To ensure accuracy and precision, it is necessary to obtain at least two serum total testosterone measurements in an early morning fashion to diagnose patients with low testosterone. Given that the direct method for free testosterone measurement is also time-consuming and labor intensive, calculation derived free testosterone measurement is more commonly used, however there is considerable variation in total testosterone assays as well as the clinical conditions that affect serum albumin and SHBG, all of which impact this measurement. The Panel recommends that clinicians use the same laboratory with the same method/instrumentation for serial total testosterone measurement. There is a great deal of variability across studies with respect to the forms of testosterone measured (total versus free), the assays utilized to measure testosterone, the time of day when the sample is obtained, and the number of testosterone measurements taken. Establishing total testosterone thresholds for a diagnosis of testosterone deficiency is challenging considering the heterogeneity that exists in the testosterone deficiency literature. 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. If SHBG levels are low/free testosterone levels are high, dose adjustment of the testosterone therapy should be considered. In men with elevated Hct and high on-treatment testosterone levels, dose adjustment should be attempted as first-line management. Several validated questionnaires are used as screening tools to identify men at high risk for testosterone deficiency, but there is an absence of concordance among the questionnaires as to what symptoms are related to low testosterone or to what extent these symptoms improve with treatment. Men who have a history of chronic corticosteroid use have been shown to be at risk for low testosterone levels. However, an analysis of Huggins' original paper reveals that this assumption was based on a single patient who was cancer and androgen therapy naïve at study onset. Using stricter criteria for inclusion (only RCTs), Cai et al.324 demonstrated minor improvements in triglycerides (-13.5 mg/dL) among testosterone treated men in 4 RCTs of men with testosterone deficiency. Using very lenient study selection criteria (all types of trials, including observational), Corona et al.325 identified improvements in total cholesterol, triglycerides, and high-density lipoproteins (HDL). For trough total testosterone values 300 ng/dL are achieved at the end of an injection period. In contrast to topical agents where a percentage of men have difficulty achieving therapeutic levels within standard dosing ranges, injectable testosterone preparations are able to achieve therapeutic levels in almost any clinical scenario. While mid-cycle testing is convenient for patients, there may be value in assessing peak level (18-36 hours after injection) as the adverse events (e.g., polycythemia, hyperestrogenism) are likely at least partially related to the peak level. Sixty-nine of 73 men (90%) had an average testosterone concentration within the specified normal range for the study (300-1,050 ng/dL). There is no consistent data at this time that demonstrate that one agent achieves higher serum levels than others. 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.
