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 In men with testosterone deficiency, testosterone therapy results in increased lean muscle mass and reduced fat mass, but no overall changes in BMI. 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. 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. You must first understand that the total testosterone level is not a true marker by which qualitative and quantitive symptoms can be gauged. The dose of hCG for off label use in hypogonadotropic men is between 500 to 2000 IU two or three times a week.111 Serum testosterone after hCG administration should be in the mid adult male range and dose can be adjusted to keep testosterone within this range. The prescription instructions indicate 2 to 6 implants will last 3 to 4 months; however, clinical studies showed that 6 to 12 pellets increased serum testosterone concentration in hypogonadal men to the adult male range within a month. Dose adjustment was based on the trough testosterone level (at the lower reference range) before the next injection. This oral testosterone undecanoate provides adult male range levels in 72 to 88% of hypogonadal men, and has been tentatively approved by the FDA.70 A new oral formulation of testosterone undecanoate in self-emulsifying drug delivery system (Jatenzo®) was able to increase serum testosterone concentration to the adult male range when administered with food twice a day66,67. Most testosterone gels maintain serum testosterone concentrations within the adult male range for about 24 hours. This is why we carefully titrate the prescribed dose of testosterone and HCG according to effect. The aim of Testosterone Optimisation Therapy (TOT) is to optimise your androgen levels so that you feel the qualitative and quantitative benefits of having healthy hormonal levels. The aim of Testosterone Replacement Therapy (TRT) is to restore your androgen levels to within normal physiological parameters. Testosterone treatment induces reversible suppression of spermatogenesis; if fertility is desired in the near future, human chronic gonadotropin, selective estrogen receptor modulator, estrogen antagonist or an aromatase inhibitor that stimulate endogenous testosterone production may be used. All approved testosterone replacement methods, when used according to recommendations, can restore normal serum testosterone concentrations, and relieve symptoms in most hypogonadal men. Meta-analyses that are limited to only including RCTs may be restricted to a small number of studies and relevant studies may be excluded that could provide sufficient power to make alternative conclusions. 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. 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. 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. Testosterone enanthate administered weekly by an autoinjector may provide a viable option for some men with hypogonadism.76 Testosterone undecanoate in castor oil is also available as a 250 mg/mL deep intramuscular injection (Aveed®) in the United States. The short acting testosterone propionate was available in 1939 and the medium longer acting testosterone enanthate in 1954. Because only about 10 percent of testosterone is absorbed into the subdermal tissues, the rest remains on the skin until it is washed off. A 2% testosterone lotion (Axiron, not hydroalcoholic) was developed to be applied to the axilla. Treatment with the 100 mg gel resulted in a 173% increase in mean Cavg from baseline compared with the T patch group, with 95% of patients in the 100 mg gel group achieving mean Cavg above 10.4 nmol/L (300 ng/dl). Within 30 days of treatment, the increase in mean Cavg from baseline was similar in the 50 mg gel and T patch groups (50%). The primary efficacy endpoint was met, with 77.5% (100/129) of patients achieving Cavg within the normal range, defined as 10.4 to 39.5 nmol/L (300–1140 ng/dl), on day 90. FORTESTA® is available with a metered‐dose pump delivering 0.5 g gel (10 mg of T) per pump actuation, with the recommended starting dose of 40 mg of T (4 pump actuations) applied once daily to the thighs in the morning.67 The PK profile and safety of FORTESTA®, a 2% T gel, were evaluated in a multicenter, 90‐day, open‐label non‐comparative trial of 149 men with TD.68 Men started with a 40 mg dose, and adjustments were made on days 14, 35, and 60 in 10 mg increments to between 10 and 70 mg/day. The primary endpoint was met, with 81.6% (146/179) of patients achieving Cavg within the pre‐specified range (10.4–34.7 nmol/L, or 300–1000 ng/dl) on day 112. The above data demonstrates that the current recommendations regarding dose and injection frequency do not achieve this. The primary aim of TRT is to achieve stable hormone levels within the body so that homeostasis is maintained. It is recognised that there is variance of the peak and trough levels between individuals(6) and so the data cannot apply to everybody. According the British National Formulary, a single dose of 250mg Testosterone Enanthate should be injected every 2-3 weeks(1). 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 The literature indicates that men with lower baseline testosterone levels are more likely to experience PSA level increases. 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. Another multi-center study compared the effectiveness and risks of transdermal and IM testosterone in 66 men aged years old. 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 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. In another study of SC administration of testosterone enanthate (50 or 100 mg/week) with a SC autoinjector for 6 weeks in 29 hypogonadal men, only 1 participant developed ecchymosis at the injection site (25). In a study of 63 transgender men (who were trained by an experienced nurse on self-administration) receiving weekly doses of SC testosterone enanthate or cypionate at doses of 50 to 150 mg for up to 43 months, 10 injection site reactions were reported by 9 participants (28). Few studies have evaluated serum concentrations of 5-dihydrotestosterone (DHT) and estradiol after SC injection compared to the standard IM route. Mean serum total testosterone was 702 ± 212 ng/dL with a range of 357 to 1377 ng/dL (Fig. 5A). In a prospective study, the effect of switching the route of testosterone therapy (with testosterone enanthate or cypionate) from the IM to the SC route was evaluated in 14 transgender men who had been on gender-affirming hormone therapy for at least 8 weeks (24). B, Mean serum testosterone concentrations with weekly 100 mg intramuscular administration of testosterone enantathe to men with primary hypogonadism (vertical arrows represent injections, error bars represent SEM, and dashed lines represent normal range. Adapted with permission from (46). A, Mean serum total testosterone concentrations in men on 50 and 100 mg subcutaneous (SC) testosterone enanthate measured predose (0 hour) and 24 hours post dose.
