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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 • When hypogonadism is present, measure luteinizing hormone
Hypogonadism: An Endocrine Society Clinical Practice Guideline (LH) and follicle-stimulating hormone (FSH) to distinguish
between primary hypogonadism (low testosterone, high LH
DEVELOPER Endocrine Society with cosponsorship from the and FSH) and secondary hypogonadism (low testosterone,
European Society of Endocrinology normal or reduced LH and FSH) (strong recommendation,
moderate-quality evidence).

RELEASE DATE March 17, 2018


Treatment

PRIOR VERSION Testosterone Therapy in Men with Androgen • Testosterone therapy is recommended for men diagnosed
Deficiency Syndromes: An Endocrine Society Clinical Practice with hypogonadism to maintain secondary sex characteristics
Guideline, 2010 and to correct symptoms of testosterone deficiency (strong
recommendation, moderate-quality evidence).
• Testosterone therapy is not recommended for men planning
FUNDING SOURCE Endocrine Society
fertility in the near term, with breast or prostate cancer, with
a palpable prostate nodule or induration, a prostate-specific
TARGET POPULATION Adult men with testosterone deficiency 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
MAJOR RECOMMENDATIONS living at high altitude), untreated obstructive sleep apnea,
severe lower urinary tract symptoms, uncontrolled heart failure,
Testing myocardial infarction or stroke within the last 6 months, or
thrombophilia (strong recommendation, low-quality evidence).
• Hypogonadism can be established in men who have signs and
• For men >65 years who meet the diagnostic criteria for
symptomsoftestosteronedeficiencyandhaveunequivocallylow
hypogonadism, testosterone therapy can be offered after
total testosterone on ⱖ2 measurements. Free testosterone
individualized discussion of the risks and benefits
should be measured when sex hormone–binding globulin
(conditional recommendation, low-quality evidence).
(SHBG) levels may be abnormal, such as in obesity, diabetes,
nephrotic syndrome, hypothyroidism, acromegaly, and in
patients taking steroids or progestins (decreased SHBG Monitoring
levels); or in older age, HIV disease, cirrhosis and hepatitis, • Patients should be evaluated for therapeutic effect, serum
hyperthyroidism, and in patients taking certain anticonvulsants testosterone levels, hematocrit, and PSA levels several times
or those taking estrogen (increased SHBG levels). during the first year of therapy and annually thereafter.

Summary of the Clinical Problem Current clinical practice is often inconsistent with existing
Men with symptoms potentially consistent with hypogonadism standards for management. In one study, 40.2% of 410 019 US
are frequently encountered in clinical practice. The clinical fea- men prescribed testosterone therapy did not have a testosterone
tures associated with true male hypogonadism are nonspecific measurement in the 180 days prior to initiation, and an additional
and include impaired libido, erections, and fertility; reductions 9.8% did not have confirmatory testing. 3 Citing literature in
in lean muscle mass and bone density; loss of facial, axillary, which some studies, but not all, reported therapy-associated car-
and pubic hair; anemia; and changes in mood and vitality. The diovascular risk, in 2015 the US Food and Drug Administration
effects of testosterone on energy, physical performance, mood, issued a warning regarding possible increased risks for myocardial
and cardiometabolic factors continue to be explored, but in infarction and stroke with testosterone therapy, raising further
general, the treatment of hypogonadal younger men often questions about the safety of widespread treatment for aging-
improves symptoms related to testosterone deficiency. In con- related low testosterone levels. This guideline aims to educate cli-
trast, testosterone treatment for middle-aged and older men with nicians and patients on the appropriate diagnosis and treatment
functional decline, even for those with clearly low serum testoste- of true hypogonadism.
rone levels, offers modest and inconsistent benefit.1 Despite such
uncertainties, “low T” clinics and intensive direct-to-consumer Characteristics of the Guideline Source
advertising have contributed to a substantial recent increase in The Endocrine Society is a nonprofit organization established to ad-
testosterone prescribing.2 vance excellence in endocrinology, medical practice, and human

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Clinical Review & Education JAMA Clinical Guidelines Synopsis

Table. Guideline Rating


Benefits and Harms
The guideline’s structured, evidence-based approach could im-
Standard Rating prove care quality and outcomes for men with hypogonadism by
Establishing transparency Fair standardizing the diagnostic evaluation (a fasting morning total se-
Management of conflict of interest in the guideline Fair rum testosterone using an accurate and reliable assay, confirmed at
development group
Guideline development group composition Good
least once), limiting treatment only to patients meeting the diag-
nostic criteria for hypogonadism, recommending evaluation for sec-
Clinical practice guideline–systematic review intersection Good
ondary causes of hypogonadism, and avoiding prescribing testos-
Establishing evidence foundations and rating strength Good
for each of the guideline recommendations terone to patients who do not have symptomatic hypogonadism,
Articulation of recommendations Good or to those at risk of complications. The current guideline cites a re-
External review Fair cent double-blind, placebo-controlled trial of 790 symptomatic men
Updating Fair older than 65 years who had 2 serum testosterone levels lower than
Implementation issues 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
health; it does not allow industry support to influence its pro- unexplained anemia, raised hemoglobin levels.7 However, testos-
grams. An appointed task force formulated updated recommenda- terone treatment also increased coronary plaque volume,8 and in a
tions based on a systematic evidence evaluation and scored them separate study, it was associated with a short-term increased risk for
using the Grading of Recommendations Assessment, Develop- venous thromboembolism.9 Additional information about poten-
ment, and Evaluation (GRADE) system. The task force included 10 tial adverse cardiovascular and prostate outcomes is needed given
medical content experts and a methodologist with expertise in clini- evidence of both benefit and harm. The guideline does not empha-
cal practice guideline development. Conflicts of interest among the size comorbid conditions associated with low testosterone levels
participants were identified and managed prior to approval by the (eg, inactivity and obesity) and does not address potential benefits
society’s council for participation on the task force (Table). associated with lifestyle interventions, which may have important
health benefits among men with symptoms of hypogonadism but
Evidence Base whose testosterone levels are normal or inconsistently low.
The guideline was based on 2 systematic reviews and a recent ran-
domized trial.4 The first review examined the effects of testoste- Discussion
rone on sexual and physical function, fatigue, mood, cognition, The new guideline largely agrees with the 2010 Endocrine Society
anemia, and bone mineral density in men with hypogonadism. clinical practice guideline. Importantly, neither guideline suggests
There were 11 reports of 4 placebo-controlled trials among 1779 specific testosterone levels at which treatment is likely to be ben-
participants with symptomatic hypogonadism and screening total eficial. In contrast, the International Society for Sexual Medicine sug-
testosterone levels lower than 300 ng/dL. These patients were gests that men with total testosterone of 346 ng/mL or higher are
treated using testosterone or testosterone esters. The second unlikely to have testosterone deficiency and benefit from treat-
review examined the relationship between testosterone therapy ment, while the diagnosis and therapeutic benefit are more likely
and increased risk of lower urinary tract symptoms and erythrocy- at levels lower than 231 ng/dL. Regular monitoring for therapeutic
tosis; it included 9 studies of 3 placebo-controlled trials with 1581 response and adverse effects, combined with discontinuing therapy
participants using transdermal testosterone treatments. All studies in patients who do not experience clear improvement in symp-
included in both systematic reviews used randomization or toms, should increase the likelihood of benefit while limiting ex-
allocation-by-minimization with low to moderate risk of bias. pense and potential harm.

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


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

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

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