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. Men who were taking medication known to affect androgen production and/or testosterone were likewise excluded. Increasing patient age and increasing duration of prior exogenous testosterone use both significantly reduced the likelihood of reaching the 5 million TMSC benchmark. In this population, exogenous testosterone was stopped and combination high-dose hCG and SERM therapy was initiated. 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. Some research suggests it may improve growth factor receptor sensitivity, but it does not increase growth hormone levels or replace natural secretion. No evidence shows direct stimulation of testosterone production. Today these evidence-based guidelines statements represent not absolute mandates but provisional proposals for treatment under the specific conditions described in each document. 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. 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. 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. Testosterone therapy refers to all forms of treatment that are aimed at increasing serum testosterone, including exogenous testosterone as well as alternative strategies, such as selective estrogen receptor modulators (SERMs), human chorionic gonadotropin (hCG) or aromatase inhibitors (AIs). The Panel explicitly uses the term testosterone therapy rather than testosterone replacement therapy or testosterone supplementation to be in keeping with the beliefs of the current thought leaders in the field. 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. 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. RCTs have failed to categorically define if testosterone therapy increases the incidence of MACE when compared to placebo. As such, low testosterone is likely better considered as a covariate with these comorbid conditions rather than as an independent observation. Specifically, the AUA does not recommend routine PSA testing in men years of age unless they are at higher risk (e.g., positive family history, African American race), at which point decisions regarding PSA testing should be individualized. For patients who have an elevated PSA at baseline, a second PSA test is recommended to rule out a spurious elevation. Finally, a randomized trial of 76 men (mean age 50.6 years), who had at least 1 ejaculatory dysfunction symptom and at least 2 testosterone tests 182 In the IM testosterone group, there were no new cases of gynecomastia, and one patient with pre-existing gynecomastia had gynecomastia resolution.181 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. Hypogonadotropic hypogonadism can result from a number of conditions, including congenital abnormalities (e.g., Kallman syndrome), as well as pituitary or suprasellar tumors, pituitary infiltrative disorders (e.g., hemochromatosis, tuberculosis, sarcoidosis, histiocytosis), medications (i.e., chronic narcotic exposure), hyperprolactinemia, prior head trauma, pituitary apoplexy, and severe chronic illness. There are inherent challenges in testosterone measurement due to the health status of patients at the time of testing, circadian rhythms in testosterone production, intra-individual variability, and inconsistencies in the assays themselves. One strategy is to further evaluate patients using adjunctive tests, which might strengthen an argument for a short-term trial of testosterone therapy. However, as the testosterone literature uses absolute values to define low testosterone, the absolute value is ultimately the most important factor to determine whether patients may expect to achieve benefits with testosterone therapy. Other population-based studies have attempted to measure prevalence, but have not used standard methodology, which makes arriving at a definitive number of testosterone deficiency difficult. 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). Randomized controlled trials (RCTs) were sought for effectiveness questions, whereas both randomized and non-randomized studies were sought for adverse events and questions of association and risk factors.
