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ICSI


At the recent Andrology in the Nineties conference in Belgium there was much debate about the use of intracytoplasmic sperm injection (ICSI) from oligoasthenozoospermic (OAT) men and genetic risk. Peter Vogt reported on the increased incidence of Y-chromosome delections and sex chromosome anomalies in such men, and there seems to be evidence of a general increase of paternally inherited anomalies in offspring (see also the somewhat restricted series for women of advanced maternal age reported by In't Veld in Lancet 346: 773, 1995).

While the excellent data from the Brussels group reported by Van Steirteghem does not give rise to urgent concern, Moosani et al (Fertility & Sterility 1995 64(4):811-817) in an analysis of sperm nuclei by fluorescence in situ hybridization report a significant increase in the frequency of disomy for chromosome I and XY disomy for infertile men.

The take-home message is that any AOT men and their partners seeking ICSI for infertility should be given rigorous genetic counselling and advice about the possible consequences, especially for male offspring. Screening for satellite deletions in the AZF region of the Y chromosome should be mandatory IMHO.

In Belgium now 1% of all births arise from some form of assisted reproductive technology, and this is likely to rise, according to Frank Comhaire. If we assume that the incidence of infertility is 10-15% and that now nearly all cases can be "treated" by ICSI it is logical to assume that a similar proportion of all births will result. Even if only 10% of OAT men carry a risk of genetic abormality this is still a highly disturbing scenario for the next generation. These conditions can *only* be transmitted iatrogenically - unlike diabetes, for example, where couples have the choice of reproducing or not reproducing. With the incredible acceleration of ICSI into the "run of the mill" IVF clinics without access to intensive genetic and paediatric services the long-term implications for health care costs makes the low-birthweight problems of conventional IVF babies look almost trivial.

Turning to the technique of round spermatid injection pregnancies reported earlier this year by Sofikitis et al, there are two additional publications. Fishel et al (Lancet 345: 1641-2, June 24, 1995) report an ongoing pregnancy in Nottingham, UK. Tesarik et al (New England J Medicine 333: 325, August 1995) report the birth of a boy and another healthy ongoing pregnancy that delivered a short while ago.

The French results prompted intense debate and the leader of the team (Jacques Testart) has been attacked by Axel Kahn from the Cochin Institute of Molecular Genetics in Paris with the statement that ROSNI constitutes
"the biggest ethical problem since the development of medially assisted procreation" (Nature 28 September 1995: 277). Kahn also argues that the procedure contravenes the 1947 Nuremburg code of medical ethics starting
that experiments on humans should be preceded by animal experimentation. "For the first time since the Nuremburg code was drafted, we have embarked on human experiments aimed at creating humans without any great urgency for such experiments".

The French national bioethics consultative committee last year advised that ICSI (ROSNI hadn't yet hit the scene) should only be allowed after comprehensive animal testing. This was dismissed as irrelevant by Testart, and his comment is accurate to the point that no good animal models exist for spermatogenic arrest: the birth of live rabbits and mice following spermatid injection tell us nothing about the genetic background or implications for infertile men.

Ironically, in 1986 Testart called for a moratorium on embryo research and on preimplantation genetic diagnosis. Given that ICSI embryos from severely infertile men do indeed have a higher risk of carrying sex chromosomal anomalies as well as cystic fibrosis mutations (associated with congenital absence of the vas deferens) one wonders whether he will reconsider this position. It is clear that we need to increase the rigour of genetic
screening for infertile men, and I for one think that preimplantation genetic diagnosis is ethically essential if there is a defined risk to the embryo.
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Cummins, J.M., and Jequier, A.M. (1994). Treating male infertility needs more clinical andrology, not less.
Human Reproduction., 9, 1214-1219.

Cummins, J.M., and Jequier, A.M. (1995b). Concerns and recommendations for ICSI treatment. Human Reprod., 10 Suppl. 1, "Andrology in the Nineties", In Press. [See URL http://Numbat.murdoch.edu.au/spermatology/spermhp.html for a link to this MS and also the full version indexed on http://Numbat.murdoch.edu.au/spermatology/androl90s_ToC.html ]

de Kretser, D.M. (1995). The potential of intracytoplasmic sperm injection (ICSI) to transmit genetic defects causing male infertility. Reproduction, Fertility, & Development., 7, 137-142.

Martin, and Du, P.R. (1993). Causes hormonales de sterilite masculine et leur traitement.
Schweiz Rundsch Med Prax., 82, 934-7.

Martin, R.H. (1993). Detection of genetic damage in human sperm. Reprod Toxicol., ,

Martin-Dupan, R.C., Sakkas, D., Stalberg, A., Bianchi, P.G., Deboccard, G., and Campana, A. (1995). Treatment of male infertility by intracytoplasmic sperm injection - a critical evaluation [German]. Schweizerische Medizinische Wochenschrift. Journal Suisse de Medecine., 125, 1483-1488.

Moosani, N., Pattinson, H.A., Carter, M.D., Cox, D.M., Rademaker, A.W., and Martin, R.H. (1995). Chromosomal analysis of sperm from men with idiopathic infertility using sperm karyotyping and fluorescence in situ hybridization. Fertility & Sterility., 64, 811-817.

Sofikitis, N., Miyagawa, I., Sharlip, I., Hellstrom, W., Mekras, G., and Mastelou, E. (1995). Human pregnancies achieved by intra-ooplasmic injections of round spermatid (RS) nuclei isolated from testicular tissue of azoospermic men. Las Vegas, Nevada: AUA Meeting Abstracts/PRISM Productions, 0616.

Van der Zwalmen, P., Lejeune, B., Nijs, M., Segalbertin, G., Van Damme, B., and Schoysman, R. (1995). Fertilization of an oocyte microinseminated with a spermatid in an in-vitro fertilization programme. Human Reproduction., 10, 502-503.

Vogt, P., Chandley, A.C., Hargreave, T.B., Keil, R., Ma, K., and Sharkey, A. (1992). Microdeletions in interval 6 of the Y chromosome of males with idiopathic sterility point to disruption of AZF, a human spermatogenesis
gene. Hum Genet., 89, 491-6.

Vogt, P.H. (1995). Genetic aspects of artificial fertilization. Human Reproduction., In Press,

Zuffardi, O., and Tiepolo, L. (1982). Frequencies and types of chromosome abnormalities associated with human male infertility. In P. G. Crosignani, & B. L. Rubin (ed), Genetic Control of Gamete Production and Function.
London, Academic Press, pp 261-273.

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