A 32-year-old man presented with 1 year of infertility. He and his 34-year-old wife have been having unprotected, properly timed intercourse for 1.5 years. They have been married 4 years; she was previously taking oral contraceptives for birth control. Results of an evaluation with her gynecologist are within normal limits.
The patient’s own past medical and surgical histories are noncontributory, with no medicines, allergies, or prior procedures. He has fathered no prior pregnancies, denies smoking or illicit drug use, and has no relevant family history. He is employed and denies any personal history of toxic or radioactive exposures or genitourinary trauma.
Results of a physical examination are within normal limits, excepting 14 cc testes that were bilaterally descended and without masses. There are no varicoceles, hernias, spermatocele, or hydrocele evident. A semen analysis demonstrates normal volume azoospermia. There are no sperm identified on centrifugation, and results for fructose testing are positive. A semen volume of 3.5 mL is reported, as well as a semen pH of 8.4.
A repeat semen analysis 2 weeks later on appropriate abstinence interval was similar. A serum hormonal panel drawn that morning was remarkable only for a follicle-stimulating hormone level of 24.2 (Table 1); testosterone, luteinizing hormone, estradiol, and prolactin were all within normal limits.
The diagnosis and management of nonobstructive azoospermia can be confusing for both practitioners and patients. Simple questions such as “Why am I like this?” or “What should my partner and I do?” often do not have clear-cut answers. The proper management of the current patient, whose history and initial laboratory workup gave no suggestion of an acquired or obstructive cause, depends on an appropriate genetic evaluation, including a serum karyotype, and an assay of the Y chromosome for deletions of the DAZ region (proximal Yq).1 Karyotypic abnormalities and DAZ deletions account for approximately 40% of nonobstructive azoospermia. Patients should be reminded that they are likely to have a normal result on these tests; however, if the test results are abnormal, the information obtained is hugely important. Abnormal results, including the identification of Klinefelter syndrome (47,XXY on serum karyotype) or microdeletion of the AZFa region on Y-chromosome assay, are prognostic. The first result carries a chance of spermatogenesis, whereas the second does not.2,3
The management of patients with nonobstructive azoospermia requires microdissection testicular sperm extraction (mTESE) and in vitro fertilization with intracytoplasmic sperm injection (IVF-ICSI). There are also questions of logistics (coordination of the interventions for men and women as opposed to treating the men first and cryopreserving any identified sperm), in addition to concerns about cost, success rates, and risk of congenital abnormalities in the offspring.4-6 mTESE and IVF-ICSI are reasonable options to offer couples if specific conditions are uncovered in a genetic evaluation. As mentioned above, these conditions include Klinefelter syndrome on karyotype (47,XXY) or an AZFc microdeletion of the Y chromosome. mTESE has an approximate 60% chance of identifying sperm in either of these cases.7 Unfortunately, no other prognostics have been shown in these patients to predict the likelihood of identification of sperm. Patients need to be made aware of the possibility of a negative mTESE. And if they have pursued coordinated mTESE at the same time as IVF-ICSI, they need to be prepared for either oocyte cryopreservation or the use of donor sperm if sperm are not found.
Finally, there is a large group of patients with nonobstructive azoospermia for whom a genetic evaluation does not reveal an abnormality. Patients need to understand that this simply means they do not have a karyotypic abnormality or a Y-chromosome deletion that explains their condition. A normal genetic evaluation does not prove the absence of a genetic explanation for their condition. All of the genes involved in fertility in men are not known yet; ongoing research in this field is vital. In the patient with a normal karyotype and Y chromosome, there is a 55% chance of identifying sperm with mTESE.8
In the current patient, genetic testing revealed a rare translocation of the distal end of the Y chromosome (Figures 1 and 2). The SRY gene found at the end of this chromosome results in phenotypic maleness through a cascade of embryologic events.9 However, without any of the long arm of the Y chromosome, there is no chance of identifying sperm in this patient through surgical extraction of sperm. This couple ultimately became pregnant through the use of donor sperm. Again, the prognostic utility of evaluating this patient appropriately rests with the goal of avoiding mTESE with no chance of success and an unnecessary IVF-ICSI cycle for the patient’s wife.
