The recommend starting dose for TE is the same as TC per the USA FDA and Endocrine Society guidelines (3,43). As cottonseed oil is the formulation vehicle, TC use is contraindicated in anyone with a known hypersensitivity to testosterone synthesized from soy. TU has the longest carbon side chain, consisting of 11 carbon atoms compared to seven and eight for TC and TE respectively, which accounts for its longer duration of action (39,40). These products differ based on the carbon side chain esterified to the 17β position of testosterone (Figure 2). The three IM preparations that are USA FDA approved are testosterone cypionate (TC), TE, and TU. Esterification increases the solubility of testosterone in oil, which allows for slower release once injected into the muscle. Current formulations have a prolonged duration of action as they are synthesized through esterification of the 17β carbon of natural testosterone.
Finally, men with elevated Hct and on-treatment low/normal total and free testosterone levels should be referred to a hematologist for further evaluation and possible coordination of phlebotomy. In men with elevated Hct and high on-treatment testosterone levels, dose adjustment should be attempted as first-line management. Men with total testosterone levels of 171 Testosterone deficient patients with low or low/normal LH levels can be considered candidates for SERM use as a treatment for testosterone deficiency, particularly those wishing to preserve their fertility.170 However, an LH level below which SERM response is optimized is not firmly established. Conversely, a recent study exposing patient testes to radiation (3 patients 17Gy and 4 patients 24Gy) demonstrated normal testosterone levels up to 3 years after radiation exposure.147 Men who have had exposure of their testes during radiation therapy, either through direct or scatter radiation, are possibly at risk for low testosterone and the Panel recommends total testosterone measurement in such patients.
This reduced dosing regimen was approved in 2011, and manufacturer data show that following 28 days of transdermal T application, 97% (34/35) men with TD were able to achieve Cavg within 10.4 to 35.7 nmol/L (300–1030 ng/dl).51 Mean Cmax values with 2.0 mg/day and 4.0 mg/day treatment were 22.5 ± 5.0 nmol/L (648 ± 145 ng/dl) and 24.1 ± 5.5 nmol/L (696 ± 158 ng/dl), respectively. Peak T levels were reached approximately 8.2 h after application, with a Cmax of 26.5 ± 9.6 nmol/L (765 ± 277 ng/dl). In a retrospective review of medical records collected from 6 different institutions from 380 men, the mean Cmax occurred 1 month post‐implantation, regardless of the number of pellets implanted (T Cavg for 6–7 pellets, 24.7 nmol/L 712 ng/dl; 8–9 pellets, 24.9 nmol/L 719 ng/dl; ≥10 pellets, 27.6 nmol/L 795 ng/dl).48 The more T pellets (10–12; 750–900 mg) that were implanted, the higher and more sustained levels of T that could be achieved and maintained. TC is available in two strengths, 100 and 200 mg/ml concentrations prepared in cottonseed oil.34 The recommended dose is 50 to 400 mg administered every 2 to 4 weeks for IM TC. Esterification increases the solubility of T in oil, allowing for slower release of T with IM injection.13, 33 The three IM formulations that are approved by the FDA for use as TTh are testosterone cypionate (TC), TE, and testosterone undecanoate (TU). This product is supplied as a single‐dose auto‐injector that patients self‐administer in the abdominal region once a week. Some T replacement options provide intraday T level variations similar to normal circadian secretion, and others provide a flatter exposure profile reflective of depot release.
The 75 mg implantable subdermal T pellet (TESTOPEL®) received FDA approval in 1972, and the recommended dosing regimen is 150 to 450 mg (2–6 pellets) implanted subcutaneously every 3 to 6 months; dosing is adjustable depending on the patient's age and diagnosis, and how the patient responds to treatment.45 However, data from the medical literature suggest that insertion of at least 10 pellets (≥750 mg) may be common in clinical practice.47, 48, 49, 50 Treatment with either 100 mg/week or 200 mg every 2 weeks was able to lower the initially elevated luteinizing hormone (LH) and follicle‐stimulating hormone (FSH) concentrations. After the last dose of each regimen, mean Cavg values were 36.6 nmol/L (1055 ng/dl), 32.7 nmol/L (943 ng/dl), 30.6 nmol/L (883 ng/dl), and 25.3 nmol/L (729 ng/dl) for the 100, 200, 300, and 400 mg doses, respectively. These large fluctuations in serum T over the 2‐week dosing period differ greatly from what is observed in normal, diurnal T variation of healthy young or older men. During the week 12 dosing interval, there was little fluctuation in dihydrotestosterone (DHT) and estradiol (E2). The Cmax (27.4 ± 7.5 nmol/L, or 789.8 ± 215.4 ng/dl; Table 1) and Cmin (15.1 ± 3.8 nmol/L, or 435.6 ± 109.2 ng/dl) measured during the 7‐day period at week 12 yielded a peak‐to‐trough ratio of 1.8.
Other common adverse effects with TC use are local inflammation and pain at the site of injection, also due to IM administration (41). The mean Cmax was supratherapeutic (1,112±297 ng/dL) and occurred between days four and five post-injection. The USA FDA recommended starting dose for male hypogonadism is 50 to 400 mg IM every 2 to 4 weeks (41).
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. While seven of the trials in the above analysis showed decreased, but statistically insignificant, odds of having a cardiac event while on testosterone therapy, one trial did show an increased risk. A meta-analysis of RCTs developed in support of this guideline indicate that there is no significant difference in MACE in men on testosterone therapy when compared to placebo.

Gender: Female

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