ANAHEIM, CA (UroToday.com) - Dr. Delores Lamb presented the Ramon Guiteras Lecture “Genetics of Male Infertility” at the Wednesday Plenary Session of the AUA in Anaheim, May 23, 2007. She is a Professor or Urology and Molecular Biology at Baylor University.

Dr. Lamb discussed that infertility is most commonly due to a varicocele (42%), idiopathic in 23%, and obstruction in 15%, but genetics are felt to play some role in up to 80%. While artificial reproductive techniques such as ICSI bypass the problem of male infertility, the cause can still be passed on to offspring.

Normal men have 22 pairs of autosomes and 1 set of sex chromosomes. The Y chromosome is sex determining. A karyotype analysis tells us if all the chromosomes are present and if they are whole. Chromosomal abnormalities are increased 10-fold in infertile men compared to fertile men, making up 6% of diagnosed etiologies of infertility. Sex chromosome abnormalities include Klinefelter’s syndrome (XXY-XXXXY), which is most common. Structural chromosome abnormalities include mutations, deletions, translocations and rearrangements. The diagnosis is made by high resolution banding karyotype analysis and all oligospermic and nonobstructive azoospermic men should have this test as part of their evaluation. Y chromosome deletions have been identified on the Yq region and the specific microdeletion can be identified by a PCR based assay. Microdeletions are rare in fertile men, but it increases to as high as 35% in sertoli cell only syndrome. The azoospermia region (AZF) that is deleted needs to be identified as AZFa or AZFc regions are known to have a poor prognosis even with ICSI. Y chromosome microdeletions can be inherited by offspring of these patients. Proper diagnosis can save patients financial and emotional investment in ICSI as well as side effects from fertility treatments.

Single gene defects such as congenital absence of the vas deference (CBAVD). This is due to a cystic fibrosis transmembrane conduction defect. Over 1,300 gene mutations have been identified in cystic fibrosis to date. All men with CBAVD have a mutation in the cystic fibrosis gene.

Many genetic defects are multifactorial, but researchers are dissecting out the specific causes, Dr. Lamb said. However, there are thousands of genes involved in the fertility process and it makes the genetic identification of defects complex. Spermatogenic defects include chromosomal deletion or gain and offspring with birth defects may result from defective spermatogenesis. This can result in syndromes such as Down’s, Klinefelter’s or Turner’s, for example. FISH can detect whether chromosomes are haploid, diploid or aneuploid. Increased sperm aneuploidy is increased in infertile men. Oligospermic and oligoasthenozoospermic men and those with recurrent pregnancy loss should be assessed for spermatogenic defects, so that patients can be informed that their offspring could be born with a syndrome such as Down’s syndrome (chromosome 21 abnormality).

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Written by Christopher P. Evans, MD, a Contributing Editor with UroToday.

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