The diagnosis of male infertility: an analysis of the evidence to support the development of global WHO guidance—challenges and future research opportunities

Abstract

BACKGROUNDHerein, we describe the consensus guideline methodology, summarize the evidence-based recommendations we provided to the World Health Organization (WHO) for their consideration in the development of global guidance and present a narrative review of the diagnosis of male infertility as related to the eight prioritized (problem or population (P), intervention (I), comparison (C) and outcome(s) (O) (PICO)) questions. Additionally, we discuss the challenges and research gaps identified during the synthesis of this evidence.OBJECTIVE AND RATIONALEThe aim of this paper is to present an evidence-based approach for the diagnosis of male infertility as related to the eight prioritized PICO questions.SEARCH METHODSCollating the evidence to support providing recommendations involved a collaborative process as developed by WHO, namely: identification of priority questions and critical outcomes; retrieval of up-to-date evidence and existing guidelines; assessment and synthesis of the evidence; and the formulation of draft recommendations to be used for reaching consensus with a wide range of global stakeholders. For each draft recommendation the quality of the supporting evidence was then graded and assessed for consideration during a WHO consensus.OUTCOMESEvidence was synthesized and recommendations were drafted to address the diagnosis of male infertility specifically encompassing the following: What is the prevalence of male infertility and what proportion of infertility is attributable to the male? Is it necessary for all infertile men to undergo a thorough evaluation? What is the clinical (ART/non ART) value of traditional semen parameters? What key male lifestyle factors impact on fertility (focusing on obesity, heat and tobacco smoking)? Do supplementary oral antioxidants or herbal therapies significantly influence fertility outcomes for infertile men? What are the evidence-based criteria for genetic screening of infertile men? How does a history of neoplasia and related treatments in the male impact on (his and his partner's) reproductive health and fertility options? And lastly, what is the impact of varicocele on male fertility and does correction of varicocele improve semen parameters and/or fertility?WIDER IMPLICATIONSThis evidence synthesis analysis has been conducted in a manner to be considered for global applicability for the diagnosis of male infertility.

A systematic review and standardized clinical validity assessment of male infertility genes

“…The recommendations for genetic testing during the diagnostic work-up of male infertility have only minimally changed over the last 20 years and most of these recommendations still focus on the well-known and common causes of male infertility that were already known in the 1990’s (Barratt et al 2017; Jungwirth 2018). For cost-efficiency, there are guidelines to help stratify patient groups to receive pre-conceptive genetic tests such as karyotype analysis, AZF deletion tests or a screening for pathogenic variants in a single gene involved in a specific phenotype such as CBAVD or Kallmann syndrome.…”

“…For cost-efficiency, there are guidelines to help stratify patient groups to receive pre-conceptive genetic tests such as karyotype analysis, AZF deletion tests or a screening for pathogenic variants in a single gene involved in a specific phenotype such as CBAVD or Kallmann syndrome. A recent World Health Organization study on the diagnosis on male infertility suggested to at least perform karyotyping and AZF deletion tests in men with non-obstructive azoospermia or extreme oligoasthenoteratozoospermia (OAT) without a history of a known cause of spermatogenic failure such as chemotherapy, varicocele, orchitis or bilateral cryptorchidism (Barratt et al 2017). However, after stratification, in approximately 40% of all male infertility patients no genetic cause is found with the above mentioned tests (Krausz and Riera-Escamilla 2018) and this strongly suggests that much more genetic research is required and at the same time the use of other diagnostic assays should be considered.…”

“…The second reason underlying a disappointingly low diagnostic yield for male infertility is that the interpretation of genetic data is hampered by gaps in our understanding of the biology of male spermatogenesis and (in)fertility. This urgent need for better understanding of cellular, molecular biochemical and genetic mechanism(s) is highlighted by a recent study of the World Health Organization, who listed this need as one of the key areas of research focus (Barratt et al 2017).…”

Efficacy of the Oestrogen Antagonist Tamoxifen on Sperm Parameters in Patients with Idiopathic Oligoathenoteratozoospermia

“…Idiopathic oligoathenoteratozoospermia (iOAT) is a common finding in the evaluation of male infertility and is defined as a reduced spermatogenesis of unknown aetiology consisting of oligozoospermia (< 39 × 10 6 spermatozoa/ejaculate), asthenozoospermia (< 32% progressive motile spermatozoa) and teratozoospermia (< 4% normal forms) [1][2][3]. In the last years, the oestrogen antagonist, tamoxifen, has been suggested as an empiric (off-label) treatment option for iOAT [4].…”

A phenotypic screening platform utilising human spermatozoa identifies new compounds with contraceptive activity

“…Though some potential sperm-specific contraceptive drug targets have been identified (Lishko and Mannowetz, 2018), our relatively poor understanding of the spermatozoon makes target-agnostic strategies more attractive (Barratt et al , 2017). Phenotypic drug discovery is undergoing a renaissance in a number of therapeutic areas because it can uncover novel biology in an unbiased way.…”