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. For patients on daily medication, the Panel recommends that patients use medication the day of follow-up blood work. In addition to issues relating to the reliability of compounded products themselves, appropriate clinical studies on pharmacokinetics are lacking. In contrast to commercial pharmaceutical manufacturing, which is regulated by the FDA, compounded medications are regulated by state laws and, therefore, vary significantly from one region to another.405 While testosterone gels and creams are the most commonly used forms of compounded testosterone therapies and are routinely less expensive than branded forms of testosterone, these preparations by individual pharmacies occur without direct FDA oversight and approval. + FDA approved for use in males with hypogonadotropic hypogonadism and pediatric patients with cryptorchidism. Despite these effects, neither treatment led to significant changes in semen parameters.403 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. Inconsistent dosing, contamination, residual solvents, and improper storage conditions can significantly increase risk. These studies have generally demonstrated low toxicity, strong tolerance, and minimal adverse effects across a range of doses. Most of the available data on BPC-157 comes from animal and preclinical studies. 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. Clinicians should be aware that symptomatic gynecomastia or other breast symptoms are an uncommon side effect in men on testosterone therapy. For men who develop gynecomastia/breast symptoms while on treatment (e.g., breast pain, breast tenderness, nipple tenderness), a period of monitoring based on clinical judgment should be considered, as breast symptoms sometimes abate. 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. 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. It is unclear if the transferred testosterone remained biologically active. Populations at increased risk of adverse effects from transference include women and children, however very limited data are available on the true risks of transference with topical agents. Topical testosterone preparations (e.g., gels, creams, liquids) have the potential to result in transference to others. Given the availability of other approved testosterone therapies, the use of 17-alpha-akylated androgens is not appropriate. 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. Finally, testosterone pellets are also available in branded form, with no generic agents currently available. 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 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. 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. An exception can be made if patients do not have symptoms but have documented BMD loss. Testing intervals are the expert opinion of the Panel and are provided as a guide to aid clinicians in the follow-up of such patients. Please refer to Table 7 below for a summary of follow-up testing for men being treated for testosterone deficiency. Patients who are on long-acting SQ pellets require two separate assessments of testosterone to determine the dose and frequency required. 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). 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.
