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Diagnosis and Treatment of Infertility in Men: AUA/ASRM Guideline

SUMMARY

Purpose
Infertility is due in whole or in part to the male in approximately one-half of all infertile couples. Although many couples can achieve a pregnancy with– intrauterine insemination (IUI) and assisted reproductive technologies (ART) (in vitro fertilization [IVF] with or without intracytoplasmic sperm injection [ICSI]), evaluation of the male is important to most appropriately direct therapy. Some male factor conditions are treatable with medical or surgical therapy, and others may require donor sperm or adoption, if appropriate. Some conditions are life threatening, while others have health and genetic implications for the patient and potential offspring. A male evaluation is necessary to adequately design the management of the patient and the couple. Without an adequate male infertility workup, unnecessary costly, time-consuming, and invasive treatment might be pursued for the female partner.

The purpose of this Guideline is to outline the appropriate evaluation and management of the male partner in an infertile couple. Recommendations proceed from obtaining an appropriate history and physical exam (Appendix I), as well as diagnostic testing, where indicated. Medical therapies, surgical techniques, and use of IUI and ART are covered to allow for optimal patient management. Recommendations are based on a strict process of evaluation of published literature as discussed in the Methodology section. This process is based on the PICO question approach (Problem/Patient/Population, Intervention/Indicator, Comparison, and Outcome) as described in the Methodology section. In this Guideline, the term “male” is used to refer to biological or genetic men.

Methodology
The Emergency Care Research Institute (ECRI) Evidence-based Practice Center team searched PubMed®, EMBASE® (Excerpta Medica), and Medline from January 2000 through May 2019. An experienced medical librarian developed an individual search strategy for each individual key question using medical subject headings terms and key words appropriate for each question’s PICO framework. When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions. In 2023, the Male Infertility Guideline was updated through the AUA amendment process in which newly published literature is reviewed and integrated into previously published guidelines. ECRI’s medical research librarian conducted literature searches of EMBASE (Excerpta Medica)/Medline and PubMed (PreMedline) from May 30, 2019, through August 30, 2023, yielding 4,093 new abstracts. ECRI’s research analysts performed abstract screening and data extraction of 125 eligible study abstracts meeting inclusion criteria. There were 22 studies of interest that were included in the evidence base.

GUIDELINE STATEMENTS

Assessment

  1. For initial infertility evaluation, clinicians should initiate concurrent assessment of both male and female partners. (Expert Opinion)
  2. Clinicians should include a reproductive history during initial evaluation of the male for fertility. (Clinical Principle) Clinicians should also include one or more semen analyses (SAs) during initial evaluation of the male. (Strong Recommendation; Evidence Level: Grade B)
  3. Male reproductive experts should evaluate patients with a complete history and physical examination as well as other directed tests, when indicated by one or more abnormal semen parameters or presumed male infertility. (Expert Opinion)
  4. In couples with failed assisted reproductive technology cycles or recurrent pregnancy losses (RPL) (two or more), clinicians should evaluate the male partner. (Moderate Recommendation; Evidence Level: Grade C)

Lifestyle Factors and Relationships Between Infertility and General Health

  1. Clinicians should counsel infertile males or males with abnormal semen parameters on the health risks associated with abnormal sperm production. (Moderate Recommendation; Evidence Level: Grade B)
  2. For infertile males with specific, identifiable causes of male infertility, clinicians should inform the patient of relevant, associated health conditions. (Moderate Recommendation; Evidence Level: Grade B)
  3. Clinicians should advise couples with advanced paternal age (≥40) that there is an increased risk of adverse health outcomes for their offspring. (Expert Opinion)
  4. Clinicians may discuss risk factors (i.e., lifestyle, medication usage, environmental exposures, occupational exposures) associated with male infertility, and counsel the patients that the current data on the majority of risk factors are limited. (Conditional Recommendation; Evidence Level: Grade C)

Diagnosis/Assessment/Evaluation 

  1. Clinicians should use the results from the semen analysis to guide management of the patient. In general, results are of greatest clinical significance when multiple abnormalities are present. (Expert Opinion)
  2. Clinicians should obtain hormonal evaluation including follicle-stimulating hormone (FSH) and testosterone for infertile males with impaired libido, erectile dysfunction, oligozoospermia or azoospermia, atrophic testes, or evidence of hormonal abnormality on physical evaluation. (Expert Opinion)
  3. Clinicians should initially evaluate azoospermic males with physical exam, semen volume, semen pH, and serum follicle-stimulating hormone levels to differentiate genital tract obstruction from impaired sperm production. (Expert Opinion)
  4. Clinicians should recommend karyotype testing for males with primary infertility and azoospermia or sperm concentration <5 million sperm/mL when accompanied by elevated follicle-stimulating hormone, testicular atrophy, or a diagnosis of impaired sperm production. (Expert Opinion)
  5. Clinicians should recommend Y-chromosome microdeletion analysis for males with primary infertility and azoospermia or sperm concentration ≤1 million sperm/mL when accompanied by elevated follicle-stimulating hormone, testicular atrophy, or a diagnosis of impaired sperm production. (Moderate Recommendation; Evidence Level: Grade B)
  6. Clinicians should recommend Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutation carrier testing (including assessment of the 5T allele) in males with vasal agenesis or idiopathic obstructive azoospermia. (Expert Opinion)
  7. For males who harbor a CFTR mutation or have absence of the vas deferens (unilateral or bilateral), clinicians should recommend genetic evaluation of the female partner. (Expert Opinion)
  8. Clinicians should not recommend sperm deoxyribonucleic acid (DNA) fragmentation analysis in the initial evaluation of the infertile couple. (Moderate Recommendation; Evidence Level: Grade C)
  9. In males with increased round cells on semen analysis (>1million/mL), clinicians should evaluate the patient further to differentiate white blood cells (pyospermia) from germ cells. (Expert Opinion)
  10. In patients with pyospermia, clinicians should evaluate the patient for the presence of infection. (Clinical Principle)
  11. Clinicians should not perform antisperm antibody (ASA) testing in the initial evaluation of male infertility. (Expert Opinion)
  12. For couples with recurrent pregnancy loss, clinicians should evaluate the male partner with karyotype (Expert Opinion) and sperm DNA fragmentation. (Moderate Recommendation; Evidence Level: Grade C)
  13. Clinicians should not routinely perform diagnostic testicular biopsy to differentiate between obstructive azoospermia and non-obstructive azoospermia (NOA). (Expert Opinion)

Imaging

  1. Clinicians should not routinely perform scrotal ultrasound in the initial evaluation of the infertile male. (Expert Opinion)
  2. Clinicians should not perform transrectal ultrasonography (TRUS) or pelvic magnetic resonance imaging (MRI) as part of the initial evaluation of the infertile male. Clinicians may recommend TRUS or pelvic MRI in males with semen analysis suggestive of ejaculatory duct obstruction (EDO) (i.e., acidic, azoospermic semen with volume <1.4mL, with normal serum T, palpable vas deferens). (Expert Opinion)
  3. Clinicians should not routinely perform abdominal imaging for the sole indication of an isolated small or moderate right varicocele. (Expert Opinion)
  4. Clinicians should recommend renal ultrasonography for patients with vasal agenesis to evaluate for renal abnormalities. (Expert Opinion)

Treatment

Varicocele Repair/Varicocelectomy

  1. Clinicians should consider surgical varicocelectomy in males attempting to conceive who have palpable varicocele(s), infertility, and abnormal semen parameters, except for azoospermic males. (Moderate Recommendation; Evidence Level: Grade B)
  2. Clinicians should not recommend varicocelectomy for males with non-palpable varicoceles detected solely by imaging. (Strong Recommendation; Evidence Level: Grade C)
  3. For males with clinical varicocele and non-obstructive azoospermia, clinicians should inform couples of the absence of definitive evidence supporting varicocele repair prior to surgical sperm retrieval with assisted reproductive technologies. (Expert Opinion)

Sperm Retrieval

  1. For males with non-obstructive azoospermia undergoing sperm retrieval, clinicians should perform a microdissection testicular sperm extraction (micro-TESE). (Moderate Recommendation; Evidence Level: Grade C)
  2. In males undergoing surgical sperm retrieval by a clinician, intracytoplasmic sperm injection may be performed with fresh or cryopreserved sperm. (Conditional Recommendation; Evidence Level: Grade C)
  3. In males with azoospermia due to obstruction undergoing surgical sperm retrieval, clinicians may extract sperm from either the testis or the epididymis. (Conditional Recommendation; Evidence Level: Grade C)
  4. Clinicians may consider the utilization of testicular sperm in nonazoospermic males with an elevated sperm DNA Fragmentation Index (DFI). (Clinical Principle)
  5. For males with aspermia, clinicians may perform surgical sperm extraction or induced ejaculation (sympathomimetics, vibratory stimulation or electroejaculation) depending on the patient’s condition and clinician’s experience. (Expert Opinion)
  6. Clinicians may treat infertility associated with retrograde ejaculation (RE) with sympathomimetics (with or without alkalinization and/or urethral catheterization), induced ejaculation, or surgical sperm retrieval. (Expert Opinion)

Obstructive Azoospermia, Including Post-Vasectomy Infertility

  1. Clinicians should counsel couples desiring conception after vasectomy that surgical reconstruction, surgical sperm retrieval, or both reconstruction and simultaneous sperm retrieval for cryopreservation are viable options. (Moderate Recommendation; Evidence Level: Grade C)
  2. Clinicians should counsel males with vasal or epididymal obstructive azoospermia that microsurgical reconstruction may be successful in returning sperm to the ejaculate. (Expert Opinion)
  3. For infertile males with ejaculatory duct obstruction, clinicians may consider transurethral resection of ejaculatory ducts (TURED) and/or surgical sperm extraction. (Expert Opinion)

Medical and Nutraceutical Interventions for Fertility

  1. Clinicians may manage male infertility with assisted reproductive technology. (Expert Opinion)
  2. Clinicians may advise an infertile couple with a low total motile sperm count on repeated semen analyses that intrauterine insemination success rates may be reduced, and treatment with assisted reproductive technology (in vitro fertilization/intracytoplasmic sperm injection) may be considered. (Expert Opinion)
  3. In a patient presenting with hypogonadotropic hypogonadism (HH), clinicians should evaluate the patient to determine the etiology of the disorder and treat based on diagnosis. (Clinical Principle)
  4. Clinicians may use aromatase inhibitors (AIs), human chorionic gonadotropin (hCG), selective estrogen receptor modulators (SERMs), or a combination thereof for infertile males with low serum testosterone. (Conditional Recommendation; Evidence Level: Grade C)
  5. For the male interested in current or future fertility, clinicians should not prescribe exogenous testosterone therapy. (Clinical Principle)
  6. For the infertile male with hyperprolactinemia, clinicians should evaluate the patient for the etiology and treat accordingly. (Expert Opinion)
  7. Clinicians should inform the male with idiopathic infertility that the use of selective estrogen receptor modulators has limited benefits relative to results of assisted reproductive technology. (Expert Opinion)
  8. Clinicians should counsel patients that the benefits of supplements (e.g., antioxidants, vitamins) are of questionable clinical utility in treating male infertility. Existing data are inadequate to provide recommendation for specific agents to use for this purpose. (Moderate Recommendation; Evidence Level: Grade B)
  9. For males with idiopathic infertility, clinicians may consider treatment using a follicle-stimulating hormone analogue with the aim of improving sperm concentration, pregnancy rate, and live birth rate. (Conditional Recommendation; Evidence Level: Grade B)
  10. In patients with non-obstructive azoospermia, clinicians may inform the patient of the limited data supporting pharmacologic manipulation with selective estrogen receptor modulators, aromatase inhibitors, and gonadotropins prior to surgical intervention. (Conditional Recommendation; Evidence Level: Grade C)

Gonadotoxic Therapies and Fertility Preservation

  1. Clinicians should discuss the effects of gonadotoxic therapies and other cancer treatments on sperm production with patients prior to commencement of therapy. (Moderate Recommendation: Evidence Level: Grade C)
  2. Clinicians should inform patients undergoing chemotherapy and/or radiation therapy to avoid initiating a pregnancy for a period of at least 12 months after completion of treatment. (Expert Opinion)
  3. Clinicians should encourage males to bank sperm, preferably multiple specimens when possible, prior to commencement of gonadotoxic therapy or other cancer treatment that may affect fertility in males. (Expert Opinion)
  4. Clinicians may inform patients that a semen analysis should be performed at least 12 months (and preferably 24 months) after completion of gonadotoxic therapies. (Conditional Recommendation; Evidence Level: Grade C)
  5. Clinicians should inform patients undergoing a retroperitoneal lymph node dissection (RPLND) of the risk of aspermia or retrograde ejaculation. (Clinical Principle)
  6. Clinicians should obtain a post-orgasmic urinalysis for males with aspermia after retroperitoneal lymph node dissection and reduced volume ejaculate who are interested in fertility. (Clinical Principle)
  7. Clinicians should inform males seeking paternity who are persistently azoospermic after gonadotoxic therapies that microdissection testicular sperm extraction is a treatment option. (Strong Recommendation; Evidence Level: Grade B)



Brannigan RE, Hermanson L, Kaczmarek J, Kim SK, Kirkby E, Tanrikut C. Updates to male infertility: AUA/ASRM guideline (2024). J Urol. Published online August 15, 2024. doi:10.1097/JU.0000000000004180. https://www.auajournals.org/doi/10.1097/JU.0000000000004180

The Journal of urology. 2020 Dec 09 [Epub]

Panel Members
Peter N. Schlegel, MD; Mark Sigman, MD; Barbara Collura; Christopher J. De Jonge, PhD; Michael L. Eisenberg, MD; Dolores J. Lamb, PhD; John P. Mulhall, MD; Craig Niederberger MD; Jay I. Sandlow, MD; Rebecca Z. Sokol, MD, MPH; Steven D. Spandorfer, MD; Cigdem Tanrikut, MD; Armand Zini, MD

Amendment Panel
Robert E. Brannigan, MD; Cigdem Tanrikut, MD

Staff and Consultants
Sennett K. Kim; Erin Kirkby, MS; Linnea Hermanson, MA; Janice Kaczmarek, MS; Jeffrey T. Oristaglio, PhD; Jonathan R. Treadwell, PhD

Published 2020; Amended 2024

Unabridged version of this Guideline [pdf]
Guideline Amendment Summary [pdf]
Algorithm associated with this Guideline [pdf]

Related Content: Updates to Male Infertility: AUA/ASRM Guideline (2024)
Diagnosis and Treatment of Infertility in Men: AUA/ASRM Guideline PART I
Diagnosis and Treatment of Infertility in Men: AUA/ASRM Guideline PART II