Keywords

FormalPara Key Points

  • Infertility is defined as the inability to achieve a natural pregnancy within 1 year in sexually active couple.

  • The American Urological Association (AUA), the American Society for Reproductive Medicine (ASRM), and the European Association of Urology (EAU) are three predominant organizations that regularly develop and update guidelines for the diagnosis and management of the infertile male.

  • Comprehensive medical history and physical examination with two semen analyses are the essential components of the initial evaluation for the infertile male.

  • The AUA and ASRM recommend andrological evaluation if the patient has abnormal findings on initial assessment or one of two semen analyses. The EAU differs in its recommendation, requiring two abnormal semen analyses prior to proceeding with andrological evaluation.

  • Differences between accepted WHO semen analysis reference values create potential for discrepancies between patients selected for andrological evaluation. The EAU and ASRM reference the latest criteria published in 2010, while the AUA still cites the 1999 version.

1 Introduction

Classically, infertility is defined the inability to conceive a natural pregnancy within 1 year in a sexually active couple [1]. The American Society for Reproductive Medicine describes infertility as the result of any disease process (an interruption, cessation, or systemic disorder) of the male or female genital tracts that prevents natural conception over a 1-year period or, in females, the inability to maintain a pregnancy to delivery [2]. Recent estimates predict between 8 and 15% of couples are unable to conceive with regular, unprotected intercourse at 12 months [2]. While recent cross-sectional studies within limited populations suggested male infertility rates are around one in ten or 10.1% (CI 9.2–11.1), a recent collaboration by the WHO suggests that numerous confounding factors, variation in geographical fertility rates, and lack of uniformly accepted criteria for infertility make global estimates extremely difficult [3, 4].

Male factor infertility can be due to a number of congenital or acquired urogenital irregularities. Systemic diseases, environmental/lifestyle (e.g., obesity, gonatotoxins, smoking, etc.) erectile dysfunction, genetic abnormalities, variations in scrotal temperature (i.e., varicocele), urogenital tract infections, urogenital trauma, and improper coital habits can all result in some degree of male infertility [5]. Nearly half of all cases fail to determine an identifiable cause for male infertility. In large part, this is due to limited understanding of the intricacies that underlie natural conception and the limited capability of current diagnostic testing to identify abnormalities [6]. The AUA estimates that, despite best management efforts, nearly 5% of couples will remain unable to conceive due to some combination of male or female factor infertility [7]. There are emerging interests into developing new treatments for unexplained male factor infertility. These efforts are largely centered upon stem cell biology and gene therapy, but have yet to transition into guideline-based practice and are typically used empirically after conventional management has failed [8].

Recent recognition for the need and utility of clinical guidelines to aid practitioners in the assessment of the infertile male has been spurred by increased understanding of the medical complexities that underlie infertility. Standardized diagnosis and treatments have been outlined in these guidelines in order to help improve efficiency. Well-known organizations from around the world have developed guidelines through multidisciplinary collaborations in order to achieve this goal [2, 7, 9, 10]. Of these sources, urologists and practitioners specializing in reproductive medicine commonly utilize three predominant guidelines for the evaluation and treatment of male infertility: (i) American Urological Association (AUA) best practice statements for the evaluation of the infertile male [7], (ii) the ASRM Practice Committee Report on the diagnostic evaluation of the infertile male [2], and (iii) the European Association of Urology (EAU) guidelines on male infertility [9].

While several concurrent collaborations from different organizations have developed expert opinion panels and best practice statements, the previously cited institutions present the most comprehensive and up-to-date guidelines. These organizations utilize multidisciplinary teams using clinical evidence to develop recommendations. These recommendations meet the criteria for “Clinical Practice Guidelines” created by the Institute of Medicine (IOM) . The IOM defines clinical practice guidelines as “statements that include recommendations, intended to optimize patient care, that are informed by a systematic review of evidence and an assessment of the benefits and harms of alternative care options” [11]. Guidelines are not intended to be used as a legal agent. They should be employed as a set of principles that provide a template for standardization of care and help to improve diagnostic efficiency while preserving physician autonomy. A combination of physician judgement and guideline-based management is likely most representative of the current standard of care [12].

2 AUA Best Practice Statement: Optimal Evaluation of the Infertile Male

The AUA Board of Directors initially created the Male Infertility Best Practice Policy Committee in 1999. This subsequently became a collaborative initiative between the AUA and the ASRM in 2001 with a goal of developing a series of best practice statements in regards to management of male factor infertility. The initial goal of the committee was “to develop recommendations, based on expert opinion, for optimal clinical practices in the diagnosis and treatment of male infertility.” In the most recent update entitled “The optimal evaluation of the infertile male: Best practice statement,” the AUA Practice Guidelines Committee selected a ten-person panel composed of nine urologists and one research andrologist [7]. The members of the panel were not reimbursed for their contributions and provided disclosures regarding conflicts of interest to the AUA before participating.

In 2015, the AUA released the American Urological Association Clinical Practice Guidelines Development Standard Operating Procedure [13]. This document details the methodology for the formulation of AUA best practice statements and guidelines across all non-oncologic subdisciplines within urology. This is outlined on the AUA website and an unabridged version is available for free download. Initially, topics for guidelines are nominated by either Practice Guidelines Committee members or by AUA members online. Depending on the topic in question, a panel is formed with special attention paid to the particular expertise of the candidate members. As previously stated, these potential panel members cannot have a conflict of interest with the guideline under consideration. The panel then develops the scope of study by setting parameters for exclusion/inclusion criteria and creating research questions to be investigated. An initial literature review is performed and the results of which are subjected to data extraction, analysis, and synthesis prior to the development of an evidence report. At this point, a final literature review is performed and the guidelines are written for peer review [13]. This methodology, adopted in 2015, has yet to be implemented into the development of AUA infertility guidelines as the most recent update was released in 2011.

In the 2011 update of the AUA Best Practice Statement: Optimal Evaluation of the Infertile Male, the panel suggests that initial infertility workup should be performed if natural pregnancy has not occurred by 1 year of regular unprotected vaginal intercourse. Consideration for earlier workup is recommended if the male and/or his female partner have known infertility risk factors. The best practice statement provided in the manuscript recommends the initial evaluation for male infertility includes both a thorough reproductive history with a urogenital physical exam and two properly obtained semen samples. Additional tests should be considered if (i) abnormalities are identified during the initial evaluation, (ii) the etiology of infertility cannot otherwise be identified, and (iii) problems with infertility continue despite appropriate treatment of the female partner. Table 62.1 details the breadth and methodology used in the creation of the AUA guidelines .

Table 62.1 AUA, ASRM, and EAU: Scope and methods for development of guidelines for the evaluation of the infertile male
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3 ASRM Guidelines

The ASRM recommendations and best practice statements have undergone multiple revisions since its inception in 2006. Initially presented in conjunction with the AUA as detailed above, the Practice Committee of the ASRM has released updated guidelines and best practice statements in 2012 and again republished in 2015 in Fertility and Sterility [2]. This committee was composed of 125 physicians and basic science researchers from the fields of urology, reproductive andrology, gynecology, family medicine and primary care, andrology, and reproductive medicine. The 2012 revision entitled “Diagnostic evaluation of the infertile male: a committee opinion” has garnered the approval of the Board of Directors of the AUA and the ASRM. The stated goal of the Practice Committee’s report is “to provide clinicians with principles and strategies for the evaluation of couples with male infertility problems” [2]. This document suggests that it stands to serve as an adjunct to clinical care stating, “although this document reflects appropriate management of a problem encountered in the practice of reproductive medicine, it is not intended to be the only approved standard of practice or to dictate an exclusive course of treatment. Other plans of management may be appropriate, taking into account the needs of the individual patient, available resources, and institutional or clinical practice limitations” [2]. An itemized summary of the breadth and methodology used to develop the ASRM guidelines can be found in Table 62.1. A comparison of AUA and ASRM guidelines and major recommendations can be found in Table 62.2.

Table 62.2 AUA (2011) and ASRM (2012) guidelines
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4 European Association of Urology Guidelines

The European Association of Urology (EAU) guidelines office (given this title in 2004 after its conception in 1996) was challenged with the task of developing European clinical urological guidelines [16]. This panel, consisting predominantly of urologists, gynecologists, and reproductive endocrinologists, created the “EAU Male Infertility Guidelines.” Since its initial release in 2001, these guidelines have undergone regular updates with the most recent edition published as a full-text update in 2015 [9]. While many non-urologic medical practitioners commonly utilize these guidelines. The EAU has made it their focus to create a resource for urologists. The respective members of the panel (all of which were members of the EAU) were required to submit nondisclosure statements and inform the EAU of any potential conflicts of interest prior to participating in the development of guidelines. Panel members were considered on the basis of their scientific and clinical merits and their willingness to commit considerable amounts of time to produce well-founded and thorough guidelines. Each member’s commitment is for a 4-year term which may be renewed for one additional term. The panel is led by an EAU guidelines office appointment chairman. In an interest to keep the focus of these guidelines within the field of urology, the chairman appointed is always a board-certified and full-time urologist . Once the panel has formulated a preliminary guideline, new edition, or best practice statement, a minimum of 3–4 reviewers are asked to provide an assessment and formal review of the document submitted. These reviewers may or may not be associated with the EAU and receive no monetary compensation [9]. As of the last update in 2015, the EAU significantly reduced the volume of text in non-oncology guidelines and standardized formatting for ease of use [9].

Development of evidence-based recommendations has long been an emphasis of the committee. This is due to the fact that the EAU clinical guidelines are predominantly intended to enhance the practitioner’s clinical decision-making. In accordance with this goal, the development of incremental levels of evidence and the associated grades for each recommendation helps quantify each recommendation based on the quality of underlying evidence. This helps to preserve physician autonomy and allows clinicians to gauge how strictly they adhere to each individual recommendation [9, 16]. Table 62.1 provides a summary of the scope and methods used by the committee to formulate the EAU guidelines.

In creating new guidelines or new editions of current guidelines, the panel gathers and appraises evidence from current literature. In the 2015 update, a total of 409 unique records were initially collected from an extensive literature review and screened for validity and relevance. Of these, nine publications were selected for inclusion into the formulation of new recommendations [16]. This information gets formulated into a series of statements. The statements are summarized as recommendations and presented along with their associated levels of evidence. The strength of each recommendation is graded (grade of recommendation = GR) depending upon the quality of underlying evidence (level of evidence = LE) (Appendix 1). The GR does not always follow a linear relationship with LE. This is due, in large part, to the variability of study design, limitations in methodology, and/or disparity in available data on a given recommendation. The inverse is also true. Statements without high-level evidence may receive high-grade recommendations if dictated by overwhelming clinical experience and/or general consensus. These instances are typically documented in the text as “upgraded based on panel consensus” [9]. A comprehensive evaluation of each recommendation is performed after a grade is assigned to ensure that each statement, while supported by underlying scientific evidence or group consensus, is equitable with value, preference, and costs. As of the 2018 update, the EUA reported using a modified GRADE methodology, a structured approach in assessing the evidence used in formulating recommendations [15, 17]. This essentially aims to eliminate the ambiguity of a grade A, B, or C recommendation and recategorizes the statements as either “strong” or “weak” recommendations [16]. Additionally, meta-analyses are only utilized as part of a systematic review if multiple randomized control trials address the same question and the outcomes are reported in a similar manner. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance is followed in these instances [18].

The clinical practice guidelines supplied by the EAU address 13 different topics within male infertility. These include epidemiology and etiology, disorders of ejaculation, testicular dysfunction, varicocele, obstructive azoospermia, genetic disorders, germ cell malignancy with testicular microcalcification, and semen cryopreservation. Table 62.3 provides selected recommendations from the EAU that are aimed at helping the clinician evaluate and manage male factor infertility. Many national urological associations have filed formal replies to incorporate EAU guidelines into their respective guidelines. Over 50 national societies from around the world have submitted endorsements of EAU guidelines [16].

Table 62.3 EAU (2018) guideline recommendations on the evaluation of the infertile male
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5 An Assessment of the Guidelines for the Evaluation of the Infertile Male

Given the AUA’s and ASRM’s history of collaboration, it is not surprising that many of the guidelines and best practice statements overlap. In fact, the first editions from each organization produced in 2001 were developed by the AUA’s Male Infertility Best Practice Policy Committee in concordance with the Practice Committee of the ASRM [19]. These documents were subsequently reviewed and updated with AUA revisions in 2010/2011 and ASRM revisions in 2006/2012. These documents do differ in varying capacities from the ones provided by the EAU [9].

While many similarities exist between the AUA/ASRM and EAU guidelines, there are some notable discordances. For instance, the AUA/ASRM guidelines recommend a minimum initial evaluation of the infertile male including a medical/surgical history and semen analysis [2, 7]. The EAU guidelines opt not to specify a minimum initial workup. It makes mention that history and physical exam are “standard assessments” in all patients and that a semen analysis should be included [9]. AUA and ASRM documents suggest that a full evaluation must be done by a urologist or other reproductive specialists when an initial evaluation reveals an abnormal semen analysis or the clinical history/findings are suggestive of endocrinopathy. On the contrary, the EAU guidelines state a complete andrological evaluation should only be performed if a minimum of two semen analyses are abnormal per WHO criteria [20]. This implies that normal semen analyses exclude dysfunctional sperm as the etiology for infertility, while many patients with unexplained infertility have normal semen characteristics. Unexplained infertility occurs when female factors of infertility have been excluded and the male has no identifiable cause on history, physical examination, and semen analysis [6]. The reported prevalence of unexplained infertility is highly variable (between 6 and 30%) and dependent on diagnostic criteria and population demographics [5, 6, 21,22,23].

Despite the aforementioned discrepancies between guidelines, all three committees clearly place an emphasis on the diagnostic importance of the traditional semen analysis. In all three guidelines, an abnormal semen analysis (two in the EAU guidelines) is required before a full andrological evaluation can be performed. The latest guidelines from the EAU and ASRM consider the updated 2010 WHO [20] semen analysis criteria, while the AUA guidelines still adhere to the version published in 1999 [24]. This discrepancy can have major clinical implications as the lower reference ranges for normal semen parameters in the updated 2010 version may exclude many patients from further evaluation. Up to 15% of men with at least one abnormal parameter in the 1999 WHO criteria were reclassified within normal limits in the 2010 WHO criteria in comparison study [24, 25]. Another study with similar methodology found that upwards of 19% of men were reclassified as “normal” after having at least one abnormal semen analysis on the 1999 WHO criteria [26]. While many men who were originally eligible for a full evaluation may be excluded with the adoption of new criteria, an argument can be made that the new reference values provide a more accurate representation of natural variance. This may provide a more cost-effective parameter to eliminate unnecessary evaluations and will certainly be a topic for further research going forward.

Regardless of reference values and guideline specifics, it is clear that all three associations place a significant emphasis on the diagnostic value of the conventional semen analysis. This calls into question the validity of the test as a marker for male infertility [27]. Semen parameters aimed to delineate between fertile and infertile males are not always well defined and only ~40% of infertile men fall within the accepted reference ranges [28,29,30]. While inherent natural variability among semen samples does exist, confounding factors like diagnostic errors, the functionality of accessory sex organs, and ejaculatory abstinence do exist and should not be ignored [31,32,33,34,35]. Recent evidence has suggested that variability can exist both within individuals and particular laboratories performing the semen analysis. One study comparing intra-facility variation in semen analysis suggested that the highest variability in measurements were seen with morphology (coefficient variability above 80%) and count (coefficient variability greater than 60%) [36]. Another component of this study suggested that standardizing training for evaluating specific semen parameters only showed subsequent improvement with morphology. Another study assessing intraindividual variability using healthy participants over a 10-week interval showed the highest variation among sperm concentration (26.8%), then morphology (19.6%), and progressive motility (15.2%) [32]. The lowest variability was seen among assessments for vitality (10.3%).

The utility of parameters formed from population means and analysis of semen characteristics is largely linked to the individual variability within each characteristic. Reference values for those semen characteristics with significant variability may offer limited clinical value [37, 38]. Analysis of semen from donors for artificial insemination showed regression towards the mean when selecting those samples with abnormal characteristics in the first test. This result was amplified when repeated in a second test [37]. Assessing multiple samples from each individual helps account for variability within each characteristic and, ultimately, increases the accuracy of the parameter [38]. While this has a limited effect in preventing regression towards the mean, the averages from multiple samples help reduce its magnitude.

Therefore, it stands to question the legitimacy of a single “normal” semen analysis , as suggested by guidelines from both the AUA and the ASRM. A recent retrospective review using 2010 WHO criteria analyzed 5132 semen samples from 2566 patients who had provided at least two semen samples and found that 51.2% of second analyses confirmed the first [39]. When initial samples were found to be “normal,” roughly 27% of second samples were found to be pathological. Conversely, when an initial sample was found to be abnormal, 23% of the second samples were found to be normal. Even with a “normal” semen analysis, many men remain infertile for reasons not explained by conventional semen characteristics and parameters. Intrinsic sperm dysfunction seen in DNA damage or immature chromatin has been described in roughly 30% of males with “unexplained infertility.” These men’s sperm dysfunction can only be explained by functional sperm evaluations (oxidative stress, DNA/chromatin integrity, and antisperm antibody assays) [40,41,42]. While the use of semen analysis does have certain limitations, the AUA and ASRM guidelines do suggest that further workup for male factor should be considered in cases when unexplained infertility persists and female factors have been ruled out or treated.

While addressing the application and parameters of the semen analysis, all three guidelines emphasize the importance of obtaining a properly performed analysis. Institutional quality control standards from the WHO [20] or the Clinical Laboratory Improvement Amendments (CLIA) [43] have been adopted by all three guidelines. However, existing data from surveys of laboratory practice indicate that semen analyses are still poorly standardized. The need for global standardization among laboratories has been well documented [44,45,46,47,48]. A clinician should have reasonable confidence in the accuracy and reproducibility of the semen analysis given its clinical value in evaluating the infertile male.

Beyond varying interpretations of the conventional semen analysis, discrepancies between AUA/ASRM and EAU guidelines persist in regard to what defines a “full evaluation.” AUA/ASRM guidelines provide detailed descriptions of the components of the evaluation including when further procedures or invasive tests should be utilized. These include diagnostics like post-ejaculatory urinalysis, transrectal/scrotal ultrasound, sperm function tests, genetic testing, and endocrine evaluations (Table 62.2). Conversely, EAU guidelines refer to WHO manual for the standardized investigation, diagnosis, and management of the infertile couple (Box 62.1 and Table 62.4). This manual, first developed in 1993 and revised in 2000, aimed to provide detailed guides for medical history, physical examination techniques, and laboratory tests [1]. While it was reliable and accurate at the time, many argue that this manual is in need of revision to reflect significant advancements in technology and understanding over the last 18 years.

Table 62.4 Lower reference limits (fifth centiles and their 95% CIs) for semen characteristics
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Box 62.1. WHO recommendation: semen analysis

Standard evaluation in all men should include a medical history and physical exam in addition to scrotal ultrasonography and semen analysis. Andrological evaluation is should be performed when semen analysis demonstrates abnormalities when compared to reference values (Table 62.4). Standardization of laboratory reference values helps guide important treatment decisions. The WHO has provided the WHO laboratory manual for the examination and processing of human semen (fifth edn.). It is the consensus that modern spermatology must abide by these reference values (per EAU recommendations)

While many of the recommendations from both the AUA/ASRM and EAU are evidence-based, some of the guidelines are still supported by nonrandomized clinical trials, retrospective studies, and expert opinion (Table 62.3). The aforementioned GRADE methodology adopted by the EAU has attempted to address this by delineating between those guidelines with and without quality supporting data. The assigned “strong” or “weak” GR intends to simplify the grading system, yet it requires inherently subjective evaluation of the recommendation using a template of principles [15, 16]. Conversely, the AUA Practice Guidelines Committee found insufficient evidence to develop a formal evidence-based guideline, stating that the majority of recommendations are derived from nonrandomized trials, expert opinion, or some combination of the two [7]. This certainly leaves the opportunity for further research and improvement going forward.

6 Conclusion

The goal of guidelines is to provide urologists and other reproductive specialists with a reference to help improve quality and efficiency of care while protecting the patient from potentially harmful or unnecessary interventions. Of the many sources available, the most commonly referenced and up-to-date guidelines are the AUA best practice statement for the evaluation of the infertile male, the ASRM Practice Committee Report on the diagnostic evaluation of the infertile male, and the EAU guidelines on male infertility.

While these guidelines are intended to help guide the practitioner in clinical practice, variable methodology used to develop the recommendations can alter both the strength and quality of the statements provided. Of the three associations detailed in this chapter, only the EAU has committed to developing evidence-based grades for recommendations given. However, the evidence cited is often based on nonrandomized clinical trials, expert opinion, and retrospective studies. This certainly offers opportunity for further research into various areas within male infertility and for the development of higher-quality recommendations.

Despite the aforementioned differences, the AUA, ASRM, and EAU guidelines recommend similar initial evaluations for male infertility. This starts with a thorough medical/surgical history and a properly executed semen analysis. If initial screening yields abnormal medical history or semen analysis (two abnormal semen analyses in EAU guidelines), a full evaluation may be considered. Ultimately, these guidelines act as a reference. A physician’s clinical judgment should always be incorporated into the implementation of these guidelines in order to provide optimal care on a case-by-case basis.

7 Review Criteria

A systematic search of the most current and updated guidelines on the diagnosis and management of male infertility was performed for the American Urological Association (AUA), the American Society for Reproductive Medicine (ASRM), the European Association of Urology (EAU), and the World Health Organization (WHO) [semen analysis parameters] as provided on their respective web addresses. Extensive searches of the most recent relevant studies using search engines such as PubMed, Google Scholar, CINAHL Complete, and Cochrane Library were performed between September 2018 and December 2018 with the following keywords: “male infertility,” “infertility rate,” “semen analysis,” “semen analysis parameters,” “infertility diagnosis,” and “infertility guidelines.” Articles published in languages other than English were not considered. Data published for presentations, conferences, meetings, books, or websites were not included. Book chapters and specific websites were cited to help provide contextual content for discussion.