Evaluation of severe male infertility

In the accompanying article by Tjagur et al. (1), the investigators proposed a novel, intensive genetic and imaging investigation of a male with hypogonadism using whole-exome sequencing and other tests. The patient presented with a scrotal mass that was diagnosed subsequently as an inguinal hernia. Subsequent evaluation showed testis hypotrophy, elevated follicle-stimulating hormone levels, normal semen volume, and azoospermia. To identify karyotypic mosaicism (apparently not identified on initial testing), the investigators recommend whole-exome sequencing, subsequent interphase fluorescence in situ hybridization analysis of buccal cells, and chromosomal microarray analysis. The rationale for such extensive evaluation is that the 45,X/46,XY mosaicism was not detected in initial studies (but seen later on repeat karyotypic evaluation).

The initial evaluation of the subject patient identified the presence of nonobstructive azoospermia on the basis of testis volume, normal semen volume, and elevated follicle-stimulating hormone level. Guidelines for male infertility evaluation recommend the appropriate genetic study of men with nonobstructive azoospermia with Y chromosome microdeletion analysis and karyotype (2). These studies are necessary and sufficient to determine the management of men presenting with nonobstructive azoospermia. Additional testing, including whole-exome sequencing, can always further provide information on the details of a man’s genetic condition. However, the published case report suggests that all men with nonobstructive azoospermia need whole-exome sequencing. This is not accurate. In most cases, the extent of Y microdeletion analysis determines whether treatment is possible—that is, whether segments AZFa and AZFb are present in the patient (3). In addition, standard karyotype analysis will almost always reflect clinically relevant mosaicism in peripheral blood cells. The major other determinant of whether treatment is possible (that sperm production may be present) is based on whether the testis has cells with adequate components of the Y chromosome within its germ cells. Unfortunately, this determination is not possible without biopsy and/or testicular tissue analysis—that is essentially the same as microsurgical testicular sperm search, i.e., standard treatment for men with nonobstructive azoospermia.

In summary, complete genetic analysis of infertile men, including whole-exome sequencing, will provide additional information on men with nonobstructive azoospermia. However, further evaluation of all men with nonobstructive azoospermia with whole-exome sequencing is unnecessary when evidence-based evaluation, as outlined in the American Society for Reproductive Medicine Male Infertility Guidelines, provides the guidance necessary for appropriate and ideal contemporary patient care.

Declaration of Interests

P.N.S. has nothing to disclose.