Chromosomal abnormalities in 1663 infertile men with azoospermia

STUDY QUESTION: What is the prevalence of chromosomal abnormalities in azoospermic men and what are the clinical consequences in terms of increased risk for absent spermatogenesis, miscarriages and offspring with congenital malformations? SUMMARY ANSWER: The prevalence of chromosomal abnormalities in azoospermia was 14.4%, and the number of azoospermic men needed to be screened (NNS) to identify one man with a chromosomal abnormality with increased risk for absence of spermatogenesis was 72, to prevent one miscarriage 370.739 and to prevent one child with congenital malformations 4751.23 757. WHAT IS KNOWN ALREADY: Infertility guidelines worldwide advise screening of non-iatrogenic azoospermic men for chromosomal abnormalities, but only few data are available on the clinical consequences of this screening strategy. STUDY DESIGN, SIZE, DURATION: This retrospective multicentre cross-sectional study of non-iatrogenic azoospermic men was performed at the University Hospital Brussels, Belgium, and the University Medical Centre Groningen, The Netherlands, between January 2000 and July 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Analysis of clinical registries retrospectively identified 1663 non-iatrogenic azoospermic men with available results of karyotyping and FSH serum levels. Iatrogenic azoospermia was an exclusion criterion, defined as azoospermia after spermatotoxic medical treatment, exogenous androgen suppletion or vasectomy and/or vasovasostomy. Also, men with a clinical diagnosis of anejaculation or hypogonadotropic hypo-androgenism and/or FSH values <1.0 U/l were excluded. Chromosomal abnormalities were categorized according to their (theoretical) impact on clinical consequences for the patient (i.e. an increased risk for absence of spermatogenesis) and adverse pregnancy outcomes (i.e. miscarriage or offspring with congenital malformations), in both normogonadotropic (FSH < 10 U/l) and hypergonadotropic (FSH ≥ 10 U/l) azoospermia. We estimated the NNS for chromosomal abnormalities to identify one man with absence of spermatogenesis and to prevent one miscarriage or one child with congenital malformations, and calculated the surgical sperm retrieval rates per chromosomal abnormality. MAIN RESULTS AND THE ROLE OF CHANCE: The overall prevalence of chromosomal abnormalities in azoospermia was 14.4% (95% CI 12.7.16.1%), its prevalence being higher in hypergonadotropic azoospermia (20.2%, 95% CI 17.8.22.7%) compared to normogonadotropic azoospermia (4.9%, 95% CI 3.2.6.6%, P < 0.001). Klinefelter syndrome accounted for 83% (95% CI 77.87%) of abnormalities in hypergonadotropic azoospermia. The NNS to identify one man with increased risk for absence of spermatogenesis was 72, to prevent one miscarriage 370.739, and to prevent one child with congenital malformations 4751.23 757. There was no clinically significant difference in NNS between men with normogonadotropic and hypergonadotropic azoospermia. The surgical sperm retrieval rate was significantly higher in azoospermic men with a normal karyotype (60%, 95% CI 57.7.63.1%) compared to men with a chromosomal abnormality (32%, 95% CI 25.9.39.0%, P < 0.001). The sperm retrieval rate in Klinefelter syndrome was 28% (95% CI 20.7.35.0%). LIMITATIONS, REASONS FOR CAUTION: The absolute number of chromosomal abnormalities associated with clinical consequences and adverse pregnancy outcomes in our study was limited, thereby increasing the role of chance. Further, as there are currently no large series on outcomes of pregnancies in men with chromosomal abnormalities, our conclusions are partly based on assumptions derived from the literature. WIDER IMPLICATIONS OF THE FINDINGS: The NNS found can be used in future cost-effectiveness studies and the evaluation of current guidelines on karyotyping in non-iatrogenic azoospermia.