Human Reproduction, Vol. 14, No. 7, 1722-1726,
July 1999
© 1999 European Society of Human Reproduction and Embryology
Men with infertility caused by AZFc deletion can produce sons by intracytoplasmic sperm injection, but are likely to transmit the deletion and infertility
1 Howard Hughes Medical Institute, Whitehead Institute and Department of Biology, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, and 2 Infertility Center of St Louis, St Luke's Hospital, St Louis, MO 63017, USA
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Abstract |
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Deletion of the AZFc region of the Y chromosome is the most frequent molecularly defined cause of spermatogenic failure. We report three unrelated men in whom azoospermia or severe oligozoospermia was caused by de-novo AZFc deletions, and who produced sons by intracytoplasmic sperm injection (ICSI). We employed polymerase chain reaction (PCR) assays to examine the Y chromosomes of their four infant sons. All four sons were found to have inherited the Y chromosome deletions. Such sons are likely to be infertile as adults. This likelihood should be taken into account when counselling couples considering ICSI to circumvent infertility due to severe oligozoospermia or non-obstructive azoospermia.
Key words: /chromosome deletions/ICSI/PCR
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Introduction |
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Intracytoplasmic sperm injection (ICSI) has become the preferred method for circumventing severe male-factor infertility (Palermo et al., 1992
; Tarlatzis and Bili, 1998). Such infertility is common: ~2% of men exhibit severe oligozoospermia or azoospermia (de Kretser, 1997). Deletion of the AZFc region of the Y chromosome is the most frequent molecularly-defined cause of spermatogenic failure. AZFc deletions have been reported by various investigators to account for 2–21% of cases of non-obstructive azoospermia and severe oligozoospermia (Reijo et al., 1995, 1996; Najmabadi et al., 1996; Nakahori et al., 1996; Qureshi et al., 1996; Vogt et al., 1996; Foresta et al., 1997; Girardi et al., 1997; Kremer et al., 1997; Pryor et al., 1997; Simoni et al., 1997; van der Ven et al., 1997; Vereb et al., 1997). AZFc-deleted men and their partners are candidates for ICSI, since in most cases spermatozoa or mature spermatids suitable for the procedure can be recovered from semen or from testis biopsies (Mulhall et al., 1997; Silber et al., 1998). In fact, AZFc-deleted men have fathered daughters via ICSI; in these cases the men transmitted their intact X chromosomes rather than their deleted Y chromosomes (Mulhall et al., 1997). Concerns have been voiced that AZFc deletions, and the resultant infertility, might be transmitted readily from fathers to sons via ICSI (Bhasin et al., 1994; Silber et al., 1995; Engel et al., 1996; Morris and Gleicher, 1996). However, such transmission has not been documented, and its likelihood is unknown.
Kent-First and colleagues conducted the first study of Y-chromosomal DNA sequences in boys conceived by ICSI (Kent-First et al., 1996). In that study, none of the 32 ICSI fathers tested were found to have a deletion of the AZFc region of the Y chromosome. In one family, the ICSI-conceived son was found to have a de-novo AZFc/AZFb deletion, which was not present in his father. In another family, transmission via ICSI was found of a small Y deletion that mapped outside the regions that have been clearly implicated in spermatogenic failure (AZFa, AZFb, AZFc) (Vogt et al., 1996). This small deletion might be an `insignificant polymorphism' of no clinical importance (Kent-First et al., 1996). In no case was transmission observed of an AZFc deletion from father to son (Kent-First et al., 1996).
The pressing clinical question is whether infertile, AZFc-deleted men are likely to father sons via ICSI, and if so, whether those sons will carry the same deletions and thus be infertile. In theory, if simple Mendelian principles apply, Y chromosome deletions should be transmitted to all sons. The possibility that AZFc deletions would be transmitted via ICSI has been underscored by the finding of AZFc-deleted, Y-bearing spermatozoa in the semen of an oligozoospermic, AZFc-deleted man (Reijo et al., 1996), and by reports that, on rare occasions, AZFc deletions have been transmitted naturally (Vogt et al., 1996). Could this event, which is uncommon under natural circumstances (where AZFc-deleted men are rarely fertile), become routine when ICSI (which circumvents male infertility) is employed? These concerns have been so great that the possible effects of ICSI on the frequency of AZFc deletions in the general population have been modelled mathematically (Kremer et al., 1998). However, in no case has ICSI-mediated father-to-son transmission of an AZFc deletion been documented. Given the dearth of direct evidence, some investigators have prudently cautioned against premature conclusions as to the risks of genetic transmission via ICSI (Morris and Gleicher, 1996; Kupker et al., 1997).
Rather than studying the Y chromosomes of a set of unselected ICSI boys, (see Kent-First et al., 1996), we chose to focus on the ICSI sons of men with demonstrated AZFc deletions. From a large, ongoing study of Y-chromosomal DNA sequences in men with spermatogenic failure (Reijo et al., 1995; Mulhall et al., 1997; Silber et al., 1998), we identified three infertile couples who had had at least one son via ICSI, and in which the man carried an AZFc deletion. Using DNA probes of the Y chromosome, we investigated whether the sons had inherited the AZFc deletions present in their fathers' Y chromosomes.
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Materials and methods |
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Three unrelated couples were referred to the Infertility Center at St Luke's Hospital after 2–3 years primary infertility attributed to non-obstructive azoospermia. All six adults were otherwise healthy, had normal karyotypes as judged by analysis of peripheral blood leukocytes, and were aged 30–33 years. In three of the men, standard semen analyses had failed to reveal spermatozoa, and vasography had demonstrated no obstruction. As described below, we identified a few spermatozoa in ejaculates from two of the men, but only after semen centrifugation and extensive searching. In each case, testicular biopsy had revealed maturation arrest, with normal appearing spermatogonia and spermatocytes, but virtually no spermatids, mature or immature, except in rare tubules. The hormone concentrations for men from families 1, 2, and 3 were: follicle stimulating hormone (FSH) 1.6, 5.5, and 15 IU/l; luteinizing hormone (LH) 6.0, 4.3, and 6.0 IU/l; and testosterone 413, 320, and 393 ng/100 ml respectively.
Family 1
The couple underwent a single cycle of in-vitro fertilization (IVF) with ICSI. The woman was treated with s.c. leuprolide acetate, a gonadotrophin-releasing hormone (GnRH) agonist, to inhibit gonadotrophin secretion and then with FSH and human menopausal gonadotrophin (HMG), given i.m. to stimulate ovarian follicle development. Human chorionic gonadotrophin (HCG) was administered i.m., and 22 oocytes were retrieved 36 h later. Spermatozoa (n = 15) were recovered by centrifuging the man's ejaculated semen and searching through 25 concentrated microdroplets. A single spermatozoon was injected into each of 15 oocytes, nine of which underwent normal fertilization, as indicated by the presence of two pronuclei and two polar bodies. After 2 days, six embryos were transferred to the woman's Fallopian tube. She received daily i.m. injections of progesterone in oil (50 mg) until fetal cardiac activity was demonstrated by ultrasonography. By 2 weeks after embryo transfer, serum concentrations of ß-HCG had increased to 478 IU/l. Ultrasonography was carried out 4 weeks later and demonstrated two intrauterine sacs, both with fetal heartbeats. At 28 weeks gestation, twin A appeared normal as judged by ultrasonography, but twin B exhibited pulmonary atresia and a small right ventricle. Two boys were delivered by Caesarian section at 37 weeks gestation; twin A weighed 2640 g and twin B 1900 g. Twin A was healthy at birth and remains so at age 11 months. Twin B required intubation shortly after birth. Echocardiography of twin B confirmed the pulmonary atresia and right ventricular hypoplasia detected prenatally. Balloon atrial septostomy was attempted, but was unsuccessful due to redundant atrial septal tissue. Poor myocardial contractility led to Twin B's death shortly after an attempted atrial septectomy. We know of no other case in which congenital heart disease has been associated with deletion of the AZFc region. No increase in the incidence of such cardiac defects has been observed among babies conceived by ICSI (Bonduelle et al., 1998). We suspect that congenital heart disease, observed in ~1% of all newborn children (Hoffman, 1995), was not caused by Y deletion in this case. Instead, it is probably an unfortunate coincidence of independent aetiology. Chromosome 22, whose anomalies have been implicated in some congenital heart defects (Goldmuntz and Emanuel, 1997), was scrutinized by cytogenetic methods in both parents; no abnormalities were detected (M.Watson, personal communication).
Family 2
The couple underwent a single cycle of IVF with ICSI, as described for Family 1. A total of 13 oocytes were retrieved. Eight spermatozoa were recovered by centrifuging the man's ejaculated semen and searching through 25 concentrated microdroplets. A single spermatozoon was injected into each of eight oocytes, five of which underwent normal fertilization. After 2 days, four embryos were transferred to the woman's Fallopian tube. Serum concentrations of ß-HCG increased to 640 IU/l by 2 weeks after embryo transfer, and to 1684 IU/l 2 days later. Three weeks later, ultrasonography revealed two intrauterine sacs, both with fetal heartbeats. Both twins appeared normal by ultrasonography at 28 weeks gestation, and healthy twins were born by vaginal delivery at 35 weeks: a boy (1560 g) and a girl (1790 g). Both twins are healthy at age 4 months.
Family 3
The couple underwent four cycles of IVF with testicular sperm extraction (TESE) and ICSI. No spermatozoa were observed after centrifuging ejaculated semen. In the first cycle of TESE/ICSI, 10 oocytes were injected with spermatozoa retrieved from the testis, three oocytes underwent normal fertilization, and three embryos were transferred. In the second cycle, eight oocytes were injected, two oocytes were fertilized, and two embryos were transferred. In the third cycle, eight oocytes were injected, six oocytes were fertilized, and five embryos were transferred. No pregnancy was achieved in the first three cycles. In the fourth cycle, 10 oocytes were injected, four oocytes were fertilized, and four embryos were transferred. Serum concentrations of ß-HCG increased to 268 IU/l by 2 weeks after embryo transfer, and to 969 IU/l 3 days later. Four weeks later, ultrasonography revealed a single intrauterine sac, with a fetal heartbeat. A healthy boy, weighing 3008 g, was delivered by Caesarian section at 38 weeks gestation. The boy required monitoring at home for several months because of gastric reflux, but is healthy at 3 months.
Y DNA analysis
All tests were performed on DNAs purified from blood leukocytes, obtained by venipuncture or from umbilical cords. All Y-DNA markers employed had been placed previously on a physical map of the chromosome (Foote et al., 1992; Vollrath et al., 1992). The markers represented all known genes and gene families in the non-recombining region of the Y chromosome (Lahn and Page, 1997; Vogt et al., 1997).
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Results |
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In each of the three families studied, we employed polymerase chain reaction (PCR) to test the father, the ICSI son or sons, and the paternal grandfather for the presence or absence of 38 DNA landmarks distributed across the entirety of the Y chromosome. The DNA landmarks tested included all three regions of the Y chromosome that have been clearly implicated, when deleted, in spermatogenic failure. The results of our Y-DNA analysis are summarized in Table I
. Data for selected Y-DNA markers are shown in Figure 1. The three infertile men, although unrelated, have similar deletions on their Y chromosomes. Each of these infertile men (WHT3305, WHT3362, and WHT3111) carries most of the Y chromosome, including the sex-determining gene SRY (Sinclair et al., 1990), the AZFa and AZFb regions (implicated in some cases of spermatogenic failure) (Vogt et al., 1996), and the heterochromatic region comprising the distal long arm. However, in each of these three men, the Y chromosome lacks the DAZ gene cluster as well as other markers of the AZFc region. As judged by these assays, the extent of these Y deletions is typical of those that have been observed in many azoospermic or severely oligozoospermic men (Reijo et al., 1995, 1996; Najmabadi et al., 1996; Nakahori et al., 1996; Qureshi et al., 1996; Vogt et al., 1996; Foresta et al., 1997; Girardi et al., 1997; Kremer et al., 1997; Pryor et al., 1997; Simoni et al., 1997; van der Ven et al., 1997; Vereb et al., 1997). The Y deletions found in these ICSI fathers were also found in each of their sons (Table I, Figure 1).
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If the Y deletions are the cause of the ICSI fathers' infertility, then the deletions should be de novo, i.e., they should not exist in the paternal grandfathers of the ICSI children. Indeed, the Y chromosomes of the paternal grandfathers (WHT3513, WHT3449, and WHT3257) appear to be intact (Table I
, Figure 1). We conclude that, in each of these families, the infertile man's deletion arose de novo. This is in keeping with previous evidence that nearly all cases of AZFc deletions examined represent de-novo mutations (Reijo et al., 1995, 1996; Vogt et al., 1996; Foresta et al., 1997; Girardi et al., 1997; Kremer et al., 1997; Pryor et al., 1997). In each of the families described here, we can be confident that the de-novo deletion of the AZFc region is the cause of the infertile man's spermatogenic failure. These de-novo AZFc deletions could have arisen either in germ cells of the paternal grandfathers, or zygotically or post-zygotically in the ICSI fathers (Edwards and Bishop, 1997). |
Discussion |
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The three families that we describe demonstrate that AZFc-deleted men can father sons via ICSI. In keeping with simple Mendelian expectations, all four boys inherited their fathers' AZFc-deleted Y chromosomes. When used in ICSI, AZFc-deleted spermatozoa are capable of fertilizing oocytes and eliciting full developmental potential. Nearly all AZFc deletions identified in previous studies represented new mutations (Reijo et al., 1995
, 1996; Vogt et al., 1996; Foresta et al., 1997; Girardi et al., 1997; Kremer et al., 1997; Pryor et al., 1997). This observation implies that the great majority of AZFc-deleted men are infertile, and leads to the prediction that the three surviving boys in these three families will themselves be azoospermic or oligozoospermic as adults, barring the discovery of an effective therapeutic intervention. At present, we anticipate no further evaluation of these boys' fertility potential until puberty, at which point it may be advisable to begin periodic evaluation of testicular volume, semen quality, and reproductive hormone concentrations.
Our observations provide a concrete foundation for alerting couples to the likelihood of transmitting infertility-causing Y deletions by ICSI. Since AZFc deletions are the most common molecularly defined cause of spermatogenic failure (Reijo et al., 1995, 1996; Najmabadi et al., 1996; Nakahori et al., 1996; Qureshi et al., 1996; Vogt et al., 1996; Foresta et al., 1997; Girardi et al., 1997; Kremer et al., 1997; Pryor et al., 1997; Simoni et al., 1997; van der Ven et al., 1997; Vereb et al., 1997), we expect that significant numbers of AZFc-deleted boys will be fathered through ICSI.
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Acknowledgments |
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We thank Michael Watson for cytogenetic analysis; Alison Whelan for reviewing clinical information; Paul Bain, Bruce Lahn, Steve Rozen, Chao Sun, and Jeremy Wang for comments on the manuscript; and Loreall Pooler, Mary Goodheart, and Marta Velez-Stringer for technical assistance. The National Institutes of Health supported Y-DNA studies (but no clinical services).
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3 To whom correspondence should be addressed
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References |
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Agulnik, A.I., Mitchell, M.J., Lerner, J.L. et al. (1994) A mouse Y chromosome gene encoded by a region essential for spermatogenesis and expression of male-specific minor histocompatibility antigens. Hum. Mol. Genet., 3, 873–878.
Bhasin, S., de Kretser, D.M. and Baker, H.W.G. (1994) Pathophysiology and natural history of male infertility. J. Clin. Endocrinol. Metab., 79, 1525–1529.[ISI][Medline]
Bonduelle, M., Aytoz, A., Van Assche, E. et al. (1998) Prospective follow-up study of 1,987 chilidren born after intracytoplasmic sperm injection (ICSI). Treatment of infertility: The new frontiers. Communications Media for Education., pp. 445–461.
de Kretser, D.M. (1997) Male infertility. Lancet, 349, 787–790.[ISI][Medline]
Edwards, R.B. and Bishop, C.E. (1997) On the origin and frequency of Y chromosome deletions responsible for severe male infertility. Mol. Hum. Reprod., 3, 549–554.
Engel, W., Murphy, D. and Schmid, M. (1996) Are there genetic risks associated with microassisted reproduction? Hum. Reprod., 11, 2359–2370.
Foote, S., Vollrath, D., Hilton, A. and Page, D.C. (1992) The human Y chromosome: Overlapping DNA clones spanning the euchromatic region. Science, 258, 60–66.
Foresta, C., Ferlin, A., Garolla, A. et al. (1997) Y-chromosome deletions in idiopathic severe testiculopathies. J. Clin. Endocrinol. Metab., 82, 1075–1080.
Girardi, S.K., Mielnik, A. and Schlegel, P.N. (1997) Submicroscopic deletions in the Y chromosome of infertile men. Hum. Reprod., 12, 1635–1641.
Goldmuntz, E. and Emanuel, B.S. (1997) Genetic disorders of cardiac morphogenesis: The DiGeorge and velocardiofacial syndromes. Circ. Res., 80, 437–443.
Hoffman, J.I.E. (1995) Incidence of congenital heart disease: I. Postnatal incidence. Pediatr. Cardiol., 16, 103–113.[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, 943–950.
Kremer, J.A., Tuerlings, J.H., Meuleman, E.J. et al. (1997) Microdeletions of the Y chromosome and intracytoplasmic sperm injection: From gene to clinic. Hum. Reprod., 12, 687–691.
Kremer, J.A.M., Tuerlings, J.H.A.M., Borm, G. et al. (1998) Does intracytoplasmic sperm injection lead to a rise in the frequency of microdeletions in the AZFc region of the Y chromosome in future generations? Hum. Reprod., 13, 2808–2811.
Kupker, W., Tarlatzis, B. and Diedrich, K. (1997) Pregnancy outcome after assisted fertilization–a short survey. Int. J. Androl., 20 (Suppl. 3), 65–68.
Lahn, B.T. and Page, D.C. (1997) Functional coherence of the human Y chromosome. Science, 278, 675–680.
Ma, K., Inglis, J.D., Sharkey, A., et al. (1993) A Y chromosome gene family with RNA-binding protein homology: Candidates for the azoospermia factor AZF controlling human spermatogenesis. Cell, 75, 1287–1295.[ISI][Medline]
Morris, R.S. and Gleicher, N. (1996) Genetic abnormalities, male infertility, and ICSI. Lancet, 347, 1277.[ISI][Medline]
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 intracytoplasmic sperm injection. Hum. Reprod., 12, 503–508.
Najmabadi, H., Huang, V., Yen, P. et al. (1996) Substantial prevalence of microdeletions of the Y-chromosome in infertile men with idiopathic azoospermia and oligozoospermia detected using a sequence-tagged site-based mapping strategy. J. Clin. Endocrinol. Metab., 81, 1347–1352.[Abstract]
Nakahori, Y., Kuroki, Y., Komaki, R. et al. (1996) The Y chromosome region essential for spermatogenesis. Horm. Res., 46 (Suppl. 1), 20–23.
Palermo, G., Joris, H., Devroey, P. and Van Steirteghem, A.C. (1992) Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet, 340, 17–18.[ISI][Medline]
Pryor, J.L., Kent-First, M., Muallem, A. et al. (1997) Microdeletions in the Y chromosome of infertile men. N. Engl. J. Med., 336, 534–539.
Qureshi, S.J., Ross, A.R., Ma, K. et al. (1996) Polymerase chain reaction screening for Y chromosome microdeletions: A first step towards the diagnosis of genetically-determined spermatogenic failure in men. Mol. Hum. Reprod., 2, 775–779.
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, 1290–1293.[ISI][Medline]
Reijo, R., Lee, T.Y., Salo, P. et al. (1995) Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene. Nature Genet., 10, 383–393.[ISI][Medline]
Schiebel, K., Winkelmann, M., Mertz, A. et al. (1997) Abnormal XY interchange between a novel isolated protein kinase gene, PRKY, and its homologue, PRKX, accounts for one third of all (Y+)XX males and (Y-)XY females. Hum. Mol. Genet., 6, 1985–1989.
Silber, S.J., Alagappan, R., Brown, L.G. and Page, D.C. (1998) Y chromosome deletions in azoospermic and severely oligozoospermic men undergoing intracytoplasmic sperm injection after testicular sperm extraction. Hum. Reprod., 13, 3332–3337.
Silber, S.J., Nagy, Z., Liu, J., et al. (1995) The use of epididymal and testicular spermatozoa for intracytoplasmic sperm injection: The genetic implications for male infertility. Hum. Reprod., 10, 2031–2043.
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, 542–547.[ISI][Medline]
Sinclair, A.H., Berta, P., Palmer, M.S. et al. (1990) A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature, 346, 240–244.[Medline]
Tarlatzis, B.C. and Bili, H. (1998) Survey on intracytoplasmic sperm injection: Report from the ESHRE ICSI Task Force. Hum. Reprod., 13 (Suppl. 1), 165–177.
van der Ven, K., Montag, M., Peschka, B. et al. (1997) Combined cytogenetic and Y chromosome microdeletion screening in males undergoing intracytoplasmic sperm injection. Mol. Hum. Reprod., 3, 699–704.
Vereb, M., Agulnik, A.I., Houston, J.T. et al. (1997) Absence of DAZ gene mutations in cases of non-obstructed azoospermia. Mol. Hum. Reprod., 3, 55–59.
Vogt, P.H., Affara, N., Davey, P. et al. (1997) Report of the Third International Workshop on Y Chromosome Mapping 1997. Cytogenet. Cell, Genet., 79, 1–20.[Medline]
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, 933–943.
Vollrath, D., Foote, S., Hilton, A. et al. (1992) The human Y chromosome: A 43-interval map based on naturally occurring deletions. Science, 258, 52–59.
Submitted on January 3, 1999; accepted on April 8, 1999.
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O. Khorram, P. Patrizio, C. Wang, and R. Swerdloff Reproductive Technologies for Male Infertility J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2373 - 2379. [Full Text] [PDF]
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 L. Shanner and J. Nisker Bioethics for clinicians: 26. Assisted reproductive technologies Can. Med. Assoc. J., May 1, 2001; 164(11): 1589 - 1594. [Abstract] [Full Text] [PDF]
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 C. Foresta, E. Moro, and A. Ferlin Y Chromosome Microdeletions and Alterations of Spermatogenesis Endocr. Rev., April 1, 2001; 22(2): 226 - 239. [Abstract] [Full Text]
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S.E. Kleiman, B.B.-S. Maymon, L. Yogev, G. Paz, and H. Yavetz The prognostic role of the extent of Y microdeletion on spermatogenesis and maturity of Sertoli cells Hum. Reprod., March 1, 2001; 16(3): 399 - 402. [Abstract] [Full Text] [PDF]
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R. J.T. van Golde, A. M.M. Wetzels, R. de Graaf, J. H.A.M. Tuerlings, D. D.M. Braat, and J. A.M. Kremer Decreased fertilization rate and embryo quality after ICSI in oligozoospermic men with microdeletions in the azoospermia factor c region of the Y chromosome Hum. Reprod., February 1, 2001; 16(2): 289 - 292. [Abstract] [Full Text] [PDF]
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S. L. Liow, E. L. Yong, and S. C. Ng Prognostic value of Y deletion analysis: How reliable is the outcome of Y deletion analysis in providing a sound prognosis? Hum. Reprod., January 1, 2001; 16(1): 9 - 12. [Abstract] [Full Text] [PDF]
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J. Ramalho-Santos, P. Sutovsky, C. Simerly, R. Oko, G. M. Wessel, L. Hewitson, and G. Schatten ICSI choreography: fate of sperm structures after monospermic rhesus ICSI and first cell cycle implications Hum. Reprod., December 1, 2000; 15(12): 2610 - 2620. [Abstract] [Full Text] [PDF]
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C. Le Bourhis, J. P. Siffroi, K. McElreavey, and J. P. Dadoune Y chromosome microdeletions and germinal mosaicism in infertile males Mol. Hum. Reprod., August 1, 2000; 6(8): 688 - 693. [Abstract] [Full Text] [PDF]
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C. Krausz, L. Quintana-Murci, and K. McElreavey Prognostic value of Y deletion analysis: What is the clinical prognostic value of Y chromosome microdeletion analysis? Hum. Reprod., July 1, 2000; 15(7): 1431 - 1434. [Abstract] [Full Text] [PDF]
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