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Evaluation and Management of Testosterone Deficiency: AUA Guideline
John P. Mulhall , Landon W. Trost , Robert E. Brannigan , Emily G. Kurtz , J. Bruce Redmon , Kelly A. Chiles , Deborah J. Lightner , Martin M. Miner , M. Hassan Murad , Christian J. Nelson , Elizabeth A. Platz , Lakshmi V. Ramanathan , Ronald W. Lewis
PII: S0022-5347(18)42817- DOI: 10.1016/j.juro.2018.03. Reference: JURO 15524
To appear in: The Journal of Urology Accepted Date: 21 March 2018
Please cite this article as: Mulhall JP, Trost LW, Brannigan RE, Kurtz EG, Redmon JB, Chiles KA, Lightner DJ, Miner MM, Murad MH, Nelson CJ, Platz EA, Ramanathan LV, Lewis RW, Evaluation and Management of Testosterone Deficiency: AUA Guideline, The Journal of Urology® (2018), doi: 10.1016/ j.juro.2018.03.115.
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EVALUATION AND MANAGEMENT OF TESTOSTERONE DEFICIENCY:
AUA GUIDELINE
John P. Mulhall, MD, Landon W. Trost, MD, Robert E. Brannigan, MD, Emily G. Kurtz, MD, J. Bruce Redmon, MD, Kelly A. Chiles, MD, MSc, Deborah J. Lightner, MD, Martin M. Miner, MD, M. Hassan Murad, MD, MPH, Christian J. Nelson, PhD, Elizabeth A. Platz, ScD, MPH, Lakshmi V. Ramanathan, PhD, Ronald W. Lewis, MD
MeSH: Testosterone, Testosterone/deficiency, Hypogonadism, Men’s Health, Androgens
Word Count: Abstract 238; Summary: 3958
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Background
Testosterone testing and prescriptions have nearly tripled in recent years; however, it is clear from clinical practice that there are many men using testosterone without a clear indication.1,2, Some studies estimate that up to 25% of men who receive testosterone therapy do not have their testosterone tested prior to initiation of treatment. Of men who are treated with testosterone, nearly half do not have their testosterone levels checked after therapy commences.2,3^ While up to a third of men who are placed on testosterone therapy do not meet the criteria to be diagnosed as testosterone deficient,2,3^ there are a large percentage of men in need of testosterone therapy who fail to receive it due to clinician concerns, mainly surrounding prostate cancer development and cardiovascular events, although current evidence fails to definitely support these concerns.
Guideline Statements Please see Table One for more information on the American Urological Association (AUA) nomenclature system that was used to arrive at statement type and body of evidence strength.
Diagnosis of Testosterone Deficiency
1. Clinicians should use a total testosterone level below 300 ng/dL as a reasonable cut- off in support of the diagnosis of low testosterone. (Moderate Recommendation; **Evidence Level: Grade B)
- The diagnosis of low testosterone should be made only after two total testosterone** measurements are taken on separate occasions with both conducted in an early **morning fashion. (Strong Recommendation; Evidence Level: Grade A)
- The clinical diagnosis of testosterone deficiency is only made when patients have low** total testosterone levels combined with symptoms and/or signs. (Moderate **Recommendation; Evidence Level: Grade B)
- Clinicians should consider measuring total testosterone in patients with a history of** unexplained anemia, bone density loss, diabetes, exposure to chemotherapy, exposure to testicular radiation, HIV/AIDS, chronic narcotic use, male infertility, pituitary dysfunction, and chronic corticosteroid use even in the absence of
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symptoms or signs associated with testosterone deficiency. (Moderate Recommendation; Evidence Level: Grade B)
5. The use of validated questionnaires is not currently recommended to either define which patients are candidates for testosterone therapy or monitor symptom response in patients on testosterone therapy. (Conditional Recommendation; Evidence Level: Grade C)
The diagnosis of testosterone deficiency requires both a low testosterone measurement as well as the presence of select symptoms and/or signs. The Panel defines the threshold for low testosterone as being consistently <300 ng/dL on at least two serum total testosterone measurements obtained in an early morning fashion, preferably using the same laboratory with the same method/instrumentation for measurement.2,4^ (Figure One)
Clinicians should make note of any patient-reported symptoms associated with low testosterone, such as reduced energy, reduced endurance, diminished work and/or physical performance, fatigue, visual field changes (bitemporal hemianopsia), anosmia, depression, reduced motivation, poor concentration, impaired memory, irritability, infertility, reduced sex drive, and changes in erectile function.5,
Clinicians should also conduct a targeted physical exam to examine patients for signs that are associated with low testosterone. This assessment should include evaluation of general body habitus; virilization status (examination of body hair patterns and amounts in androgen dependent areas); body mass index or waist circumference; gynecomastia; testicular evaluation including presence, size, consistency and masses; varicocele presence; and prostate size and morphology.5,
A meta-analysis of the literature suggests that men who have a history of unexplained anemia,^7 bone density loss,^8 diabetes,^9 exposure to chemotherapy,^10 direct or scatter radiation therapy to the testes,^11 HIV,^12 a history of chronic narcotic use,^13 infertility,^14 pituitary disorders,^15 and chronic corticosteroid use^16 are at risk for low testosterone. The Panel recommends measuring testosterone in all patients who have a history of these conditions, even in the absence of symptoms or signs listed above.
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9. Serum estradiol should be measured in testosterone deficient patients who present with breast symptoms or gynecomastia prior to the commencement of testosterone therapy. (Expert Opinion)
Men who have elevated baseline estradiol measurements should be referred to an endocrinologist. While it is not uncommon for estradiol levels to increase while patients are on testosterone therapy as total testosterone increases, clinicians should be aware that symptomatic gynecomastia or other breast symptoms are uncommon. For men who develop gynecomastia/breast symptoms on treatment (e.g., breast pain, breast tenderness, nipple tenderness), a period of monitoring based on clinical judgment should be considered as breast symptoms sometimes abate.
10. Men with testosterone deficiency who are interested in fertility should have a reproductive health evaluation performed prior to treatment. (Moderate Recommendation; Evidence Level: Grade B)
Men diagnosed with testosterone deficiency who are interested in preserving their current fertility should undergo testicular exam to evaluate testicular size, consistency, and descent and have their serum follicle stimulating hormone measured to assess their underlying reproductive health status.^21 Elevated follicle stimulating hormone levels in the setting of testosterone deficiency (hypergonadatropic hypogonadism) is typically indicative of impaired spermatogenesis;^6 therefore, clinicians should consider adjunctive fertility testing, such as a semen analysis, in such patients. Patients who have severe oligospermia (sperm concentration < million sperm per mL) or non-obstructive azoospermia should be offered reproductive genetics testing consisting of karyotype testing and Y-chromosome analysis for microdeletions.^21
11. Prior to offering testosterone therapy, clinicians should measure hemoglobin and hematocrit and inform patients regarding the increased risk of polycythemia. (Strong Recommendation; Evidence Level: Grade A)
Prior to commencing testosterone therapy, all patients should undergo a baseline measurement of hemoglobin/hematocrit (Hct). If the Hct exceeds 50%, clinicians should consider withholding testosterone therapy until the etiology is formally investigated. While on testosterone therapy, a
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Hct ≥54% warrants intervention, such as dose reduction or temporary discontinuation. While the incidence of polycythemia for one particular modality of testosterone compared to another cannot be determined, trials have indicated that injectable testosterone is associated with the greatest treatment-induced increases in hemoglobin/Hct.^22
12. PSA should be measured in men over 40 years of age prior to commencement of testosterone therapy to exclude a prostate cancer diagnosis. (Clinical Principle)
It is the opinion of this Panel that serum PSA levels should be measured prior to the commencement of testosterone therapy in patients over 40 years of age in order to minimize the risk of prescribing testosterone therapy to men with occult prostate cancer.
For patients who have an elevated PSA at baseline, a second PSA test is recommended to rule out a spurious elevation. In patients who have two PSA levels at baseline that raise suspicion for the presence of prostate cancer, a more formal evaluation, potentially including reflex testing (e.g., 4K or phi), and prostate biopsy with/without MRI, should be considered before initiating testosterone therapy.
Patients who maintain on-treatment testosterone levels in the normal range should decide on PSA testing using a shared decision-making approach with their clinician in accordance with the American Urological Association’s Early Detection of Prostate Cancer Guideline.
Counseling Regarding Treatment of Testosterone Deficiency
13. Clinicians should inform testosterone deficient patients that low testosterone is a risk factor for cardiovascular disease. (Strong Recommendation; Evidence Level: Grade B)
Currently available literature has consistently shown that low testosterone levels are associated with an increased incidence of major adverse cardiac events (MACE), such as myocardial infarction, stroke, and possible cardiovascular-related mortality and an increased prevalence of certain atherosclerotic cardiovascular disease (ASCVD) risk factors.^23 Testosterone deficient patients should be informed that low testosterone levels place them at risk for these major
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the highly variable time course to recover sperm in the ejaculate and the variable degree to which spermatogenesis returns after stopping exogenous testosterone.^32 While two-thirds of males in contraceptive studies recovered sperm in the ejaculate within six months of exogenous testosterone therapy cessation, 10% failed to do so until the second year after cessation.^32 The recovery of spermatogenesis after discontinuing use of exogenous testosterone is also not well- established in infertile males and this important risk should be discussed with patients before starting treatment.^33
17. Clinicians should inform patients of the absence of evidence linking testosterone therapy to the development of prostate cancer. (Strong Recommendation; Evidence Level: Grade B)
The relationship between testosterone replacement therapy and the development of prostate cancer has been debated. While the US Food and Drug Administration (FDA) retains a black- box warning regarding the potential risk of prostate cancer in patients who are prescribed testosterone products, there is accumulating evidence against a link between testosterone therapy and prostate cancer development. Randomized controlled trials (RCTs) have shown that there is not a significant increase in the rate of a prostate cancer diagnosis in older, testosterone deficient men who were treated with testosterone compared to placebo.24,30,
One meta-analysis by Calof et al.^35 (2005) pooled data from 19 RCTs to determine the number of all-cause prostate events in men who were on exogenous testosterone treatment as compared to men who were on placebo. At the end of study, the total number of prostate-related events was significantly greater in the testosterone arm than in the placebo arm (OR=1.79; CI: 1.07, 2.95). The authors conceded that it was not possible to determine if each individual prostate event occurred in unique individuals since the same person might have had more than one event leading to an overestimate in incidence. When individual prostate events were analyzed separately, there was not a statistically significant difference in incidence between the two groups in terms of prostate cancer (OR=1.09), PSA elevation to >4ng/mL or PSA increase >1. ng/mL during treatment (OR=1.19), any increase in International Prostate Symptom Score (OR=1.08), or acute urinary retention (OR=0.99).
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18. Patients with testosterone deficiency and a history of prostate cancer should be informed that there is inadequate evidence to quantify the risk-benefit ratio of testosterone therapy. (Expert Opinion)
It is the opinion of this Panel that the decision to commence testosterone therapy in men with in- situ prostate cancer on active surveillance or previously treated prostate cancer is a negotiated decision based on the perceived potential benefit of treatment weighed against the limited knowledge of potential risks. Testosterone therapy in men with locally advanced or metastatic disease remains poorly understood and administration of testosterone in these scenarios should ideally be performed under research settings.
Post-Radical Prostatectomy Patients. Testosterone therapy can be considered in men who have undergone radical prostatectomy with favorable pathology (e.g., negative margins, negative seminal vesicles, negative lymph nodes), and who have undetectable PSA postoperatively. Limited data have demonstrated no significant increases in prostate cancer recurrence in men treated with testosterone compared to controls, although an increase in PSA among men in high- risk groups receiving testosterone has been shown, highlighting the need for appropriate patient selection.^36 It should be noted that currently available studies are underpowered and of too short of a duration to be able to detect any effects attributable to testosterone therapy.
Radiation Therapy (RT). Available studies evaluating the safety of testosterone therapy in men treated with RT have suggested that post-RT patients (with or without a history of androgen deprivation therapy) do not experience recurrence or progression of prostate cancer and experienced either a steady decline in PSA values to <0.1 ng/mL or had non-significant changes in PSA.^37
Active Surveillance. There are limited data in men on active surveillance who are candidates for testosterone therapy. Available literature indicate that patients with and without high-grade prostatic intraepithelial neoplasias who were on testosterone therapy did not experience significant increases in PSA or subsequent cancer diagnosis compared to men not receiving testosterone.^38
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symptoms, such as chest pain, shortness of breath, dizziness, or transient loss of consciousness, during routine follow-up visits.
21. All men with testosterone deficiency should be counseled regarding lifestyle modifications as a treatment strategy. (Conditional Recommendation; Evidence Level: Grade B)
Men with testosterone deficiency should be counseled that lifestyle modifications, such as losing weight, or maintaining weight within the recommended range, along with increasing physical activity, has the potential to increase total testosterone levels and/or reduce signs and symptoms associated with testosterone deficiency.^42 High body mass index coupled with low testosterone could put the patient at risk for a cardiovascular event, and patients who are overweight or obese should be counseled regarding weight loss programs concurrent with testosterone therapy.
Treatment of Testosterone Deficiency
22. Clinicians should adjust testosterone therapy dosing to achieve a total testosterone level in the middle tertile of the normal reference range. (Conditional Recommendation; Evidence Level: Grade C)
The goal of testosterone therapy is the normalization of total testosterone levels combined with improvement in symptoms or signs.5,43^ The Panel recommends that testosterone treatment programs use the minimal dosing necessary to drive testosterone levels to the normal physiologic range of 450-600 ng/dL. In the event that patients do not experience symptomatic relief after reaching the specified target testosterone levels or remain testosterone deficient in the setting of symptom/sign improvement, testosterone therapy should be stopped.
23. Exogenous testosterone therapy should not be prescribed to men who are currently trying to conceive. (Strong Recommendation; Evidence Level: Grade A)
Exogenous testosterone therapy has been shown to interrupt normal spermatogenesis and can put patients in severely oligospermic or azoospermic states and should not be used in men trying to conceive. A systematic review of 33 RCTs suggested that although higher doses of testosterone
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were more likely to result in azoospermia than lower doses, a dose-response effect was not consistently seen.^44
24. Testosterone therapy should not be commenced for a period of three to six months in patients with a history of cardiovascular events. (Expert Opinion)
The currently available literature does not provide enough evidence to offer clear guidance on the use of testosterone therapy in men with existing, stable ASCVD and/or a remote history of a myocardial infarction, or a cerebrovascular accident. It is the opinion of the Panel that testosterone therapy with close monitoring to ensure appropriate dosing and safety surveillance may be considered in these patients after a three to six month waiting period from most recent cardiac event.
25. Clinicians should not prescribe alkylated oral testosterone. (Moderate Recommendation; Evidence Level: Grade B)
Given the availability of other approved testosterone therapies, the use of 17-alpha-akylated androgens is not appropriate. Methyl testosterone is approved in the United States for treatment of testosterone deficiency. However, its use is associated with liver toxicity, including abnormal liver function tests, cholestasis, and jaundice.^45
26. Clinicians should discuss the risk of transference with patients using testosterone gels/creams. (Strong Recommendation; Evidence Level: Grade A)
Topical testosterone preparations (e.g., gels, creams, liquids) have the potential to result in transference to others. Women and children are at the highest risk for adverse events, such as virilization, precocious puberty, and hyperandrogrenism. To address the issue, the FDA includes medication guides with topical testosterone preparations and recommends observing for signs and symptoms of early puberty in children as well as avoiding contact with the unwashed or uncovered areas where the drug has been applied.^46
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Follow up of Men on Testosterone Therapy
29. Clinicians should measure an initial follow-up total testosterone level after an appropriate interval to ensure that target testosterone levels have been achieved. **(Expert Opinion)
- Testosterone levels should be measured every 6-12 months while on testosterone** **therapy. (Expert Opinion)
- Clinicians should discuss the cessation of testosterone therapy three to six months** after commencement of treatment in patients who experience normalization of total testosterone levels but fail to achieve symptom or sign improvement. (Clinical Principle)
It is the opinion of this Panel that total testosterone should be tested after the commencement of therapy at a time point that allows a patient to be sufficiently established on a dosing regimen before determining if therapeutic levels have been achieved and if dosing alterations are required. (Figure Two)
Patients on topical gels, patches, and intranasal formulations should have their testosterone checked between two to four weeks after commencement of therapy. The therapy should be applied on the day when testing is to be obtained. Patients using anastrozole, clomiphene citrate, or hCG should be tested no earlier than four weeks.
The Panel recommends that patients on short-acting intramuscular or subcutaneous testosterone (testosterone cypionate or enanthate) have their testosterone measured no earlier than three to four cycles.
Patients who are on long-acting intramuscular testosterone (testosterone undecanoate) should have blood work tested halfway between the first two 10-week injections.
Patients who are on long-acting subcutaneous pellets require two separate testosterone assessments. The first testosterone measurement should be obtained two to four weeks after initial implant to determine if the number of inserted pellets needs to be increased or decreased to
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achieve the appropriate therapeutic level. Patients should then be tested after 10-12 weeks to determine when the next administration should occur.
After therapeutic levels have been achieved, all patients on testosterone therapy should have serum testosterone levels checked every 6-12 months to ensure maintenance of target levels.
Please refer to Table 3 for a summary of follow-up testing for men being treated for testosterone deficiency. Testing intervals are the expert opinion of the Panel based on pharmacokinetic dosing principle of measuring steady state and with the intent of achieving therapeutic levels between 450-600 ng/dL. These are provided to guide clinicians in the follow-up of such patients. In cases where measurement falls outside of the recommended range, dose and/or frequency of administration may be adjusted accordingly.
If patients achieve target testosterone levels, but do not feel that they have sufficient improvement in their symptoms, clinicians should question whether testosterone deficiency is the etiology of their symptoms/signs. There is no utility in continuing testosterone therapy in men who achieve target testosterone levels without symptom/sign improvement.
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