Clinical Review & Education
JAMA Clinical Guidelines Synopsis
Evaluation and Treatment of Male Hypogonadism
Robert M. Sargis, MD, PhD; Andrew M. Davis, MD, MPH
GUIDELINE TITLE Testosterone Therapy in Men With
Hypogonadism: An Endocrine Society Clinical Practice Guideline
DEVELOPER Endocrine Society with cosponsorship from the
European Society of Endocrinology
RELEASE DATE March 17, 2018
PRIOR VERSION Testosterone Therapy in Men with Androgen
Deficiency Syndromes: An Endocrine Society Clinical Practice
Guideline, 2010
FUNDING SOURCE Endocrine Society
TARGET POPULATION Adult men with testosterone deficiency
MAJOR RECOMMENDATIONS
Testing
• Hypogonadism can be established in men who have signs and
symptomsoftestosteronedeficiencyandhaveunequivocallylow
total testosterone on ⱖ2 measurements. Free testosterone
should be measured when sex hormone–binding globulin
(SHBG) levels may be abnormal, such as in obesity, diabetes,
nephrotic syndrome, hypothyroidism, acromegaly, and in
patients taking steroids or progestins (decreased SHBG
levels); or in older age, HIV disease, cirrhosis and hepatitis,
hyperthyroidism, and in patients taking certain anticonvulsants
or those taking estrogen (increased SHBG levels).
Summary of the Clinical Problem
Men with symptoms potentially consistent with hypogonadism
are frequently encountered in clinical practice. The clinical fea-
tures associated with true male hypogonadism are nonspecific
and include impaired libido, erections, and fertility; reductions
in lean muscle mass and bone density; loss of facial, axillary,
and pubic hair; anemia; and changes in mood and vitality. The
effects of testosterone on energy, physical performance, mood,
and cardiometabolic factors continue to be explored, but in
general, the treatment of hypogonadal younger men often
improves symptoms related to testosterone deficiency. In con-
trast, testosterone treatment for middle-aged and older men with
functional decline, even for those with clearly low serum testoste-
rone levels, offers modest and inconsistent benefit.1 Despite such
uncertainties, “low T” clinics and intensive direct-to-consumer
advertising have contributed to a substantial recent increase in
testosterone prescribing.2
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• When hypogonadism is present, measure luteinizing hormone
(LH) and follicle-stimulating hormone (FSH) to distinguish
between primary hypogonadism (low testosterone, high LH
and FSH) and secondary hypogonadism (low testosterone,
normal or reduced LH and FSH) (strong recommendation,
moderate-quality evidence).
Treatment
• Testosterone therapy is recommended for men diagnosed
with hypogonadism to maintain secondary sex characteristics
and to correct symptoms of testosterone deficiency (strong
recommendation, moderate-quality evidence).
• Testosterone therapy is not recommended for men planning
fertility in the near term, with breast or prostate cancer, with
a palpable prostate nodule or induration, a prostate-specific
antigen (PSA) level >4.0 ng/mL (or >3.0 ng/mL with a high risk of
prostate cancer), elevated hematocrit (>48% or >50% for men
living at high altitude), untreated obstructive sleep apnea,
severe lower urinary tract symptoms, uncontrolled heart failure,
myocardial infarction or stroke within the last 6 months, or
thrombophilia (strong recommendation, low-quality evidence).
• For men >65 years who meet the diagnostic criteria for
hypogonadism, testosterone therapy can be offered after
individualized discussion of the risks and benefits
(conditional recommendation, low-quality evidence).
Monitoring
• Patients should be evaluated for therapeutic effect, serum
testosterone levels, hematocrit, and PSA levels several times
during the first year of therapy and annually thereafter.
Current clinical practice is often inconsistent with existing
standards for management. In one study, 40.2% of 410 019 US
men prescribed testosterone therapy did not have a testosterone
measurement in the 180 days prior to initiation, and an additional
9.8% did not have confirmatory testing. 3 Citing literature in
which some studies, but not all, reported therapy-associated car-
diovascular risk, in 2015 the US Food and Drug Administration
issued a warning regarding possible increased risks for myocardial
infarction and stroke with testosterone therapy, raising further
questions about the safety of widespread treatment for aging-
related low testosterone levels. This guideline aims to educate cli-
nicians and patients on the appropriate diagnosis and treatment
of true hypogonadism.
Characteristics of the Guideline Source
The Endocrine Society is a nonprofit organization established to ad-
vance excellence in endocrinology, medical practice, and human
(Reprinted) JAMA Published online March 17, 2018 E1
 Clinical Review & Education JAMA Clinical Guidelines Synopsis

Table. Guideline Rating

Standard
Establishing transparency
Management of conflict of interest in the guideline
development group
Guideline development group composition
Clinical practice guideline–systematic review intersection
Establishing evidence foundations and rating strength
for each of the guideline recommendations
Articulation of recommendations
External review
Updating
Implementation issues
health; it does not allow industry support to influence its pro-
grams. An appointed task force formulated updated recommenda-
tions based on a systematic evidence evaluation and scored them
using the Grading of Recommendations Assessment, Develop-
ment, and Evaluation (GRADE) system. The task force included 10
medical content experts and a methodologist with expertise in clini-
cal practice guideline development. Conflicts of interest among the
participants were identified and managed prior to approval by the
society’s council for participation on the task force (Table).
Evidence Base
The guideline was based on 2 systematic reviews and a recent ran-
domized trial.4 The first review examined the effects of testoste-
rone on sexual and physical function, fatigue, mood, cognition,
anemia, and bone mineral density in men with hypogonadism.
There were 11 reports of 4 placebo-controlled trials among 1779
participants with symptomatic hypogonadism and screening total
testosterone levels lower than 300 ng/dL. These patients were
treated using testosterone or testosterone esters. The second
review examined the relationship between testosterone therapy
and increased risk of lower urinary tract symptoms and erythrocy-
tosis; it included 9 studies of 3 placebo-controlled trials with 1581
participants using transdermal testosterone treatments. All studies
included in both systematic reviews used randomization or
allocation-by-minimization with low to moderate risk of bias.
Benefits and Harms
The guideline’s structured, evidence-based approach could im-
Rating prove care quality and outcomes for men with hypogonadism by
Fair standardizing the diagnostic evaluation (a fasting morning total se-
Fair rum testosterone using an accurate and reliable assay, confirmed at
Good
least once), limiting treatment only to patients meeting the diag-
nostic criteria for hypogonadism, recommending evaluation for sec-
Good
ondary causes of hypogonadism, and avoiding prescribing testos-
Good
terone to patients who do not have symptomatic hypogonadism,
Good or to those at risk of complications. The current guideline cites a re-
Fair cent double-blind, placebo-controlled trial of 790 symptomatic men
Fair older than 65 years who had 2 serum testosterone levels lower than
Good 275 ng/dL that found modest benefit in sexual function and mood,
some improvement in walking distance, but no benefit in vitality.5
Testosterone increased bone mineral density,6 and among men with
unexplained anemia, raised hemoglobin levels.7 However, testos-
terone treatment also increased coronary plaque volume,8 and in a
separate study, it was associated with a short-term increased risk for
venous thromboembolism.9 Additional information about poten-
tial adverse cardiovascular and prostate outcomes is needed given
evidence of both benefit and harm. The guideline does not empha-
size comorbid conditions associated with low testosterone levels
(eg, inactivity and obesity) and does not address potential benefits
associated with lifestyle interventions, which may have important
health benefits among men with symptoms of hypogonadism but
whose testosterone levels are normal or inconsistently low.
Discussion
The new guideline largely agrees with the 2010 Endocrine Society
clinical practice guideline. Importantly, neither guideline suggests
specific testosterone levels at which treatment is likely to be ben-
eficial. In contrast, the International Society for Sexual Medicine sug-
gests that men with total testosterone of 346 ng/mL or higher are
unlikely to have testosterone deficiency and benefit from treat-
ment, while the diagnosis and therapeutic benefit are more likely
at levels lower than 231 ng/dL. Regular monitoring for therapeutic
response and adverse effects, combined with discontinuing therapy
in patients who do not experience clear improvement in symp-
toms, should increase the likelihood of benefit while limiting ex-
pense and potential harm.

ARTICLE INFORMATION REFERENCES 5. Snyder PJ, Bhasin S, Cunningham GR, et al.

Author Affiliations: University of Illinois at Chicago
(Sargis); University of Chicago, Chicago, Illinois
(Davis).
Corresponding Author: Andrew M. Davis, MD,
MPH, Section of General Internal Medicine,
University of Chicago, 5841 S Maryland, Chicago, IL
60637 (amd@uchicago.edu).
1. Handelsman DJ. Testosterone and male aging:
faltering hope for male rejuvenation. JAMA. 2017;
317(7):699-701.
2. Layton JB, Kim Y, Alexander GC, Emery SL.
Association between direct-to-consumer
advertising and testosterone testing and initiation
in the United States, 2009-2013. JAMA. 2017;317
Effects of testosterone treatment in older men.
N Engl J Med. 2016;374(7):611-624.
6. Snyder PJ, Kopperdahl DL, Stephens-Shields AJ,
et al. Effect of testosterone treatment on
volumetric bone density and strength in older men
with low testosterone: a controlled clinical trial.
JAMA Intern Med. 2017;177(4):471-479.

Published Online: March 17, 2018.
doi:10.1001/jama.2018.3182
Conflict of Interest Disclosures: The authors
have completed and submitted the ICMJE Form
for Disclosure of Potential Conflicts of Interest.
Dr Sargis reports receiving honoraria from
CVS Health. No other disclosures were reported.
(11):1159-1166.
3. Layton JB, Li D, Meier CR, et al. Testosterone lab
testing and initiation in the United Kingdom and the
United States, 2000 to 2011. J Clin Endocrinol Metab.
2014;99(3):835-842.
4. Bhasin S, Brito JC, Cunningham GR, et al.
Testosterone Therapy in Men With Hypogonadism:
an Endocrine Society Clinical Practice Guideline.
https://academic.oup.com/jcem/article-lookup/doi
/10.1210/jc.2018-00229. March 17, 2018.
7. Roy CN, Snyder PJ, Stephens-Shields AJ, et al.
Association of testosterone levels with anemia in
older men. JAMA Intern Med. 2017;177(4):480-490.
8. Budoff MJ, Ellenberg SS, Lewis CE, et al.
Testosterone treatment and coronary artery plaque
volume in older men with low testosterone. JAMA.
2017;317(7):708-716.
9. Martinez C, Suissa S, Rietbrock S, et al.
Testosterone treatment and risk of venous
thromboembolism. BMJ. 2016;355:i5968.

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