Clinical Review & Education
JAMA Clinical Guidelines Synopsis
Diagnosis and Treatment of Infertility in Men
Joshua A. Halpern, ME, MS; Andrew M. Davis, MD, MPH; Robert E. Brannigan, MD
GUIDELINE TITLE Diagnosis and Treatment of Infertility in
Men: AUA/ASRM Guideline, Parts I and II
RELEASE DATE January 2021
DEVELOPER AND FUNDING SOURCE American Urological
Association (AUA) and American Society for Reproductive
Medicine (ASRM)
TARGET POPULATION Individual men or couples with
potentially impaired reproductive potential
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 (expert opinion)
• Infertile men and men with abnormal semen parameters
should be advised of the relevant, associated health risks
and conditions (moderate recommendation [MR], level
of evidence [LOE]: B)
• Surgical correction of palpable varicocele(s) should be
considered for infertile men with sperm in the ejaculate
and abnormal semen parameters (MR, LOE: B)
• For men with nonobstructive azoospermia who are
undergoing sperm retrieval, microdissection testicular
sperm extraction should be performed (MC, LOE: C)
• 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 (MR, LOE: C)
• 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
(conditional recommendation, LOE: C)
Summary of the Clinical Problem
Infertility affects about 15% of couples and is due to a male factor
alone in 20% and combined male and female factors in 30% to 40%.1
In 25% of couples, no clear cause for infertility can be identified. This
guideline addresses the evaluation of male infertility, which can arise
from a wide array of conditions, and discusses issues that may affect
infertility treatment or the health of the patient and offspring.
Characteristics of the Guideline Source
The guideline was jointly developed by the AUA and ASRM and
funded by the AUA. It was written by a volunteer development panel
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of 15 individuals with expertise in urology, male infertility, primary
care, laboratory medicine, reproductive endocrinology, and public
health, with representation from patient-based organizations
(Table).1,2 Panel members disclosed potential financial and nonfi-
nancial conflicts of interest.
Evidence Base
An Emergency Care Research Institute Evidence-based Practice Cen-
ter team evaluated observational studies, randomized clinical trials
(RCTs), and meta-analyses to provide an evidence base for the
guideline.1,2 Initial guideline statements support basic screening of
both male and female partners, with detailed evaluation (endo-
crine, genetic) of men with 1 or more abnormal semen parameters,
or for couples with failed assisted reproductive technology (ART)
cycles or recurrent pregnancy losses.1 They note consistent asso-
ciations between abnormal semen parameters and conditions such
as testicular cancer, cystic fibrosis, and Klinefelter syndrome. Asso-
ciations between infertility and other conditions (such as diabetes,
hypothyroidism, elevated prolactin, and multiple sclerosis) have been
suggested in some studies. These statements are based on retro-
spective and population-based cohort studies, and as such, they are
appropriately characterized as having a moderate evidence base.1
The guideline emphasizes the potential harms of exogenous tes-
tosterone on male fertility due to possible azoospermia after nega-
tive feedback on the hypothalamus and pituitary, citing a multi-
center trial of testosterone enanthate for male contraception, which
resulted in at least oligospermia (or azoospermia) in 97.8% of
participants.3 Multiple guideline statements address the gonado-
toxic effects of cancer treatments, such as chemotherapy and ra-
diation therapy, referencing a series of observational studies find-
ing decline in semen parameters, often to the point of azoospermia,
within months of initiating these therapies.4
Surgery-related guideline statements address the role of vari-
cocelectomy, microdissection testicular sperm extraction (micro-
TESE), and vasectomy reversal in managing male infertility. The
guideline cites a meta-analysis that included both RCTs and obser-
vational studies and demonstrated approximately 35% and 42%
pregnancy rates after inguinal and subinguinal microsurgical vari-
cocelectomy, respectively, vs 17% without intervention.5 Similarly,
Table. Guideline Rating
Standard Rating
Establishing transparency Good
Management of conflict of interest in the guideline development group Good
Guideline development group composition Good
Clinical practice guideline-systematic review intersection Fair
Establishing evidence foundations and rating strength for each Good
of the guideline recommendations
Articulation of recommendations Good
External review Good
Updating Fair
Implementation issues Fair
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 JAMA Clinical Guidelines Synopsis Clinical Review & Education

when considering men with nonobstructive azoospermia (NOA), Discussion

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
[95% CI, 1.4-1.6]). Testicular sperm aspiration was less successful
than cTESE.6
Benefits and Harms
The guideline prioritizes treating causes of male factor infertility when
possible, while minimizing the harm from invasive procedures. In-
terventions such as subinguinal microsurgical varicocelectomy can
improve spontaneous pregnancy rates from 13.9% to 32.9%.7 How-
ever, this procedure has potential risks including injury to the tes-
ticle that could jeopardize spermatogenesis and testosterone
production.2,5-8 The guideline recommends that men with clini-
cally palpable varicoceles, infertility, and semen parameter abnor-
malities (except azoospermia) are most likely to benefit from
correction.2 By contrast, the guidelines recommend against surgi-
cal correction of varicoceles detected only on imaging studies (non-
palpable “subclinical varicoceles”), given the lack of demonstrable
clinical benefit in semen parameters or pregnancy rates.
Sperm extraction in the setting of nonobstructive azoosper-
mia can potentially lead to hematoma, infection, testicular fibrosis
and atrophy, or long-term hypogonadism. To attain the best re-
trieval rates and minimize the risk of these sequelae, the guideline
recommends microTESE for men with NOA instead of cTESE or per-
cutaneous approaches,2 with 1 study suggesting only 3% of men de-
velop chronic fibrosis with microTESE vs 30% of men with cTESE.9
The guideline also notes that male factor infertility may be man-
aged using ART (eg, in vitro fertilization). While this may be an ef-
fective and expeditious therapeutic approach for some couples, this
treatment strategy may result in greater morbidity (eg, ovarian hy-
perstimulation) 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 impor-
tance of both male and female partner evaluation for all couples at-
tempting to conceive. Given the high prevalence of male factor infer-
tility,anditslessfrequentevaluation,itisimportantforallmalepartners
to undergo timely evaluation. A useful appendix describes physical ex-
amination findings potentially relevant to male reproductive health.1
The guideline raises awareness regarding the broad health im-
plications of male infertility. Statements 5 and 6 address the higher
rates of malignancy and possibly greater mortality in subfertile men,
although there is less discussion of the robust observational evi-
dence linking infertility and metabolic syndrome.1 Paternal age is
mentioned as a risk factor for adverse health outcomes in off-
spring, and it likely impacts fertility as well. Additionally, the discus-
sion of oncofertility provides specific time intervals for deferring con-
ception after treatment and obtaining initial semen analysis after
therapy. While these statements are predominantly based on ex-
pert opinion and older observational studies, they provide impor-
tant new guidance for men undergoing gonadotoxic therapies.
Areas in Need of Future Study or Ongoing Research
Additional research is needed in reproductive genetics, specifically to
further identify and characterize the wide array of genetic causes of in-
fertility. This will be challenging for multiple reasons. Many genetic
anomalies can affect reproductive system development and function,
and thus impair reproductive potential. To date, more than 3600 gene
abnormalities are associated with male infertility and another 3200
linkedwithgenitourinarybirthdefects.Moreover,giventhebroadrange
of genes involved in sperm production, it is not surprising for male in-
fertilitytobeassociatedwithotherhealthissues,includingimmuneand
metabolic disorders, as well as malignancy. The potential role of germ-
line gene therapy is also controversial and can pose ethical concerns,
including that genome editing can cause unintended, potentially del-
eterious“off-target”effects,thatis,unintendedcleavageandmutations
at untargeted genomic sites similar to the target site. Despite these ob-
stacles, promising research in novel therapeutics is underway, includ-
ing germ cell transplantation (NCT04452305) and techniques to
support in vitro spermatogenesis (NCT02972801).

ARTICLE INFORMATION
Author Affiliations: Department of Urology,
Northwestern University, Feinberg School of
Medicine, Chicago, Illinois (Halpern, Brannigan);
Section of General Internal Medicine, University of
Chicago Medicine, Chicago, Illinois (Davis).
Corresponding Author: Andrew M. Davis, MD,
MPH, Section of General Internal Medicine,
University of Chicago Medicine, 5841 S Maryland
Ave, Chicago, IL 60637 (amd@uchicago.edu).
Additional Contributions: We acknowledge the
contributions of Richard J. Fantus, MD, in the
development of this article, for which he was not
compensated.
REFERENCES
1. Schlegel PN, Sigman M, Collura B, et al. Diagnosis
and treatment of infertility in men: AUA/ASRM
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2. Schlegel PN, Sigman M, Collura B, et al. Diagnosis
5. Wang J, Xia SJ, Liu ZH, et al. Inguinal and
subinguinal micro-varicocelectomy, the optimal
surgical management of varicocele. Asian J Androl.
2015;17(1):74-80.
6. Bernie AM, Mata DA, Ramasamy R, Schlegel PN.
Comparison of microdissection testicular sperm
extraction, conventional testicular sperm
extraction, and testicular sperm aspiration for
nonobstructive azoospermia. Fertil Steril.
2015;104(5):1099-103.e1, 3.

Conflict of Interest Disclosures: Dr Halpern
reported serving as an investigator for an ongoing
clinical trial in male infertility for Ferring
Pharmaceuticals Inc and board of director member
for the Society of Male Reproduction and Urology,
an affiliate organization of the ASRM. Dr Brannigan
reported serving as co-investigator of a clinical trial
for Ferring Pharmaceuticals, receiving personal fees
from the American Board of Urology, and serving
on an editorial committee for the AUA. No other
disclosures were reported.
and treatment of infertility in men: AUA/ASRM
guideline part II. J Urol. 2021;205(1):44-51.
3. World Health Organization Task Force on
Methods for the Regulation of Male Fertility.
Contraceptive efficacy of testosterone-induced
azoospermia and oligozoospermia in normal men.
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4. Meistrich ML. Effects of chemotherapy and
radiotherapy on spermatogenesis in humans. Fertil
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7. Abdel-Meguid TA, Al-Sayyad A, Tayib A,
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9. Amer M, Ateyah A, Hany R, Zohdy W.
Prospective comparative study between
microsurgical and conventional testicular sperm
extraction in non-obstructive azoospermia. Hum
Reprod. 2000;15(3):653-656.

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