Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-76fb5796d-vfjqv Total loading time: 0 Render date: 2024-04-29T11:45:23.127Z Has data issue: false hasContentIssue false

Chapter 16 - Implementing Genetic Testing of Male Infertility in the Clinic

from Section 3 - Clinical Evaluation and Treatment of Male Infertility

Published online by Cambridge University Press:  06 December 2023

By
Ahmad Majzoub ,
Chak Lam Cho  and
Sandro C. Esteves
Edited by
Douglas T. Carrell ,
Alexander W. Pastuszak  and
James M. Hotaling
Douglas T. Carrell
Affiliation:
Utah Center for Reproductive Medicine
Alexander W. Pastuszak
Affiliation:
University of Utah
James M. Hotaling
Affiliation:
Utah Center for Reproductive Medicine
Get access

Summary

Male factor infertility contributes to roughly 50% of the causes of infertility among couples. Advancements in the diagnostic field of reproduction allowed for the recognition of various etiologies for male factor infertility. Various pretesticular, testicular, and posttesticular etiologies have been identified and are believed to arise from genetic causes in 15–30% of cases. While a number of laboratory tests are available, the indication of genetic testing relies primarily on the findings in the history, physical examination, and semen analysis. Men with suspicion of nonobstructive azoospermia and those with idiopathic severe oligozoospermia are investigated with karyotype and Y-chromosome microdeletion assays. Analysis of the cystic fibrosis transmembrane conductance regulator (CFTR) gene is reserved for patients with obstructive azoospermia secondary to a unilateral or bilateral complete absence of the vas deference. In addition to the more commonly adopted tests, the genetic evaluation may have a role in patients with congenital hypogonadotropic hypogonadism and androgen insensitivity syndrome. Genetic testing of male infertility is a rapidly evolving field in andrology. Epigenetics, next-generation DNA sequencing, and microarray-based technologies represent some of the promising development in the area and may further expand the clinical utilization of genetic evaluation.

Keywords

male infertilitygenetic testingazoospermiaoligozoospermiaY chromosomekaryotype
Type
Chapter
Information
Men's Reproductive and Sexual Health Throughout the Lifespan
An Integrated Approach to Fertility, Sexual Function, and Vitality
 , pp. 127 - 134
Publisher: Cambridge University Press
Print publication year: 2023

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Mascarenhas, MN, Flaxman, SR, Boerma, T, Vanderpoel, S, Stevens, GA. National, regional, and global trends in infertility prevalence since 1990: a systematic analysis of 277 health surveys. PLoS Med. 2012;9:e1001356.Google Scholar
Brugh, VM, Lipshultz, LI. Male factor infertility: evaluation and management. Med Clin North Am. 2004;88:367–385.Google Scholar
Plaseska-Karanfilska, D, Noveski, P, Plaseski, T, Maleva, I, Madjunkova, S, Moneva, Z. Genetic causes of male infertility. Balkan J Med Genet. 2012;15:31–34.CrossRefGoogle ScholarPubMed
Ferlin, A, Raicu, F, Gatta, V, Zuccarello, D, Palka, G, Foresta, C. Male infertility: role of genetic background. Reprod Biomed Online. 2007;14:734–745.Google Scholar
Turriff, A, Macnamara, E, Levy, HP, Biesecker, B. The impact of living with Klinefelter syndrome: a qualitative exploration of adolescents and adults. J Genet Couns. 2017;26:728–737.CrossRefGoogle ScholarPubMed
Spaziani, M, Radicioni, AF. Metabolic and cardiovascular risk factors in Klinefelter syndrome. Am J Med Genet C Semin Med Genet. 2020;184:334–343.CrossRefGoogle ScholarPubMed
O’Flynn O’Brien, KL, Varghese, AC, Agarwal, A. The genetic causes of male factor infertility: a review. Fertil Steril. 2010;93:1–12.Google Scholar
Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile male: a committee opinion. Fertil Steril. 2015;103:e18–25.Google Scholar
Practice Committee of the American Society for Reproductive Medicine. Management of nonobstructive azoospermia: a committee opinion. Fertil Steril. 2018;110:1239–1245.CrossRefGoogle Scholar
Salonia, A, Bettocchi, C, Carvalho, J, et al. Guidelines on sexual and reproductive health - 2021 update: Male sexual dysfunction. Eur Urol. 2021;80(3):333–357.CrossRefGoogle ScholarPubMed
Jarow, J, Sigman, M, Kolettis, PN, et al. The optimal evaluation of the infertile male: AUA best practice statement. In: AUAEa, ed. Research. American Urological Association, Inc.; 2010:1–38.Google Scholar
Esteves, SC, Miyaoka, R, Agarwal, A. An update on the clinical assessment of the infertile male. [corrected]. Clinics (Sao Paulo). 2011;66:691–700.Google Scholar
Hamada, AJ, Esteves, SC, Agarwal, A. A comprehensive review of genetics and genetic testing in azoospermia. Clinics (Sao Paulo). 2013;68(Suppl. 1):39–60.CrossRefGoogle ScholarPubMed
Kohn, TP, Kohn, JR, Owen, RC, Coward, RM. The prevalence of Y-chromosome microdeletions in oligozoospermic men: a systematic review and meta-analysis of European and North American studies. Eur Urol. 2019;76:626–636.Google Scholar
Bates, SE. Classical cytogenetics: karyotyping techniques. Methods Mol Biol. 2011;767:177–190.Google Scholar
Thirumavalavan, N, Gabrielsen, JS, Lamb, DJ. Where are we going with gene screening for male infertility? Fertil Steril. 2019;111:842–850.CrossRefGoogle ScholarPubMed
Donker, RB, Vloeberghs, V, Groen, H, Tournaye, H, van Ravenswaaij-Arts, CMA, Land, JA. Chromosomal abnormalities in 1663 infertile men with azoospermia: the clinical consequences. Hum Reprod. 2017;32:2574–2580.Google Scholar
ElBardisi, H, Majzoub, A. Klinefelter syndrome. In: Aziz, N, Agarwal, A, eds. The Diagnosis and Treatment of Male Infertility. Springer; 2017:133–150.CrossRefGoogle Scholar
Stahl, PJ, Schlegel, PN. Genetic evaluation of the azoospermic or severely oligozoospermic male. Curr Opin Obstet Gynecol. 2012;24:221–228.Google Scholar
Hotaling, J, Carrell, DT. Clinical genetic testing for male factor infertility: current applications and future directions. Andrology. 2014;2:339–350.Google Scholar
Schiff, JD, Palermo, GD, Veeck, LL, Goldstein, M, Rosenwaks, Z, Schlegel, PN. Success of testicular sperm extraction [corrected] and intracytoplasmic sperm injection in men with Klinefelter syndrome. J Clin Endocrinol Metab. 2005;90:6263–6267.Google Scholar
Majzoub, A, Arafa, M, Al Said, S, et al. Outcome of testicular sperm extraction in nonmosaic Klinefelter syndrome patients: what is the best approach? Andrologia. 2016;48:171–176.Google Scholar
Arshad, MA, Majzoub, A, Esteves, SC. Predictors of surgical sperm retrieval in non-obstructive azoospermia: summary of current literature. Int Urol Nephrol. 2020;52:2015–2038.Google Scholar
Okada, H, Goda, K, Muto, S, Maruyama, O, Koshida, M, Horie, S. Four pregnancies in nonmosaic Klinefelter’s syndrome using cryopreserved-thawed testicular spermatozoa. Fertil Steril. 2005;84:1508.CrossRefGoogle ScholarPubMed
Bourne, H, Stern, K, Clarke, G, Pertile, M, Speirs, A, Baker, HW. Delivery of normal twins following the intracytoplasmic injection of spermatozoa from a patient with 47,XXY Klinefelter’s syndrome. Hum Reprod. 1997;12:2447–2450.CrossRefGoogle ScholarPubMed
Vicdan, K, Akarsu, C, Vicdan, A, et al. Birth of a healthy boy using fresh testicular sperm in a patient with Klinefelter syndrome combined with Kartagener syndrome. Fertil Steril. 2011;96:577–579.Google Scholar
Ferhi, K, Avakian, R, Griveau, JF, Guille, F. Age as only predictive factor for successful sperm recovery in patients with Klinefelter’s syndrome. Andrologia. 2009;41:84–87.CrossRefGoogle ScholarPubMed
Okada, H, Goda, K, Yamamoto, Y, et al. Age as a limiting factor for successful sperm retrieval in patients with nonmosaic Klinefelter’s syndrome. Fertil Steril. 2005;84:1662–1664.CrossRefGoogle ScholarPubMed
de la Chapelle, A. The etiology of maleness in XX men. Hum Genet. 1981;58:105–116.CrossRefGoogle ScholarPubMed
Rajender, S, Rajani, V, Gupta, NJ, Chakravarty, B, Singh, L, Thangaraj, K. SRY-negative 46,XX male with normal genitals, complete masculinization and infertility. Mol Hum Reprod. 2006;12:341–346.Google Scholar
Dauwerse, JG, Hansson, KB, Brouwers, AA, Peters, DJ, Breuning, MH. An XX male with the sex-determining region Y gene inserted in the long arm of chromosome 16. Fertil Steril. 2006;86:463 e1–5.Google Scholar
Vorona, E, Zitzmann, M, Gromoll, J, Schuring, AN, Nieschlag, E. Clinical, endocrinological, and epigenetic features of the 46,XX male syndrome, compared with 47,XXY Klinefelter patients. J Clin Endocrinol Metab. 2007;92:3458–3465.Google Scholar
Majzoub, A, Arafa, M, Starks, C, Elbardisi, H, Al Said, S, Sabanegh, E. 46 XX karyotype during male fertility evaluation; case series and literature review. Asian J Androl. 2017;19:168–172.Google Scholar
Peschka, B, Leygraaf, J, Van der Ven, K, et al. Type and frequency of chromosome aberrations in 781 couples undergoing intracytoplasmic sperm injection. Hum Reprod. 1999;14:2257–2263.Google Scholar
Mau-Holzmann, UA. Somatic chromosomal abnormalities in infertile men and women. Cytogenet Genome Res. 2005;111:317–336.Google Scholar
Morin, SJ, Eccles, J, Iturriaga, A, Zimmerman, RS. Translocations, inversions and other chromosome rearrangements. Fertil Steril. 2017;107:19–26.CrossRefGoogle ScholarPubMed
Oliver-Bonet, M, Ko, E, Martin, RH. Male infertility in reciprocal translocation carriers: the sex body affair. Cytogenet Genome Res. 2005;111:343–346.CrossRefGoogle ScholarPubMed
Suzumori, N, Sugiura-Ogasawara, M. Genetic factors as a cause of miscarriage. Curr Med Chem. 2010;17:3431–3437.Google Scholar
Güney, AI, Javadova, D, Kırac, D, et al. Detection of Y chromosome microdeletions and mitochondrial DNA mutations in male infertility patients. Genet Mol Res. 2012;11:1039–1048.Google Scholar
Noordam, MJ, Repping, S. The human Y chromosome: a masculine chromosome. Curr Opin Genet Dev. 2006;16:225–232.CrossRefGoogle ScholarPubMed
Kaluarachchi, NP, Randunu, MH, Jainulabdeen, M, Thavarajah, A, Padeniya, P, Galhena, P. Complex Y chromosome anomalies in an infertile male. JBRA Assist Reprod. 2020;24:510–512.Google Scholar
Nuti, F, Krausz, C. Gene polymorphisms/mutations relevant to abnormal spermatogenesis. Reprod Biomed Online. 2008;16:504–513.Google Scholar
Krausz, C, Casamonti, E. Spermatogenic failure and the Y chromosome. Hum Genet. 2017;136:637–655.Google Scholar
Esteves, SC. Clinical management of infertile men with nonobstructive azoospermia. Asian J Androl. 2015;17:459–470.Google Scholar
Gunes, S, Esteves, SC. Role of genetics and epigenetics in male infertility. Andrologia. 2020:e13586.Google Scholar
Goncalves, C, Cunha, M, Rocha, E, et al. Y-chromosome microdeletions in nonobstructive azoospermia and severe oligozoospermia. Asian J Androl. 2017;19:338–345.Google Scholar
Stahl, PJ, Masson, P, Mielnik, A, Marean, MB, Schlegel, PN, Paduch, DA. A decade of experience emphasizes that testing for Y microdeletions is essential in American men with azoospermia and severe oligozoospermia. Fertil Steril. 2010;94:1753–1756.Google Scholar
Park, SH, Lee, HS, Choe, JH, Lee, JS, Seo, JT. Success rate of microsurgical multiple testicular sperm extraction and sperm presence in the ejaculate in Korean men with Y chromosome microdeletions. Korean J Urol. 2013;54:536–540.CrossRefGoogle ScholarPubMed
Fraietta, R, Zylberstejn, DS, Esteves, SC. Hypogonadotropic hypogonadism revisited. Clinics (Sao Paulo). 2013;68(Suppl. 1):81–88.Google Scholar
Sizar, O, Schwartz, J. Hypogonadism. In: StatPearls. StatPearls Publishing Copyright © 2020, StatPearls Publishing LLC.; 2020.Google Scholar
Festa, A, Umano, GR, Miraglia Del Giudice, E, Grandone, A. Genetic evaluation of patients with delayed puberty and congenital hypogonadotropic hypogonadism: is it worthy of consideration? Front Endocrinol (Lausanne). 2020;11:253.Google Scholar
Sonne, J, Lopez-Ojeda, W. Kallmann syndrome. In: StatPearls. StatPearls Publishing Copyright © 2020, StatPearls Publishing LLC.; 2020.Google Scholar
Casarini, L, Crépieux, P, Reiter, E, et al. FSH for the treatment of male infertility. Int J Mol Sci. 2020;21:2270.Google Scholar
Hiort, O. Clinical and molecular aspects of androgen insensitivity. Endocr Dev. 2013;24:33–40.Google Scholar
Xiao, F, Lan, A, Lin, Z, et al. Impact of CAG repeat length in the androgen receptor gene on male infertility: a meta-analysis. Reprod Biomed Online. 2016;33:39–49.Google Scholar
Singh, S, Ilyayeva, S. Androgen insensitivity syndrome. In: StatPearls. StatPearls Publishing Copyright © 2020, StatPearls Publishing LLC.; 2020.Google Scholar
Castellani, C, Linnane, B, Pranke, I, Cresta, F, Sermet-Gaudelus, I, Peckham, D. Cystic fibrosis diagnosis in newborns, children, and adults. Semin Respir Crit Care Med. 2019;40:701–714.Google Scholar
Quinzii, C, Castellani, C. The cystic fibrosis transmembrane regulator gene and male infertility. J Endocrinol Invest. 2000;23:684–689.Google Scholar
Mak, V, Zielenski, J, Tsui, LC, et al. Proportion of cystic fibrosis gene mutations not detected by routine testing in men with obstructive azoospermia. JAMA. 1999;281:2217–2224.CrossRefGoogle Scholar
Kanavakis, E, Tzetis, M, Antoniadi, T, Pistofidis, G, Milligos, S, Kattamis, C. Cystic fibrosis mutation screening in CBAVD patients and men with obstructive azoospermia or severe oligozoospermia. Mol Hum Reprod. 1998;4:333–337.Google Scholar
Giuliani, R, Antonucci, I, Torrente, I, Grammatico, P, Palka, G, Stuppia, L. Identification of the second CFTR mutation in patients with congenital bilateral absence of vas deferens undergoing ART protocols. Asian J Androl. 2010;12:819–826.Google Scholar
Esteves, SC, Lee, W, Benjamin, DJ, Seol, B, Verza, S, Jr., Agarwal, A. Reproductive potential of men with obstructive azoospermia undergoing percutaneous sperm retrieval and intracytoplasmic sperm injection according to the cause of obstruction. J Urol. 2013;189:232–237.Google Scholar
Miyaoka, R, Esteves, SC. Predictive factors for sperm retrieval and sperm injection outcomes in obstructive azoospermia: do etiology, retrieval techniques and gamete source play a role? Clinics (Sao Paulo). 2013;68(Suppl. 1):111–119.Google Scholar
Salwan, A, Abdelrahman, A. Congenital absence of vas deferens and ectopic kidney. Int J Surg Case Rep. 2017;34:90–92.Google Scholar
Kolettis, PN, Sandlow, JI. Clinical and genetic features of patients with congenital unilateral absence of the vas deferens. Urology. 2002;60:1073–1076.Google Scholar
Mickle, J, Milunsky, A, Amos, JA, Oates, RD. Congenital unilateral absence of the vas deferens: a heterogeneous disorder with two distinct subpopulations based upon aetiology and mutational status of the cystic fibrosis gene. Hum Reprod. 1995;10:1728–1735.CrossRefGoogle ScholarPubMed
Grover, MM, Jenkins, TG. Transgenerational epigenetics: a window into paternal health influences on offspring. Urol Clin North Am. 2020;47:219–225.Google Scholar
Sharma, P, Ghanghas, P, Kaushal, N, Kaur, J, Kaur, P. Epigenetics and oxidative stress: a twin-edged sword in spermatogenesis. Andrologia. 2019;51:e13432.Google Scholar
Spadafora, C. Transgenerational epigenetic reprogramming of early embryos: a mechanistic model. Environ Epigenet. 2020;6:dvaa009.Google Scholar
Cioppi, F, Casamonti, E, Krausz, C. Age-dependent de novo mutations during spermatogenesis and their consequences. Adv Exp Med Biol. 2019;1166:29–46.Google Scholar
Phillips, N, Taylor, L, Bachmann, G. Maternal, infant and childhood risks associated with advanced paternal age: The need for comprehensive counseling for men. Maturitas. 2019;125:81–84.Google Scholar
Menezo, Y, Dale, B, Elder, K. The negative impact of the environment on methylation/epigenetic marking in gametes and embryos: a plea for action to protect the fertility of future generations. Mol Reprod Dev. 2019;86:1273–1282.Google Scholar
Darbandi, M, Darbandi, S, Agarwal, A, et al. Reactive oxygen species-induced alterations in H19-Igf2 methylation patterns, seminal plasma metabolites, and semen quality. J Assist Reprod Genet. 2019;36:241–253.Google Scholar
Santana, VP, Miranda-Furtado, CL, Pedroso, DCC, et al. The relationship among sperm global DNA methylation, telomere length, and DNA fragmentation in varicocele: a cross-sectional study of 20 cases. Syst Biol Reprod Med. 2019;65:95–104.CrossRefGoogle ScholarPubMed
Poorang, S, Abdollahi, S, Anvar, Z, et al. The impact of methylenetetrahydrofolate reductase (MTHFR) sperm methylation and variants on semen parameters and the chance of recurrent pregnancy loss in the couple. Clin Lab. 2018;64:1121–1128.Google Scholar
Yu, M, Du, G, Xu, Q, et al. Integrated analysis of DNA methylome and transcriptome identified CREB5 as a novel risk gene contributing to recurrent pregnancy loss. EBioMedicine. 2018;35:334–344.Google Scholar
Patel, B, Parets, S, Akana, M, et al. Comprehensive genetic testing for female and male infertility using next-generation sequencing. J Assist Reprod Genet. 2018;35:1489–1496.Google Scholar
Yuen, RK, Merkoulovitch, A, MacDonald, JR, et al. Development of a high-resolution Y-chromosome microarray for improved male infertility diagnosis. Fertil Steril. 2014;101:1079–1085.e3.CrossRefGoogle ScholarPubMed
Jorgez, CJ, Weedin, JW, Sahin, A, et al. Aberrations in pseudoautosomal regions (PARs) found in infertile men with Y-chromosome microdeletions. J Clin Endocrinol Metab. 2011;96:E674–E679.Google Scholar
Sawyer, SL, Mukherjee, N, Pakstis, AJ, et al. Linkage disequilibrium patterns vary substantially among populations. Eur J Hum Genet. 2005;13:677–686.Google Scholar

Save book to Kindle

To save this book to your Kindle, first ensure coreplatform@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×