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Male accessory gland infection and subfertility: a diagnostic challenge

Trum, J.W.

Publication date 1999

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Citation for published version (APA): Trum, J. W. (1999). Male accessory gland infection and subfertility: a diagnostic challenge.

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M^HMM^HM Chapter Introduction

Male accessory gland infection (MAGI) is an ascending infection of the urethra, prostate, seminal vesicles or the epididymo-testicular tract. To diagnose MAGI the World Health

Organization (WHO) has proposed the criteria summarized in table 1 (1,2). MAGI is diag­ nosed when a combination of a previous genitourinary tract infection with physical signs and/or ejaculate signs is present.

Table 1 Male accessory gland infection according to WHO guidelines

A History and physical signs: History of urinary infection, And/or epididymitis, And/or sexually transmitted disease, And/or thickened or tender epididymis, And or thickened vas deferens, And/or abnormal rectal examination.

B Prostatic fluid: Abnormal prostatic expression fluid And/or abnormal urine after prostatic massage.

C Ejaculate signs: > 1.10 leukocytes /ml semen and/or culture with significant growth of pathogenic bacteria and/or abnormal appearance, viscosity, pH, or biochemistry of the seminal plasma

Any of the following combinations should be present : A history or physical sign with a prostatic sign Or a history or physical sign with an ejaculate sign Or a prostatic sign with an ejaculate sign Or at least two ejaculate signs in each ejaculate

; Due to the large variety of criteria in the definition, the diagnosis of MAGI may reflect different underlying conditions. For instance, a patient with bacterial prostatitis, seen by an urologist, is a different patient from the one with a history of sexually transmitted dise­ ase (STD) and leukocytospermia seen by a gynecologist in an infertility clinic. Both patients, however, are diagnosed with MAGI. As a result of the WHO criteria men with

MAGI do not represent a homogeneous group of patients and this may account for the conflicting data in terms of treatment results and the difficulty of comparing different stu­ dies (3-6). Furthermore, various criteria are difficult to assess as for instance a history of urinary infection and/or epididymitis. Studies in which genital tract specimens are examin­ ed, report that 50 to 80% of men with a positive culture do not experience genito-urinary symptoms, and have a so-called subclinical MAGI (7-10).

Physical signs may be difficult to assess. Palpation of the genital glands usually provides little insight into the nature of the underlying condition (11). Furthermore, whether an ascending infection in men leads to anatomical changes with subsequent function loss of the male sex glands and impaired fertility is controversial (9,12-20).

The value of ejaculate signs may also be difficult to assess. Leukocytospermia, according to the WHO criteria is associated with MAGI. Only one study has examined the relationship between genital tract infection and leukocytospermia to assess whether detecting leukocy­ tospermia is of diagnostic value for determining active microbial infection (21). This preli­ minary study among potential semen donors concluded that seminal peroxidase-positive cells are not an adequate indicator of asymptomatic MAGI. However, only a small number of subjects with leukocytospermia was included in this study.

Culture of semen is advocated to detect pathogenic bacteria. MAGI may be difficult to diagnose due to the antibacterial effects of semen, contamination from urethral organisms, and the difficulty in culturing for all of the potential pathogens (12). ~---Ji At present the most reliable way to detect these organisms is by culturing a urethral swab after digital prostatic massage and not by culturing a semen aliquot (22,23). To differentia­ te between colonization of the distal urethra and an ascending infection, lower tract bacte­ rial localization patterns can be used (24). However, these tests are expensive and time consuming and are reported as a negative experience by most men.

In view of these considerations, men attending an infertility clinic with a subclinical infec­ tion are not likely to be screened this way, resulting in a reservoir of unrecognized MAGI.

Several less disincentive tests like ultrasonography and cytokine quantification in semen, have been proposed in the diagnosis of MAGI.

Ultrasonographic features indicating MAGI are dilatation of the periprostatic plexus, thick­ ening of the prostate capsule, beehive configuration of the seminal vesicles, prostatic or testicular cysts, calcifications, hypervascularity of the testes and dilatation of the epididy­ mides (25-29). However some of these characteristics are found in healthy controls as well

(30). It is questionable whether the above mentioned anatomical changes lead to physical palpable signs as described in the WHO definition.

Cytokines are the main mediators of infection and inflammation. Inflammatory cytokines like interleukine-6 (11-6) and tumor necrosis factor-a (TNF-alfa), are produced mainly by macrophages in response to pathogens and also to chronic inflammation (31).

Interleukine-8 (U-8), which is a chemo tactic and activating factor for neutrophils, has been detected in high levels in seminal plasma of infertile patients with leukocytospermia (32).

In addition, the concentrations of 11-6, 11-8 and Interferon gamma (IFNgamma) seem to be related to MAGI (33,34).

In none of the cited studies, however, cytokine levels were compared with the actual pre­ sence of microorganisms in the genital tract. In summary, men diagnosed with MAGI do not represent a homogeneous group of patients. Due to the paucity of symptoms, the true number of bacterial accessory gland infections in an infertility population may be underestimated.

Detection, however, is important because sexually transmitted organisms like C. trachoma­

tis, U. urealyticum and M. hominis may lead to salpingitis, pelvic inflammatory disease and severe damage of the female genital tract with subsequent infertility (35-39).

Aim of the present study

The aim of this study is to answer the following questions:

1. What is the prevalence of sexually transmitted microorganisms in the genital tract

of a male subfertility population?

2. What is the value of various laboratory tests like leukocyte count in semen, cervi­

cal culture of female partners and cytokine measurement in semenplasma in the

diagnosis of bacterial MAGI, compared to urethral swab culture after digital pro­

static massage as the reference strategy?

3. What is the accuracy of the PACE2 DNA hybridization assay relative to a poly­

merase chain reaction in the diagnosis of Chlamydia trachomatis infection?

4. What is the role of scrotal ultrasonography with color Doppler flow in the diag­

nosis of varicocele?

5. What is the role of transrectal- and scrotal ultrasonography in the diagnosis of

MAGI?

6. Does a previous Chlamydia trachomatis infection lead to anatomical changes in

the male genital tract? Outline of the thesis

Chapter 2 describes a prospective clinical study on the prevalence of microbial infections in a male infertility population and evaluates whether detection of leukocytospermia in a routine semen analysis is of diagnostic value in selecting men with an "actual" microbial infection. The association of leukocytospermia and a history of bacterial and viral infecti­ ons is assessed.

Chapter 3 focuses on the accuracy of the PACE2 DNA hybridization assay in the diagno­ sis of Chlamydia trachomatis infection in a population with low prevalence of disease.

With this test the presence of genetic material of C. trachomatis can be measured. After

RNA-DNA hybridization, the chemiluminescence signals are recorded. This test is compa­ red to a polymerase chain reaction (PCR), in which genetic material is amplified. After amplification, amplicons can be detected by an enzyme immuno assay. The PCR is nowa­ days the reference strategy.

Chapter 4 evaluates in a prospective study, the accuracy of the PACE2 hybridization assay of the cervix and the cervical culture in female partners in the diagnosis of MAGI.

Chapter 5 focuses on the accuracy of measurement of cytokines in semen plasma to detect men with subclinical MAGI. Furthermore the question whether the presence of mycoplas­ mas in the distal urethra of men in an infertility population, reflects colonization rather than infection is discussed. Chapter 6 evaluates the accuracy of scrotal Doppler ultrasonography in the diagnosis of varicocele.

Chapter 7 presents the results of an intra- and inter-observer analysis for the reproducibili­ ty of ultrasound abnormalities that may be related to MAGI.

Chapter 8 gives the prevalence of reproducible anatomical changes that may be related to

MAGI in an infertility population by means of transrectal (TRUS) and scrotal ultrasono­ graphy (SUS). The question whether urethral swab culture after digital prostatic massage can be challenged by TRUS and SUS is explored.

Chapter 9 focuses on the impact of a previous Chlamydia trachomatis infection in a male infertility population. Men with serologic evidence of a previous C. trachomatis infection are compared to men without evidence of a previous infection. The outcome measures are reproducible anatomical changes in the male accessory glands as seen with ultrasonogra­ phy. Furthermore the outcome measures are related to men with a clinical C. trachomatis infection in the past and compared to those who did not experience symptoms of a previ­ ous C. trachomatis infection.

Chapter 10 summarizes the accuracy of different laboratory tests in the diagnosis of

MAGI and evaluates the role ultrasonography may play in the work-up of male infertility patients. The chapter concludes with implications for further research.

ppr™:;' References:

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