Proper Diagnosis and Management of Nonobstructive Azoospermia

June 2017

Case of the Month Proper Diagnosis and Management of Nonobstructive Azoospermia NYU Case of the Month, June 2017 Joseph Alukal, MD Department of Urology, NYU Langone Medical Center, New York, NY [Rev Urol. 2017;19(2):142–144 doi: 10.3909/riu0764] ® © 2017 MedReviews , LLC 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 142 • Vol. 19 No. 2 • 2017 • Reviews in Urology 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. Discussion 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 Proper Diagnosis and Management of Nonobstructive Azoospermia TABLE 1 Hormone Panel Indicator Value Reference Interval (Adult Man) Total testosterone (men) 449 300–720 ng/dL Sex hormone-binding globulin Bioavailable testosterone 14 11–80 nmol/L 250 131–682 ng/dL Free testosterone 94 47–244 pg/mL Free testosterone (%) Luteinizing hormone Follicle-stimulating hormone Estradiol Prolactin 2.7 4.2 24.4 32 12.5 1.6–2.9% 1.2–11.0 mIU/mL 1.6–9.7 mIU/mL 24–43 pg/ML 5–18 ng/mL 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 Management The management of patients with nonobstructive azoospermia Notes The concentrations of free and bioavailable testosterone are derived from mathematic expressions based on constants for the binding of testosterone to albumin and/or sex hormonebinding globulin The concentration of free testosterone is derived from a mathematic expression based on the constant for the binding of testosterone to sex hormone-binding globulin Abnormally elevated 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 Vol. 19 No. 2 • 2017 • Reviews in Urology • 143 Proper Diagnosis and Management of Nonobstructive Azoospermia continued 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. Figure 1. Karyotype of a man with 46,XX testicular disorder. References 1. 2. 3. 4. 5. 6. 7. 8. 9. Figure 2. Fluorescent in situ hybridization analysis of the SRY gene in a man with 46,XX testicular disorder. 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 144 • Vol. 19 No. 2 • 2017 • Reviews in Urology Krausz C, Quintana-Murci L, McElreavey K. Prognostic value of Y deletion analysis: what is the clinical prognostic value of Y chromosomal microdeletion analysis? Hum Reprod. 2000;15:1431. Hopps CV, Mielnik A, Goldstein M, et al. Detection of sperm in men Y chromosome microdeletions with microdeletions of AZFa, AZFb, AZFc regions. Hum Reprod. 2003;18:1660-1665. Reijo R, Lee TY, Salo P, et al. Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene. Nat Genet. 1995;10:383-393. Kolettis PN, Sabanegh ES. Significant medical pathology discovered during a male infertility evaluation. J Urol. 2001;166:178-180. Meng MV, Greene KL, Turek PJ. Surgery or assisted reproduction? A decision analysis of treatment costs in male infertility. J Urol. 2005:174:1926-1931. Alukal JP, Lipshultz LI. Safety of assisted reproduction, assessed by risk of abnormalities in children born after use of in vitro fertilization techniques. Nat Clin Pract Urol. 2008;5:140-150. Simoni M, Bakker E, Krausz, C. EAA/EMQN best practice guidelines for molecular diagnosis of Y chromosomal microdeletions. State of the Art 2004. Int J Androl. 2004:27:240-249. Schlegel PN. Testicular sperm extraction: microdissection improves sperm yield with minimal tissue excision. Hum Reprod. 1999;14:131-135. DiNapoli L, Capel B. SRY and the standoff in sex determination. Mol Endocrinol. 2008;22:1-9.