Without a doubt, male genitourinary tract infections significantly contribute to male-factor infertility. Considering that as many as half of all cases of couple infertility may be attributable to the male, it follows that the effect of genitourinary tract infections on seminal quality — and, indirectly, on the female reproductive tract — is substantial.

The effects of genitourinary tract infections on the male may take several different directions. The first is that of direct damage or other noxious effects to the sperm or, secondarily, the seminal fluid. Fortunately, these are the most easily treatable of the potential deleterious effects. Usually, simple elimination of the offending agent is required for cure. A second effect may be seen on the development of sperm, either by direct or by indirect actions. The severity of the infectious process may affect the body constitutionally and, as such, may divert the body’s metabolic energy toward fighting the infection and away from activity that is less vital to an individual’s immediate survival and recovery needs, such as the synthesis or maturation of spermatozoa. The adverse effects of systemic illness on fertility as well as the anti-infective agents used to treat them have been established. It has been demonstrated that while some antibiotics may affect spermatogenesis, others may impact seminal fluid quality.

Over the years, controversy regarding the effects of infectious genitourinary disease and its consequent antibiotic treatment on fertility has emerged, as the specific etio-logic agents have not always been positively elucidated. On the other hand, the literature also abounds with reports of improvements in seminal quality and even improved pregnancy outcomes following empiric antibiotic treatment of the male. Unfortunately, many of these reports are not controlled well enough to be able to draw cause-and-effect conclusions. It is possible that the microorganisms that may be causing the infection are not detectable by the usual investigations. Although several studies have focused on organisms such as Chlamydia, Mycoplasma, and Ureaplasma, among others, the findings, with some regard to cause and effect, have been inconsistent at best. Interestingly, some researchers have detected bacterial deoxyribonucleic acid (DNA) and other bacterial genetic fingerprints in the genitourinary tract of infertile males, but in no way does this prove the causative nature of bacteria in infertility.

Classification of male genitourinary tract infections

Prostatitis

The strict, original definition of prostatitis referred to an infectious or inflammatory process in the prostate gland. This disease entity, however, was typically accompanied by a rather amorphous set of signs and symptoms that were not quantified. Over time, this definition was expanded by the work of Meares and Stamey, which showed that the prostate gland could sequester and thus shield bacteria from the body’s host defense mechanisms as well as the actions of antibiotics. Their data helped to provide a greatly improved understanding of the pathophysiologic mechanism for chronic bacterial prostatitis. Most recently, the definition of prostatitis has been further elaborated to include not only bacterial infections, but also nonbacterial and noninflammatory conditions. As most of these conditions involve pain, this symptom has evolved into the defining factor of prostatitis. A symptom score sheet has been developed and validated to assist in the evaluation of the prostatitis patient.

The bacterial types of prostatitis (Categories I and II) are easily understood; however, it remains unclear which organisms may be considered pathologic and which commensal. Many cases are self-evident, but others can be confusing. For example, some cases of both A and B category III prostatitis may, in fact, be category II prostatitis, when the results of the cultures are assessed accurately. In the absence of culrurable bacteria, fastidious organisms such as Mycoplasma, Chlamydia, and Ureaplasma can be the inciting organisms. It is still unclear if these agents cause the same symptoms as bacterial infections; however, they have been implicated in male infertility, especially in cases of Chlamydia infection. In the absence of an etiologic agent, category III prostatitis remains an enigma, and its role in male infertility is not well defined.

Urethritis

Urethral infection / inflammation commonly causes infertility by direct effects of the infectious organisms on sperm. Fortunately, this is uncommon, because symptoms caused by the infection limit continuation of exposure. Tissue scarring subsequent to infection represents the main pathologic mechanism that could interfere with sperm deposition in the female by reducing the count or the volume, or both.

In the past, the most common agent implicated in urethritis was Neisseria gonorrhea. This gram-negative diplococcus is sexually transmitted and easily identified on Gram stains of urethral discharge. Even though this organism has become increasingly resistant to many antibiotics, its incidence has diminished in both relative and absolute numbers. Chlamydia trachomatis and other species are the typical etiologic agents for most cases of so-called nonspecific urethritis. These pathogens cause more cases of urethritis than does Neisseria, but the inflammatory response is not as exuberant and thus the incidence of scarring (urethral stricture disease) is not as common. Urethritis may also be caused by more unusual organisms such as Trichomonas vaginalis and Candida albicans, but the impact of these organisms on fertility tends to be limited, especially if adequately treated. Ureaplasma species are thought to be etiologic in cases of both male and female infertility, but because the organism has also been isolated in the urethrae of fertile males, the significance of this finding is not clear.

There are also forms of noninfectious urethritis that may result from irritants such as latex condoms, spermicidal jelly, soaps, fabric softeners, detergents, and others. Allergic responses to these agents may be seen as well. Reiter’s syndrome, a constellation of symptoms that is part of a group of collagen vascular diseases, is a relatively unusual cause of urethral inflammation; the corticosteroid treatment of this condition, however, may actually be more deleterious to fertility than the disease itself. In all, these forms of urethritis account for a small minority of cases, but should be borne in mind, clinically.

Epididymitis / Orchitis

Infection of the testicle and its appendicular structures can be extremely hazardous to future fertility. The lacy microscopic network of tubules that makes up the epi-didymis is particularly susceptible to damage from infection or inflammation. Although most of these infections tend to be sexually transmitted, they also usually occur only in a well-defined age range. Over the ages of 40 to 50 years, the most common etiologic agents gradually change from Neisseria, Chlamydia, Ureaplasma, and Mycoplasma to gram-negative rods, chiefly the Enterobacteriaceae. This alteration occurs not only because of changes in sexual behavior, but also from the increasing age-related incidence of symptomatic benign prostaric hyperplasia and obstructive voiding, both of which predispose men to bacterial urinary tract infections. Either type of bacteria will greatly diminish fertility, both acutely and chronically, but in later years, fertility typically becomes less of a concern in men.

Noninfectious epididymoorchiris is probably quite common, although little epidemiologic data are available. Chemical irritation from the reflux of urine into the ejaculatory ducts can cause a condition almost indistinguishable from bacterial epididymiris, often preceded by an episode of straining or vigorous physical activity with a full bladder. There may also be intense inflammation and subsequent drainage, even in the absence of a definable bacterial infection. These symptoms are usually recurring, because the ejaculatory duct may be aberrantly inserted or otherwise more susceptible to urinary reflux than normal.

Mechanisms of Infertility

Evaluation

History

Probably the most important information obtainable in the history is whether or not the patient has ever had a sexually transmitted disease. Because of the multifaceted injury that these diseases may cause, the impact on fertility is dramatic. Questions regarding the sexual history of both partners may also be helpful. Treatment of any sexually transmitted disease, either proven or empiric, should be queried as well. Traumatic injuries to the patient, with specific emphasis on the genitourinary tract, should be discussed. Even relatively minor events such as straddle injuries may have important implications. Trauma may take on an even subtler connotation, in that certain repetitive activities, not always considered to be of a traumatic nature, may nonetheless be injurious. Motorcycle or bicycle riding, horseback riding, and any of the contact sports or martial arts may cause this type of problem. A history of prior surgery in the area should be elicited, as hydrocele or hernia surgery may result in injury to the vas deferens. Orchiopexy, either for cryptorchidism or for torsion, is even more obvious as a potential cause of male-factor infertility. Even prior urethral catheterizarion for surgery unrelated to the genitourinary tract may cause damage. With the improvement and widespread ability of modern immunizations, infection with certain agents, such as mumps, occurs rarely; therefore, a history of postpubertal mumps would be considered highly significant. Lastly, a history of congenital defects as well as cryptorchidism should be elicited.

Physical Examination

Clues to the cause of infertility may be obtained from the physical examination, but those that are related to inflammation or infection are relatively few. Prior infection may damage a testicle such that a size discrepancy may be discernable. This is most commonly due to mumps orchitis, but bacterial infections may cause the same outcome. Epididymiris may cause palpable scarring or cyst formation. Whereas epididymal cysts are not the exclusive result of infection, the inflammation may cause obliteration of the tubules, resulting in obstruction. If severe enough, the obstruction may cause cystic changes in the proximal tubules. Examination of the prostate may give a few clues to the etiology of infection. Although changes in prostatic consistency, such as the identification of boggy or spongy areas, have been recognized as being consistent with an inflammation, these findings have never been scientifically correlated. Similarly, prostatic tenderness may signal an inflammatory condition, but some patients may be sufficiently apprehensive to be tender even in the absence of infection. Lastly, palpable scarring on the ventrum of the penis or in the perineum may lend clues to the existence of stricture disease.

Laboratory Tests

The most consistent and useful laboratory test is the semen analysis. Infections may cause a host of nonspecific abnormalities in the seminal fluid and may include oligospermia, which results from damage to the germinal epithelium, the epididymis, ejaculatory duct, and prostate, or a combination thereof. Asthenospermia may be a result of stress in the system at some level or may possibly be due to the previously mentioned bacterial products that are toxic to sperm metabolism. Similar effects may be seen in the condition of leukocy-tospermia, with certain proteins and cytokines elaborated by the white blood cells. One of the major concerns is proper identification of the cells present in the ejaculate. Specifically, some of the cells that have the appearance of white blood cells may actually be immature spermatozoa. These cells are typically round and have a visible nucleus. If not white blood cells, they may be spermatids or even spermatocytes. A number of stains are available to assist in determining the cell’s origin, such as benzidine-cyanosine or Papanicolaou. More recently, fluorescence-activated cell sorting as well as flow cytometry has been employed to more accurately identify the species of cell present.

Once a genitourinary tract infection has been documented, some effort should be made to ascertain the eriologic agent. This is especially important, considering the plethora of adverse side effects associated with the use of antibiotics, ranging from life-threatening diarrhea and allergic reactions to negative results on semen quality or even on the germinal epithelium. Culturing the semen has been shown to be an effective means of isolating organisms. This material should be obtained fresh, and bacterial cultures should include the more fastidious agents such as Chlamydia, Mycoplasma, and Ureaplasma, as well as obligate intra-cellular organisms. Newer alginate swab DNA tests for these latter agents are likely to be more sensitive and less labor intensive for the laboratory. The four-glass technique, as described by Meares and Stamey, is also an excellent way of confirming the causative agent but is time consuming and expensive. This technique, however, is considered to be the gold standard for localizing infections. It has also been suggested that obtaining a urine sample after prostate massage (VB3) is as accurate an investigation as is necessary, since the precise location of the infection may be less important than the identity and sensitivity pattern of the organism. It is currently advocated that a mid-stream sample and either a semen culture or a VB3 should be obtained.

Molecular Techniques

Most recently, molecular techniques have been developed that are able to detect very small amounts of bacteria by utilizing RT-PCR with primers for 16S ribosomal ribonucleic acid (rRNA). It must be noted, however, that these bacterial “fingerprints” do not necessarily imply that an infection is present, but only that bacteria are present. The genus and species of the bacteria may be determined by sequencing the rRNA and comparing it to banked rRNA information. On occasion, the bacteria cannot be fully identified, as information banks may not be complete. Criteria need to be established with respect to the significance of finding bacterial genetic material in parts of the genitourinary tract, and its relationship to infertility.

Treatment

Antibiotics

The treatment of bacterial infection in the genitourinary tract must take into account three principles: bacterial sensitivity, genitourinary penetration, and gonadotoxicity. Most of the time, bacterial sensitivity will have been determined by specific testing. In this case, the other two principles must take precedence. If the clinician has made the decision to treat empirically and if one of the fastidious organisms is suspected, one might choose either the macrolide or the tetracycline group of antibiotics. For Chlamydia, doxycycline administered 100 mg twice daily for 10 days or erythromycin 500 mg four times daily are considered to be equally effective. These agents are effective and have fair penetration into tissue (prostatic fluid and ejaculate). Tetracyclines also have an adequate gram-negative spectrum, whereas macrolides are most appropriate to cover gram-positive species. The fluoro-quinolone group of antibiotics has several advantages: a very broad spectrum in addition to obligate intracellular organisms coverage, high penetration into the genitourinary tract, and good concentration in the prostatic tissue — all achieved after a single dose. Some of the other antibiotic classes have a good spectrum of activity, but the genitourinary penetration is only fair. The cephalosporin group is widely utilized because of its spectrum and safety, but the penetration is marginal. Penicillins are similarly concerning, even though both penicillins and cephalosporins are highly excreted in the urine. Of the penicillins, carbenicillin indanyl sodium is specifically indicated for chronic prostariris. This drug, however, has no coverage for intracellular bacteria, and is dosed four times per day. Aminoglycosides have very little penetration except in the urine and are only rarely appropriate in this scenario. The issue of culture-negative WBC elevations is controversial. Treatment with anti-inflammatory agents is reasonable, but a clear benefit has not been demonstrated.

The gonadotoxicity of agents used in the treatment of male genital infections must also be considered. Nitrofurantoin, commonly used for the treatment of urinary tract infection, as well as various tetracyclines (doxycycline, minocycline) that are frequently used for the treatment of sexually transmitted diseases, can impair the ability of the sperm to penetrate the zona pellucida of the ovum and further impair fertility. The sulfas and aminoglycosides have also been shown to have deleterious effects on sperm function and motility. The antifungal agent, ketoconazole, has a marked antiandrogen effect and may affect spermatogenesis via that mechanism.

Ancillary Treatment

For further information on ancillary treatments, including surgery and assisted reproductive techniques: “Treatment of Male Reproductive Function”

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