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.
Highlights
Azoospermia is a relatively frequent cause of infertility occurring in about 1–2% of men in the general population
Germline MLH3 variants have been reported in hereditary Lynch syndrome-associated brain tumours patients [102], and a common polymorphism (C2531T) in the 3’UTR of the gene has been associated with clinical outcomes of colorectal cancer, in terms of increased risks of relapse or metastasis in patients with heterozygous genotype [103]
Certain chromosomal anomalies and gene defects underlying azoospermia can be responsible for a wide spectrum of health issues beside azoospermia, including metabolic/cardiovascular disorders, autoimmune diseases, hypogonadism, syndromic conditions and cancers
Summary
Azoospermia (absence of spermatozoa in the ejaculate) is a relatively frequent cause of infertility occurring in about 1–2% of men in the general population. Similar to histology, folliclestimulating hormone (FSH) and luteinizing hormone (LH) levels, testis volume, and degree of androgenization can vary among NOA men. This intrinsic clinical heterogeneity implies the involvement of several different acquired and congenital genetic factors. The known genetic factors underlying the NOA phenotype account for almost 30% of cases and include primarily chromosomal abnormalities Men with azoospermia present a 2.9 times higher risk to develop cancer in respect to the general population [8]. Med. 2021, 10, x FOR PEER REVIEW tients, identifying those azoospermic men who are unlikely to have testicular spermatozoa, those who are at higher risk for general health problems and would have an impact on the health of their descendants (Figure 1)
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