[Assessment of the man in the infertile couple]. / Évaluation de l'homme du couple infertile.

BACKGROUND: Among couples consulting for infertility, there is a male component, either alone or associated with a female aetiology in around one in 2 cases. MATERIAL AND METHODS: Bibliographic search in PubMed using the keywords "male infertility", "diagnosis", "management" and "evaluation" limited to clinical articles in English and French prior to 1/01/2023. RESULTS: The AFU recommends: (1) a complete medical history including: family history, patient history affecting fertility, lifestyle habits (toxicity), treatments, symptoms, sexual dysfunctions; (2) a physical examination including: BMI, signs of hypogonadism, secondary sexual characteristics, scrotal examination (volume and consistency of testes, vas deferens, epididymal or testicular nodules, presence of varicocele); (3) two spermograms, if abnormal on the first; (4) a systematic scrotal ultrasound,± an endorectal ultrasound depending on the clinic; (5) a hormonal work-up (testosterone, FSH; if testosterone is low: LH assay to differentiate between central or peripheral hypogonadism); (6) karyotype if sperm concentration≤10 million/mL; (7) evaluation of Y chromosome microdeletions if concentration≤1 million/mL; (8) evaluation of the CFTR gene in cases of suspected bilateral or unilateral agenesis of the vas deferens and seminal vesicles. The role and usefulness of direct and indirect tests to assess the effects of oxidative stress on sperm DNA will also be explained. CONCLUSION: This review complements and updates the AFU/SALF 2021 recommendations.

An analysis of the frequency of Y-chromosome microdeletions and the determination of a threshold sperm concentration for genetic testing in infertile men.

OBJECTIVE: To describe the prevalence of Y-chromosome microdeletions in a multi-ethnic urban population in London, UK. To also determine predictive factors and a clinical threshold for genetic testing in men with Y chromosome microdeletions. PATIENTS AND METHODS: A retrospective cohort study of 1473 men that were referred to a tertiary Andrology centre with male factor infertility between July 2004 and December 2016. All had a genetic evaluation, hormonal profile and 2 abnormal semen analyses. Those with abnormal examination findings also had targeted imaging performed. RESULTS: The prevalence of microdeletions was 4% (n = 58) in this study. These microdeletions were partitioned into the following regions: Azoospermia factors (AZF); AZFc (75%), AZFb+c (13.8%), AZFb (6.9%), AZFa (1.7%), and partial AZFa (1.7%). A high follicle-stimulating hormone level (P < 0.001) and a low sperm concentration (P < 0.05) were both found to be significant predictors for the identification of a microdeletion. Testosterone level, luteinising hormone level and testicular volume did not predict the presence of a microdeletion. None of the men with an AZF microdeletion had a sperm concentration of >0.5 million/mL. Lowering the sperm concentration threshold to this level retained the high sensitivity (100%) and increased the specificity (31%). This would produce significant cost savings when compared to the European Academy of Andrology/European Molecular Genetics Quality Network and European Association of Urology guidelines. The surgical sperm retrieval (SSR) rate after microdissection testicular sperm extraction was 33.2% in men with AZFc microdeletion. CONCLUSIONS: The prevalence of Y-chromosome microdeletions in infertile men appears to vary between populations and countries. A low sperm concentration was a predictive factor (P < 0.05) for identifying microdeletions in infertile males. A threshold for genetic testing of 0.5 million/mL would increase the specificity and lower the relative cost without adversely affecting the sensitivity. The rate of SSR was lower than that previously described in the literature.

Age-Dependent De Novo Mutations During Spermatogenesis and Their Consequences.

Spermatogenesis is a highly complex biological process during which germ cells undergo recurrent rounds of DNA replication and cell division that may predispose to random mutational events. Hence, germ cells are vulnerable to the introduction of a range of de novo mutations, in particular chromosomal aberrations, point mutations and small indels. The main mechanisms through which mutations may occur during spermatogenesis are (i) errors in DNA replication, (ii) inefficient repair of non-replicative DNA damage between cell divisions and (iii) exposure to mutagens during lifetime. Any genetic alteration in the spermatozoa, if not repaired/eliminated, can be passed on to the offspring, potentially leading to malformations, chromosomal anomalies and monogenic diseases. Spontaneous de novo mutations tend to arise and accumulate with a higher frequency during testicular aging. In fact, there is an increased incidence of some chromosomal aberrations and a greater risk of congenital disorders, collectively termed paternal age effect (PAE), in children conceived by fathers with advanced age. PAE disorders are related to well-characterized de novo point mutations leading to a selective advantage on the mutant spermatogonial stem cells that cause a progressive enrichment over time of mutant spermatozoa in the testis.The purpose of this chapter is to provide a summary on the spontaneous genetic alterations that occur during spermatogenesis, focusing on their underlying mechanisms and their consequences in the offspring.

Y-microdeletions: a review of the genetic basis for this common cause of male infertility.

The human Y-chromosome contains genetic material responsible for normal testis development and spermatogenesis. The long arm (Yq) of the Y-chromosome has been found to be susceptible to self-recombination during spermatogenesis predisposing this area to deletions. The incidence of these deletions is estimated to be 1/4,000 in the general population but has been found to be much higher in infertile men. Currently, Y-microdeletions are the second most commonly identified genetic cause of male infertility after Klinefelter syndrome. This has led to testing for these deletions becoming standard practice in men with azoospermia and severe oligospermia. There are three commonly identified Y-microdeletions in infertile males, termed azoospermia factor (AZF) microdeletions AZFa, AZFb and AZFc. With increased understanding and investigation of this genetic basis for infertility a more comprehensive understanding of these deletions has evolved, with several other deletion subtypes being identified. Understanding the genetic basis and pathology behind these Y-microdeletions is essential for any clinician involved in reproductive medicine. In this review we discuss the genetic basis of Y-microdeletions, the various subtypes of deletions, and current technologies available for testing. Our understanding of this issue is evolving in many areas, and in this review we highlight future testing opportunities that may allow us to stratify men with Y-microdeletion associated infertility more accurately.

A different look at genetic factors in individuals with non-obstructive azoospermia or oligospermia in our research study: To whom, which threshold, when, in what way?

INTRODUCTION: In our study, we sought answers to many questions about male infertility from a different perspective. The first step in male infertility is anamnesis, physical examination and sperm count. The European Academy of Andrology recommends examination of genetic causes in individuals with fewer than 5million/ml semen counts. The American Urological Association and American Society for Reproductive Medicine have guidelines recommending performing karyotype and AZF subgroup deletion testing in azoospermia and fewer than 5 million sperm total count. Klinefelter syndrome and Y chromosome microdeletions are still very important in male infertility. Based on patients with Klinefelter syndrome or Y microdeletion, we sought answers to many questions in male infertility. MATERIALS AND METHODS: In the presented study 327 male patients with having fewer than 15millionsperm/ml detected in at least two consecutive sperm analysis were examined. Patients were divided into sub-groups according to the presence of semen count, chromosomal anomaly and Y microdeletion. In addition, FSH, LH and testosterone levels were analyzed. RESULTS: Numerical chromosomal anomalies were observed in 34 (10.4%) of 327 patients, and all of these anomalies were found as 47, XXY. Individuals with no AZF microdeletion constituted 95.1% (n=311) of the study group. The overall frequency of AZF microdeletions was 4.9% (16/327). No AZF microdeletions were detected for the patients who have sperm counts above 2million/ml. FSH, LH and testosterone levels were found significantly different between the groups. DISCUSSION: The results of our study provide another layer of evidence to demonstrate the controversial threshold value of the EAA. In light of our data and current literature, we recommend to set the threshold value at 2million/ml for semen analysis. Further studies conducted in different ethnic groups and larger patient groups would contribute to clarify what exact value should be used to apply genetic tests.

Genetic diagnostics of male infertility in clinical practice.

Approximately 15% of couples are infertile. Male factors contribute to infertility in over 50% of cases. Identifiable genetic abnormalities contribute to 15%-20% of the most severe forms of male infertility, azoospermia. In this chapter, we explore known genetic causes of male infertility such as Klinefelter syndrome, XYY men, Kallmann syndrome, y-microdeletions, Robertsonian translocations, autosomal inversions, mixed gonadal dysgenesis, x-linked and autosomal gene mutations, and cystic fibrosis transmembrane conductance regulator abnormalities. We also briefly comment on novel biomarkers for male infertility.

Genetic Risk of Azoospermia Factor (AZF) Microdeletions in Idiopathic Cases of Azoospermia and Oligozoospermia in Central Indian Population.

BACKGROUND: Genetic factors cause about 15% of male infertility. Azoospermia factors (AZFa, AZFb, and AZFc) present on Yq are most important for spermatogenesis. We have made an attempt to evaluate the frequencies of microdeletions of AZFa, AZFb, AZFc in idiopathic cases of azoospermia and oligozoospermia from central Indian population. MATERIALS AND METHODS: We have analyzed a total of 156 subjects (95 oligozoospermia and 61 azoospermia) & 50 control subjects. DNA samples were analyzed for microdeletions of Y chromosome by PCR-screening of 18 sequences-tagged-site (STS) markers from different region of the AZF on Yq and SRY on Yp. RESULTS: Out of 156 cases analyzed, 13 (8.33%) subjects (8 azoospermia and 5 oligozoospermia) showed partial deletion of AZF regions, of which deletion in AZFc region was the most common (84.6%) followed by AZFb (15.4%) and AZFa (15.4%). The sites and sizes of deletions varied among patients. Histological study of the testicular tissue of the available subjects, who showed microdeletions of Y chromosome, showed spermatogenic arrest at different stages. The frequency of Y chromosome microdeletion in our subjects was 8.33%. CONCLUSION: Some Indian studies reported low frequencies of microdeletions than that of our result. We suggest that the frequency of deletions may be affected by the involvement of different genetic factors, ethnic population and different geographical regions. PCR based Y chromosome screening for microdeletions will be useful and great help to infertility clinics for genetic counselling and assisted reproduction.

Y chromosome microdeletions in Brazilian fertility clinic patients

Microdeletions in Yq are associated with defects in spermatogenesis, while those in the AZF region are considered critical for germ cell development. We examined microdeletions in the Y chromosomes of patients attended at the Laboratory of Human Reproduction of the Clinical Hospital of the Federal University of Goiás as part of a screening of patients who plan to undergo assisted reproduction. Analysis was made of the AZF region of the Y chromosome in men who had altered spermograms to detect possible microdeletions in Yq. Twenty-three patients with azoospermia and 40 with severe oligozoospermia were analyzed by PCR for the detection of six sequence-tagged sites: sY84 and sY86 for AZFa, sY127 and sY134 for AZFb, and sY254 and sY255 for AZFc. Microdeletions were detected in 28 patients, including 10 azoospermics and 18 severe oligozoospermics. The patients with azoospermia had 43.4% of their microdeletions in the AZFa region, 8.6% in the AZFb region and 17.4% in the AZFc region. In the severe oligozoospermics, 40% were in the AZFa region, 5% in the AZFb region and 5% in the AZFc region. We conclude that microdeletions can be the cause of idiopathic male infertility, supporting conclusions from previous studies.