Male infertility represents one of the clearest examples of a complex disease with a substantial genetic basis. Numerous male mouse models, mutation screening and association studies reported over the last few years reveal the high prevalence of genetic causes of spermatogenic impairment, accounting for 10-15% of severe male infertility, including chromosomal aberrations and single gene mutations. Natural selection prevents the transmission of mutations causing infertility, but this protective mechanism may be overcome by assisted reproduction techniques. Consequently, the identification of genetic factors is important for appropriate management of the infertile couple. However, a large proportion of infertile males are diagnosed as idiopathic, reflecting poor understanding of the basic mechanisms regulating spermatogenesis and sperm function. Furthermore, the molecular mechanisms underlying spermatogenic damage in cases of genetic infertility (for example Yq microdeletions) are not known. These problems can be addressed only by large scale association studies and testicular or spermatozoal expression studies in well-defined alterations of spermatogenesis. It is conceivable that these studies will have important diagnostic and therapeutic implications in the future. This review discusses the genetic causes of male infertility known to date, the genetic polymorphisms possibly associated with male infertility, and reports novel results of global gene expression profiling of normal human testis by microarray technology.

Klinefelter Syndrome (KS) is characterized by an extreme heterogeneity in its clinical and genetic presentation. The relationship between clinical phenotype and genetic background has been partially disclosed; nevertheless, physicians are aware that several aspects concerning this issue are far to be fully understood. By improving our knowledge on the role of some genetic aspects as well as on the KS, patients’ interindividual differences in terms of health status will result in a better management of this chromosomal disease. The aim of this review is to provide an update on both genetic and clinical phenotype and their interrelationships.

Cryptorchidism is the most frequent congenital birth defect in male children (2-4% in full-term male births), and it has the potential to impact the health of the human male. In fact, although it is often considered a mild malformation, it represents the best-characterized risk factor for reduced fertility and testicular cancer. Furthermore, some reports have highlighted a significant increase in the prevalence of cryptorchidism over the last few decades. Etiology of cryptorchidism remains for the most part unknown, and cryptorchidism itself might be considered a complex disease. Major regulators of testicular descent from intraabdominal location into the bottom of the scrotum are the Leydig-cell-derived hormones testosterone and insulin-like factor 3. Research on possible genetic causes of cryptorchidism has increased recently. Abundant animal evidence supports a genetic cause, whereas the genetic contribution to human cryptorchidism is being elucidated only recently. Mutations in the gene for insulin-like factor 3 and its receptor and in the androgen receptor gene have been recognized as causes of cryptorchidism in some cases, but some chromosomal alterations, above all the Klinefelter syndrome, are also frequently involved. Environmental factors acting as endocrine disruptors of testicular descent might also contribute to the etiology of cryptorchidism and its increased incidence in recent years. Furthermore, polymorphisms in different genes have recently been investigated as contributing risk factors for cryptorchidism, alone or by influencing susceptibility to endocrine disruptors. Obviously, the interaction of environmental and genetic factors is fundamental, and many aspects have been clarified only recently.

No abstract

This extensive clinical research expands the knowledge on genotype-phenotype relationships and confirms that the identification of Yq microdeletions has significant diagnostic and prognostic value, adding useful information for genetic counseling in these patients.