Guideline sources The following summarized guidelines for the evaluation and management of male infertility are prepared by our editorial team based on guidelines from the European Association of Urology (EAU 2023), the European Reference Network on Rare Adult Solid Cancers (EURACAN/ESMO 2022), the American Urological Association (AUA/ASRM 2021), the European Society for Sexual Medicine (ESSM 2021), the American Urological Association (AUA 2019; 2014), and the Canadian Urological Association (CUA 2017). 1 2 3 4 5 6 8 9 10 Guidelines 1. Screening and diagnosis Indications for evaluation: As per EAU 2023 guidelines: https://web.pathway.md/diseases/recRBJLnXAutKAXZN 1/11 6/29/23, 6:18 AM Male infertility Pathway Evaluate all males seeking medical help for fertility issues, including patients with abnormal semen parameters for urogenital abnormalities. A Evaluate for infertility after 6 months of attempted conception if the female partner is aged > 35 years. B As per AUA 2021 guidelines: Consider obtaining an evaluation of the male partner of couples with failed assisted reproductive technology cycles or recurrent ( 2) pregnancy losses. E Refer male patients with 1 abnormal semen parameters or presumed male infertility to a male reproductive specialist for a complete history, physical examination, and other tests when indicated. E Evaluation of female partner: As per EAU 2023 guidelines: Evaluate both partners simultaneously to categorize the cause of infertility. A Obtain parallel evaluation of the fertility status of the female partner, including assessment of the ovarian reserve, in the diagnosis and management of male infertility to help decision- making in terms of timing and therapeutic strategies (such as assisted reproductive technology versus surgical intervention). A As per AUA 2021 guidelines, obtain concurrent evaluation of both male and female partners in the initial evaluation of infertility. E 2. Diagnostic investigations History and physical examination: As per EAU 2023 guidelines, elicit a complete medical history and perform a physical examination in the evaluation of male patients with infertility. A Show 2 more As per AUA 2021 guidelines: Elicit a reproductive history in the initial evaluation for male infertility. B Perform a physical examination and assess the semen volume to help differentiate genital tract obstruction from impaired sperm production in patients with azoospermia. E Semen analysis: As per EAU 2023 guidelines: Obtain SA in the initial evaluation of male infertility. Obtain semen analyses according to the most recent WHO Laboratory Manual for the Examination and Processing of Human Semen indications and reference criteria. A Obtain a full andrological assessment in all male patients with couple infertility, particularly when the SA is abnormal in at least two consecutive tests. A As per AUA 2021 guidelines, obtain 1 semen analyses in the initial evaluation of male infertility. B https://web.pathway.md/diseases/recRBJLnXAutKAXZN 2/11 6/29/23, 6:18 AM Male infertility Pathway Show 3 more Hormone testing: As per EAU 2023 guidelines: Obtain hormonal evaluation, including serum total testosterone and FSH/LH, in patients with oligozoospermia and azoospermia. B Obtain hormonal evaluation to investigate the underlying etiology and associated comorbidities in patients with non-obstructive azoospermia. A As per AUA 2021 guidelines: Obtain hormonal testing, including FSH and testosterone, in male patients with infertility and impaired libido, erectile dysfunction, oligozoospermia or azoospermia, atrophic testes, or evidence of hormonal abnormality on physical examination. E Measure FSH levels to help differentiate genital tract obstruction from impaired sperm production in patients with azoospermia. E Diagnostic imaging, scrotal ultrasound: As per EAU 2023 guidelines, obtain scrotal ultrasound in male patients with infertility because of the higher risk of testicular cancer. B As per ASRM/AUA 2021 guidelines, do not obtain routine scrotal in the initial evaluation of male infertility. D Diagnostic imaging, transrectal ultrasound: As per EAU 2023 guidelines, obtain transrectal ultrasound in patients with suspected partial or complete distal obstruction. A As per ASRM/AUA 2021 guidelines: Do not obtain routine transrectal ultrasound in the initial evaluation of male infertility. D Obtain transrectal ultrasound in patients with SA suggestive of ejaculatory duct obstruction (acidic, azoospermic, semen volume < 1.5 mL, with normal serum testosterone, palpable vas deferens). E Diagnostic imaging, renal and abdominal imaging: As per EAU 2023 guidelines, consider obtaining imaging for renal abnormalities in patients with structural abnormalities of the vas deferens and no evidence of CFTR abnormalities. B As per ASRM/AUA 2021 guidelines: Consider obtaining renal ultrasound for the evaluation of renal abnormalities in patients with vasal agenesis. E Do not obtain routine abdominal imaging for the sole indication of isolated small or moderate right varicocele. D Genetic testing, karyotyping: As per EAU 2023 guidelines: Obtain standard karyotype analysis and provide genetic counseling in all patients with azoospermia and oligozoospermia (spermatozoa < 10 million/mL). A https://web.pathway.md/diseases/recRBJLnXAutKAXZN 3/11 6/29/23, 6:18 AM Male infertility Pathway Provide genetic counseling in couples with genetic abnormalities before any assisted reproductive technology protocols. A As per ASRM/AUA 2021 guidelines: Obtain karyotype and Y-chromosome microdeletion analysis in male patients with primary infertility and: azoospermia severe oligozoospermia (< 5 million sperm/mL) with elevated FSH testicular atrophy a presumed diagnosis of impaired sperm production as the cause of azoospermia. E Obtain karyotype E and sperm deoxyRNA fragmentation testing in the male of couples with recurrent pregnancy losses. B Genetic testing, Y-chromosome microdeletion: As per EAU 2023 guidelines, do not obtain Y-chromosome microdeletion testing in patients with pure obstructive azoospermia, as spermatogenesis will be normal. D Show 2 more As per ASRM/AUA 2021 guidelines, obtain Y-chromosome microdeletion testing in male patients with primary infertility and azoospermia or severe oligozoospermia (< 5 million sperm/mL) with elevated FSH levels, testicular atrophy, or a presumed diagnosis of impaired sperm production as the cause of azoospermia. E Genetic testing, CFTR mutation: As per EAU 2023 guidelines, obtain CFTR gene mutation testing (including common point mutations and the 5T allele) in a male patient with structural abnormalities of the vas deferens (unilateral or bilateral absence with no renal agenesis) and his female partner. A As per ASRM/AUA 2021 guidelines: Obtain CFTR mutation carrier testing (including assessment of the 5T allele) in patients with vasal agenesis or idiopathic obstructive azoospermia. E Obtain genetic evaluation of the female partner if the male carries a CFTR mutation. E Genetic testing, sperm DNA fragmentation: As per EAU 2023 guidelines, obtain sperm deoxyRNA fragmentation testing in the evaluation of couples with recurrent pregnancy losses from natural conception and assisted reproductive technology or male patients with unexplained infertility. A As per ASRM/AUA 2021 guidelines: Do not obtain sperm deoxyRNA fragmentation testing in the initial evaluation of couple infertility. D Obtain sperm deoxyRNA fragmentation testing in the evaluation of couples with recurrent pregnancy losses. B Antisperm antibodies: do not obtain antisperm antibodies in the initial evaluation of male infertility. D https://web.pathway.md/diseases/recRBJLnXAutKAXZN 4/11 6/29/23, 6:18 AM Male infertility Pathway Reactive oxygen species testing: do not obtain reactive oxygen species testing in the diagnosis and management of the male partner with couple infertility. D 3. Diagnostic procedures Testicular biopsy: As per EAU 2023 guidelines, consider obtaining a multidisciplinary team discussion concerning invasive diagnostic modalities (such as US-guided testicular biopsy with frozen section versus radical orchidectomy versus surveillance) in male patients with infertility with ultrasound- detected indeterminate testicular lesions, especially in the presence of additional risk factors for malignancy. C As per AUA 2021 guidelines, do not perform a routine testicular biopsy to differentiate between obstructive and non-obstructive azoospermia. D 4. Medical management Hormonal therapy, general principles: As per EAU 2023 guidelines: Insufficient evidence to support the use of selective estrogen receptor modulators, steroidal (testolactone) or nonsteroidal (anastrozole and letrozole) aromatase inhibitors in male patients with idiopathic infertility. I Do not initiate routine medical therapy (including recombinant FSH, highly purified FSH, human chorionic gonadotrophin, aromatase inhibitors, and selective estrogen receptor modulators) before testicular sperm extraction in patients with non-obstructive azoospermia. D As per ASRM/AUA 2021 guidelines, inform patients with non-obstructive azoospermia of the limited data supporting pharmacologic treatment with selective estrogen receptor modulators, aromatase inhibitors, and gonadotropins before surgical intervention. B Show 2 more Hormonal therapy, FSH analogs: As per EAU 2023 guidelines, initiate FSH treatment in patients with idiopathic oligozoospermia and FSH values within the normal range to ameliorate spermatogenesis outcomes. Avoid using high-dose FSH in patients with idiopathic infertility and before (microdissection) testicular sperm extraction. B As per ASRM/AUA 2021 guidelines, consider initiating FSH analogs to improve sperm concentration, pregnancy rate, and live birth rate in male patients with idiopathic infertility. C Hormonal therapy, testosterone therapy: As per EAU 2023 guidelines, do not initiate testosterone therapy for the treatment of male infertility. D https://web.pathway.md/diseases/recRBJLnXAutKAXZN 5/11 6/29/23, 6:18 AM Male infertility Pathway As per ASRM/AUA 2021 guidelines, do not initiate testosterone monotherapy in male patients interested in current or future fertility. D Management of ejaculatory dysfunction: As per AUA 2021 guidelines, consider offering sympathomimetics and alkalinization of urine with or without urethral catheterization, induced ejaculation, or surgical sperm retrieval in patients with infertility associated with retrograde ejaculation. E As per ESSM 2021 guidelines, recognize that male partners of couples with infertility are at higher risk of reporting premature ejaculation. B Show 2 more Management of erectile dysfunction: recognize that male partners of couples with infertility are at higher risk of reporting erectile dysfunction, and a worse seminal profile is associated with more severe erectile dysfunction. B Show 2 more Treatment of active infections: Consider treating infections of accessory glands to improve sperm quality, although it does not necessarily improve the probability of increasing conception. C Refer sexual partners of patients with accessory gland infections known or suspected to be caused by sexually transmitted diseases for evaluation and treatment. A 5. Nonpharmacologic interventions Lifestyle changes: consider advising lifestyle changes, including weight loss, increased physical activity, smoking cessation, and alcohol intake reduction, to improve sperm quality and the chances of conception in male patients with idiopathic oligoasthenoteratozoospermia. C Dietary supplements: As per EAU 2023 guidelines, insufficient evidence to support the use of antioxidants for the treatment of patients with idiopathic infertility, although antioxidants may improve semen parameters. I As per AUA 2021 guidelines, insufficient evidence to support the use of supplements (such as antioxidants, vitamins) for the treatment of patients with male infertility. I 6. Therapeutic procedures Conservative sperm retrieval: consider offering induced ejaculation in patients with aspermia, including using sympathomimetics, vibratory stimulations, and electroejaculation depending on the patient's condition and clinician's experience. E Testicular sperm aspiration: avoid performing FNA and testicular sperm aspiration in patients with non-obstructive azoospermia given the lower probability of positive sperm retrieval compared to conventional testicular sperm extraction and microdissection testicular sperm extraction. D https://web.pathway.md/diseases/recRBJLnXAutKAXZN 6/11 6/29/23, 6:18 AM Male infertility Pathway Show 3 more Assisted reproductive technologies: consider offering assisted reproductive technologies in male patients with infertility. E Show 2 more 7. Surgical interventions Surgical sperm retrieval: As per EAU 2023 guidelines, consider offering surgical sperm retrieval in male patients eligible for assisted reproductive technology (intracytoplasmic sperm injection). Do not perform surgery in patients with complete AZFa and AZFb microdeletions. B Show 2 more As per AUA 2021 guidelines, consider performing surgical sperm retrieval in male patients with infertility and aspermia or azoospermia and ejaculatory duct obstruction. E Show 2 more Microsurgical vasoepididymostomy: As per EAU 2023 guidelines, perform microsurgical vasovasostomy or epididymovasostomy for azoospermia caused by epididymal or vasal obstruction in patients with female partners of good ovarian reserve. A As per AUA 2021 guidelines, consider performing microsurgical reconstruction to return sperm to the ejaculate in patients with vasal or epididymal obstructive azoospermia. E Transurethral resection of ejaculatory ducts: consider performing transurethral resection of ejaculatory ducts in patients with azoospermia and ejaculatory duct obstruction. E 8. Specific circumstances Patients with hypogonadotropic hypogonadism: As per EAU 2023 guidelines: Initiate combined hCG and FSH (recombinant FSH, highly purified FSH) or pulsed GnRH via pump therapy to stimulate spermatogenesis in patients with hypogonadotropic hypogonadism (secondary hypogonadism), including congenital causes. Induce spermatogenesis by effective medical therapy (hCG, human menopausal gonadotropins, recombinant FSH, highly purified FSH) in patients with hypogonadotropic hypogonadism. A Initiate testosterone therapy in symptomatic patients with primary or secondary hypogonadism not considering parenthood. A As per AUA 2021 guidelines, obtain evaluation for the etiology and treat accordingly in patients presenting with hypogonadotropic hypogonadism. B Patients with hyperprolactinemia: As per EAU 2023 guidelines, consider initiating dopamine agonist therapy to improve spermatogenesis in patients with hyperprolactinemia. C https://web.pathway.md/diseases/recRBJLnXAutKAXZN 7/11 6/29/23, 6:18 AM Male infertility Pathway As per AUA 2021 guidelines, obtain evaluation for the etiology and treat accordingly in patients with hyperprolactinemia. E Patients with varicocele: As per EAU 2023 guidelines, do not treat varicocele in patients with infertility and a normal SA or patients with subclinical varicocele. D Show 2 more As per AUA 2021 guidelines, consider performing surgical varicocelectomy in patients attempting to conceive and having palpable varicocele, infertility, and abnormal semen parameters, except for patients with azoospermia. C Show 2 more Patients with cryptorchidism: As per EAU 2023 guidelines, do not use hormonal treatment for cryptorchidism in postpubertal patients. D Show 3 more As per CUA 2017 guidelines: Consider performing orchiectomy in < 50 years old postpubertal patients with hypotrophic/atrophic undescended testicles. Consider offering observation in patients aged > 50 years. C Offer orchiectomy in patients with unilateral intra-abdominal or inguinal hypotrophic testes identified after puberty. B As per AUA 2014 guidelines, consider performing orchiectomy in patients with a normal contralateral testis meeting 1 of the following criteria: very short testicular vessels and vas deferens dysmorphic or very hypoplastic affected testis postpubertal age. C Patients with testicular microcalcification: do not obtain follow-up scrotal ultrasound, abdominal or pelvic CT, biochemical tumor markers, or testicular biopsy in patients with isolated testicular microcalcification without associated risk factors (such as infertility, cryptorchidism, testicular cancer, or atrophic testis). D Show 3 more Patients with testicular cancer: As per EAU 2023 guidelines, manage patients treated for testicular germ cell tumors in a multidisciplinary team setting with a dedicated late-effects clinic since they are at increased risk of developing hypogonadism, sexual dysfunction, and cardiovascular risk. B Show 2 more As per EAU 2023 guidelines, discuss the option of sperm banking with all patients before initiating treatment for testicular cancer. A As per ESMO 2022 guidelines, obtain SA and offer sperm cryopreservation in all patients with testicular cancer, preferably before orchiectomy. B https://web.pathway.md/diseases/recRBJLnXAutKAXZN 8/11 6/29/23, 6:18 AM Male infertility Pathway As per AUA 2019 guidelines, counsel patients about the risks of hypogonadism and infertility before definitive management for testicular cancer B and offer sperm banking when appropriate. Consider offering sperm banking before orchiectomy in patients without a normal contralateral testis or with known subfertility. B Patients after vasectomy: counsel couples desiring conception after vasectomy that surgical reconstruction, surgical sperm retrieval, or both reconstruction and simultaneous sperm retrieval for cryopreservation are viable options. B 9. Patient education General counseling: As per EAU 2023 guidelines, counsel male patients with infertility or abnormal semen parameters of the associated health risks. B As per AUA 2021 guidelines, counsel male patients with infertility or abnormal semen parameters on the health risks associated with abnormal sperm production. B Show 3 more Genetic counseling: provide genetic counseling in all couples with a genetic abnormality identified on clinical or genetic evaluation and in patients with a (potential) inheritable disease. Provide genetic counseling in couples with genetic abnormalities before any assisted reproductive technology protocols. A Clinical findings Symptoms Past medical history Anejaculation Cryptorchidism Decreased libido Cystic fibrosis Erectile dysfunction Disorders of sexual development Inability to conceive Epididymitis Retrograde ejaculation Hyperprolactinemia Semen volume Hypogonadotropic hypogonadism Past surgical history Klinefelter syndrome Vasectomy Obesity Orchitis Lab findings Pelvic radiation therapy Asthenozoospermia Prader-willi syndrome Azoospermia Sexually transmitted diseases Oligozoospermia Testicular cancer Teratozoospermia Varicocele serum testosterone https://web.pathway.md/diseases/recRBJLnXAutKAXZN 9/11 6/29/23, 6:18 AM Male infertility Pathway sperm concentration Genitourinary exam Imaging findings Testicular atrophy Testicular enlargement Testicular microlithiasis Serological findings anti-sperm antibodies Genetic testing Azf microdeletions References 1. A. 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