time, presence of macrophages, sperm aggregations, sperm agglutination, and debris [26]. The greater is the extension of MAGI, the higher is their negative impact on sperm parameters. Therefore, patients with prostate-vesiculo-epididymitis have significantly worst sperm parameters compared to patients with prostatitis alone or prostate-vesiculitis who experience only slight effects on sperm parameters [43]. In addition, we subsequently showed that patients with bilateral prostate-vesiculo-epididymitis have sperm parameters significantly worse than patients with unilateral prostate-vesiculo-epididymitis [46]. Moreover, infertile patients with hypertrophic-congestive MAGI have a better sperm quality but higher oxidative stress in semen compared to patients with fibrosclerotic MAGI. [28]. Altogether, these findings suggest that patients with MAGI and particularly those with complicated MAGI who seek fertility benefit from antioxidant prescription.

Antioxidants can be used both in microbial and inflammatory forms of MAGI with different sequential treatment strategy after removal of the prooxidant factors, such as germs and/or leukocytes [44, 45].

The protective antioxidant system comprehends enzymatic factors that interact with each other to ensure an optimal protection against the oxidative stress. A deficiency of one of them may result in a decrease of total plasma antioxidant capacity [47].

The main antioxidant commercially available or currently used is discussed below, whereas other used compounds are reported in Table 5.2.