1 Institute of Reproductive Medicine and 2 Department of Obstetrics and Gynaecology of the University, Domagkstr. 11, D48129 Münster, Germany
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: DAZ/CDYa/ICSI/microdeletions/Y chromosome
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Apart from sporadic cases of natural transmission of similar or identical Y chromosome microdeletions (Vogt et al., 1996; Pryor et al., 1997
), the majority of deletions are believed to be de novo, i.e. somatic events arising randomly in some germ cells of fertile men (Edwards and Bishop, 1997
) who thereby produce an infertile son with a Y chromosomal defect in his genome. Such an individual would normally be infertile and further transmission of the genetic defect would not occur. However, intracytoplasmic sperm injection (ICSI) now offers an effective therapeutic option for these men and is believed to allow transmission of genetically determined infertility to the male offspring. Accordingly, analysis of microdeletions should be performed in all patients who are candidates for ICSI. When deletions are found, patients should be counselled about the possibility of producing an infertile son bearing the same deletion (Meschede et al., 1998
).
Notwithstanding, some patients with severe oligozoospermia could be carriers of mosaicisms, with the Y chromosome being deleted in leukocytes but normal in the germ cell lineage (Kent-First et al., 1996). If these subjects undergo ICSI, they produce healthy male offspring with a normal Y chromosome. Here we report the ICSI-mediated transmission of a deletion involving the DAZ and the CDY1 genes by a man with severe oligozoospermia.
![]() |
Case report |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Male medical history revealed acute pancreatitis in 1993 and two resolved, acute episodes of Crohn's disease in 1987 and 1993. Although unlikely, it cannot be excluded that the previous Crohn's disease or its therapy (which was completed 4 years before the ICSI treatment) had an influence on the current patient's spermatogenesis or epididymal function. Apart from a first-degree varicocele, genital examination was normal. Combined testes volume was 33 ml with slightly decreased hypodense homogeneous architecture shown by ultrasound examination. Initial semen analysis (WHO, 1992) showed hypergonadotrophic [serum follicle stimulating hormone (FSH): 12.1 U/l] azoospermia with decreased glucosidase concentrations (a marker of epididymal function) and normal markers for the seminal vesicles (fructose) and prostate (zinc). Because of the decreased glucosidase concentrations and the detection of increased leukocytes in the ejaculate (2.5 x106/ml), a genital tract infection was suspected and the patient was treated with tetracyclines for 10 days. Upon completion of antibiotic treatment repeated semen analyses revealed resolution of the genital tract infection with sperm concentrations now ranging between <0.1 x106/ml and 0.1 x106/ml (Table I), whereas serum FSH values remained constantly elevated. Following genetic counselling (Meschede et al., 1998
), ICSI was performed (Koppers et al., 1998
). After injection of 16 oocytes, three embryos were transferred resulting in a singleton pregnancy. A normal pregnancy led to delivery of a son without evidence of minor or major malformations.
|
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In agreement with previous reports, this case demonstrates the fertilizing capacity of spermatozoa from patients with AZFc deletions resulting in both spontaneous (Kobayashi et al., 1994; Stuppia et al., 1996
; Vogt et al., 1996
) and ICSI-induced (Kent-First et al., 1996
) pregnancies. This suggests that although some gene(s) in the AZFc region might be necessary for normal spermatogenesis, they are not relevant for the fertilization process.
The occurrence of spontaneous pregnancies induced by men with deletions involving candidate AZF genes during their youth (Kobayashi et al., 1994; Stuppia et al., 1996
; Vogt et al., 1996
; Simoni et al., 1997
) suggests the possibility of a gradual worsening of spermatogenesis due to the genetic defect. Unfortunately, in most studies fathers carrying the same deletion as their infertile sons were identified only after diagnosis in the sons, i.e. long after the time of procreation, when semen parameters were not available. Semen parameters of the fathers around the time of procreation are known in only two studies (Kent-First et al., 1996
; Mullhall et al., 1997). Moreover, both azoospermic and oligozoospermic phenotypes and histology can occur in the presence of the same deletion, a finding difficult to reconcile with the concept of deletion-specific histological lesions (Vogt et al., 1996
). Taken together, these data support the idea of a progression from oligozoospermia to azoospermia over time (see patient Mü2v in Vogt et al., 1996
; patient no. 9 in Pryor et al., 1997
; patient nos 3 and 5 in Simoni et al., 1997
).
The prognosis resulting from the inherited Y chromosome microdeletion for the fertility of ICSI sons is presently unknown. It is, therefore, important to advise such patients to undergo andrological examination, including semen analysis, soon after puberty. If further evidence of progression from oligozoospermia to azoospermia accumulates, the ICSI sons should consider inducing a pregnancy early in life and/or cryopreserving their semen before they become azoospermic. Moreover, prior knowledge that natural conception could be problematic and that assisted reproduction techniques might be necessary could prevent years of frustrating search for help by the infertile couple (Kent-First et al., 1996). We recommend that all sons of Y chromosome-deleted fathers should be tested for AZF deletions early in life.
![]() |
Acknowledgments |
---|
![]() |
Notes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Graves, J.M. (1995) The origin and function of the mammalian Y chromosome and Y-borne genes- an evolving understanding. BioEssays, 17, 311320.[ISI][Medline]
Gromoll, J., Pekel, E. and Nieschlag, E. (1996) The stricture and organization of the human follicle-stimulating hormone receptor (FSHR) gene. Genomics., 35, 308311.[ISI][Medline]
Kent-First, M.G., Kol, S., Muallem, A. et al. (1996) The incidence and possible relevance of Y-linked microdeletions in babies born after intracytoplasmic sperm injection and their infertile fathers. Mol. Hum. Reprod., 2, 943959.[Abstract]
Kobayashi, K., Mizuno, K., Hida, A. et al. (1994) PCR analysis of the Y chromosome long arm in azoospermic patients: evidence for a second locus required for spermatogenesis. Hum. Mol. Genet., 3, 16951697.[ISI][Medline]
Koppers, B., Gassner, P., Behre, H.M. and Nieschlag, E. (1998) Prognostic value of male diagnostic profiles in intracytoplasmic sperm injection (ICSI). Int. J. Androl., 21, 227232.[ISI][Medline]
Lahn, B. and Page, D.C. (1999) Retroposition of autosomal mRNA yielded testis-specific gene family on human Y chromosome. Nat. Genet., 21, 429433.[ISI][Medline]
Meschede, D., Lemcke, B., Exeler, J.R. et al. (1998) Chromosome abnormalities in 447 couples undergoing intracytoplasmic sperm injection prevalence, types, sex distribution and reproductive relevance. Hum. Reprod., 13, 576582.[Abstract]
Mulhall, J.P., Reijo, R., Alagappan, R. et al. (1997) Azoospermic men with deletion of the DAZ gene cluster are capable of completing spermatogenesis: fertilization, normal embryonic development and pregnancy occur when retrieved testicular spermatozoa are used for intracytoplasmatic sperm injection. Hum. Reprod., 12, 503508.[ISI][Medline]
Pryor, J.L., Kent-First, M., Muallem, A. et al. (1997) Microdeletion of the Y chromosome of infertile men. N. Engl. J. Med., 336, 534539.
Reijo, R., Lee, T-Y., Salo, P. et al. (1995) Diverse spermatogenic defects in human humans caused by Y chromosome deletions encompassing a novel RNA binding protein gene. Nature Genet., 10, 383393.[ISI][Medline]
Reijo, R., Alagappan, R.K., Patrizio, P. and Page, D.C. (1996) Severe oligozoospermia resulting from deletions of azoospermia factor gene on Y chromosome. Lancet, 347, 12901293.[ISI][Medline]
Salo, P., Ignatius, J., Simola, K.O. et al. (1995) Clinical features of 9 males with molecular defined deletions of the Y chromosome long arm. J. Med. Genet., 32, 711715.[Abstract]
Simoni, M., Gromoll, J., Dworniczak, B. et al. (1997) Screening for deletions of the Y chromosome involving the DAZ (Deleted in AZoospermia) gene in azoospermia and severe oligozoospermia. Fertil. Steril., 67, 542547.[ISI][Medline]
Simoni, S., Kamischke, A. and Nieschlag, E. (1998) Significance of the molecular diagnosis of Y chromosomal microdeletions in the diagnostic workup of male infertility. Hum. Reprod., 13, 17641768.
Stuppia, L., Calabrese, G., Guanciali Franchi, P. et al. (1996) Widening of a Y chromosome interval-6 deletion transmitted from a father to his infertile son accounts for an oligozoospermia critical region distal to the RBM1 and DAZ genes. Am. J. Hum. Genet., 59, 13931395.[ISI][Medline]
Vogt, P.H. (1998) Human chromosome deletions in Yq11, AZF candidate genes and male infertility, history and update. Mol. Hum. Reprod., 4, 739744.[Abstract]
Vogt, P.H., Edelmann, A., Kirsch, S. et al. (1996) Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11. Hum. Mol. Genet., 5, 933943.
Vollrath, D., Foote, S., Hilton, A. et al. (1992) The human Y chromosome: a 43-intervall map based on naturally occurring deletions. Science, 258, 5259.
World Health Organization (1992) WHO Laboratory Manual for the Examination of Human Semen and Spermcervical Mucus Interaction, 3rd edn. Cambridge University Press, Cambridge.
Submitted on April 8, 1999; accepted on June 10, 1999.