Genetic Causes of Male Infertility

Infertility is a major health problem today, affecting about 15.0% of couples trying to have a child. Impaired fertility of the male is causative in 20.0% of infertile couples and contributory in up to another 30.0-40.0%. Infertility already affects about 5.0-7.0% of the general male population and may further increase in the future, considering the apparent trend of declining sperm count in industrialized countries. Despite enormous progress in the understanding of human reproductive physiology, the underlying cause of male infertility remains undefined in about 50.0% of cases, which are referred to as idiopathic infertility [1]. Most idiopathic cases are likely to be of genetic origin because the number of genes involved in human spermatogenesis is probably over 1 thousands. At present, only a few of the genes implicated in the processes of testis determination, testis descent and spermatogenesis have routine clinical importance. These include the cystic fibrosis transmembrane conductance regulator (CFTR) gene, whose mutations cause cystic fibrosis and absence of vas deferens and the androgen receptor (AR) gene, whose mutations cause the androgen insensitivity syndrome and spermatogenic damage. Common Genetic Causes of Male Infertility. Chromosomal anomalies and microdeletions of the azoospermia factor (AZF) regions of the Y chromosome are the only commonly known genetic causes of spermatogenic failure. The frequency of these two genetic anomalies increases with the severity of the spermatogenic defect, reaching up to an overall 30.0% (15.0% karyotype abnormalities and 15.0% of AZF microdeletions) in azoospermic men. Sex chromosome aneuploidies, such as 47,XXY (Klinefelter’s syndrome), 47,XYY and 46,XX males are the most common chromosome anomalies occurring at birth and in the population of infertile males [2]. Klinefelter’s syndrome is a form of primary testicular failure with a high prevalence in infertile men, up to 5.0% in severe oligozoospermia and 10.0% in azoospermia. Y chromosome microdeletions represent the etiological factor of 10.0-15.0% of idiopathic azoospermia and severe oligozoospermia [3]. The frequency of AZF deletions in infertile men ranges from 5.0 to 20.0% in worldwide surveys [4]. Y chromosome microdeletions are found almost exclusively in patients with azoospermia or severe oligozoospermia [5]. The prevalence of Y chromosome microdeletions in the infertile males from the Republic of Macedonia is 6.4%, in patients with azoospermia 16.7% and 2.8% in those with severe oligozoosperGENETIC CAUSES OF MALE INFERTILITY