ASRM PAGES Management of nonobstructive azoospermia: a committee opinion The Practice Committee of the American Society for Reproductive Medicine American Society for Reproductive Medicine, Birmingham, Alabama The management of nonobstructive azoospermia in the context of fertility treatment is discussed. This document replaces the ASRM document titled ‘‘Evaluation of azoospermia,’’ last published in 2008. (Fertil SterilÒ 2018;110:1239–45. Ó2018 by American Society for Reproductive Medicine.) Earn online CME credit related to this document at www.asrm.org/elearn Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility- and-sterility/posts/39085-27020 pproximately 5%–10% of men GOALS OF MANAGEMENT health-relevant conditions that are A evaluated for infertility are azoo- FOR MEN WITH NOA discovered during their diagnostic eval- spermic (1, 2).Surveydatafrom uation. These management objectives Men with NOA are entitled to a the United States suggests that there are are best met with a multidisciplinary diagnostic evaluation that targets approximately 600,000 azoospermic clinical team that includes a reproduc- identification of treatable, genetically reproductive-aged U.S. men at any tive urologist or other specialist in transmissible, prognostic, and/or time, most of whom have nonobstructive male reproductive medicine (6). health-relevant conditions. This evalua- azoospermia (NOA) (3). Nonobstructive tion should include a comprehensive azoospermia results from severe deficits clinical history, physical examination, in spermatogenesis that most commonly DIAGNOSIS OF GENETIC serum testing of total testosterone and result from primary testicular dysfunc- ABNORMALITIES IN MEN follicle-stimulating hormone (FSH) tion, but that may also result from levels, and further diagnostic testing in WITH NOA impairment of the hypothalamus or pitu- some cases based on results of the initial The majority of patients with NOA have itary. The development and widespread diagnostic evaluation (4). Each azoo- primary testicular failure. Genetic adoption of intracytoplasmic sperm in- spermic man's female partner should testing is indicated to evaluate for jection (ICSI) has revolutionized treat- also undergo a systematic, cost- transmissible and health-relevant ge- ment for NOA and enabled biological effective evaluation in preparation for netic lesions that are critical to consider paternityinmanymenusingsurgically assisted reproduction using ICSI, which when counseling and treating affected retrieved spermatozoa. is required for reproduction in the vast couples (7). Cytogenetic evaluation by Practice patterns for the manage- majority of NOA cases. Evaluation of karyotyping will identify cytogenetic ment of azoospermic men are variable the female partner should include clin- abnormalities in approximately 5% of within the United States. In some cen- ical assessment of ovulatory function men with NOA (8); nonmosaic Klinefel- ters, procedures for sperm retrieval are and the structure and patency of the fe- ter syndrome (47,XXY) is the most coordinated with oocyte retrieval so male reproductive tract (5). commonly detected cytogenetic anom- that fresh sperm are used for ICSI. In Men with NOA are also entitled to aly (9). The diagnosis of Klinefelter syn- contrast, other centers offer sperm counseling regarding therapeutic alter- drome informs treatment decisions retrieval with cryopreservation with natives to immediate sperm retrieval about sperm retrieval and has impor- the intention of using thawed sperm when appropriate, counseling about tant relevance to the health of affected at a later date. Finally, the methods the advantages and disadvantages of men, who are at increased risk for used for sperm retrieval in men with available sperm-retrieval procedures testosterone deficiency (TD), osteopo- NOA are variable. and protocols, and treatment of rosis, metabolic syndrome, type 2 dia- betes, breast cancer, and extragonadal Received September 14, 2018; accepted September 21, 2018. germ-cell tumors (10). Other cytoge- Correspondence: Practice Committee, American Society for Reproductive Medicine, 1209 Montgom- ery Highway, Birmingham, Alabama 35216 (E-mail: [email protected]). netic abnormalities detected in azoo- spermic men include Robertsonian Fertility and Sterility® Vol. 110, No. 7, December 2018 0015-0282/$36.00 Copyright ©2018 American Society for Reproductive Medicine, Published by Elsevier Inc. translocations, reciprocal transloca- https://doi.org/10.1016/j.fertnstert.2018.09.012 tions, and chromosomal inversions. VOL. 110 NO. 7 / DECEMBER 2018 1239 ASRM PAGES Some of these genetic lesions predispose to sperm and embryo pathophysiology of NOA (16). It is therefore rational that ther- aneuploidy that can affect the genetic health of offspring apy directed at improving the hormonal environment for conceived with assisted reproductive technology (ART) (11– spermatogenesis might be beneficial. Ejaculated sperm have 13). been reported in men with NOA after treatment with the aro- Men with NOA associated with primary testicular failure matase inhibitor letrozole (17–19). One small nonrandomized should also undergo Y chromosome microdeletion testing. study reported successful sperm retrieval after human Testing for Y chromosome microdeletions is essential for chorionic gonadotropin (hCG) therapy in 6 of 28 men who counseling affected men about the risk of infertility in poten- had previously undergone failed sperm-retrieval attempts, tial male offspring, and to avoid unnecessary surgery in pa- compared with 0 of 20 men (P<.05) in whom a second sperm tients with a very poor prognosis for sperm retrieval. retrieval was attempted without any hormonal therapy (20). Approximately 4% of American men with NOA carry trans- In a larger nonrandomized multicenter study of 442 men missible azoospermia factor (AZF) C deletions that will be in- with NOA who underwent sperm retrieval, sperm-retrieval herited by any sons conceived with ART, and approximately rates were superior in the hormonal-optimization group 6% of men with NOA carry more severe Y-chromosome mi- (57%) to the group that underwent immediate sperm-retrieval crodeletions involving the complete AZFa and AZFb regions surgery without hormonal therapy (34%). In this study, that confer a very poor prognosis for sperm retrieval (14). hormonal-optimization therapy was administered using a Genetic testing should also be considered in NOA associ- stepwise protocol starting with clomiphene citrate and ated with congenital forms of hypogonadotropic hypogonad- titrated to biochemical response using hCG and human meno- ism (HH), to inform patients about the risks of HH in their pausal gonadotropin in nonresponders (21). Despite these sig- offspring. Mutations in a number of genes have been nals from the literature that hormonal-optimization therapy described, including but not limited to the Kallman syndrome may be beneficial in men with NOA, the quantity and quality (KAL) family of genes that is implicated in anosmic congenital of the availability of evidence is insufficient to recommend hypogoandism. Overall, genetic lesions with variable inheri- hormonal-optimization therapy as standard clinical practice. tance patterns are detectable in one third of cases. Testing af- fords clinicians the opportunity to counsel patients about the MEDICAL THERAPY FOR NOA ASSOCIATED risks of HH in their offspring, and empowers clinicians to WITH HYPOGONADOTROPIC screen for unaffected embryos using preimplantation genetic testing for aneuploidy (PGT-A) (15). HYPOGONADISM Hypogonadotropic hypogonadism is an uncommon cause of MANAGEMENT OF DETECTED GENETIC male infertility, affecting approximately 1%–2% of infertile ABNORMALITIES IN MEN WITH NOA men. HH is characterized by hypothalamic or pituitary dysfunction, low/suppressed serum gonadotropins, and Detection of any genetic abnormality during the diagnostic decreased testicular function that manifests clinically as evaluation of NOA should prompt genetic counseling by an testosterone deficiency, oligospermia/azoospermia and/or appropriately trained health-care provider before treatment. decreased testicular volume. Failure of spermatogenesis Counseling should focus on the impact of the specifically de- results from lack of gonadotropin stimulation. HH may be tected genetic lesion on the patient's health and his prognosis congenital, acquired, or idiopathic. Common notable etio- for sperm retrieval, and on the risks posed by the detected ge- logies of HH are Kallman syndrome, which results from defi- netic lesion to the health and fertility of any potential cient gonadotropin-releasing hormone (GnRH) secretion from offspring conceived using surgically retrieved sperm. Detec- the hypothalamus, and anabolic steroidÀinduced hypogo- tion of cytogenetic abnormalities seen on peripheral blood nadism (ASIH), which results from prolonged suppression of karyotyping should trigger consideration of PGT-A during the hypothalamicÀpituitaryÀgonadal axis from exogenous in vitro fertilization (IVF). Men discovered to harbor complete androgen excess. Other acquired forms of HH are related to AZFa or AZFb deletions upon Y chromosome microdeletion trauma, radiation, chronic opioid use, and cerebral tumors. testing should be counseled to consider use of donor sperm Management strategies are tailored to the age of presentation or adoption, given that sperm identification is rare. Physi- and underlying etiology. cians treating men with AZFc