Genetic concerns for the subfertile male in the era of ICSI

The treatment of severe male factor infertility has seen remarkable advance s in the last five years with the introduction and widespread use of intrac ytoplasmic sperm injection (ICSI). Although ICSI represents one of the most important advances in the treatment of the subfertile male, significant co ncerns exist regarding the potential for transmission of abnormal genes to the offspring because many of the natural barriers to conception have been bypassed. Because these couples were not able to conceive prior to ICSI, th e long-term genetic consequences in these offspring are largely undefined a t this time. Genetic abnormalities related to male infertility need to be c onsidered in terms of being (1) causative for male infertility and (2) pote ntially transmissible to the offspring. Reasons for pursuing a genetic eval uation include (1) establishing a diagnosis, (2) establishing a possible ge netic origin, (3) clarifying the pattern of inheritance, and (4) providing information on natural history, variation and expression. The three most co mmon known genetic factors related to male infertility are cystic fibrosis gene mutations leading to congenital absence of the vas deferens, Y-chromos ome microdeletions leading to spermatogenic impairment, and karyotype abnor malities. When congenital bilateral absence of the vas deferens with azoosp ermia is encountered, cystic fibrosis transmembrane conductance regulator ( CFTR) gene mutations are commonly the underlying cause. When testicular fai lure is manifest by azoospermia or severe oligoszoospermia, Y-chromosome mi crodeletions may be present in approximately 10-15 per cent of otherwise no rmal appearing men. Karyotyping can uncover potentially transmissible genet ic abnormalities in the infertile male including structural chromosomal dis orders such as Klinefelter's (classic 47,XXY), mixed gonadal dysgenesis, ch romosomal translocations and XYY syndromes. Finally, potential male inferti lity genes in animal models are reviewed. Without question, advances in cli nical and basic research raise scientific and social issues that must be ad dressed. Copyright (C) 1998 John Wiley & Sons, Ltd.