Diagnosis and Treatment of Infertility in Men: JAMA Clinical Guidelines Synopsis

The guideline was jointly developed by the AUA and ASRM and funded by the AUA. It was written by a volunteer development panel of 15 individuals with expertise in urology, male infertility, primary care, laboratory medicine, reproductive endocrinology, and public health, with representation from patient-based organizations.

An Emergency Care Research Institute Evidence-based Practice Center team evaluated observational studies, randomized clinical trials (RCTs), and meta-analyses to provide an evidence base for the guideline. Initial guideline statements support basic screening of both male and female partners, with detailed evaluation (endocrine, genetic) of men with 1 or more abnormal semen parameters, or for couples with failed assisted reproductive technology (ART) cycles or recurrent pregnancy losses. They noted consistent associations between abnormal semen parameters and conditions such as testicular cancer, cystic fibrosis, and Klinefelter syndrome. Associations between infertility and other conditions (such as diabetes, hypothyroidism, elevated prolactin, and multiple sclerosis) have been suggested in some studies.

The guideline emphasizes the potential harms of exogenous testosterone on male fertility due to possible azoospermia after negative feedback on the hypothalamus and pituitary, citing a multicenter trial of testosterone enanthate formale contraception, which resulted in at least oligospermia (or azoospermia) in 97.8% of participants. Multiple guideline statements address the gonadotoxic effects of cancer treatments, such as chemotherapy and radiation therapy, referencing a series of observational studies finding decline in semen parameters, often to the point of azoospermia, within months of initiating these therapies.

Surgery-related guideline statements address the role of varicocelectomy, microdissection testicular sperm extraction (microTESE), and vasectomy reversal in managing male infertility. The guideline cites a meta-analysis that included both RCTs and observational studies and demonstrated approximately 35% and 42% pregnancy rates after inguinal and subinguinal microsurgical varicocelectomy, respectively, vs 17% without intervention. Similarly, when considering men with nonobstructive azoospermia (NOA), the guideline references a meta-analysis that was based mostly on observational studies demonstrating a 1.5-fold higher chance of sperm retrieval with microTESE vs conventional nonmicrosurgical testicular sperm extraction (cTESE) (52% vs 35%; odds ratio, 1.5). Testicular sperm aspiration was less successful than cTESE.

The guideline prioritizes treating causes of male factor infertility when possible, while minimizing the harm from invasive procedures. Interventions such as subinguinal microsurgical varicocelectomy can improve spontaneous pregnancy rates from 13.9% to 32.9%. However, this procedure has potential risks including injury to the testicle that could jeopardize spermatogenesis and testosterone production. The guideline recommends that men with clinically palpable varicoceles, infertility, and semen parameter abnormalities (except azoospermia) are most likely to benefit from correction. By contrast, the guidelines recommend against surgical correction of varicoceles detected only on imaging studies (nonpalpable "subclinical varicoceles"), given the lack of demonstrable clinical benefit in semen parameters or pregnancy rates.

Sperm extraction in the setting of nonobstructive azoospermia can potentially lead to hematoma, infection, testicular fibrosis and atrophy, or long-term hypogonadism. To attain the best retrieval rates and minimize the risk of these sequelae, the guideline recommends microTESE for men with NOA instead of cTESE or percutaneous approaches, with 1 study suggesting only 3% of men develop chronic fibrosis with microTESE vs 30% of men with cTESE.

The guideline also notes that male factor infertility may be managed using ART (eg, in vitro fertilization). While this may be an effective and expeditious therapeutic approach for some couples, this treatment strategy may result in greater morbidity (eg, ovarian hyperstimulation) in the female partner– vs male partner–directed therapies that may be similarly efficacious. Moreover, ART for male factor infertility is often associated with significantly greater costs vs treatment involving lifestyle modification or simpler medical and surgical approaches.

This first guideline on male infertility appropriately stresses the importance of both male and female partner evaluation for all couples attempting to conceive. Given the high prevalence of male factor infertility, and its less frequent evaluation, it is important for all male partners to undergo timely evaluation. A useful appendix describes physical examination findings potentially relevant to male reproductive health.

The guideline raises awareness regarding the broad health implications of male infertility. Paternal age is mentioned as a risk factor for adverse health outcomes in offspring, and it likely impacts fertility as well. Additionally, the discussion of oncofertility provides specific time intervals for deferring conception after treatment and obtaining initial semen analysis after therapy. While these statements are predominantly based on expert opinion and older observational studies, they provide important new guidance for men undergoing gonadotoxic therapies.

Additional research is needed in reproductive genetics, specifically to further identify and characterize the wide array of genetic causes of infertility. This will be challenging for multiple reasons. Many genetic anomalies can affect reproductive system development and function, and thus impair reproductive potential. Moreover, given the broad range of genes involved in sperm production, it is not surprising for male infertility to be associated with other health issues, including immune and metabolic disorders, as well as malignancy. The potential role of germline gene therapy is also controversial and can pose ethical concerns, including that genome editing can cause unintended, potentially deleterious off-target" effects, that is, unintended cleavage and mutations targeted genomic sites similar to the target site.

MAJOR RECOMMENDATIONS

• Semen analysis should guide management, and clinicians should obtain hormonal evaluation including follicle-stimulating hormone and testosterone for men with impaired libido, erectile dysfunction, oligozoospermia (<15 million sperm/mL) or azoospermia, atrophic testes, or evidence of hormonal abnormality on physical evaluation
• Infertile men and men with abnormal semen parameters should be advised of the relevant, associated health risks and conditions
• Surgical correction of palpable varicocele(s) should be considered for infertile men with sperm in the ejaculate and abnormal semen parameters
• For men with nonobstructive azoospermia who are undergoing sperm retrieval, microdissection testicular sperm extraction should be performed
• Men should be informed about the adverse effects of cancer treatments (chemotherapy, radiation therapy, surgery) on fertility and offered sperm cryopreservation before initiation of these therapies
• Testosterone monotherapy should not be prescribed for men interested in current or future fertility, but other therapies (aromatase inhibitors, human chorionic gonadotropin, selective estrogen receptor modulators) can be used in these men to treat low testosterone