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Evaluation and Management of 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 and Ronald W. Lewis

From the American Urological Association Education and Research, Inc., Linthicum, Maryland

Purpose: There has been a marked increase in testosterone prescriptions in the past decade resulting in a growing need to give practicing clinicians proper Abbreviations and Acronyms guidance on the evaluation and management of the testosterone deficient ¼ patient. ASCVD atherosclerotic cardio- vascular disease Materials and Methods: A systematic review utilized research from the Mayo AUA ¼ American Urological Clinic Evidence Based Practice Center and additional supplementation by the Association authors. Evidence-based statements were based on body of evidence strength ¼ Grade A, B, or C and were designated as Strong, Moderate, and Conditional FDA U.S. Food and Drug Administration Recommendations with additional statements presented in the form of Clinical Principles or Expert Opinions (table 1 in supplementary unabridged guideline, Hct ¼ http://jurology.com/). hCG ¼ human chorionic Results: This guideline was developed by a multi-disciplinary panel to inform clinicians on the proper assessment of patients with testosterone deficiency and LH ¼ luteinizing the safe and effective management of men on testosterone therapy. Additional MACE ¼ major adverse cardiac statements were developed to guide the clinician on the appropriate care of pa- event tients who are at risk for or have or as RCTs ¼ randomized controlled well as patients who are interested in preserving . trials Conclusions: The care of testosterone deficient patients should focus on accurate RT ¼ radiation therapy assessment of total testosterone levels, symptoms, and signs as well as proper on- VTE ¼ venous thromboembolism treatment monitoring to ensure therapeutic testosterone levels are reached and symptoms are ameliorated. Future longitudinal observational studies and clin- Accepted for publication March 22, 2018. ical trials of significant duration in this space will improve diagnostic techniques The complete unabridged version of the guideline is available at http://jurology.com/. and treatment of men with testosterone deficiency as well as provide more data This document is being printed as submitted on the adverse events that may be associated with testosterone therapy. independent of editorial or peer review by the editors of The Journal of UrologyÒ. Key Words: testosterone, , men’s health,

BACKGROUND have their testosterone tested prior to Testosterone testing and pre- initiation of treatment. Of men who scriptions have nearly tripled in are treated with testosterone, nearly recent years; however, it is clear from half do not have their testosterone clinical practice that there are many levels checked after therapy com- men using testosterone without a mences.2,3 While up to a third of men clear indication.1e3 Some studies who are placed on testosterone ther- estimate that up to 25% of men who apy do not meet the criteria to be receive testosterone therapy do not diagnosed as testosterone deficient,2,3

0022-5347/18/2002-0423/0 https://doi.org/10.1016/j.juro.2018.03.115 THE JOURNAL OF UROLOGY® Vol. 200, 423-432, August 2018 www.jurology.com j 423 Ó 2018 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH,INC. Printed in U.S.A. 424 AUA GUIDELINE ON TESTOSTERONE DEFICIENCY

there are a large percentage of men in need of anosmia, depression, reduced motivation, poor con- testosterone therapy who fail to receive it due to centration, impaired memory, irritability, , clinician concerns, mainly surrounding prostate reduced drive, and changes in erectile cancer development and cardiovascular events, function.5,6 although current evidence fails to definitely support Clinicians should also conduct a targeted phys- these concerns. ical exam to examine patients for signs that are associated with low testosterone. This assessment should include evaluation of general body habitus; GUIDELINE STATEMENTS status (examination of pat- Diagnosis of Testosterone Deficiency terns and amounts in dependent areas); 1. Clinicians should use a total testosterone or waist circumference; gyneco- level below 300 ng/dL as a reasonable cut-off mastia; testicular evaluation including presence, in support of the diagnosis of low testos- size, consistency and masses; presence; terone. (Moderate Recommendation; Evidence and prostate size and morphology.5,6 Level: Grade B) A meta-analysis of the literature suggests that 2. The diagnosis of low testosterone should be men who have a history of unexplained anemia,7 made only after two total testosterone mea- density loss,8 diabetes,9 exposure to chemo- surements are taken on separate occasions with therapy,10 direct or scatter radiation therapy to the both conducted in an early morning fashion. testes,11 HIV,12 a history of chronic narcotic use,13 (Strong Recommendation; Evidence Level: infertility,14 pituitary disorders,15 and chronic corti- Grade A) costeroid use16 are at risk for low testosterone. The 3. The clinical diagnosis of testosterone defi- Panel recommends measuring testosterone in all pa- ciency is only made when patients have low tients who have a history of these conditions, even in total testosterone levels combined with symp- the absence of symptoms or signs listed above. toms and/or signs. (Moderate Recommendation; Screening questionnaires are not an appropriate Evidence Level: Grade B) tool to identify candidates for testosterone therapy 4. Clinicians should consider measuring total and should not be used at the expense of a full patient testosterone in patients with a history of unex- evaluation and laboratory testosterone measure- plained anemia, loss, diabetes, ment. Specificities and sensitivities vary greatly exposure to chemotherapy, exposure to testic- amongst available questionnaires making them ill- ular radiation, HIV/AIDS, chronic narcotic use, suited for screening or for use as a surrogate for , pituitary dysfunction, and testosterone laboratory testing.4 chronic use even in the absence of symptoms or signs associated with testos- Adjunctive Testing terone deficiency. (Moderate Recommendation; 6. In patients with low testosterone, clinicians Evidence Level: Grade B) should measure serum 5. The use of validated questionnaires is not levels. (Strong Recommendation; Evidence currently recommended to either define Level: Grade A) which patients are candidates for testos- Measuring luteinizing hormone levels may help to terone therapy or monitor symptom response establish the etiology of testosterone deficiency and in patients on testosterone therapy. (Condi- may be an important factor in determining if adjunc- tional Recommendation; Evidence Level: tive tests should be ordered (Appendix C in supple- Grade C) mentary unabridged guideline, http://jurology.com/).17 The diagnosis of testosterone deficiency requires Testosterone deficient patients with low or low/normal both a low testosterone measurement as well as the LH levels are also candidates for selective presence of select symptoms and/or signs. The Panel modulator use as a treatment for testosterone defines the threshold for low testosterone as being deficiency, particularly those wishing to preserve their consistently <300 ng/dL on at least two serum total fertility.18 testosterone measurements obtained in an early 7. Serum levels should be morning fashion, preferably using the same labo- measured in patients with low testosterone ratory with the same method/instrumentation for levels combined with low or low/normal measurement (fig. 1).2,4 luteinizing hormone levels. (Strong Recom- Clinicians should make note of any patient- mendation; Evidence Level: Grade A) reported symptoms associated with low testos- 8. Patients with persistently high prolactin terone, such as reduced energy, reduced endurance, levels of unknown etiology should undergo diminished work and/or physical performance, fa- evaluation for endocrine disorders. (Strong tigue, visual field changes (bitemporal hemianopsia), Recommendation; Evidence Level: Grade A) AUA GUIDELINE ON TESTOSTERONE DEFICIENCY 425

Figure 1. Diagnostic algorithm

Serum prolactin should be measured in patients While it is not uncommon for levels to in- who have low total testosterone and low or low/normal crease while patients are on testosterone therapy as LH levels to screen for hyperprolactinemia. If patients total testosterone increases, clinicians should be have elevated prolactin levels, prolactin measurement aware that symptomatic or other should be repeated to ensure that the initial elevation symptoms are uncommon. For men who was not spurious. Persistently elevated prolactin develop gynecomastia/breast symptoms on treat- levels can indicate the presence of pituitary tumors, ment (e.g., breast pain, breast tenderness, nipple such as ,19 and the Panel recommends tenderness), a period of monitoring based on clinical that such patients should be referred to an endocri- judgment should be considered as breast symptoms nologist for further evaluation. Men with total sometimes abate. testosterone levels of <150 ng/dL in combination with 10. Men with testosterone deficiency who a low or low/normal LH should undergo a pituitary are interested in fertility should have a MRI regardless of prolactin levels, as non-secreting reproductive health evaluation performed adenomas may be identified.20 prior to treatment. (Moderate Recommenda- 9. Serum estradiol should be measured in tion; Evidence Level: Grade B) testosterone deficient patients who present Men diagnosed with testosterone deficiency who with breast symptoms or gynecomastia prior are interested in preserving their current fertility to the commencement of testosterone therapy. should undergo testicular exam to evaluate testic- (Expert Opinion) ular size, consistency, and descent and have their Men who have elevated baseline estradiol mea- serum follicle-stimulating hormone measured to surements should be referred to an endocrinologist. assess their underlying reproductive health status.21 426 AUA GUIDELINE ON TESTOSTERONE DEFICIENCY

Elevated follicle-stimulating hormone levels in the risk factor for cardiovascular disease. (Strong setting of testosterone deficiency (hypergonadatropic Recommendation; Evidence Level: Grade B) hypogonadism) is typically indicative of impaired Currently available literature has consistently ;6 therefore, clinicians should shown that low testosterone levels are associated consider adjunctive fertility testing, such as a semen with an increased incidence of major adverse car- analysis, in such patients. Patients who have severe diac events, such as , , ( concentration <5 million sperm and possible cardiovascular-related mortality and per mL) or non-obstructive should be an increased prevalence of certain atherosclerotic offered reproductive genetics testing consisting of cardiovascular disease risk factors.23 Testosterone karyotype testing and Y- analysis for deficient patients should be informed that low microdeletions.21 testosterone levels place them at risk for these 11. Prior to offering testosterone therapy, major cardiovascular events, and clinicians should clinicians should measure hemoglobin and assess all testosterone deficient patients for ASCVD hematocrit and inform patients regarding the risk factors, both fixed (e.g., older age, male gender) increased risk of . (Strong and modifiable (e.g., dyslipidemia, hypertension, Recommendation; Evidence Level: Grade A) diabetes, current cigarette smoking). Prior to commencing testosterone therapy, all 14. Patients should be informed that testos- patients should undergo a baseline measurement of terone therapy may result in improvements in hemoglobin/hematocrit. If the Hct exceeds 50%, erectile function, low sex drive, anemia, bone clinicians should consider withholding testosterone mineral density, lean body mass, and/or therapy until the etiology is formally investigated. depressive symptoms. (Moderate Recommen- While on testosterone therapy, a Hct 54% war- dation; Evidence Level: Grade B) rants intervention, such as dose reduction or tem- 15. Patients should be informed that the porary discontinuation. While the incidence of evidence is inconclusive whether testosterone polycythemia for one particular modality of testos- therapy improves cognitive function, mea- terone compared to another cannot be determined, sures of diabetes, energy, fatigue, pro- trials have indicated that injectable testosterone is files, and quality of life measures. (Moderate associated with the greatest treatment-induced in- Recommendation; Evidence Level: Grade B) creases in hemoglobin/Hct.22 The main purpose of testosterone therapy is to 12. PSA should be measured in men over 40 achieve therapeutic testosterone levels and provide years of age prior to commencement of relief of symptoms or signs. In trials, patients with testosterone therapy to exclude a prostate low testosterone have demonstrated statistically cancer diagnosis. (Clinical Principle) significant improvements in erectile function,24 sex It is the opinion of this Panel that serum PSA levels drive,24 anemia,25 bone mineral density,26 lean body should be measured prior to the commencement of mass,27 and depressive symptoms.24 However, given testosterone therapy in patients over 40 years of age in the limitations of the underlying studies and diffi- order to minimize the risk of prescribing testosterone culties in assessing symptoms, it is unclear how therapy to men with occult . clinically meaningful these improvements may be in For patients who have an elevated PSA at base- some cases. line, a second PSA test is recommended to rule out a Theevidenceislessconclusiveastowhetherornot spurious elevation. In patients who have two PSA testosterone therapy improves cognitive function,28 levels at baseline that raise suspicion for the pres- measures of diabetes,29 energy,30 fatigue,30 lipid ence of prostate cancer, a more formal evaluation, profiles,29 and quality of life measures.31 Despite the potentially including reflex testing (e.g., 4K or phi), absence of definitive evidence, the Panel suggests and prostate biopsy with/without MRI, should be that patients with these symptoms may be counseled considered before initiating testosterone therapy. regarding the possibility of improvement on testos- Patients who maintain on-treatment testosterone terone therapy. levels in the normal range should decide on PSA 16. The long-term impact of exogenous testing using a shared decision-making approach testosterone on spermatogenesis should be with their clinician in accordance with the Amer- discussed with patients who are interested in ican Urological Association’s Early Detection of future fertility. (Strong Recommendation; Prostate Cancer Guideline. Evidence Level: Grade A) For men on exogenous testosterone who are Counseling Regarding Treatment of Testosterone planning future reproduction, testosterone cessa- Deficiency tion should occur in advance of initiation of any 13. Clinicians should inform testosterone effort to conceive. Patients need to be made aware of deficient patients that low testosterone is a the highly variable time course to recover sperm in AUA GUIDELINE ON TESTOSTERONE DEFICIENCY 427

the ejaculate and the variable degree to which treated prostate cancer is a negotiated decision spermatogenesis returns after stopping exogenous based on the perceived potential benefit of treat- testosterone.32 While two-thirds of males in con- ment weighed against the limited knowledge of po- traceptive studies recovered sperm in the ejaculate tential risks. Testosterone therapy in men with within six months of exogenous testosterone ther- locally advanced or metastatic disease remains apy cessation, 10% failed to do so until the second poorly understood and administration of testos- year after cessation.32 The recovery of spermato- terone in these scenarios should ideally be per- genesis after discontinuing use of exogenous formed under research settings. testosterone is also not well-established in infertile Post-Radical Prostatectomy. Testosterone therapy males and this important risk should be discussed can be considered in men who have undergone with patients before starting treatment.33 radical prostatectomy with favorable pathology 17. Clinicians should inform patients of the (e.g., negative margins, negative , absence of evidence linking testosterone negative lymph nodes), and who have undetectable therapy to the development of prostate can- PSA postoperatively. Limited data have demon- cer. (Strong Recommendation; Evidence strated no significant increases in prostate cancer Level: Grade B) recurrence in men treated with testosterone The relationship between testosterone therapy compared to controls, although an increase in PSA and the development of prostate cancer has been among men in high-risk groups receiving debated. While the U.S. Food and Drug Adminis- testosterone has been shown, highlighting the tration retains a warning regarding the potential need for appropriate patient selection.36 It should risk of prostate cancer in patients who are pre- be noted that currently available studies are scribed testosterone products, there is accumu- underpowered and of too short of a duration to be lating evidence against a link between testosterone able to detect any effects attributable to therapy and prostate cancer development. Ran- testosterone therapy. domized controlled trials have shown that there is not a significant increase in the rate of a prostate Radiation Therapy. Available studies evaluating cancer diagnosis in older, testosterone deficient the safety of testosterone therapy in men treated men who were treated with testosterone compared with RT have suggested that after RT patients (with to placebo.24,30,34 or without a history of androgen deprivation ther- One meta-analysis by Calof et al.35 (2005) pooled apy) do not experience recurrence or progression of data from 19 RCTs to determine the number of all- prostate cancer and experienced either a steady cause prostate events in men who were on exoge- decline in PSA values to <0.1 ng/mL or had non- nous testosterone treatment as compared to men significant changes in PSA.37 who were on placebo. At the end of study, the total Active Surveillance. There are limited data on men number of prostate-related events was significantly on active surveillance who are candidates for testos- greater in the testosterone arm than in the placebo terone therapy. Available literature indicate that pa- arm (OR¼1.79; CI: 1.07, 2.95). The authors tients with and without high-grade prostatic conceded that it was not possible to determine if intraepithelial neoplasias who were on testosterone each individual prostate event occurred in unique therapy did not experience significant increases in individuals since the same person might have had PSAorsubsequentcancerdiagnosiscomparedto more than one event leading to an overestimate in men not receiving testosterone.38 incidence. When individual prostate events were analyzed separately, there was not a statistically PSA Monitoring. Prostate cancer patients on significant difference in incidence between the two testosterone therapy should have their PSA levels groups in terms of prostate cancer (OR¼1.09), PSA monitored on the same schedule as men without elevation to >4 ng/mL or PSA increase >1.5 ng/mL testosterone deficiency; however, clinicians may during treatment (OR¼1.19), any increase in In- choose to increase the frequency of testing. PSA ternational Prostate Symptom Score (OR¼1.08), or recurrence in men on testosterone therapy should be acute (OR¼0.99). evaluated in the same fashion as untreated men. A 18. Patients with testosterone deficiency discussion regarding the benefit of stopping testos- and a history of prostate cancer should be terone therapy should include the possibility of a informed that there is inadequate evidence to decline in PSA. quantify the risk-benefit ratio of testosterone 19. Patients should be informed that there is therapy. (Expert Opinion) no definitive evidence linking testosterone It is the opinion of this Panel that the decision to therapy to a higher incidence of venous throm- commence testosterone therapy in men with in-situ boembolic events. (Moderate Recommendation; prostate cancer on active surveillance or previously Evidence Level: Grade C) 428 AUA GUIDELINE ON TESTOSTERONE DEFICIENCY

The literature examining the relationship be- level in the middle tertile of the normal tween testosterone therapy and increased incidence reference range. (Conditional Recommenda- of venous thromboembolic events has returned tion; Evidence Level: Grade C) conflicting results. The concern about the possible The goal of testosterone therapy is the normali- association between testosterone therapy and VTE zation of total testosterone levels combined with led the FDA to require pharmaceutical companies to improvement in symptoms or signs.5,43 The Panel add a warning to their product labeling regarding recommends that testosterone treatment programs post-marketing reports of VTE; however, this deci- use the minimal dosing necessary to drive testos- sion was based on anecdotal cases and not peer- terone levels to the normal physiologic range of reviewed literature. Since the FDA warning in 450-600 ng/dL. In the event that patients do not June 2014, observational studies have not shown an experience symptomatic relief after reaching the association between testosterone therapy and an specified target testosterone levels or remain testos- increased risk of VTE.39 terone deficient in the setting of symptom/sign 20. Prior to initiating treatment, clinicians improvement, testosterone therapy should be stopped. should counsel patients that, at this time, it 23. Exogenous testosterone therapy should cannot be stated definitively whether testos- not be prescribed to men who are currently terone therapy increases or decreases the risk of trying to conceive. (Strong Recommendation; cardiovascular events (e.g., myocardial infarc- Evidence Level: Grade A) tion, stroke, cardiovascular-related death, all- Exogenous testosterone therapy has been shown cause mortality). (Moderate Recommendation; to interrupt normal spermatogenesis and can put Evidence Level: Grade B) patients in severely oligospermic or azoospermic Current evidence consistently shows that un- states and should not be used in men trying to treated low testosterone levels are associated with conceive. A systematic review of 33 RCTs suggested an increased risk of MACE; however, studies that that although higher doses of testosterone were measure cardiovascular benefit or harm in men on more likely to result in azoospermia than lower testosterone therapy have returned inconsistent and doses, a dose-response effect was not consistently controversial results.23,40,41 Until there is definitive seen.44 evidence proving an association between testos- 24. Testosterone therapy should not be terone therapy and subsequent MACE, the Panel commenced for a period of three to six months recommends that clinicians counsel patients that the in patients with a history of cardiovascular current scientific literature does not definitively events. (Expert Opinion) demonstrate that testosterone therapy increases the The currently available literature does not pro- risk of MACE. Men who are on testosterone therapy vide enough evidence to offer clear guidance on the should be advised to report the occurrence of any use of testosterone therapy in men with existing, possible cardiovascular symptoms, such as chest pain, stable ASCVD and/or a remote history of a myocar- shortness of breath, dizziness, or transient loss of dial infarction, or a cerebrovascular accident. It is consciousness, during routine follow-up visits. the opinion of the Panel that testosterone therapy 21. All men with testosterone deficiency with close monitoring to ensure appropriate dosing should be counseled regarding lifestyle modi- and safety surveillance may be considered in these fications as a treatment strategy. (Conditional patients after a three to six month waiting period Recommendation; Evidence Level: Grade B) from most recent cardiac event. Men with testosterone deficiency should be coun- 25. Clinicians should not prescribe alky- seled that lifestyle modifications, such as losing lated oral testosterone. (Moderate Recom- weight, or maintaining weight within the recom- mendation; Evidence Level: Grade B) mended range, along with increasing physical activity, Given the availability of other approved testos- has the potential to increase total testosterone levels terone therapies, the use of 17-alpha-akylated an- and/or reduce signs and symptoms associated with drogens is not appropriate. Methyl testosterone is testosterone deficiency.42 High body mass index approved in the United States for treatment of coupled with low testosterone could put the patient at testosterone deficiency. However, its use is associ- risk for a cardiovascular event, and patients who are ated with toxicity, including abnormal liver overweight or obese should be counseled regarding function tests, cholestasis, and jaundice.45 weight loss programs concurrent with testosterone 26. Clinicians should discuss the risk of therapy. transference with patients using testosterone /creams. (Strong Recommendation; Evi- Treatment of Testosterone Deficiency dence Level: Grade A) 22. Clinicians should adjust testosterone Topical testosterone preparations (e.g., gels, therapy dosing to achieve a total testosterone creams, liquids) have the potential to result in AUA GUIDELINE ON TESTOSTERONE DEFICIENCY 429

transference to others. Women and children are at after commencement of treatment in patients the highest risk for adverse events, such as virili- who experience normalization of total testos- zation, precocious , and . terone levels but fail to achieve symptom or To address the issue, the FDA includes sign improvement. (Clinical Principle) guides with topical testosterone preparations and It is the opinion of this Panel that total testos- recommends observing for signs and symptoms of terone should be tested after the commencement of early puberty in children as well as avoiding contact therapy at a time point that allows a patient to be with the unwashed or uncovered areas where the sufficiently established on a dosing regimen before drug has been applied.46 determining if therapeutic levels have been achieved 27. Clinicians may use inhibitors, and if dosing alterations are required (fig. 2). human chorionic gonadotropin, selective es- Patients on topical gels, patches, and intranasal trogen receptor modulators, or a combination formulations should have their testosterone checked thereof in men with testosterone deficiency between two to four weeks after commencement of desiring to maintain fertility. (Conditional therapy. The therapy should be applied on the day Recommendation; Evidence Level: Grade C) when testing is to be obtained. Patients using Exogenous testosterone has inhibitory effects on , clomiphene citrate, or hCG should be the production of intratesticular testosterone, which tested no earlier than four weeks. is imperative to maintain normal spermatogenesis. The Panel recommends that patients on short- For this reason, alternative therapies, including acting intramuscular or subcutaneous testosterone select modulators,47 human cho- ( or enanthate) have their rionic gonadotropin,48 and aromatase inhibitors49 testosterone measured no earlier than three to four are commonly used to promote the endogenous cycles. production of testosterone. While these agents share Patients who are on long-acting intramuscular the common overall treatment effect of increasing testosterone () should intrinsic production of testosterone, there are sub- have blood work tested halfway between the first stantial differences in pharmacologic characteristics two 10-week injections. and mechanisms of action between them. Clinicians Patients who are on long-acting subcutaneous should understand that of these agents, only hCG pellets require two separate testosterone assess- has been approved by the FDA for use in males. ments. The first testosterone measurement should 28. Commercially manufactured testos- be obtained two to four weeks after initial implant terone products should be prescribed rather to determine if the number of inserted pellets needs than compounded testosterone, when to be increased or decreased to achieve the appro- possible. (Conditional Recommendation; Evi- priate therapeutic level. Patients should then be dence Level: Grade C) tested after 10-12 weeks to determine when the next While testosterone gels and creams are the most administration should occur. commonly used forms of compounded testosterone After therapeutic levels have been achieved, all therapies and are routinely less expensive than patients on testosterone therapy should have serum branded forms of testosterone, individual pharmacies testosterone levels checked every 6-12 months to operate without direct FDA oversight and approval, ensure maintenance of target levels. resulting in considerable variation in potency and Please refer to table 7 in the supplementary quality, even between samples from the same phar- abridged guideline (http://jurology.com/) for a sum- macy. Clinicians issuing prescriptions for com- mary of follow-up testing for men being treated for pounded testosterone need to consider performing testosterone deficiency. Testing intervals are the additional monitoring and dose adjustments to assure expert opinion of the Panel based on pharmacoki- appropriate therapeutic levels if compounded prepa- netic dosing principle of measuring steady state and rations are prescribed.50 with the intent of achieving therapeutic levels be- tween 450-600 ng/dL. These are provided to guide Follow-up of Men on Testosterone Therapy clinicians in the follow-up of such patients. In cases 29. Clinicians should measure an initial follow- where measurement falls outside of the recom- up total testosterone level after an appropriate mended range, dose and/or frequency of adminis- interval to ensure that target testosterone tration may be adjusted accordingly. levels have been achieved. (Expert Opinion) If patients achieve target testosterone levels, but 30. Testosterone levels should be measured do not feel that they have sufficient improvement in every 6-12 months while on testosterone their symptoms, clinicians should question whether therapy. (Expert Opinion) testosterone deficiency is the etiology of their 31. Clinicians should discuss the cessation symptoms/signs. There is no utility in continuing of testosterone therapy three to six months testosterone therapy in men who achieve target 430 AUA GUIDELINE ON TESTOSTERONE DEFICIENCY

Figure 2. Treatment algorithm AUA GUIDELINE ON TESTOSTERONE DEFICIENCY 431

testosterone levels without symptom/sign The guideline text may include information or rec- improvement. ommendations about certain drug uses (‘off label’) that are not approved by the Food and Drug Administration (FDA), or about or DISCLAIMER substances not subject to the FDA approval process. This document was written by the Evaluation and AUA urges strict compliance with all government Management of Testosterone Deficiency Guideline regulations and protocols for prescription and use of Panel of the American Urological Association Edu- these substances. The physician is encouraged to cation and Research, Inc., which was created in carefully follow all available prescribing informa- 2016. The Practice Guidelines Committee (PGC) of tion about indications, contraindications, pre- the AUA selected the committee chair. Panel cautions and warnings. These guidelines and best members were selected by the chair. Membership of practice statements are not intended to provide the Panel included specialists in urology, cardiology, legal advice about use and misuse of these family medicine, and psychology with specific substances. expertise on this disorder. The mission of the Panel Although guidelines are intended to encourage was to develop recommendations that are analysis- best practices and potentially encompass available based or consensus-based, depending on Panel technologies with sufficient data as of close of the processes and available data, for optimal clinical literature review, they are necessarily time-limited. practices in the treatment of muscle-invasive Guidelines cannot include evaluation of all data on bladder cancer. emerging technologies or management, including Funding of the Panel was provided by the those that are FDA-approved, which may immedi- AUA. Panel members received no remuneration ately come to represent accepted clinical practices. for their work. Each member of the Panel pro- For this reason, the AUA does not regard tech- vides an ongoing conflict of interest disclosure to nologies or management which are too new to be the AUA. addressed by this guideline as necessarily experi- While these guidelines do not necessarily estab- mental or investigational. lish the standard of care, AUA seeks to recommend and to encourage compliance by practitioners with current best practices related to the condition being CONFLICT OF INTEREST (COI) DISCLOSURES treated. As medical knowledge expands and tech- All panel members completed COI disclosures. nology advances, the guidelines will change. Today Disclosures listed include topic and non-topic these evidence-based guidelines statements repre- related relationships. Any author not listed had sent not absolute mandates but provisional pro- nothing to disclose. posals for treatment under the specific conditions Consultant/Advisor: John P. Mulhall, Pfizer, described in each document. For all these reasons, Lilly; Leadership Position: Robert E. Brannigan, the guidelines do not pre-empt physician judgment The American Society for ; in individual cases. John P. Mulhall, Association of Peyronie’s Disease Treating physicians must take into account var- Advocates; Scientific Study or Trial: Kelly A. Chiles, iations in resources, and patient tolerances, needs, Pfizer; Christian J. Nelson, National Institutes of and preferences. Conformance with any clinical Health; Other: Robert E. Brannigan, National In- guideline does not guarantee a successful outcome. stitutes of Health.

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