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Copyright R 1997 American Society for Reproductive Medicine

Published by Elsevier Science Inc.

Oligospermic men: the intracytoplasmic sperm

Vol. 67, No. 4, April 1997

Printed on acid-free paper in U. S. A.

role of karyotype analysis prior to injection

Louise E. Wilkins-Haug, M.D., Ph.D. Mitchell S. Rein, M.D. Mark D. Hornstein, M.D.*

Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts

In vitro fertilization was originally designed to permit fertilization and pregnancy in cases in which anatomic abnormalities made pregnancies impossi- ble or improbable. With the advent of intracytoplas- mic sperm injection (ICSI), fertilization and preg- nancy also have become possible in situations in which sperm numbers are so depleted that conven- tional IVF’ is unlikely to be successful. This new tech- nology, however, has again raised one of the issues voiced in the early days of IVF, namely, the normal- ity of pregnancies produced by these advanced tech- nologies. In the case of ICSI, fertilization is possible in the most severe cases of male infertility. As ICSI becomes standard treatment for severe male factor infertility, it may be instructive to examine the cur- rent genetic knowledge about oligospermic men.

Historically, oligospermia has not been associated with the same high rate of chromosome aneuploidy as was noted originally among azoospermic men. When azoospermia is present, peripheral blood chro- mosome analyses traditionally yielded an 8% to 15% prevalence of chromosome abnormalities. Predomi- nantly, these abnormalities involved the sex chromo- somes, with 47,XXY (Klinefelter’s syndrome) noted most frequently (1). Studies of men with oligosper- mia revealed a smaller, though clinically significant, increased rate of chromosome abnormalities con- sisting almost exclusively of autosomal transloca-

Received September 24, 1996; revised and accepted January 7, 1997.

* Reprint requests: Mark D. Hornstein, M.D., Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115 (FAX: 617-566-7752).

The opinions and commentary expressed in Editor’s Corner ar- ticles are solely those of the author. Its publication does not imply endorsement by the Editor or American Society for Reproductive Medicine.

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tions rather than numeric sex chromosome aneuploi- dies. In men with very few but not absent sperm, both reciprocal and Robertsonian translocations pre- dominate without apparent preference for specific autosomes. Sex chromosome abnormalities, if pres- ent, usually involve structural alterations of the Y chromosome.

Among oligospermic men, the lower the sperm count, the greater the likelihood of a peripheral blood chromosome abnormality. Studies of men with oligo- spermia (defined as <20 x lO’?mL>, found an overall 1.5% and 4.9% rate of aneuploidy among 464 and 326 men, respectively (2, 3). In both series, autosomal translocations predominated. Among men with se- vere levels of oligospermia (< 10 x lO’?mL>, periph- eral blood chromosome translocations occurred at even higher rates: 5.8% and 6.1%. Again, the pre- dominant abnormality was autosomal translocation with a relative minority of sex chromosome aneu- ploidy identified (4, 5).

Recently, Baschet et al. reported a 6.3% (2/32) fre- quency of chromosomal translocations in men with severe oligospermia diagnosed prior to ICSI (6). Sperm counts in this study population ranged from 2 to 10 million spermatozoa per milliliter. Whereas the overall percentage of oligospermic men in whom a balanced translocation is identified is relatively small (1.5% to 6.1%), the implications of transloca- tion for men in ICSI programs is significant. In the few cases of Y chromosome alteration, only the male offspring would be at risk for similar reproductive abnormalities. However, autosomal translocations either in a reciprocal or Robertsonian fashion place these infertile couples at risk for karyotypically un- balanced offspring with associated phenotypic ab- normalities. Almost uniformly, unbalanced products from an inherited autosomal translocation result in

0015-0282/97/$17.00 PI1 SOO15-0282(97)00019-8

variable birth defects, as well as both mental and physical developmental delay, or spontaneous abor- tion.

In the ICSI population, the actual risk faced by men with a balanced autosomal translocation for the birth of a chromosomally unbalanced child is diffi- cult to assess. With naturally occurring conceptions, the risk at second-trimester amniocentesis of an un- balanced chromosome distribution from a paternal reciprocal translocation can range from 1.5% to 23.8% (7). The size of the chromosomal segments, the specific chromosomes, and the type of transloca- tion all influence this range. These rates in the sec- ond trimester in naturally occurring populations, however, are markedly less than the theorized alter- nate, adjacent 1 and adjacent 2 segregations of translocation. Comparably, sperm karyotype analy- sis from carriers of balanced translocations supports a 40% to 60% rate of unbalanced segregants (8). De- creased fertility and spontaneous loss are two pro- posed mechanisms accounting for the markedly lower aneuploid rate in the natural conceptions from these men.

al. (131, found a 1% incidence of chromosomal abnor- malities in karyotypes of ICSI pregnancies. Five of the six chromosomal abnormalities involved the sex chromosomes. Recently, Wennerholm et al. (14) re- ported no karyotypic abnormalities in 58 amniocent- eses from ICSI pregnancies. In one of the largest follow-up studies of ICSI conceptions, a 1.6% (12/ 756) rate of karyotype abnormality was found. Of note, half of these were familial structural aberra- tions all inherited from the father (15).

Theoretically and supported by sperm karyotype analysis in balanced translocation males, as many as two thirds of sperm from a balanced translocation carrier may be unbalanced (8). While many of the conceptions resulting from these aneuploid sperm will be lost as spontaneous abortions, for some chro- mosomes, a substantial risk could exist for delivery of an infant with a nonlethal but handicapping chro- mosomal imbalance. Technical options to prevent this high rate of aneuploid conception among these men are limited. Morphologic assessment of the sperm before they are used has not proven helpful in determining which are chromosomally abnormal (9, 10). In addition, assessment of embryo quality before transfer shows poor correlation with chromo- somal normality (11). Preimplantation chromosome analysis by fluorescence in situ hybridization (FISH) is evolving and theoretically can provide an avenue for transferring only those embryos unaffected by the translocation. However, for this indication, FISH technology is currently limited to those specific chro- mosomal regions for which DNA probes are avail- able. Invasive prenatal diagnostic testing, including chorionic villus sampling or amniocentesis, remains a diagnostic option for these couples. Given the higher rate of multiple gestations among the IVF population, the complexities of prenatal diagnosis with multiple gestations and the resultant risks of multifetal reduction should be considered.

The preponderance of data suggest a slightly in- creased risk of balanced translocations in men with oligospermia. Furthermore, the risk of chromosomal abnormalities in ICSI conceptions from oligospermic men with unbalanced translocations remains un- known, although it may be significantly increased over the risks in natural conceptions. Until more reassuring data become available, we believe men with oligospermia should be counseled regarding karyotype analysis before their partners undergo IVF-ICSI. Although the prevalence of chromosomal abnormalities in such a population is probably small, it may match or exceed the percentage of couples with recurrent abortions who have a balanced trans- location identified (3% to 6%) (16, 17).

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Chromosomal analyses on offspring conceived after ICSI show mixed results. In’t Veld et al. (12) reported an elevated rate of sex chromosomal abnor- malities in selected ICSI patients and Liebaers et

11.

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12. In’t Veld P, Brandenbung H, Verhoeft A, Dhait M, Los F. Sex chromosomal abnormalities and intracytoplasmic sperm injection. Lancet 1995;346:773.

13. Liebaers I, Borduelle M, Van Assche E, Devroey P, Van Steir- teghem A. Sex chromosome abnormalities after intracy- toplasmic sperm injection. Lancet 1995;346:1095.

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15. Bonduelle ML, Wilikens A, Buysse A, Van Assche E, Devroey P, Steirteghem AC, et al. Prospective follow-up study of 1228 children born after intracytoplasmic sperm injection (ICSI). Am J Hum Genet 1996;59:A88.

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17. Avirachan T, Tharapel S, Bannerman R. Recurrent preg- nancy losses and parental chromosome abnormalities: a re- view. Br J Ob Gyn 1985;92:899-914.

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