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• W2004773313 abstract "We assessed the frequency of CFTR mutations in groups with varying degrees of sub-fertility and compared these groups to a fertile male group with proven paternity. Screening for CFTR mutations should be routine for all azoospermic males, irrespective of obstructive or non-obstructive etiology, prior to proposing ICSI treatment. CFTR testing has no value in the investigation of non-azoospermic infertile males. We assessed the frequency of CFTR mutations in groups with varying degrees of sub-fertility and compared these groups to a fertile male group with proven paternity. Screening for CFTR mutations should be routine for all azoospermic males, irrespective of obstructive or non-obstructive etiology, prior to proposing ICSI treatment. CFTR testing has no value in the investigation of non-azoospermic infertile males. Wong et al. (1Wong L.J. Alper O.M. Hsu E. Woo M.S. Margetis M.F. The necessity of complete CFTR mutational analysis of an infertile couple before in vitro fertilization.Fertil Steril. 2004; 82: 947-949Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar) report the case of a child conceived with the help of intracytoplasmic sperm injection (ICSI) who was diagnosed with cystic fibrosis (CF). The National Institutes of Health Consensus Development Conference Statement (2Genetic Testing for Cystic Fibrosis NIH Consensus Development Conference Statement. 1997, April 14–16; 15: 1-37Google Scholar) evaluated the cost (direct and ancillary) associated with a single CF birth at $800,000.Many males with oligozoospermia and all with azoospermia will require treatment involving extensive micromanipulation of gametes using ICSI and subsequent bypass of “natural” fertilization.Concerns have been expressed about the outcome for children if poor-quality semen is used (3Cummins J.M. Jequier A.M. Concerns and recommendations for intracytoplasmic sperm injection (ICSI) treatment.Hum Reprod. 1995; : 138-143Crossref PubMed Scopus (56) Google Scholar, 4Retzloff M.G. Hornstein M.D. Is intracytoplasmic sperm injection safe?.Fertil Steril. 2003; 80: 851-859Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 5Belva F. Henriet S. Liebaers I. Van Steirteghem A. Celestin-Westreich S. Bonduelle M. Medical outcome of 8-year-old singleton ICSI children (born ≥ 32 weeks' gestation) and a spontaneously conceived comparison group.Hum Reprod. 2007; 22: 506-515Crossref PubMed Scopus (144) Google Scholar). While it is clearly established that CF males owe their azoospermia to the presence of abnormal CFTR alleles, no strong evidence exists to suggest that CFTR gene mutations contribute to so-called nonobstructive azoospermia in otherwise healthy men.There are very few studies specifically looking at the incidence and role of CFTR gene mutations in oligo- and azoospermic men without congenital bilateral absences of the vas deferens (CBAVD), abnormal karyotypes, or Y chromosome deletions. Furthermore, many of the studies to date show conflicting results (6van der Ven K. Messer L. van der Ven H. Jeyendran R.S. Ober C. Cystic fibrosis mutation screening in healthy men with reduced sperm quality.Hum Reprod. 1996; 11: 513-517Crossref PubMed Scopus (166) Google Scholar, 7Meng M.V. Black L.D. Cha I. Ljung B.M. Pera R.A. Turek P.J. Impaired spermatogenesis in men with congenital absence of the vas deferens.Hum Reprod. 2001; 16: 529-533Crossref PubMed Scopus (56) Google Scholar, 8Tuerlings J.H. Mol B. Kremer J.A. Looman M. Meuleman E.J. te Meerman G.J. et al.Mutation frequency of cystic fibrosis transmembrane regulator is not increased in oligozoospermic male candidates for intracytoplasmic sperm injection.Fertil Steril. 1998; 69: 899-903Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 9Ravnik-Glavac M. Svetina N. Zorn B. Peterlin B. Glavac D. Involvement of CFTR gene alterations in obstructive and nonobstructive infertility in men.Genet Test. 2001; 5: 243-247Crossref PubMed Scopus (31) Google Scholar, 10Larriba S. Bonache S. Sarquella J. Ramos M.D. Gimenez J. Bassas L. et al.Molecular evaluation of CFTR sequence variants in male infertility of testicular origin.Int J Androl. 2005; 28: 284-290Crossref PubMed Scopus (20) Google Scholar).A number of reports in the Irish population have helped determine the most frequent mutations found within Northern Ireland (11Hughes D.J. Hill A.J. Macek Jr., M. Redmond A.O. Nevin N.C. Graham C.A. Mutation characterization of CFTR gene in 206 Northern Irish CF families: thirty mutations, including two novel, account for approximately 94% of CF chromosomes.Hum Mutat. 1996; 8: 340-347Crossref PubMed Scopus (20) Google Scholar) and the Republic of Ireland (12McQuaid S. Joyce C. Ward A. Ryan F. Clabby C. McDevitt T. et al.The Irish Cystic Fibrosis database—a year 2000 update.J Med Genet. 2000; 37 (sp6.17)Google Scholar, 13Cashman S.M. Patino A. Delgado M.G. Byrne L. Denham B. De Arce M. The Irish cystic fibrosis database.J Med Genet. 1995; 32: 972-975Crossref PubMed Scopus (24) Google Scholar).We set out to determine the frequency of the 31 most common CFTR mutations in two groups: a control fertile group with proven paternity (no family history of CF) and five large subfertile groups characterized by variable sperm counts measured using World Health Organization criteria (14World Health Organization WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction.4th ed. Cambridge University Press, New York1999Google Scholar).The samples for the subfertile group originated from males who were attending the Human Assisted Reproduction Ireland (HARI) Unit in the Rotunda Hospital, Dublin, for investigation and treatment for their infertility. Whole blood was taken for DNA extraction and sent for karyotype and Y deletion analysis as a routine part of the investigations of male factor infertility (15Harrison R.F. Barrett T. Stallings R. Cytogenetic analysis is essential before ICSI.Hum Reprod. 1997; 12: 1835Crossref PubMed Scopus (3) Google Scholar). The inclusion criteria were men with a semen analysis suggesting ICSI, all tests performed at HARI, and a minimum of two samples performed for diagnosis (16Gordon A.C. Harrison R.F. McMahon A. Fawzy. Establishing an intracytoplasmic sperm injection (ICSI) programme for the treatment of male factor infertility in Ireland.Ir J Med Sci. 1997; 166: 65-69Crossref PubMed Scopus (7) Google Scholar). The exclusion criteria included males with CF or a family history of CF, males with karyotype abnormalities or AZF deletions, males with known CBAVD, or known carriers of CF as these conditions can cause different degrees of sperm count abnormalities and can account for male subfertility (15Harrison R.F. Barrett T. Stallings R. Cytogenetic analysis is essential before ICSI.Hum Reprod. 1997; 12: 1835Crossref PubMed Scopus (3) Google Scholar, 17Pandiyan N. Jequier A.M. Mitotic chromosomal anomalies among 1210 infertile men.Hum Reprod. 1996; 11: 2604-2608Crossref PubMed Scopus (84) Google Scholar, 18De Braekeleer M. Dao T.N. Cytogenetic studies in male infertility: a review.Hum Reprod. 1991; 6: 245-250PubMed Google Scholar). All azoospermic males were referred for urological opinion to rule out CBAVD as part of the investigation of infertility and before testicular biopsy. All samples used in this study were anonymized at source, and ethical approval was obtained from the Rotunda Hospital, Our Lady's Children's Hospital, Crumlin, and the Coombe Women's Hospital Ethics Committees. The multiplex polymerase chain reaction (PCR) oligonucleotide ligation assay (OLA) technique was chosen as it has a negligible false-positive rate in detecting the CF mutations targeted and is expected to detect approximately 94% of CF alleles described in the Irish population.The molecular analysis was carried out in the Molecular Pathology Laboratory at the Coombe Women's Hospital using the CF OLA commercial kit (ABI, Foster City, CA and Abbott Diagnostics, Sligo, Ireland). Briefly, DNA was diluted to a final concentration of 50 ng/μL and PCR amplified using the primers flanking regions (exons 4, 7, 9, 10, 11, 20, and 221, intron 17) of the CFTR gene. The presence of a CFTR mutation was determined by two fluorescent labeled primers and a common unlabeled primer. Labeled products are formed depending on the presence of a mutation or wild-type alleles and the action of a high-fidelity ligase. Products were distinguished by fluorescence and size separation on a capillary electrophoresis 310 Genetic Analyser (ABI) and analyzed using Genescan Analysis software (version 2.1, ABI). Specific CFTR gene mutations (n = 31) were determined using Genotyper software (version 2.5, ABI).The null hypothesis was that infertile males presenting with azoospermia not related to abnormal karyotype, Y deletions, or known CBAVD do not have a significantly higher CF carrier rate compared with the general fertile male population. We assumed a 1:19 (5.2%) carrier rate in the general population according to the incidence of CF at birth in Ireland (14World Health Organization WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction.4th ed. Cambridge University Press, New York1999Google Scholar). The detection rate of CF alleles using the 31-mutation PCR-OLA technique (AB) is 94%. Assuming that the CF carrier rate is 5% in the general (fertile) population, to detect a rate of at least 15% in the infertile group with a 90% chance of success, the samples size required was 207. The data collected underwent descriptive analysis using the Statistical Package for the Social Sciences, version 11 (SPSS, Chicago). Differences were considered significant at P≤.05.A total of 702 samples were analyzed. One hundred sixteen samples from fertile controls and 586 samples from subfertile males were studied.A total of seven different mutations were observed. Of these, 83% were F508del, 3.7% R117H, G551D, and 621+1G>T, and 1.85% R560T, G542X, and I507del. No tested individual had mutations in both CFTR alleles. All positive results were retested for confirmation. No false positives were identified. When comparing the incidence of CF mutations in the azoospermic group with the other subfertile groups, a significant difference was evident across the infertile categories (Table 1). Within the subfertile group, men with azoospermia not related to abnormal karyotype or Y deletions were significantly more likely to have an abnormal CF allele compared with other subfertile males (extreme oligozoospermia [P = .03], severe oligozoospermia [P = .01], oligozoospermia [P = .02], normozoospermia [P = .01]).Table 1CF carriage in all studied men.CountSamples analyzedCF carrierNo mutation detectedn%n%Fertile11697.810792.2Total infertile586457.754193AzoospermiaNo sperm seen841416.77083.3Extreme oligozoospermia<1 million/mL11686.8aP = .03.10893.2Severe oligozoospermia1–5 million/mL11565.2bP = .01.10994.8Oligozoospermia5–20 million/mL13996.5cP = .02.13093.5Normozoospermia>20 million/mL13286.1dP = .01.12493.9a P = .03.b P = .01.c P = .02.d P = .01. Open table in a new tab We showed no statistical difference in CFTR mutations between azoospermic males and the fertile population (P = .051). This confirms earlier results (10Larriba S. Bonache S. Sarquella J. Ramos M.D. Gimenez J. Bassas L. et al.Molecular evaluation of CFTR sequence variants in male infertility of testicular origin.Int J Androl. 2005; 28: 284-290Crossref PubMed Scopus (20) Google Scholar) suggesting that CFTR testing is not necessary for the characterization of infertile males other than azoospermic ones.Men with subfertility and in particular azoospermic ones (representing 1% of all men [19Willot G.M. Frequency of azoospermia.Forensic Sci Int. 1982; 20: 9-10Abstract Full Text PDF PubMed Scopus (110) Google Scholar] and 10%–20% of infertile men [20Jarrow J.P. Espeland M.A. Lipshultz L.I. Evaluation of the azoospermic patient.J Urol. 1989; 142: 62-65PubMed Google Scholar]) should be extensively investigated to establish a diagnosis. While up to 15.4% of such cases are due to abnormal karyotype (21Chandley A.C. Edmond P. Christie S. Goeans L. Fletcher J. Franckiewicz A. et al.Cytogenetics and infertility in man. I. Karyotype and seminal analysis: results of five-year survey of men attending a subfertility clinic.Ann Hum Genet. 1975; 39: 231-254Crossref PubMed Scopus (165) Google Scholar) and between 5% and 18% are due to Y microdeletions (22Cruger D.G. Agerholm I. Byriel L. Fedder J. Bruun-Petersen G. Genetic analysis of males from intracytoplasmic sperm injection couples.Clin Genet. 2003; 64: 198-203Crossref PubMed Scopus (43) Google Scholar), a large proportion, with the exception of CF patients and males with vas obstruction, are unexplained.Cruger et al. (22Cruger D.G. Agerholm I. Byriel L. Fedder J. Bruun-Petersen G. Genetic analysis of males from intracytoplasmic sperm injection couples.Clin Genet. 2003; 64: 198-203Crossref PubMed Scopus (43) Google Scholar), while analyzing the four most common Danish CF mutations in 392 infertile men, showed that 11.7% of men with non-CBAVD azoospermia had one CFTR mutation. Similar figures to ours were evident in his subfertile groups: extreme oligozoospermia (6.4%), severe oligozoospermia (5.4%), normozoospermia (4.4%), and fertile controls (7%).One limitation of our study, although it is the largest to date, is that the clinical data available on the azoospermic patients as this study were anonymized at source, thus the higher CFTR mutation frequency in the group of azoospermic males could, in part, be due to undiagnosed vas abnormalities.From a clinical perspective, the differentiation between obstructive azoospermia and nonobstructive is almost impossible without testicular biopsy. As such, we propose that all cases of azoospermia are considered obstructive unless proven otherwise.Many times the diagnosis of obstructive azoospermia is not straightforward and clinical clues like low volume, low pH, and low fructose levels are not always available nor is the knowledge to interpret them always present. Furthermore, with the introduction of ICSI, the interest in fully investigating (clinically, biochemically, and genetically) infertile men has declined worldwide. This is a slippery slope and does not help in understanding the etiology of male factor infertility.This study clearly identifies a group of patients with significantly increased iatrogenic risk of transmitting a life-threatening, and life-long incapacitating disease to their offspring. While these patients are naturally sterile, medical intervention could potentially help them father children without being aware of the “silent” genotype in the background.A CFTR gene mutation screen should become a routine part of the investigation of all azoospermic males, irrespective of the clinical presence or absence of the vas deferens. This will allow for a causal diagnosis of male factor infertility and appropriate screen of the female partner if the male is a carrier, followed by genetic counseling and treatment, with appropriate referral for preimplantation genetic diagnosis when necessary. Wong et al. (1Wong L.J. Alper O.M. Hsu E. Woo M.S. Margetis M.F. The necessity of complete CFTR mutational analysis of an infertile couple before in vitro fertilization.Fertil Steril. 2004; 82: 947-949Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar) report the case of a child conceived with the help of intracytoplasmic sperm injection (ICSI) who was diagnosed with cystic fibrosis (CF). The National Institutes of Health Consensus Development Conference Statement (2Genetic Testing for Cystic Fibrosis NIH Consensus Development Conference Statement. 1997, April 14–16; 15: 1-37Google Scholar) evaluated the cost (direct and ancillary) associated with a single CF birth at $800,000. Many males with oligozoospermia and all with azoospermia will require treatment involving extensive micromanipulation of gametes using ICSI and subsequent bypass of “natural” fertilization. Concerns have been expressed about the outcome for children if poor-quality semen is used (3Cummins J.M. Jequier A.M. Concerns and recommendations for intracytoplasmic sperm injection (ICSI) treatment.Hum Reprod. 1995; : 138-143Crossref PubMed Scopus (56) Google Scholar, 4Retzloff M.G. Hornstein M.D. Is intracytoplasmic sperm injection safe?.Fertil Steril. 2003; 80: 851-859Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 5Belva F. Henriet S. Liebaers I. Van Steirteghem A. Celestin-Westreich S. Bonduelle M. Medical outcome of 8-year-old singleton ICSI children (born ≥ 32 weeks' gestation) and a spontaneously conceived comparison group.Hum Reprod. 2007; 22: 506-515Crossref PubMed Scopus (144) Google Scholar). While it is clearly established that CF males owe their azoospermia to the presence of abnormal CFTR alleles, no strong evidence exists to suggest that CFTR gene mutations contribute to so-called nonobstructive azoospermia in otherwise healthy men. There are very few studies specifically looking at the incidence and role of CFTR gene mutations in oligo- and azoospermic men without congenital bilateral absences of the vas deferens (CBAVD), abnormal karyotypes, or Y chromosome deletions. Furthermore, many of the studies to date show conflicting results (6van der Ven K. Messer L. van der Ven H. Jeyendran R.S. Ober C. Cystic fibrosis mutation screening in healthy men with reduced sperm quality.Hum Reprod. 1996; 11: 513-517Crossref PubMed Scopus (166) Google Scholar, 7Meng M.V. Black L.D. Cha I. Ljung B.M. Pera R.A. Turek P.J. Impaired spermatogenesis in men with congenital absence of the vas deferens.Hum Reprod. 2001; 16: 529-533Crossref PubMed Scopus (56) Google Scholar, 8Tuerlings J.H. Mol B. Kremer J.A. Looman M. Meuleman E.J. te Meerman G.J. et al.Mutation frequency of cystic fibrosis transmembrane regulator is not increased in oligozoospermic male candidates for intracytoplasmic sperm injection.Fertil Steril. 1998; 69: 899-903Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 9Ravnik-Glavac M. Svetina N. Zorn B. Peterlin B. Glavac D. Involvement of CFTR gene alterations in obstructive and nonobstructive infertility in men.Genet Test. 2001; 5: 243-247Crossref PubMed Scopus (31) Google Scholar, 10Larriba S. Bonache S. Sarquella J. Ramos M.D. Gimenez J. Bassas L. et al.Molecular evaluation of CFTR sequence variants in male infertility of testicular origin.Int J Androl. 2005; 28: 284-290Crossref PubMed Scopus (20) Google Scholar). A number of reports in the Irish population have helped determine the most frequent mutations found within Northern Ireland (11Hughes D.J. Hill A.J. Macek Jr., M. Redmond A.O. Nevin N.C. Graham C.A. Mutation characterization of CFTR gene in 206 Northern Irish CF families: thirty mutations, including two novel, account for approximately 94% of CF chromosomes.Hum Mutat. 1996; 8: 340-347Crossref PubMed Scopus (20) Google Scholar) and the Republic of Ireland (12McQuaid S. Joyce C. Ward A. Ryan F. Clabby C. McDevitt T. et al.The Irish Cystic Fibrosis database—a year 2000 update.J Med Genet. 2000; 37 (sp6.17)Google Scholar, 13Cashman S.M. Patino A. Delgado M.G. Byrne L. Denham B. De Arce M. The Irish cystic fibrosis database.J Med Genet. 1995; 32: 972-975Crossref PubMed Scopus (24) Google Scholar). We set out to determine the frequency of the 31 most common CFTR mutations in two groups: a control fertile group with proven paternity (no family history of CF) and five large subfertile groups characterized by variable sperm counts measured using World Health Organization criteria (14World Health Organization WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction.4th ed. Cambridge University Press, New York1999Google Scholar). The samples for the subfertile group originated from males who were attending the Human Assisted Reproduction Ireland (HARI) Unit in the Rotunda Hospital, Dublin, for investigation and treatment for their infertility. Whole blood was taken for DNA extraction and sent for karyotype and Y deletion analysis as a routine part of the investigations of male factor infertility (15Harrison R.F. Barrett T. Stallings R. Cytogenetic analysis is essential before ICSI.Hum Reprod. 1997; 12: 1835Crossref PubMed Scopus (3) Google Scholar). The inclusion criteria were men with a semen analysis suggesting ICSI, all tests performed at HARI, and a minimum of two samples performed for diagnosis (16Gordon A.C. Harrison R.F. McMahon A. Fawzy. Establishing an intracytoplasmic sperm injection (ICSI) programme for the treatment of male factor infertility in Ireland.Ir J Med Sci. 1997; 166: 65-69Crossref PubMed Scopus (7) Google Scholar). The exclusion criteria included males with CF or a family history of CF, males with karyotype abnormalities or AZF deletions, males with known CBAVD, or known carriers of CF as these conditions can cause different degrees of sperm count abnormalities and can account for male subfertility (15Harrison R.F. Barrett T. Stallings R. Cytogenetic analysis is essential before ICSI.Hum Reprod. 1997; 12: 1835Crossref PubMed Scopus (3) Google Scholar, 17Pandiyan N. Jequier A.M. Mitotic chromosomal anomalies among 1210 infertile men.Hum Reprod. 1996; 11: 2604-2608Crossref PubMed Scopus (84) Google Scholar, 18De Braekeleer M. Dao T.N. Cytogenetic studies in male infertility: a review.Hum Reprod. 1991; 6: 245-250PubMed Google Scholar). All azoospermic males were referred for urological opinion to rule out CBAVD as part of the investigation of infertility and before testicular biopsy. All samples used in this study were anonymized at source, and ethical approval was obtained from the Rotunda Hospital, Our Lady's Children's Hospital, Crumlin, and the Coombe Women's Hospital Ethics Committees. The multiplex polymerase chain reaction (PCR) oligonucleotide ligation assay (OLA) technique was chosen as it has a negligible false-positive rate in detecting the CF mutations targeted and is expected to detect approximately 94% of CF alleles described in the Irish population. The molecular analysis was carried out in the Molecular Pathology Laboratory at the Coombe Women's Hospital using the CF OLA commercial kit (ABI, Foster City, CA and Abbott Diagnostics, Sligo, Ireland). Briefly, DNA was diluted to a final concentration of 50 ng/μL and PCR amplified using the primers flanking regions (exons 4, 7, 9, 10, 11, 20, and 221, intron 17) of the CFTR gene. The presence of a CFTR mutation was determined by two fluorescent labeled primers and a common unlabeled primer. Labeled products are formed depending on the presence of a mutation or wild-type alleles and the action of a high-fidelity ligase. Products were distinguished by fluorescence and size separation on a capillary electrophoresis 310 Genetic Analyser (ABI) and analyzed using Genescan Analysis software (version 2.1, ABI). Specific CFTR gene mutations (n = 31) were determined using Genotyper software (version 2.5, ABI). The null hypothesis was that infertile males presenting with azoospermia not related to abnormal karyotype, Y deletions, or known CBAVD do not have a significantly higher CF carrier rate compared with the general fertile male population. We assumed a 1:19 (5.2%) carrier rate in the general population according to the incidence of CF at birth in Ireland (14World Health Organization WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction.4th ed. Cambridge University Press, New York1999Google Scholar). The detection rate of CF alleles using the 31-mutation PCR-OLA technique (AB) is 94%. Assuming that the CF carrier rate is 5% in the general (fertile) population, to detect a rate of at least 15% in the infertile group with a 90% chance of success, the samples size required was 207. The data collected underwent descriptive analysis using the Statistical Package for the Social Sciences, version 11 (SPSS, Chicago). Differences were considered significant at P≤.05. A total of 702 samples were analyzed. One hundred sixteen samples from fertile controls and 586 samples from subfertile males were studied. A total of seven different mutations were observed. Of these, 83% were F508del, 3.7% R117H, G551D, and 621+1G>T, and 1.85% R560T, G542X, and I507del. No tested individual had mutations in both CFTR alleles. All positive results were retested for confirmation. No false positives were identified. When comparing the incidence of CF mutations in the azoospermic group with the other subfertile groups, a significant difference was evident across the infertile categories (Table 1). Within the subfertile group, men with azoospermia not related to abnormal karyotype or Y deletions were significantly more likely to have an abnormal CF allele compared with other subfertile males (extreme oligozoospermia [P = .03], severe oligozoospermia [P = .01], oligozoospermia [P = .02], normozoospermia [P = .01]). We showed no statistical difference in CFTR mutations between azoospermic males and the fertile population (P = .051). This confirms earlier results (10Larriba S. Bonache S. Sarquella J. Ramos M.D. Gimenez J. Bassas L. et al.Molecular evaluation of CFTR sequence variants in male infertility of testicular origin.Int J Androl. 2005; 28: 284-290Crossref PubMed Scopus (20) Google Scholar) suggesting that CFTR testing is not necessary for the characterization of infertile males other than azoospermic ones. Men with subfertility and in particular azoospermic ones (representing 1% of all men [19Willot G.M. Frequency of azoospermia.Forensic Sci Int. 1982; 20: 9-10Abstract Full Text PDF PubMed Scopus (110) Google Scholar] and 10%–20% of infertile men [20Jarrow J.P. Espeland M.A. Lipshultz L.I. Evaluation of the azoospermic patient.J Urol. 1989; 142: 62-65PubMed Google Scholar]) should be extensively investigated to establish a diagnosis. While up to 15.4% of such cases are due to abnormal karyotype (21Chandley A.C. Edmond P. Christie S. Goeans L. Fletcher J. Franckiewicz A. et al.Cytogenetics and infertility in man. I. Karyotype and seminal analysis: results of five-year survey of men attending a subfertility clinic.Ann Hum Genet. 1975; 39: 231-254Crossref PubMed Scopus (165) Google Scholar) and between 5% and 18% are due to Y microdeletions (22Cruger D.G. Agerholm I. Byriel L. Fedder J. Bruun-Petersen G. Genetic analysis of males from intracytoplasmic sperm injection couples.Clin Genet. 2003; 64: 198-203Crossref PubMed Scopus (43) Google Scholar), a large proportion, with the exception of CF patients and males with vas obstruction, are unexplained. Cruger et al. (22Cruger D.G. Agerholm I. Byriel L. Fedder J. Bruun-Petersen G. Genetic analysis of males from intracytoplasmic sperm injection couples.Clin Genet. 2003; 64: 198-203Crossref PubMed Scopus (43) Google Scholar), while analyzing the four most common Danish CF mutations in 392 infertile men, showed that 11.7% of men with non-CBAVD azoospermia had one CFTR mutation. Similar figures to ours were evident in his subfertile groups: extreme oligozoospermia (6.4%), severe oligozoospermia (5.4%), normozoospermia (4.4%), and fertile controls (7%). One limitation of our study, although it is the largest to date, is that the clinical data available on the azoospermic patients as this study were anonymized at source, thus the higher CFTR mutation frequency in the group of azoospermic males could, in part, be due to undiagnosed vas abnormalities. From a clinical perspective, the differentiation between obstructive azoospermia and nonobstructive is almost impossible without testicular biopsy. As such, we propose that all cases of azoospermia are considered obstructive unless proven otherwise. Many times the diagnosis of obstructive azoospermia is not straightforward and clinical clues like low volume, low pH, and low fructose levels are not always available nor is the knowledge to interpret them always present. Furthermore, with the introduction of ICSI, the interest in fully investigating (clinically, biochemically, and genetically) infertile men has declined worldwide. This is a slippery slope and does not help in understanding the etiology of male factor infertility. This study clearly identifies a group of patients with significantly increased iatrogenic risk of transmitting a life-threatening, and life-long incapacitating disease to their offspring. While these patients are naturally sterile, medical intervention could potentially help them father children without being aware of the “silent” genotype in the background. A CFTR gene mutation screen should become a routine part of the investigation of all azoospermic males, irrespective of the clinical presence or absence of the vas deferens. This will allow for a causal diagnosis of male factor infertility and appropriate screen of the female partner if the male is a carrier, followed by genetic counseling and treatment, with appropriate referral for preimplantation genetic diagnosis when necessary." @default.
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• W2004773313 date "2010-11-01" @default.
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• W2004773313 title "All azoospermic males should be screened for cystic fibrosis mutations before intracytoplasmic sperm injection" @default.
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• W2004773313 doi "https://doi.org/10.1016/j.fertnstert.2010.02.029" @default.
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