Clinical management of infertile men with nonobstructive azoospermia

Abstract

The clinical management of men with nonobstructive azoospermia (NOA) seeking fertility has been a challenge for andrologists, urologists, and reproductive medicine specialists alike. This review presents a personal perspective on the clinical management of NOA, including the lessons learned over 15 years dealing with this male infertility condition. A five-consecutive-step algorithm is proposed to manage such patients. First, a differential diagnosis of azoospermia is made to confirm/establish that NOA is due to spermatogenic failure. Second, genetic testing is carried out not only to detect the males in whom NOA is caused by microdeletions of the long arm of the Y chromosome, but also to counsel the affected patients about their chances of having success in sperm retrieval. Third, it is determined whether any intervention prior to a surgical retrieval attempt may be used to increase sperm production. Fourth, the most effective and efficient retrieval method is selected to search for testicular sperm. Lastly, state-of-art laboratory techniques are applied in the handling of retrieved gametes and cultivating the embryos resulting from sperm injections. A coordinated multidisciplinary effort is key to offer the best possible chance of achieving a biological offspring to males with NOA.

Figure 1

Step-by-step approach for the clinical management of infertile men with nonobstructive azoospermia.

Figure 2

Human Y chromosome map depicting the azoospermia factor (AZF) subregions and gene content. Central ideogram depicts the Y chromosome with the pseudoautosomal regions represented by black boxes at the tips of the chromosome (PAR1 and PAR2). Complete AZFa deletion totals 0.8 Mb and maps from approximately 12.9–13.7 Mb of the chromosome. The AZFa region contains two single copy genes, USP9Y and DDX3Y (represented in scale by two oriented triangles indicating 3’-5’ polarity; Adapted from reference 54). Complete AZFb deletions spans a total of 6.23 Mb and maps to approximately 18–24.7 Mb of the chromosome whereas complete AZFc deletions total 3.5 Mb mapping from ~23 Mb to 26.8 Mb of the chromosome. Both regions contain multiple genes as depicted in the bottom of the figure. The location of the basic set of sequence-tagged sites primers to be investigated in azoospermic men with spermatogenic failure, according to the European Association of Andrology and the European Molecular Genetics Quality Network 2013 guidelines, are identified by solid vertical lines.

Figure 3

Algorithm for the medical management of infertile men with nonobstructive azoospermia.

Figure 4

Microdissection testicular sperm extraction. The illustration depicts its main technical aspects, including the use of an operating microscope and the identification of enlarged seminiferous tubules, and initial processing of extracted specimens.