Recent investigations have suggested a high prevalence of Y chromosome submicroscopic deletions in men with severely impaired spermatogenesis. We evaluated the frequency of Y chromosome deletions in 160 infertile men using a series of 36 sequence-tagged-sites, emphasizing intervals 5 and 6 of the long arm of the Y chromosome. Peripheral leukocyte DNA was extracted and amplified with two parallel techniques to minimize potential overestimation of the frequency of deletions. The presence of deletions was evaluated relative to patient's sperm concentration, testis volume, and hormonal parameters. Men with sperm concentration <5 x 10(6)/ml had a 7% prevalence of submicroscopic Y chromosome deletions. Deletions were detected in 7% of azoospermic men, 10% of men with <1 x 10(6) spermatozoa/ml, and 8% of men with >1 x 10(6) but <5 x 10(6) spermatozoa/ml. Other clinical parameters did not identify men with Y chromosome deletions prior to polymerase chain reaction (PCR)-based testing for the presence of sequence-tagged-sites. Two distinct regions of Y chromosome deletions were detected, approximately 3.6 Mb and 1.4 Mb in length respectively. These deleted regions are present in AZFb and AZFc respectively. No deletions were detected in AZFa. The loss of these two distinct areas is supported by the finding of highly repetitive sequences along the Y chromosome, predisposing to deletion of specific intervals on the Y chromosome during meiosis. Men with severe male infertility are at high risk for Y chromosome deletions. Testing of men for these genetic abnormalities is indicated prior to treatment with assisted reproduction.

Since the first U.S. report of a successful delivery from in vitro fertilization in 1982 (65), progress in the field of assisted reproduction and micromanipulation has been truly dramatic. Perhaps the most exciting advances have been in the area of male factor infertility. Couples who previously would have been offered donor insemination or adoption are now achieving pregnancies despite severe impairments in semen quality, the presence of only single numbers of sperm in the ejaculate, or unreconstructable reproductive tract obstruction. Techniques of micromanipulation that were revolutionary less than five yr ago are now obsolete, replaced by even more successful methods. Even nonobstructive azoospermia resulting from maturation arrest or other impairments in germ cell development have been added to the list of treatable factors in male infertility, as sperm can frequently be extracted directly from testicular parenchyma that is aspirated or surgically biopsied. For patients without sperm in the testicular parenchyma, round spermatid or secondary spermatocyte injections are at least theoretically possible. Several important questions remain with regard to IVF-ICSI. 1) What should be the specific indications for IVF and IVF-ICSI? Should IVF alone ever be used for male factor infertility? 2) What are the reasons for failure to achieve pregnancy after ICSI, which still represent over half of our attempts at achieving ongoing pregnancies? 3) Can we be certain that using severely impaired or less mature sperm will not result in significant birth defects or in genetic abnormalities that could affect the offspring in adolescence or adulthood? 4) What is the most successful and cost effective approach for the infertile couple with impaired semen parameters? For couples with male factor infertility, careful evaluation and treatment of the man should be considered before assisted reproduction, including ICSI. Contemporary application of ICSI for severe male factor infertility can allow pregnancy rates up to 52% (33), with ongoing pregnancy and live delivery rates as high as 37% per IVF cycle attempt (27). As long as viable sperm are present in the ejaculate or retrievable from the reproductive tract, then ICSI procedures can be applied.

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