Male infertility: An update of genetic evaluation, "Beyond the Abstract," by Matthew S. Wosnitzer, Fujun Zhao, and Philip S. Li

BERKELEY, CA (UroToday.com) - Azoospermia (absence of sperm in ejaculate) or severe oligozoospermia (< 5 million sperm/ml ejaculate fluid) are often associated with genetic abnormalities. Genetic testing, including karyotype, Y chromosome microdeletion testing (YCMDs such as AZFa, AZFb, AZFc), congenital hypogonadotropic hypogonadism gene mutation screening, and cystic fibrosis transmembrane conductance regulator (CFTR) gene screening, may provide the abnormality associated with infertility, prognosis for successful pregnancy, and potential risks to offspring. A variety of genetic mutations have been identified that affect spermatogenesis, but the reason for infertility can be demonstrated in only approximately 20% of men with severe oligozoospermia or azoospermia, while up to 80% have an unknown genetic cause requiring additional research. Our review article summarizes the current status of the clinical workup for genetic evaluation of male infertility and significant future directions.

The key to determining the type of genetic testing required is differentiation between obstructive azoospermia (OA) or non-obstructive azoospermia (NOA) through physical examination and possible additional clinical tests (including testicular volume, and serum LH, FSH, testosterone measurement). Men with OA usually have normal gonadotropic hormone profiles and normal testicular volume, while NOA patients typically have increased gonadotropins and decreased testicular volume. Information from genetic testing carries additional information including CFTR association (associated with congenital absence of the vas deferens) with cystic fibrosis sequelae. Numerous DNA excision-repair genes (MLH1, ERCC1) associated with NOA may increase risk of certain types of cancer (Lynch syndrome). Karyotypic abnormalities associated with non-obstructive azoospermia include Klinefelter syndrome (47, XXY) and its inherent issues including delayed puberty, decreased bone mass, and learning issues. Additionally, genetic testing for suspected Kallman’s syndrome (one cause of congential hypogonadotropic hypogonadism) should be completed when there is clinical suspicion. Ultimately, genetics can help to pinpoint which medical or surgical therapy is optimal, or whether donor sperm or adoption may be necessary (AZFa, AZFb deletions for example).

Genetic counseling is critically useful for educating patients about the potential risks of genetic abnormalities being transmitted to offspring. Benefits and risks of genetic testing (including psychological ramifications) and surgical outcomes (including minimizing structural defects with use of the microscope when conducting sperm retrieval) should be a prominent component of informed consent.

Management of oligozoospermia and azoospermia includes IVF/ICSI in conjunction with microdissection testicular sperm extraction (TESE) for men with NOA with etiology amenable to this treatment (Klinefelter syndrome and AZFc microdeletion, for example). Outcomes from microTESE (for NOA) on average yield sperm in 60% of cases, and outcomes of IVF/ICSI (for severe oligozoospermia) or microsurgical epididymal sperm aspiration with IVF/ICSI (for OA not amenable to reconstruction) result in excellent outcomes.

In the future, sperm mRNA, microRNA, epigenetics (such as DNA methylation) and copy number variation (CNV) will likely refine our ability to predict sperm retrieval and ultimately pregnancy outcomes. Lastly, for histology lacking germ cells (Sertoli-cell only) or mature spermatozoa (maturation arrest), the use of stem cells may provide additional avenues to facilitate spermatogenesis.

Written by:
Matthew S. Wosnitzer,1* Fujun Zhao,2 and Philip S. Li2 as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

1Center for Male Reproductive Medicine and Microsurgery, Department of Urology, Cornell Institute for Reproductive Medicine, Weill Cornell Medical College, Cornell University, The New York Presbyterian Hospital, New York, NY 10065, USA.
2Center for Male Reproductive Medicine and Microsurgery, Department of Urology, Cornell Institute for Reproductive Medicine, Weill Cornell Medical College, Cornell University, The New York Presbyterian Hospital, New York, NY 10065, USA

Update of genetic evaluation for male infertility - Abstract

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