Ratio of 5-dihydrotestosterone and estradiol to testosterone (T) by dose and route of administration during treatment with T enanthate Serum total A, testosterone; B, 5-dihydrotestosterone; and C, estradiol concentrations after subcutaneous (SC) or intramuscular (IM) administration of 1000 mg of testosterone undecanoate. In this context, SC administration of testosterone undecanoate could potentially be a safer route, because the SC compartment is less vascularized, thus reducing the chance of introducing the drug directly into the systemic circulation. A, Serum total testosterone concentrations in 63 transgender men on weekly subcutaneous testosterone enanthate or cypionate. IM testosterone therapy was maintained for 3 weeks after enrollment before switching to self-administration of the same dose via the SC route for 8 weeks. Testosterone Cypionate, on the other hand, is a long-acting ester, offering more convenience with less frequent injections. There are numerous treatments for low testosterone, ranging from lifestyle changes to hormone replacement therapy. These injections are typically administered weekly or biweekly, ensuring consistent hormone levels in the body. Testosterone Therapy information is abundant and highlights how therapy can benefit those with low testosterone levels. When testosterone levels are low, various treatments can help restore balance. They largely superseded testosterone propionate and became the major testosterone esters used medically for over half a century. Patients who understand the pharmacology of their treatment are more likely to adhere, report symptoms accurately, and participate actively in dosage adjustments turning therapy into a collaborative, safe, and personalized process. With undecanoate, due to its longer duration and flatter curve, timing is less critical, but a standardized sampling protocol such as just prior to the next 10–12-week injection ensures consistency. Many clinicians prefer cypionate because it offers enough flexibility for individualized regimens weekly for stable levels, or biweekly for convenience. In contrast, undecanoate users typically enjoy a flatter hormonal curve, but must attend clinic-based administrations because of its viscous formulation and risk of pulmonary microembolism if injected improperly. Androgel expanded its line to include a 1.62% testosterone gel strength in April of 2013. Approximately 9-14% of the testosterone in the gel is available and active. Androgel 1% is a colorless gel that contains 25 or 50mg of testosterone dissolved in 2.5 or 5g of gel. In 2000 Androgel ™ 1% became the first testosterone gel approved for use in the United States by the FDA. Jatenzo is a combination of a testosterone molecule attached to a fatty acid. B, Total testosterone concentrations after intramuscular (IM) and SC administration of testosterone enanthate in 14 transgender men (24). 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. In a follow-up study by the same investigators, 21 men (aged years) with symptomatic testosterone deficiency self-administered weekly SC testosterone enanthate at a dose of 75 mg for 12 weeks via SC autoinjector (29). In another study, 150 hypogonadal men were started on SC testosterone enanthate 75 mg/week for 52 weeks, which was administered via a novel SC autoinjector (27). Similar to lymphatics, the hemorheological differences of the vascular compartments of the SC and IM tissues play a role in the pharmacokinetics of testosterone esters. Therefore, the pharmacokinetics of testosterone esters administered via IM vs SC route will vary according to the lymphatic circulation of the tissue. However, the hydrolysis of testosterone esters by tissue esterases is a slow process because of their high lipophilicity, with negligible spontaneous hydrolysis in water (40). This may be a future route for testosterone delivery and may potentially contribute to androgen misuse6. Nonetheless, we are now seeing the rise of online direct-to-consumer clinics that provide questionnaires to patients who self-report symptoms of erectile dysfunction or premature ejaculation. For instance, Canada had a four-fold increase in per capita testosterone prescribing due to internet pharmacies physically based in the country which are not subjected to national prohibitions of import/export controls of androgens4. In clinical trials, in particular the inTUne Trial, reported 87% of men treated with Jatenzo achieved steady state and maintained physiological testosterone levels. Recently, the FDA approve a new propriety form of testosterone undecanoate called Jatenzo. After injection supraphysiological levels of testosterone are experienced at 10 hours. A patient would have to inject testosterone almost every hour in order to maintain testosterone levels and this is not economical or practical. The most widely used form of testosterone is the intramuscular injection preparation of a testosterone ester. By the year 2000, topical testosterone gels provided men an easy once a daily application that maintained steady state testosterone levels. Jatenzo is a new and novel oral testosterone tablet that bypasses liver metabolism and maintains consistent testosterone levels. This treatment is referred to as hormone replacement therapy (HRT), or alternatively, and more specifically, as testosterone replacement therapy (TRT) or androgen replacement therapy (ART). As mentioned earlier, these are the two most common types of testosterone esters available in the United States. There are several different esters used in testosterone replacement therapy. "Fast-acting" kinds of testosterone contain esters that are less soluble in oil. Mean total testosterone concentrations gradually increased from predose values of 224 ng/dL to 374 ng/dL, 479 ng/dL, and 541 ng/dL at weeks 1, 6, and 12, respectively (29) (Fig. 4A). To the contrary, after SC administration, the drug is delivered to the hypodermis (adipose tissue underlying the dermis), which is not only less vascularized compared to skeletal muscles, but the flow in this region does not increase significantly with physical activity. Molecules smaller than 1 kDa, such as testosterone, are preferentially absorbed by the blood capillaries because of the high rate of filtration and reabsorption of fluid across vascular capillaries (39).
