madman
Super Moderator
Purpose
In 2023 the American Urological Association (AUA) requested an Update Literature Review (ULR) to incorporate new evidence generated since the2020 publication of this Guideline. The resulting 2024 Guideline Amendment addresses updated recommendations to provide guidance on the appropriate evaluation and management of the male partner in an infertile couple.
Materials and Methods
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. An updated literature search identified 4093 new abstracts. Following initial abstract screening, 125 eligible study abstracts met inclusion criteria. On data extraction,22 studies of interest were included in the final evidence base to inform the Guideline amendment.
Results
The Panel developed evidence- and consensus-based statements based on an updated review to provide guidance on evaluation and management of male infertility. These updates are detailed herein.
Conclusions
This update provides several new insights, including revised thresholds for Y-chromosome microdeletion testing, indications for pelvic MRI imaging in infertile males, and guidance regarding the use of testicular sperm in non azoospermic males. This Guideline will require further review as the diagnostic and treatment options in this space continue to evolve.
BACKGROUND
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 determine the management of the patient and the couple. Without an adequate male partner workup, the female partner may pursue unnecessary costly, time-consuming, and invasive treatment options.
Male infertility is typically diagnosed by one or more factors that may include abnormal semen quality or sperm functional parameters; anatomical, endocrine, genetic, functional, or immunological abnormalities of the male reproductive system; or sexual conditions incompatible with the ability to deposit semen in the vagina.
The common terms of semen analysis (SA) have been defined in Table 1.1,2 A summary of diagnostic and treatment recommendations are found in the Algorithm (Figure).
GUIDELINE STATEMENTS
Assessment
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 during initial evaluation of the male. (Strong Recommendation; Evidence Level: Grade B)
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)
In couples with failed assisted reproductive technology cycles or recurrent pregnancy losses (two or more), clinicians should evaluate the male partner. (Moderate Recommendation; Evidence Level: Grade C)
Lifestyle Factors and Relationships Between Infertility and General Health
Clinicians may discuss risk factors (ie, 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 and Evaluation
Clinicians should initially evaluate azoospermic males with physical exam, semen volume, semen pH, and serum follicle-stimulating hormone (FSH) levels to differentiate genital tract obstruction from impaired sperm production. (Expert Opinion)
Clinicians should recommend karyotype testing for males with primary infertility and azoospermia or sperm concentration < 5 million sperm/mL when accompanied by elevated FSH, testicular atrophy, or a diagnosis of impaired sperm production. (Expert Opinion)
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 FSH, testicular atrophy, ora diagnosis of impaired sperm production.(Moderate Recommendation; Evidence Level: Grade B)
Imaging
Clinicians should not routinely perform scrotal ultrasound in the initial evaluation of the infertile male. (Expert Opinion)
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 SA suggestive of ejaculatory duct obstruction (EDO) (ie, acidic, azoospermic semen with volume < 1.4 mL, with normal serum T, palpable vas deferens). (Expert Opinion)
Sperm Retrieval
For males with non-obstructive azoospermia undergoing sperm retrieval, clinicians should perform a micro-TESE. (Moderate Recommendation; Evidence Level: Grade C)
In males undergoing surgical sperm retrieval by a clinician, intracytoplasmic sperm injection may be performed with freshor cryopreserved sperm. (Conditional Recommendation; Evidence Level: Grade C)
Clinicians may consider the utilization of testicular sperm in non azoospermic males with an elevated sperm DNA Fragmentation Index (DFI). (Clinical Principle)
Clinicians may treat infertility associated with retrograde ejaculation with sympathomimetics (with or without alkalinization and/or urethral catheterization), induced ejaculation,or surgical sperm retrieval. (Expert Opinion)
Obstructive Azoospermia, Including Post Vasectomy Infertility
For infertile males with ejaculatory duct obstruction (EDO), clinicians may consider transurethral resection of ejaculatory ducts (TURED) and/or surgical sperm extraction. (Expert Opinion)
Medical and Nutraceutical Interventions for Fertility
Clinicians may manage male infertility with assisted reproductive technologies. (Expert Opinion)
In a patient presenting with hypogonadotropic hypogonadism, clinicians should evaluate the patient to determine the etiology of the disorder and treat based on diagnosis. (Clinical Principle)
For the male interested in current or future fertility, clinicians should not prescribe exogenous testosterone therapy. (Clinical Principle).
Exogenous testosterone administration provides negative feedback to the hypothalamus and pituitary gland, which can result in inhibition of gonadotropin secretion. Depending on the degree of testosterone-induced suppression, spermatogenesis may decrease or cease altogether, resulting in oligospermia or azoospermia.42 Although recovery of sperm to the ejaculate occurs in most azoospermic males after cessation of testosterone therapy, the time course of recovery may be prolonged and can be months or rarely years.43 Therefore, exogenous testosterone therapy should be avoided in males pursuing or planning to pursue family building in the near future. In those that may want to pursue paternity in the more distant future, testosterone therapy may be offered, but the patient should be counseled about testosterone’s inhibitory effects on spermatogenesis and the time course required for resumption of spermatogenesis after cessation. In those wanting to pursue paternity in the more distant future (soonest 6-12 months), some small studies have demonstrated preservation of spermatogenesis by adding hCG alone or combination therapy (hCG, and/or selective estrogen receptor modulate [SERM], and/or recombinant FSH) to exogenous testosterone, but the literature is too limited to recommend this approach. If a patient decides to proceed with exogenous testosterone therapy alone, then he must be counseled about the potential negative effects on spermatogenesis and the time course (and treatments) required for resumption of spermatogenesis. Some males, despite cessation of testosterone therapy, never fully recover sperm production and may remain either infertile or sub-fertile and may therefore require future fertility treatments.44,45
In data from 2 studies, use of a short-acting, nasal testosterone formulation was associated with preserved spermatogenesis.46,47 While additional studies are needed to assess long-term reproductive outcomes, including semen parameters and fecundity, the early and short-term outcomes for this modality merit further study. However, given the lack of long-term data, this agent, like other forms of exogenous testosterone, should not be routinely used by males attempting to conceive. For further information, please refer to the AUA Guideline on the Evaluation and Management of Testosterone Deficiency, Statement 16: https://www.auanet.org/guidelines-and-quality/guidelines/testosteronedeficiency-guideline
Clinicians should counsel patients that the benefits of supplements (eg, 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)
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
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)
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)
FUTURE DIRECTIONS
The genomic revolution has placed us at the forefront of vastly improving our diagnostic abilities to define precise etiologies, comorbidities, and eventually (perhaps) develop medically-based treatments for infertile males to improve not only their fertility potential, but also their overall health.
The impact of certain lifestyles and behaviors remains relatively unknown. For example, vaping and cannabis use are highly prevalent among young adults, but the short- and long-term effects of these agents on reproductive health remain unclear.59-62 While obesity and metabolic syndrome can impair male fertility via numerous pathophysiological mechanisms, the ability to restore reproductive potential through weight loss and enhanced metabolic health remains understudied. The emergence of the agonists of glucagon-like peptide-1 receptors class of drugs are proving to be highly efficacious in treating obesity and type 2 diabetes; the effect of these therapies on reproductive health remains to be determined. Translation of the newer advances discussed above will be slower but will eventually move from the laboratory to the clinical arena to provide more therapeutic options for males. The future looks promising for improving the health and fertility of the infertile male through precision medicine and the application of advanced technologies.
In 2023 the American Urological Association (AUA) requested an Update Literature Review (ULR) to incorporate new evidence generated since the2020 publication of this Guideline. The resulting 2024 Guideline Amendment addresses updated recommendations to provide guidance on the appropriate evaluation and management of the male partner in an infertile couple.
Materials and Methods
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. An updated literature search identified 4093 new abstracts. Following initial abstract screening, 125 eligible study abstracts met inclusion criteria. On data extraction,22 studies of interest were included in the final evidence base to inform the Guideline amendment.
Results
The Panel developed evidence- and consensus-based statements based on an updated review to provide guidance on evaluation and management of male infertility. These updates are detailed herein.
Conclusions
This update provides several new insights, including revised thresholds for Y-chromosome microdeletion testing, indications for pelvic MRI imaging in infertile males, and guidance regarding the use of testicular sperm in non azoospermic males. This Guideline will require further review as the diagnostic and treatment options in this space continue to evolve.
BACKGROUND
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 determine the management of the patient and the couple. Without an adequate male partner workup, the female partner may pursue unnecessary costly, time-consuming, and invasive treatment options.
Male infertility is typically diagnosed by one or more factors that may include abnormal semen quality or sperm functional parameters; anatomical, endocrine, genetic, functional, or immunological abnormalities of the male reproductive system; or sexual conditions incompatible with the ability to deposit semen in the vagina.
The common terms of semen analysis (SA) have been defined in Table 1.1,2 A summary of diagnostic and treatment recommendations are found in the Algorithm (Figure).
GUIDELINE STATEMENTS
Assessment
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 during initial evaluation of the male. (Strong Recommendation; Evidence Level: Grade B)
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)
In couples with failed assisted reproductive technology cycles or recurrent pregnancy losses (two or more), clinicians should evaluate the male partner. (Moderate Recommendation; Evidence Level: Grade C)
Lifestyle Factors and Relationships Between Infertility and General Health
Clinicians may discuss risk factors (ie, 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 and Evaluation
Clinicians should initially evaluate azoospermic males with physical exam, semen volume, semen pH, and serum follicle-stimulating hormone (FSH) levels to differentiate genital tract obstruction from impaired sperm production. (Expert Opinion)
Clinicians should recommend karyotype testing for males with primary infertility and azoospermia or sperm concentration < 5 million sperm/mL when accompanied by elevated FSH, testicular atrophy, or a diagnosis of impaired sperm production. (Expert Opinion)
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 FSH, testicular atrophy, ora diagnosis of impaired sperm production.(Moderate Recommendation; Evidence Level: Grade B)
Imaging
Clinicians should not routinely perform scrotal ultrasound in the initial evaluation of the infertile male. (Expert Opinion)
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 SA suggestive of ejaculatory duct obstruction (EDO) (ie, acidic, azoospermic semen with volume < 1.4 mL, with normal serum T, palpable vas deferens). (Expert Opinion)
Sperm Retrieval
For males with non-obstructive azoospermia undergoing sperm retrieval, clinicians should perform a micro-TESE. (Moderate Recommendation; Evidence Level: Grade C)
In males undergoing surgical sperm retrieval by a clinician, intracytoplasmic sperm injection may be performed with freshor cryopreserved sperm. (Conditional Recommendation; Evidence Level: Grade C)
Clinicians may consider the utilization of testicular sperm in non azoospermic males with an elevated sperm DNA Fragmentation Index (DFI). (Clinical Principle)
Clinicians may treat infertility associated with retrograde ejaculation with sympathomimetics (with or without alkalinization and/or urethral catheterization), induced ejaculation,or surgical sperm retrieval. (Expert Opinion)
Obstructive Azoospermia, Including Post Vasectomy Infertility
For infertile males with ejaculatory duct obstruction (EDO), clinicians may consider transurethral resection of ejaculatory ducts (TURED) and/or surgical sperm extraction. (Expert Opinion)
Medical and Nutraceutical Interventions for Fertility
Clinicians may manage male infertility with assisted reproductive technologies. (Expert Opinion)
In a patient presenting with hypogonadotropic hypogonadism, clinicians should evaluate the patient to determine the etiology of the disorder and treat based on diagnosis. (Clinical Principle)
For the male interested in current or future fertility, clinicians should not prescribe exogenous testosterone therapy. (Clinical Principle).
Exogenous testosterone administration provides negative feedback to the hypothalamus and pituitary gland, which can result in inhibition of gonadotropin secretion. Depending on the degree of testosterone-induced suppression, spermatogenesis may decrease or cease altogether, resulting in oligospermia or azoospermia.42 Although recovery of sperm to the ejaculate occurs in most azoospermic males after cessation of testosterone therapy, the time course of recovery may be prolonged and can be months or rarely years.43 Therefore, exogenous testosterone therapy should be avoided in males pursuing or planning to pursue family building in the near future. In those that may want to pursue paternity in the more distant future, testosterone therapy may be offered, but the patient should be counseled about testosterone’s inhibitory effects on spermatogenesis and the time course required for resumption of spermatogenesis after cessation. In those wanting to pursue paternity in the more distant future (soonest 6-12 months), some small studies have demonstrated preservation of spermatogenesis by adding hCG alone or combination therapy (hCG, and/or selective estrogen receptor modulate [SERM], and/or recombinant FSH) to exogenous testosterone, but the literature is too limited to recommend this approach. If a patient decides to proceed with exogenous testosterone therapy alone, then he must be counseled about the potential negative effects on spermatogenesis and the time course (and treatments) required for resumption of spermatogenesis. Some males, despite cessation of testosterone therapy, never fully recover sperm production and may remain either infertile or sub-fertile and may therefore require future fertility treatments.44,45
In data from 2 studies, use of a short-acting, nasal testosterone formulation was associated with preserved spermatogenesis.46,47 While additional studies are needed to assess long-term reproductive outcomes, including semen parameters and fecundity, the early and short-term outcomes for this modality merit further study. However, given the lack of long-term data, this agent, like other forms of exogenous testosterone, should not be routinely used by males attempting to conceive. For further information, please refer to the AUA Guideline on the Evaluation and Management of Testosterone Deficiency, Statement 16: https://www.auanet.org/guidelines-and-quality/guidelines/testosteronedeficiency-guideline
Clinicians should counsel patients that the benefits of supplements (eg, 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)
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
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)
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)
FUTURE DIRECTIONS
The genomic revolution has placed us at the forefront of vastly improving our diagnostic abilities to define precise etiologies, comorbidities, and eventually (perhaps) develop medically-based treatments for infertile males to improve not only their fertility potential, but also their overall health.
The impact of certain lifestyles and behaviors remains relatively unknown. For example, vaping and cannabis use are highly prevalent among young adults, but the short- and long-term effects of these agents on reproductive health remain unclear.59-62 While obesity and metabolic syndrome can impair male fertility via numerous pathophysiological mechanisms, the ability to restore reproductive potential through weight loss and enhanced metabolic health remains understudied. The emergence of the agonists of glucagon-like peptide-1 receptors class of drugs are proving to be highly efficacious in treating obesity and type 2 diabetes; the effect of these therapies on reproductive health remains to be determined. Translation of the newer advances discussed above will be slower but will eventually move from the laboratory to the clinical arena to provide more therapeutic options for males. The future looks promising for improving the health and fertility of the infertile male through precision medicine and the application of advanced technologies.
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