Knowledge translation tools that include the diagnosis and treatment algorithms and the list of abridged recommendations included in the guideline will be distributed among the audience of health professionals identified earlier. However, hypogonadal men with successfully treated prostate cancer may be candidates for testosterone supplementation. Conversely, concerns about testosterone supplementation promoting the development and growth of prostate cancer and benign hyperplasia have long been based on extrapolations more so than on real proof or verification. An algorithm outlining an approach to the diagnosis of testosterone deficiency is available in Figure 1. Thus, it has been suggested that, in the presence of a convincing clinical picture but uncertain laboratory results, a therapeutic trial of testosterone supplementation (of perhaps three months) is an acceptable diagnostic approach.13,14 Therefore, the task force made a weak recommendation, based on low-quality evidence, that testosterone replacement therapy in men with cardiovascular disease be restricted to those with stable disease, only after a discussion of the potential risks and benefits (Box 2). Because of the particularly controversial nature of the subject and the fluidity of the literature, two recommendations on testosterone treatment in men with stable cardiovascular disease and prostate cancer have been selected for expanded description of the evidence supporting them. The task force recognizes that the management of testosterone deficiency syndrome remains highly controversial and that, in many instances, the evidence continues to be of doubtful quality. American Urological Association A retrospective review of 399 men (mean age 37 years) with a mean total testosterone of 308 ng/dL found that 35% of patients had BMD at osteopenic levels and 3% had osteoporosis. The cut-off of 300 ng/dL was chosen based on the mean total testosterone levels cited in the best available literature with a view to maximizing the potential benefit from prescribing testosterone while minimizing the risks of such treatment. Given the growing concern and need for proper testosterone therapy, the AUA identified a need to produce an evidence-based document that informs clinicians on the proper evaluation and management of testosterone deficient patients. Given the clinical and commercial testosterone landscape, the American Urological Association (AUA) identified a need to produce an evidence-based document that informs clinicians on the proper assessment and management of patients with testosterone deficiency. Once testosterone deficiency is diagnosed, treatment involves testosterone supplementation in most cases. In the diagnosis of testosterone deficiency, the physical examination bears similar shortcomings to those of patient history, mainly because of lack of specificity. However, health professionals must deal with patients presenting with clinical manifestations and biochemical confirmation of the diagnosis. The grade was then adjusted after consideration of the risk of bias, study limitations, consistency of results, directness of the evidence, precision of the results and publication bias across the body of relevant literature. The authors of each section assessed the literature pertaining to clinically important outcomes in their respective areas and assigned a grade (high, moderate, low or very low) to describe the quality of the evidence using the procedure outlined by the GRADE Working Group.7,9 In brief, randomized controlled trials were initially rated as high-quality and observational studies as low-quality evidence. Clinicians should inform patients of the absence of evidence linking testosterone therapy to the development of prostate cancer. Prior to offering testosterone therapy, clinicians should measure hemoglobin and hematocrit and inform patients regarding the increased risk of polycythemia. This guideline is largely in agreement with the Endocrine Society’s clinical practice guideline on testosterone therapy in men with androgen deficiency syndromes published in 2010,2 which was a thorough, evidence-based assessment using the GRADE system to define the quality of the evidence and the strength of the recommendations. Clinicians should measure an initial follow-up total testosterone level after an appropriate interval to ensure that target testosterone levels have been achieved. Clinicians should adjust testosterone therapy dosing to achieve a total testosterone level in the middle tertile of the normal reference range. Serum estradiol should be measured in testosterone deficient patients who present with breast symptoms or gynecomastia prior to the commencement of testosterone therapy. Serum prolactin levels should be measured in patients with low testosterone levels combined with low or low/normal luteinizing hormone levels. While the FDA retains a warning regarding the potential risk of prostate cancer in patients who are prescribed testosterone products ("patients treated with androgens may be at increased risk for prostate cancer"), there is accumulating evidence against a link between testosterone therapy and prostate cancer development. Given the reproductive profile of the study population, the spermatogenesis results might not be generalizable to patients with testosterone deficiency.332A study of 66 males who presented with infertility while on exogenous testosterone therapy revealed several interesting findings.333 The authors used a total motile sperm count (TMSC) of 5 million as the benchmark for spermatogenesis recovery. 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. Another meta-analysis of 37 studies138 found that diabetic men had significantly lower testosterone values than those who did not have diabetes; individual studies with adjusted point estimates also support this outcome.97, 133, 139 A multivariate logistic regression model from one study of 1,089 men who had total testosterone 94 Corona et al. likewise found that the prevalence of low testosterone levels (defined as total testosterone of 107 Men who were taking medication known to affect androgen production and/or testosterone were likewise excluded. Older meta-analyses from 2007 and 2005 similarly demonstrated no impact of testosterone on lipid profiles.312, 327 No differences were identified in total cholesterol, low-density lipoproteins, or HDL. A second large RCT by Snyder et al.319 used the Functional Assessment of Chronic Illness Therapy-Fatigue scales (range 0-52) in 474 men treated with testosterone for 12 months. Duration of studies and mode of administration did not appear to impact outcomes. For brevity sake, we will not discuss in detail the benefits of T therapy in men with TD since this topic is comprehensively covered by Dr. F. Saad’s chapter in this book, entitled “Testosterone Therapy and Glucose Homeostasis in Men with Testosterone Deficiency (Hypogonadism).” Finally, considerable debate exists with respect to the potential and purported cardiovascular (CV) risks of treating TD with exogenous T. Testosterone (T) either directly or via its transformation into the more potent metabolite 5α-dihydrotestosterone (5α-DHT) or via aromatization into estradiol (E2) modulates important biochemical signaling pathways of human physiology and plays a critical role in the growth and/or maintenance of functions in a host of tissues and organs. These guidelines and best practice statements are not in-tended to provide legal advice about use and misuse of these substances. The physician is encouraged to carefully follow all available prescribing information about indications, contraindications, precautions and warnings. Hyperprolactinemia is an uncommon condition172, 173 but it is a well-established cause of secondary (central) testosterone deficiency and can lead to infertility, decreased libido, sexual dysfunction, and gynecomastia. A low or low/normal LH level points to a secondary (central) hypothalamic-pituitary defect, (hypogonadotropic hypogonadism), while an elevated LH level indicates a primary testicular defect (hypergonadotropic hypogonadism).168 In men with hypogonadotropic hypogonadism, the yield from adjunctive tests (e.g., prolactin measurement, pituitary imaging, iron studies) is increased. LH, which is routinely measured by immunoassay, may help to establish the etiology of testosterone deficiency and can be an important factor in determining if adjunctive tests should be ordered (Appendix C - refer to the Appendix C section in the left menu). Point estimates that measure the difference in testosterone levels between men with and without ED may appear statistically significant, but these estimates are not always clinically meaningful. Despite the methodological limitations, individual studies have shown a link between low testosterone levels and ED. A challenge in making the diagnosis of testosterone deficiency is that many of the symptoms reported by patients are non-specific and might be related to conditions other than low testosterone. By definition, Grade A evidence is evidence about which the Panel has a high level of certainty, Grade B evidence is evidence about which the Panel has a moderate level of certainty, and Grade C evidence is evidence about which the Panel has a low level of certainty. The categorization of evidence strength is conceptually distinct from the quality of individual studies. Evidence tables (for included studies) and evidence profiles (showing estimates of effect for the outcomes of interest) were generated and presented to the Panel. An evaluation for a prolactinoma in such patients is imperative because these benign tumors can be effectively managed using medications, such as bromocriptine or carbergoline. Their role in diagnosing testosterone deficiency is unclear, and they should not be used at the expense of a full patient evaluation, including laboratory testosterone measurement. Screening questionnaires are not an appropriate tool to identify candidates for testosterone therapy. As such, all patients who have a history of unexplained anemia should have their testosterone tested. There does appear to be a trend towards lower total testosterone and a diagnosis of ED. Other limitations included the possible subjective nature in reporting some adverse events.Conversely, the Shores, 367 Muraleedharan,233 and Baillargeon373 studies determined that there was no increased risk of MACE in men who were on testosterone therapy. Two of the retrospective studies included in the FDA review pointed to an increased risk of cardiovascular events in men on testosterone therapy. Mean peak total testosterone levels are dose-dependent, with a mean of 746, 866, and 913 ng/dL noted with 8, 10, and 12 pellets administered (not BMI adjusted).446 The duration of effect is similar, however, and is relatively independent of dosing. Men with total testosterone level 315 ng/dL declined from 100% at 4 weeks to 86%, 75%, and 14% by 12, 20, and 24 weeks, respectively.Mean peak total testosterone levels are dose-dependent, with a mean of 746, 866, and 913 ng/dL noted with 8, 10, and 12 pellets administered (not BMI adjusted).446 The duration of effect is similar, however, and is relatively independent of dosing. Administration of 750 mg of IM testosterone undecanoate at weeks 0, 4, and every 10 weeks thereafter maintained total testosterone levels between 300-1,000 ng/dL for 94% of men.438 No men experienced maximal values Adverse Effects. Strong Recommendations are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken because net benefit or net harm is substantial. Alternative testosterone therapies included SERMs, hCG, and AIs. The search yielded 15,217 references, 546 (enrolling approximately 350,000 men) of which were used to support guideline statements. The questions were developed based clinical challenges faced by urologists in daily practice. An increase in BMD is an important potential benefit of testosterone therapy for men who might be at risk for LTBF. Improvements in sex drive were also assessed in another meta-analysis performed by Bolona et al.298 Using a variety of measures, the authors demonstrated improvement with a pooled effect of 1.31 (31% increase in sex drive) among men treated with testosterone, with greater improvements noted among men with lower baseline testosterone levels. In trials, patients with low testosterone have demonstrated statistically significant improvements in erectile function, anemia, BMD, lean body mass, and depressive symptoms. However, compared to other agents, short-acting injections can result in longer times in the supra-therapeutic and sub-therapeutic ranges, which may impact overall efficacy and rates of adverse events.By definition, Grade A evidence is evidence about which the Panel has a high level of certainty, Grade B evidence is evidence about which the Panel has a moderate level of certainty, and Grade C evidence is evidence about which the Panel has a low level of certainty.Prior to initiating treatment, clinicians should counsel patients that, at this time, it cannot be stated definitively whether testosterone therapy increases or decreases the risk of cardiovascular events (e.g., myocardial infarction, stroke, cardiovascular-related death, all-cause mortality).If insufficient testosterone levels are achieved with one topical agent, including with dose adjustments, substitution with another topical agent is a viable treatment strategy.420Clinicians 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.The care of testosterone deficient patients should focus on accurate assessment of testosterone levels, symptoms and signs as well as proper on-treatment monitoring to ensure therapeutic testosterone levels are reached and symptoms are ameliorated.Furthermore, it was published at a time when highly controversial views on testosterone and cardiovascular health had not yet received such heightened attention and before the new concepts on testosterone and prostate carcinogenesis were widely publicized. For most pharmaceutical products, the usage, dosage, and application is consistent across brands, and identification by chemical compound is sufficient to communicate to the reader when to use a given medication. The AUA has made an exception for this guideline. Additionally, identifying drugs solely by their chemical compound formulation allows guidelines to remain current, despite the dynamic nature of the marketplace. Where gaps in the evidence existed, the Panel provides guidance in the form of Clinical Principles or Expert Opinion with consensus achieved using a modified Delphi technique if differences of opinion emerged. Conditional Recommendations also can be supported by any evidence strength. Adverse Events of Testosterone Deficiency The wider scope and target audience of clinicians includes Canadian primary care physicians, general internists and internal medicine subspecialists (endocrinologists and geriatricians), and urologists. A small number of professional bodies2,3 have published guidelines on the topic, yet a multidisciplinary guideline with specific Canadian content did not exist. The condition is characterized by deficient testicular production of testosterone. The discussion should include the potential benefits, harms, costs, and patient's preferences. Guideline Statement 30 These are usually men with multiple comorbidities for whom issues related to the diagnosis, management and follow-up of testosterone deficiency syndrome require a patient-centred approach. A further group of interest involves clinical biochemists, psychiatrists, nurse practitioners and pharmacists dealing with men at and beyond middle age with manifestations of testosterone deficiency syndrome. Clinicians should discontinue testosterone treatment in men with age-related low testosterone with sexual dysfunction in whom there is no improvement in sexual function (conditional recommendation; low-certainty evidence). We suggest that when clinicians institute T therapy, they aim at achieving T concentrations in the mid-normal range during treatment with any of the approved formulations, taking into consideration patient preference, pharmacokinetics, formulation-specific adverse effects, treatment burden, and cost. The original guideline search strategy was updated and used to systematically search PubMed for new evidence published between the previous search end date and February 2022. An additional aspect of androgen deficiency is the drug-induced reduction in 5α-DHT levels by the use of 5α-reductase inhibitors. Nevertheless, we believe that there is considerable body of credible evidence to suggest that T therapy of men with TD is safe and effective and provides a host of health benefits and therefore merits considerations in men with TD, irrespective of the underlying cause or etiology. The task force recommends that the initial biochemical test be total testosterone level measured in a blood sample taken in the morning (or within three hours of waking in the case of shift workers), and that determinations of bioavailable testosterone or free testosterone be restricted to patients found to have equivocal low total testosterone levels (Box 2). This guideline is intended to address clinical questions surrounding the diagnosis of testosterone deficiency and the appropriate use of testosterone replacement therapy in the management of these patients. Since the FDA warning in 2015, other studies have failed to demonstrate a risk of cardiovascular events in patients on testosterone therapy. There is no utility in continuing testosterone therapy in men who achieve target testosterone levels without symptom improvement. Patients on testosterone therapy should have serum testosterone levels checked every 6-12 months to ensure maintenance of target levels. In the absence of long-term RCTs evaluating whether testosterone therapy results in cardiovascular benefit or harm, the decision to use testosterone therapy in such patients should be based on a shared decision-making approach between clinicians and patients. For men with on-treatment testosterone levels that fall below the suggested target range but who experience complete resolution of symptoms, there is no need to titrate dosing. The optimal dosing strategy has not been defined for short-acting IM testosterone preparations. Mean testosterone values over a 7-day time period were 1,659, 896, and 422 ng/dL for IM testosterone SQ 100, and SQ 50, respectively. The half-life for IM testosterone was also shorter at 173 hours versus 240 hours for SQ testosterone. Although IM injections are the traditional route for injectable agents, the SQ route has also been described with short-acting agents.437 Taylor et al. reported that clomiphene citrate has outstanding biochemical and clinical efficacy, with increases in serum testosterone similar to those for testosterone gel.400 Additionally, these investigators found that clomiphene has a favorable side effect profile and is less expensive than testosterone gel. Finally, hCG therapy alone or in combination with SERMs has been shown to facilitate recovery of testosterone production and spermatogenesis in men with a prior history of exogenous testosterone use333 or anabolic steroid abuse.334 Return of sperm to the ejaculate in these men can be highly variable, taking up to two years after cessation of exogenous testosterone in some cases, with some men never experiencing return of sperm.334 The overall quantity and quality of studies investigating the use of these alternative agents in males are limited. While SERMs, hCG, and AIs are all categorized as "alternative therapies" to testosterone, they are actually a diverse group of agents. Furthermore, the concept of testosterone 'crash' is well recognized by clinicians, with large differences between peak and trough levels potentially leading patients to become symptomatic towards the end of the cycle despite having therapeutic trough testosterone levels. 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. Liu et al. conducted a double-blind, placebo controlled, randomized trial assessing response to hCG therapy in older men (mean age 67 years) with androgen deficiency.399 The authors found a 150% increase in total testosterone level, which they concluded demonstrates that older males retain "testicular responsiveness" to gonadotropin therapy. As with short-acting IM testosterone injections, the general recommendation is mid-cycle testing, after equilibration, and halfway between the first two 10-week injections. With respect to testosterone specifically, Grober et al. conducted an analysis of compounded testosterone creams/gels from 10 pharmacies in Toronto, Canada.410 Each pharmacy was given two prescriptions for 50 mg of testosterone, separated by 1 month to assess both intra-pharmacy and inter-pharmacy consistency. In 2001, the FDA performed an analysis of internet-purchased, compounded products following reports of contamination, poor compounding processes, and product toxicity.406, 407 Among 29 product samples analyzed, which included testosterone among multiple medications, 31% demonstrated sub-potency ranging from 59-89% below target dose. The product is provided in a metered pump that supplies 5.5 mg of testosterone per actuation. An intranasal testosterone gel applied topically into the nose was approved by the FDA in 2014. The progressive hydration tablet with a matrix containing 30 mg of testosterone is placed in position on the gum above the right or left canine and is held in position for approximately 30 seconds. Adverse effects specific to topical preparations include application site reactions (3-16% erythema or rash), and risk of transference. It is therefore difficult to extrapolate the method of diagnosing pathologic hypogonadism in younger men to clinical decisions regarding age-related testosterone decline in aging men. We conducted a systematic review to estimate the accuracy of clinical symptoms and signs for predicting low testosterone among aging men. TT levels depicted a reduction of 0.14 nmol/L per year between 20 and 44 years of age (p p Overall, tT levels from 2593 men aged 20–44 years were analyzed. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline Despite their economy and ease of administration, their availability on the Internet and the opportunity they provide patients to self-diagnose, the questionnaires cannot be relied upon in the absence of confirmatory history, physical findings and laboratory test results. However, the history and results of the examination collectively would make a strong case for the presumptive diagnosis of the syndrome, thus identifying patients who require biochemical testing. The sequela of osteoporosis becomes evident only when the hypogonadism has been present for long periods.12 None of these findings, alone or in combination, are sufficient to make a diagnosis of testosterone deficiency syndrome. The symptoms are frequently subtle and may be affected by factors such as age, general health, comorbidities and medications, as well as systemic illness and environmental factors.12 Patient history is therefore an important component in the diagnostic process. With worsening Leydig cell function, there is a reduction in the feedback mechanism resulting in elevation of LH levels (hypergonadotropic hypogonadism). In homeostasis, LH levels are typically low. Pituitary dysfunction may be a significant cause of testosterone deficiency. Testosterone deficiency is prevalent in men presenting for an infertility evaluation.159 The testes contain germ cells that produce spermatozoa and Leydig cells that produce testosterone; any pathology of the testes can result in infertility and testosterone deficiency, conditions that frequently co-exist. Clinical outcomes were evaluated by using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system and included sexual function, physical function, quality of life, energy and vitality, depression, cognition, serious adverse events, major adverse cardiovascular events, and other adverse events. This guideline is endorsed by the American Academy of Family Physicians. In men whose total T is near the lower limit of normal or who have a condition that alters sex hormone-binding globulin, we recommend obtaining a free T concentration using either equilibrium dialysis or estimating it using an accurate formula. We recommend confirming the diagnosis by repeating the measurement of morning fasting total T concentrations. The Evaluation and Management of Testosterone Deficiency AUA Guideline provides guidance to the practicing clinician on how to diagnose, treat and monitor the adult male with testosterone deficiency. We wish to clearly state that there are areas of controversies, including whether age-related androgen deficiency (functional hypogonadism) merits treatment and whether T therapy provided real proven benefits. 9 databases were searched from their inception to October 2020, yielding 6 eligible studies, with a total of 206 participants. Cross-sectional studies show inconsistent associations between fat intake and testosterone in men. The evidence also points to the importance of regular follow-up, frequently within the first year after the start of treatment and less stringent thereafter but uninterrupted for the duration of treatment. The use of validated questionnaires is not currently recommended to either define which patients are candidates for testosterone therapy or to monitor symptom response in patients on testosterone therapy. Guidance is also given on the management of patients with cardiovascular disease, men who are interested in preserving their fertility and men who are at risk for or have prostate cancer. We also believe that physicians prescribing 5α-reductase inhibitors (i.e., finasteride or dutasteride) for relief of BPH symptoms or treatment of hair loss should engage their patients in a productive discussion regarding the potential adverse side effects of these medications on their overall health and quality of life. Since the mid-20th century, there have been significant changes in dietary patterns, and men's testosterone levels have declined in western countries. Threshold testosterone levels used for reference standards also varied substantially. In addition, we discuss another critical aspect of unrecognized form of androgen deficiency resulting from inhibition of 5α-reductases with drugs, such as finasteride and dutasteride, to block transformation of T into 5α-DHT in the course of treatment of benign prostatic hyperplasia (BPH) and male pattern hair loss, also known as androgenetic alopecia (AGA).Clinicians should discontinue testosterone treatment in men with age-related low testosterone with sexual dysfunction in whom there is no improvement in sexual function (conditional recommendation; low-certainty evidence).Over a mean duration of 27.5 months, 1,223 men received testosterone therapy, and 7,486 were placed on placebo.Finally, considerable debate exists with respect to the potential and purported cardiovascular (CV) risks of treating TD with exogenous T.While seven of the trials in the above analysis showed decreased, but statistically insignificant, odds of having a cardiac event while on testosterone therapy, one trial did show an increased risk.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.Initial studies of testosterone patches demonstrated increases in total testosterone from a baseline 167 ng/dL to a peak of 1,154 ng/dL at 5.7 hours, with a decrease to 490 ng/dL over the next 12 hours.424 Following removal, the observed testosterone half-life was 116 minutes.425, 426 A multicenter, open label study confirmed mirroring of the circadian rhythm when the patch is applied in the evening with a morning peak of 740 ng/dL and a night-time trough of 213 ng/dL.427 While these guidelines do not necessarily establish the standard of care, AUA seeks to recommend and to encourage compliance by practitioners with current best practices related to the condition being treated. The mission of the Panel was to develop recommendations that are analysis-based or consensus-based, depending on Panel processes and available data, for optimal clinical practices in the treatment of muscle-invasive bladder cancer. During the subsequent year of follow-up, eight men from the placebo group and one man who had been on treatment were adjudicated to have had a definite myocardial infarction. At the end of the year-long treatment period, two men from the treatment arm had a definite myocardial infarction, and none were recorded in the placebo arm. Two of the trials and one meta-analysis pointed to an increased risk of cardiovascular events,363, 364, 366 two revealed no cardiovascular risk,233, 367 and one was neutral with respect to risk.373 The Corona meta-analysis,372 which showed that there was no increased risk of cardiovascular events, was not officially reviewed but was taken into consideration in the final analysis. The progressive hydration tablet with a matrix containing 30 mg of testosterone is placed in position on the gum above the right or left canine and is held in position for approximately 30 seconds.Mean peak total testosterone levels are dose-dependent, with a mean of 746, 866, and 913 ng/dL noted with 8, 10, and 12 pellets administered (not BMI adjusted).446 The duration of effect is similar, however, and is relatively independent of dosing.It was decided that a cut-off value was critical to define testosterone deficiency and that this cut-off be based on at least two total testosterone levels drawn in an early morning fashion at the same laboratory using the same assay.At the end of the year-long treatment period, two men from the treatment arm had a definite myocardial infarction, and none were recorded in the placebo arm.Men who have a history of chronic corticosteroid use have been shown to be at risk for low testosterone levels.Thus, a patient is considered testosterone deficient and a candidate for testosterone therapy only when he meets both criteria.The overall quantity and quality of studies investigating the use of these alternative agents in males are limited.The population addressed in this article comprises men with clinical manifestations compatible with testosterone deficiency syndrome and laboratory confirmation of testosterone deficiency in Canada. We recommend T therapy for men with symptomatic T deficiency to induce and maintain secondary sex characteristics and correct symptoms of hypogonadism after discussing the potential benefits and risks of therapy and of monitoring therapy and involving the patient in decision making. Although the study was not powered to detect cardiovascular events as a primary endpoint, the authors did not detect increased risk in the testosterone group. The authors conducted a retrospective analysis of 6,355 Medicare beneficiaries who had at least 1 testosterone injection (mean number of injections over the entire study period 8.2) and matched them to 19,065 men who were testosterone therapy naïve for the preceding 12 months. Despite the homogenous nature of the trials included, it was noted that there was a risk of publication bias since it is possible that trials favoring testosterone therapy might remain unpublished. Subcutaneous pellets Available studies are retrospective in nature but have suggested that post-RT patients (with or without ADT exposure) placed on testosterone therapy do not experience recurrence of prostate cancer. Currently published studies have not demonstrated an increased risk of biochemical cancer recurrence in post-RP patients who are on testosterone therapy, nor does it define the optimal timing for commencement of testosterone therapy. The treatment and placebo arms did not differ at baseline in terms of age (62.9 years versus 64.4 years, respectively), total testosterone level (320 ng/dL versus 344 ng/dL, respectively), or PSA measurements (1.3 ng/mL in both arms). Despite the absence of definitive evidence, the Panel recommends that patients with these symptoms be counseled regarding the possibility of improvement on testosterone therapy. For example, outcomes of meta-analyses using RCTs alone are generally more robust than those that also include cohort studies. When reviewing results from meta-analyses, it is important to recognize that the overall reliability is dependent on the quality of the weakest study included in the analysis. Patients who are on long-acting SQ pellets require two separate assessments of testosterone to determine the dose and frequency required. While definitive age-specific reference ranges do not exist, some data suggest that patient age may play a role in setting therapeutic ranges, at least in the elderly population. One RCT by Maggi et al. followed 715 testosterone deficient men for 12 weeks to evaluate the effects of a 2% transdermal testosterone agent on sex drive and energy. All patients had PSA and digital rectal exams every three months and biopsies annually. Three others did stop testosterone in response to the PSA bounce, two of whom had negative prostate biopsies. Testosterone therapy can be considered in those men who have undergone radical prostatectomy (RP) with favorable pathology (e.g., negative margins, negative seminal vesicles, negative lymph nodes), and who have undetectable PSA postoperatively. In-vitro experiments have shown that prostate cancer cells fail to proliferate in the absence of testosterone; once testosterone is introduced, an initial proliferative response is observed followed by a plateau after a certain testosterone concentration is reached. The other men in the study already had metastatic disease at the time of testosterone initiation. In this population, exogenous testosterone was stopped and combination high-dose hCG and SERM therapy was initiated. Compared to placebo, no significant changes were noted with testosterone therapy, including when the data were evaluated as a continuous or dichotomous (≥4 point change) variable.A meta-analysis of RCTs developed in support of this guideline indicate that there is no significant difference in MACE in men on testosterone therapy when compared to placebo.In the clinical trial leading to FDA approval, side effects related to nasal delivery included nasopharyngitis, rhinorrhea, and epistaxis occurring in 7-10% of men.436Patients 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.Men who are on testosterone therapy should be advised to report the occurrence of any possible cardiovascular symptoms, such as chest pain, shortness of breath, dizziness, or transient loss of consciousness, during routine follow-up visits.Mild level adverse events specific to SQ pellet insertion includes polycythemia (48-50%), ecchymosis (32-36%), tenderness (20-32%), pain (28-29%), and swelling (16-18%), all of which resolve by 4 months post-insertion.446 Moderate level adverse events were less common (e.g., pain 3%, erythema 3%, ecchymoses 7%) and improved within 1 week. Guideline Statement 14 Only one man in the treatment group was diagnosed with prostate cancer during the study period; two more who had been on treatment and one on placebo were diagnosed in the following year.229 The Testim Registry in the United States followed PSA changes in men without prostate cancer who were on testosterone therapy. The literature indicates that men with lower baseline testosterone levels are more likely to experience PSA level increases. The 2012 guideline is fundamentally in agreement with the recommendations in our guideline, but it does not include more recent publications. More information on advantages and disadvantages of available products, including costs, is outlined in Tables 7 and 8 of Appendix 1. Compounded testosterone products are available at many compounding pharmacies in Canada, but there are no published data on the safety and efficacy of these products. A persistent failure to respond to testosterone supplementation requires a reassessment of the diagnosis or consideration for referral to a more specialized facility. Monitoring is an integral and mandatory part of the management of hypogonadism. Transdermal Agents - Gels and Solutions Gynecomastia is a benign enlargement of the male breast tissue that can occur at times of male androgen/estrogen change (alteration in testosterone/estradiol E2 ratio), infancy, adolescence, or old age, and may be a sign of low serum testosterone. To minimize these effects, two morning draws for testosterone are recommended before any clinical intervention. To minimize these effects, two morning draws for testosterone are recommended before any clinical intervention.Acute Illness. Conversely, a population-based retrospective case-control study utilizing a UK clinical database of 19,215 patients with confirmed VTE showed that there was increased risk of VTE in the first 6 months of testosterone therapy.Other limitations included the possible subjective nature in reporting some adverse events.Conversely, concerns about testosterone supplementation promoting the development and growth of prostate cancer and benign hyperplasia have long been based on extrapolations more so than on real proof or verification.Of these, 14 biopsies (54%) revealed no cancer, and no patients required additional biopsy for clinical concerns.357PSA Monitoring.Given the mechanisms of action of anastrozole, clomiphene citrate, and hCG, patients using these medications should wait a longer period before follow-up blood work is performed.The potential benefits and harms that can be expected from testosterone supplementation are listed in Table 1.17,18 Lack of or an inadequate clinical response to testosterone treatment should call for changes in the form of delivery, the dose or the frequency of administration. In 2013, the AUA published the Early Detection of Prostate Cancer Guideline,222 which makes no specific statements about PSA screening in men with testosterone deficiency or in men on testosterone therapy. If the Hct exceeds 50%, clinicians should consider withholding testosterone therapy until the etiology of the high Hct is explained.187 While on testosterone therapy, a Hct ≥54% warrants intervention. Another multi-center study compared the effectiveness and risks of transdermal and IM testosterone in 66 men aged years old. After 180 days of treatment, only 1 patient in the 50mg gel arm, 3 patients in the 100mg gel arm, and no patients in the testosterone patch arm were found to have gynecomastia. In randomized, placebo-controlled trials involving testosterone therapy this has been a rarely reported adverse event. Body of evidence strength Grade C in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances but that better evidence is likely to change confidence. Body of evidence strength Grade B in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances but that better evidence could change confidence. Body of evidence strength Grade A in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances and that future research is unlikely to change confidence. The AUA nomenclature system explicitly links statement type to body of evidence strength, level of certainty, magnitude of benefit or risk/burdens, and the Panel's judgment regarding the balance between benefits and risks/burdens (Table 1 - See button below). Clinicians should be aware that symptomatic gynecomastia or other breast symptoms are an uncommon side effect in men on testosterone therapy. Furthermore, the identification of other pituitary tumors or processes may have important clinical implications for the patient beyond testosterone deficiency.178 Hypergonadotropic hypogonadism, which is not a contraindication to begin testosterone therapy, can result from a number of conditions, including congenital abnormalities (KS being the most common), iatrogenic causes (e.g., bilateral orchiectomy, testicular radiation, chemotherapy), testicular trauma, infection, or autoimmune damage. The validation studies for each questionnaire use a distinct total testosterone cut-off for defining low testosterone; however, total testosterone has been shown to correlate poorly with most questions.164, 165 Men with European ancestry may experience a greater decrease in testosterone, in response to a low-fat diet. Cochrane's risk of bias tool was used for quality assessment. Random effects meta-analyses were performed using Cochrane's Review Manager software. Display of kappa values for each study. Mild level adverse events specific to SQ pellet insertion includes polycythemia (48-50%), ecchymosis (32-36%), tenderness (20-32%), pain (28-29%), and swelling (16-18%), all of which resolve by 4 months post-insertion.446 Moderate level adverse events were less common (e.g., pain 3%, erythema 3%, ecchymoses 7%) and improved within 1 week. These data are notable as they demonstrate far less variability between peak and trough levels compared to shorter-acting preparations.441, 442 Results after the third injection demonstrated median peak and trough T levels of 813 ng/dL and 317 ng/dL, respectively, with overall median values of 476 ng/dL during the 10-week period. However, compared to other agents, short-acting injections can result in longer times in the supra-therapeutic and sub-therapeutic ranges, which may impact overall efficacy and rates of adverse events. It restores the circulating testosterone level to the physiological range. Total testosterone values obtained at 4p.m.When body of evidence strength Grade C is used, there is uncertainty regarding the balance between benefits and risks/burdens, alternative strategies may be equally reasonable, and better evidence is likely to change confidence.However, any person or company accessing AUA guidelines for promotional or commercial use must obtain a licensed copy.The document places a high priority on the identification and treatment of symptomatic men, and the improvement of patient outcomes.Expert Opinion refers to a statement, achieved by consensus of the Panel, that is based on members' clinical training, experience, knowledge, and judgment for which there is no evidence.No differences were identified in total cholesterol, low-density lipoproteins, or HDL.The testosterone therapeutic space is relatively unique.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 achieve the appropriate therapeutic level.In this article, we identify and address the knowledge gaps across disciplines to assist a variety of health professionals in their clinical decision-making in managing testosterone deficiency syndrome. It is possible that exercise programs coupled with diet may have a greater likelihood of success in achieving increases in total testosterone over calorie-restricted diets alone. Increases in testosterone for patients who lose weight might be cumulative over time. Of these, 14 biopsies (54%) revealed no cancer, and no patients required additional biopsy for clinical concerns.357 A discussion regarding the benefit of stopping testosterone therapy should include the possibility of a decline in PSA. Following inverse propensity treatment weighting, the cumulative percentage of patients who met the primary outcome 3 years post-angiography was 25.7% on treatment and 19.9% in the placebo group. In the testosterone therapy group, the raw data revealed a 2% myocardial infarction rate and a 3% cerebrovascular accident rate compared to 6% and 6%, respectively, in those patients not receiving testosterone. Vigen et al. (2013)363 conducted a retrospective analysis of patients who received a prescription for testosterone therapy after coronary angiography. Although the absolute risks of POME and anaphylaxis require ongoing study, data from 342 patients undergoing 3,022 injections (1,000 mg in 4 mL) over a period of 3.5 years demonstrated that POME occurred after 1.9% of injections (12% of patients experienced at least one POME), with coughing episodes lasting 1-10 minutes in duration.443 All episodes were managed conservatively in the clinic, with no supplemental oxygen required. One study reported comparative pharmacokinetics between IM testosterone enanthate (250 mg every 3 weeks) and IM testosterone undenaconate (1,000 mg every 9 weeks, a dosage that is only available outside the United States).440 Results demonstrated that IM testosterone enanthate achieved trough levels of 239 ng/dL compared to 470 ng/dL with IM testosterone undecanoate at the end of the 10-week cycle. In a small study of young men with acute respiratory infections, mean total testosterone levels declined by 10%, with some cohorts experiencing reductions of up to 30%.25 Where possible, clinicians should use LCMS to measure total testosterone levels to maximize accuracy and limit CV between tests in men undergoing testing, particularly in men with very low total testosterone levels. It was decided that a cut-off value was critical to define testosterone deficiency and that this cut-off be based on at least two total testosterone levels drawn in an early morning fashion at the same laboratory using the same assay. 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. Several meta-analyses have evaluated the impact of testosterone therapy on lipid profiles. Other meta-analyses that have included observational studies with less stringent inclusion criteria have demonstrated variable improvements in fasting glucose, insulin resistance, and HbA1c levels.138, 325, 326 One trial with three years of follow-up showed near linear, time-dependent improvements in BMD.202 These findings are similar to other prospective, controlled data, which report an estimated 5% per year increase in BMD in men on testosterone therapy.309 Declining bone density may necessitate additional medical intervention, such as weight bearing exercise, calcium, vitamin D, or bisphosphonate medications. Functioning prolactinomas result in hyperprolactinemia, suppressing LH production and leading to low testosterone levels. A survey of 120 patients who were treated for infertility at the University of Illinois-Chicago found that the incidence of testosterone deficiency was 45% in men with non-obstructive azoospermia, 42.9% in men with oligospermia, and 16.7% in men with obstructive azoospermia.159 At this time, identification of the optimal patient (based on age, varicocele grade, baseline testosterone level) has not been defined.75 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. 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. At baseline, 22 patients had total testosterone 375 A meta-analysis of RCTs developed in support of this guideline indicate that there is no significant difference in MACE in men on testosterone therapy when compared to placebo. Minimal data were found regarding outcomes of frailty, risk of venous thromboembolism, hyperestrogenemia, sleep apnea, prostate biopsy, recurrence of treated prostate cancer, and incidence of breast cancer. Of the outcomes included in the protocol of this systematic review, data were available on quality of life (QoL), sexual function, cardiovascular events, anemia, bone health, insulin resistance, cardiovascular risk factors, mood, cognitive function, body composition, and numerous adverse events. A systematic review of the published literature was conducted to answer these key questions and provide the evidence base for the guideline. To be scientifically accurate, the Panel chose the term testosterone deficiency. We wish to clearly state that there are areas of controversies, including whether age-related androgen deficiency (functional hypogonadism) merits treatment and whether T therapy provided real proven benefits. Today these evidence-based guidelines statements represent not absolute mandates but provisional proposals for treatment under the specific conditions described in each document. Although confounders were accounted for in the analysis, concurrent medications that may have reduced the risk for myocardial infarction or other testosterone therapies used outside of the study protocol were not controlled for or assessed. The guideline panel developed a priori 15 key questions from which guideline statements were derived. Hypogonadism has more recently been used interchangeably with the idea of low testosterone production alone. Commercially manufactured testosterone products should be prescribed rather than compounded testosterone, when possible. Clinicians should not prescribe alkylated oral testosterone. Considering the inherent confusion surrounding testosterone therapy in the current prescribing landscape, the AUA believes it is imperative to be as explicit as possible and present the reader the most complete information, which will optimize the efficacy and safety of testosterone therapy. A Clinical Principle is a statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature. When body of evidence strength Grade B is used, benefits and risks/burdens appear balanced, the best action also depends on individual patient circumstances, and better evidence could change confidence. When body of evidence strength is Grade A, the statement indicates that benefits and risks/burdens appear balanced, the best action depends on patient circumstances, and future research is unlikely to change confidence. SERMs are oral agents that block E2 feedback resulting in increased LH secretion. However, despite these limitations, several studies provide important insights into the impact of SERMs, AIs, and hCG on spermatogenesis. Clinicians should understand that of these agents, only hCG has been approved by the FDA for use in males, specifically to treat males with hypogonadotropic hypogonadism. There are conflicting results in the literature as to whether testosterone therapy has a significant impact on these symptoms. Men who seek medical care for possible testosterone therapy often present with non-specific symptoms, such as low energy and fatigue, which can be manifestations of other conditions, such as chronic stress, chronic fatigue, and depression. The rate of remission was also higher in a statistically significant manner among dysthymic men receiving testosterone therapy (53%) compared to placebo (19%).317, 318 However, the literature at this time fails to define the LH level below which such adjunctive testing is warranted. The validated instruments include ADAM, Quantitative ADAM, Aging Male Survey (AMS), MMAS, and the ANDROTEST.10, 166, 167 Specificities and sensitivities vary greatly amongst these tests making them ill-suited for screening or for use as a surrogate for testosterone laboratory testing. Radiation to the brain that exposes the pituitary gland can also result in pituitary dysfunction and low testosterone. Testosterone therapy should not be commenced for a period of three to six months in patients with a history of cardiovascular events. At the end of the study, total testosterone increased in both groups with neither group deriving more benefit than the other (p ≥ 0.244). For further information on the testosterone therapy and the risk of MACE, please see Appendix D (in the Appendix D section in the left menu). In 2014, the FDA added a warning to testosterone product labeling after reviewing five observational studies and two meta-analyses of RCTs that examined the effects of testosterone therapy on MACE. There were inconsistently defined end points to categorize severe cardiac events, which included 'softer' endpoints (e.g., edema, tachycardia, hypertension) along with myocardial infarction and stroke.194 The statistical analysis did not account for confounding factors; the duration of follow-up varied widely, from 12 weeks to 3 years; and many of the trials were not powered to detect cardiac events as primary endpoints, rather they were catalogued as adverse outcomes. Thresholds for low testosterone were not universal. If the testosterone concentration is increased further, rather than further proliferation, the cells reduce their rate of proliferation.343, 344 This phenomenon is known as the bipolar testosterone concept. 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. 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. Until there is definitive evidence proving an association between testosterone therapy and subsequent MACE, the Panel recommends that clinicians counsel patients that the current scientific literature does not definitively demonstrate that testosterone therapy increases risk. Conversely, a population-based retrospective case-control study utilizing a UK clinical database of 19,215 patients with confirmed VTE showed that there was increased risk of VTE in the first 6 months of testosterone therapy. At the end of the study, serum testosterone levels rose in those men receiving testosterone therapy; however, no rise in testosterone levels were seen within the prostate tissue itself. It is the opinion of this Panel that until there is definitive evidence demonstrating that testosterone therapy is not safe for use in prostate cancer patients, the decision to commence testosterone therapy in men with a history of prostate cancer is a negotiated decision based on the perceived potential benefit of treatment. As with all AUA guideline documents, recommendations are based where possible on data extracted from the evidence report, which was generated by methodologists from Mayo Clinic. Please refer to Table 7 below for a summary of follow-up testing for men being treated for testosterone deficiency. 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 achieve the appropriate therapeutic level. Patients on short-acting IM or short-acting SQ pellets (testosterone cypionate or enanthate) should have their testosterone measured after several cycles such that testosterone level equilibration has been achieved. Clinicians should counsel patients on the association between low testosterone and the increased risk of cardiovascular events, as well as the ill-defined cardiovascular risks and benefits of testosterone therapy in the testosterone deficient patient. Studies that randomized overweight or obese men to diet and exercise programs had significantly greater increases in total testosterone levels than men who underwent calorie reduction or exercise programs alone.378, 379 It is also postulated that men who engage in quantitatively more exercise have the greatest increases in serum testosterone from baseline.378 A study by Pastuszak et al. (2015)355 found a significant increase in biochemical recurrence in high-risk patients who received testosterone therapy after RT or RT/ADT. Across the prevalence literature, the cut-off values used to define low testosterone vary widely, heterogeneity exists in the populations studied, the forms of testosterone used to measure testosterone (total and/or free) are not consistent, and the assays utilized to measure testosterone differ. The prevalence of testosterone deficiency in the American male population is difficult to quantify. A detailed profile of the therapeutic agents discussed in this guideline can be found in Appendix B (in the Appendix B section in the left menu). Finally, testosterone pellets are also available in branded form, with no generic agents currently available.