Table 2.

Interventions and recommended actions in the clinical management of azoospermic men with nonobstructive azoospermia seeking fertility.

Clinical Management Step	Intervention	Action	Interpretation
Differential diagnosis	Medical history, physical examination, endocrine profile (FSH and testosterone levels at a minimum; LH, prolactin, thyroid hormones, 17-hydroxiprogesterone and estradiol are added as needed), and examination of pelleted semen on multiple occasions. Testicular biopsy could be considered in selected cases in which the differential diagnosis could not be determined.	Confirm that azoospermia is due to spermatogenic failure, and identify men with severely impaired spermatogenesis having few sperm in the ejaculate (cryptozoospermia).	A differential diagnosis between obstructive azoospermia, hypogonadotropic hypogonadism, and spermatogenic failure should be established as management varies according to the type of azoospermia.
Determination of proper candidates for sperm retrieval	Y chromosome microdeletion screening using multiplex PCR blood test. The basic set of PCR primers recommended by the EAA/EMQN for the diagnosis of Yq microdeletion includes: sY14 (SRY), ZFX/ZFY, sY84 and sY86 (AZFa), sY127 and sY134 (AZFb), sY254, and sY255 (AZFc).	Deselect men with microdeletions involving subregions AZFa, AZFb, and AZFb+c.	Approximately 10% of men with NOA-STF harbor microdeletions within the AZF region. SR success in men with YCMD involving the subregions AZFa, AZFb, and AZFb+c are virtually nil, and such patients should be counseled accordingly. SR success in men with AZFc deletions range from 50% to 70%. Genetic counseling should be offered to men with AZFc deletions because testicular spermatozoa used for ICSI will invariably transmit the deletion from father to son.
Identification of patients who could benefit from medical therapy or varicocele repair before sperm retrieval	Serum levels of FSH, total testosterone and estradiol.	Consider medical treatment with gonadotropins, aromatase inhibitors, or selective estrogen receptor modulators for NOA-STF patients with hypogonadism (TT < 300 ng/dL) or T/E ratio < 10. FSH therapy might be needed if FSH drop to below 1.5 mIU/mL during hCG treatment.	Patients should be informed that the evidence of a positive effect of medical treatment remains equivocal.
	Physical examination to identify the presence of clinical varicocele and analysis of testicular biopsy results (if available)	Consider microsurgical repair of clinical varicocele.	Microsurgical varicocele repair is associated with better outcomes concerning recurrence and postoperative complications. Patients with testicular histopathology indicating Sertoli cell-only are unlikely to benefit from varicocele repair. Evidence of a positive effect of varicocele repair is limited, and patients should be counseled accordingly.
Selection of the most effective surgical method for testicular sperm acquisition	Analysis of testicular biopsy results (if available) and of whether sperm have been obtained in previous treatment and by which method.	Microdissection testicular sperm extraction. Conventional testicular sperm extraction may be considered in cases of previous success with TESE, particularly when testicular histopathology indicates hypospermatogenesis.	Micro-TESE in NOA-STF is associated with higher SR success than conventional TESE. The lower tissue removal facilitates sperm processing and lessens testicular damage.
State-of-the-art laboratory techniques to handle surgically extracted testicular spermatozoa	Extraction of a minimum volume of tissue by micro-TESE facilitates tissue processing and search for sperm. Testicular tissue preparation techniques include mechanical and enzymatic mincing and erythrocyte lysis.	Sterile techniques, stable pH and temperature, and high laboratory air quality conditions are helpful to optimize micromanipulation efficiency and safety assurance. Excess sperm not used for ICSI should be cryopreserved for future attempts.	Spermatozoa collected from NOA-STF men are often compromised in quality and are more fragile than ejaculated counterparts. The reproductive potential of such gametes used for ICSI is differentially affected by NOA-STF.

EAA: European Association of Andrology; EMQN: European Molecular Genetics Quality Network; AZF: azoospermia factor; FSH: Follicle-stimulating hormone; ICSI: intracytoplasmic sperm injection; LH: luteinizing hormone; micro-TESE: microdissection testicular sperm extraction; NOA-STF: nonobstructive azoospermia due to spermatogenic failure; PCR: polymerase chain reaction; SR: sperm retrieval; T/E: testosterone to estradiol ratio; TESE: testicular sperm extraction; TT: total testosterone; YCMD: Y-chromosome microdeletions. Adapted from Esteves [5], Asian J. Androl. 17, 459–470, 2015, an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License.