Although one objective of meta-analyses is to increase study power to identify significant results, this often results in an amalgamation of studies that may have different primary and secondary endpoints, thereby reducing the reliability of the outcomes. It also highlights that treating clinicians should have specific endpoints for treatment in mind, with regular monitoring of these outcomes to assure that ongoing therapy is warranted and effective. Individual study factors, such as the heterogeneity and demographics of the study population, the comorbidities of the study population and how they are controlled in the analysis, and confidence intervals also impact overall study quality. 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. To accurately interpret the published testosterone literature, it is important to critically evaluate various aspects of study design, including the population evaluated, study inclusion/exclusion criteria, duration of follow-up, primary endpoints, adverse event reporting, statistical reporting, and clinical relevance of findings. In this clinical scenario, an argument can be made to continue testosterone therapy. Three others did stop testosterone in response to the PSA bounce, two of whom had negative prostate biopsies. There is also a dearth of data evaluating the safety of testosterone therapy in men treated with radiation therapy (RT). 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. From a clinical standpoint, it dictates that there is a testosterone threshold beyond which prostate cells (benign or malignant) cease responding. 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. Moderate 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 moderate. 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. 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. Complex statistical analysis using a methodology known a stabilized inverse propensity treatment weighting was utilized to adjust for 50 potentially confounding variables. SQ testosterone pellets were initially developed and FDA approved in 1972 and were reformulated in the USA in 2008. Findings are similar to the previously cited pharmacokinetic study (750 mg in 3 mL) in which one patient in 130 (438 It is notable that similar findings have also been observed with other oil-based testosterone preparations that are currently most often self-administered at home (typically with lower volumes of injection).445 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. While the Panel is unable to quantify what percentage of men with ED and testosterone deficiency experience clinically meaningful improvements in erectile function (in contrast to statistically significant improvements) or the ability to achieve a functional erection, it is clear that some men will have improvement in erectile function with testosterone therapy. Study duration was also short, with only one study performed for 52 weeks.229 This may underestimate the true benefits of therapy as long-term prospective data suggest ongoing and slowly progressive improvements in erectile function occurring up to three years after treatment initiation.297 In trials, patients with low testosterone have demonstrated statistically significant improvements in erectile function, anemia, BMD, lean body mass, and depressive symptoms. The Testim Registry in the United States followed PSA changes in men without prostate cancer who were on testosterone therapy. 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. While the therapeutic aim of each of these alternative therapies is to increase endogenous testosterone production, clinicians must keep in mind that the benefits of exogenous testosterone therapy in testosterone deficient men cannot be extrapolated to the benefits provided by these alternative therapies. Most studies assessing hCG efficacy have been performed in males with congenital/idiopathic hypogonadotropic hypogonadism.397, 398 While the literature regarding hCG use in adult males with symptomatic testosterone deficiency is less robust, several important reports are worth discussing. It is approved in some countries for treatment of testosterone deficiency but is not currently approved in the US. Methyltestosterone is an oral androgen modified at the 17-alpha position resulting in decreased first pass hepatic clearance and is approved in the US for treatment of testosterone deficiency. 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. The currently available literature does not provide enough evidence to offer clear guidance on the use of testosterone therapy in men with existing, stable atherosclerotic CVD and/or a remote history of a myocardial infarction or a cerebrovascular accident. A larger study that examined the contraceptive efficacy of testosterone-induced azoospermia in men was conducted by the WHO Task Force on Methods for the Regulation of Male Fertility.385 A total of 271 healthy, fertile men across 7 countries were given 200 mg IM testosterone enanthate every week for 12 months.
