Genetic Factors of Non-Obstructive Azoospermia: Consequences on Patients’ and Offspring Health

Abstract

Non-Obstructive Azoospermia (NOA) affects about 1% of men in the general population and is characterized by clinical heterogeneity implying the involvement of several different acquired and genetic factors. NOA men are at higher risk to be carriers of known genetic anomalies such as karyotype abnormalities and Y-chromosome microdeletions in respect to oligo-normozoospermic men. In recent years, a growing number of novel monogenic causes have been identified through Whole Exome Sequencing (WES). Genetic testing is useful for diagnostic and pre-TESE prognostic purposes as well as for its potential relevance for general health. Several epidemiological observations show a link between azoospermia and higher morbidity and mortality rate, suggesting a common etiology for NOA and some chronic diseases, including cancer. Since on average 50% of NOA patients has a positive TESE outcome, the identification of genetic factors in NOA patients has relevance also to the offspring’s health. Although still debated, the observed increased risk of certain neurodevelopmental disorders, as well as impaired cardiometabolic and reproductive health profile in children conceived with ICSI from NOA fathers may indicate the involvement of transmissible genetic factors. This review provides an update on the reproductive and general health consequences of known genetic factors causing NOA, including offspring’s health.

Complex Chromosomal Rearrangement Causes Male Azoospermia: A Case Report and Literature Review

“…Obstructive azoospermia (OA), caused by a blocked vas deferens with preserved spermatogenesis in the testis, occurs in 40% of men with azoospermia, whereas spermatogenetic malfunctions (nonobstructive azoospermia, NOA) occur in nearly 60% of men with azoospermia ( Matzuk and Lamb, 2008 ; Lee et al, 2011 ; Ghieh et al, 2019 ). Genetic abnormalities, including chromosomal or gene defects, are found in approximately 30% of azoospermic men ( Krausz and Cioppi, 2021 ). The frequency of chromosomal aberrations increases to 10–15% in azoospermic men ( Matzuk and Lamb, 2008 ; Kuroda et al, 2020 ).…”

Prediction Models for Successful Sperm Retrieval in Patients with Non-Obstructive Azoospermia Undergoing Microdissection Testicular Sperm Extraction: Is There Any Room for Further Studies?

“…Klinefelter syndrome (KS) is the most common chromosomal abnormality in men, and is found in about 3–4% of infertile men and in more than 10% of azoospermic men [ 4 ]. KS men have typically small, atrophic testes and hypergonadotropic hypogonadism, with tubular hyalinization as the prevalent histopathological pattern.…”

Male Infertility: A Review of Key Papers Appearing in the Reproductive Medicine and Andrology Section of the Journal of Clinical Medicine

“…A Special Issue in this journal (mdpi.com/journal/jcm/special_issues/NOA_Management) was dedicated to this argument. As more extensively detailed in the accompanying editorial [ 3 ], the Special Issue was built on the contributions of opinion leaders such as Peter N. Schlegel and his group, who illustrated how to manage patients with NOA and optimize the success of mTESE [ 4 ], as well as the reproductive chances of men with NOA according to the underlying etiologies [ 5 ]; Sandro Esteves and coworkers, who provided a detailed explanation on how to discriminate the two forms of azoospermia, obstructive vs. non-obstructive [ 6 ]; Krausz and Cioppi, who reviewed the most common genetic abnormalities in men with NOA and their possible impact on their general and reproductive health, as well as on their offspring health [ 7 ]; Goulis and colleagues, who showed how the eventual post-surgical hypogonadism may depend upon some clinical factors, including etiology of NOA, the number of previous surgical attempts, and testicular volume [ 8 ]; Aydos, who provided an in-depth review of the available procedures to select testicular sperm for ICSI [ 9 ]; Smith, who explored the possible application of microfluidic technology to isolation of sperm from testicular samples [ 10 ]; and our group, who proposed a detailed description of the microTESE surgical technique [ 11 ], reviewed the current evidence about the possible effect of hormonal treatments on the outcome of surgical sperm retrieval [ 12 ], and evaluated the studies attempting to individuate reliable predictors of sperm retrieval outcome [ 13 ].…”