Testosterone Therapy With Subcutaneous Injections: A Safe, Practical, and Reasonable Option

Abstract

Context: Injections with intramuscular (IM) testosterone esters have been available for almost 8 decades and not only result in predictable serum testosterone levels but are also the most inexpensive modality. However, they are difficult to self-administer and associated with some discomfort. Recently, subcutaneous (SC) administration of testosterone esters has gained popularity, as self-administration is easier with this route. Available data, though limited, support the feasibility of this route. Here we review the pharmacokinetics and safety of SC testosterone therapy with both long- and ultralong-acting testosterone esters. In addition, we provide guidance for clinicians on how to counsel and manage their patients who opt for the SC route.

Evidence acquisition: Systematic review of available literature on SC testosterone administration including clinical trials, case series, and case reports. We also review the pharmacology of testosterone absorption after SC administration.

Evidence synthesis: Available evidence, though limited, suggests that SC testosterone therapy in doses similar to those given via IM route results in comparable pharmacokinetics and mean serum testosterone levels. With appropriate training, patients should be able to safely self-administer testosterone esters SC with relative ease and less discomfort compared with the IM route.

Conclusion: Although studies directly comparing the safety of SC vs IM administration of testosterone esters are desirable, clinicians should consider discussing the SC route with their patients because it is easier to self-administer and has the potential to improve patient adherence.

Keywords: androgen deficiency; androgens; hypogonadism; testosterone replacement therapy; transgender.

Figure 1.

Timeline of various testosterone formulations available since Brown-Sequard’s experiments in 1889.

Figure 2.

A, Illustration of the progressive increase in lipophilicity of testosterone esters with increase in number of carbons in the side chain. B, Schematic illustration of the absorption steps of testosterone esters after intramuscular (left) or subcutaneous (right) injection. With administration using either route, the ester exits the depot via diffusion into the interstitium, from where it enters the lymphatics and subsequently reaches the circulation where it undergoes hydrolysis by intracellular esterases. Testosterone ester is also partly hydrolyzed within the interstitium, with free testosterone entering the circulation directly.

Figure 3.

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. Adapted with permission from (25). 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).

Figure 4.

A, Mean trough concentrations of testosterone in hypogonadal men on weekly 75 mg subcutaneous (SC) testosterone enanthate (29). B, Total testosterone concentrations after intramuscular (IM) and SC administration of testosterone enanthate in 14 transgender men (24). C, Trough total testosterone concentrations on SC testosterone cypionate in 11 transgender men. Adapted with permission from (47).

Figure 5.

A, Serum total testosterone concentrations in 63 transgender men on weekly subcutaneous testosterone enanthate or cypionate. The bar represents mean value and the rectangle demarcates total testosterone range. Adapted with permission from (28). B, Optimal doses needed to maintain serum total testosterone concentration within the desired range were not influenced by participant’s body mass index (bars indicate mean values). Adapted with permission from (28).

Figure 6.

Serum total A, testosterone; B, 5-dihydrotestosterone; and C, estradiol concentrations after subcutaneous (SC) or intramuscular (IM) administration of 1000 mg of testosterone undecanoate. Adapted with permission from (26).

Figure 7.

Mean A, 5-dihydrotestosterone (DHT) and B, estradiol (E₂) concentrations on weekly subcutaneous (SC) injections of 75 mg testosterone enanthate. Adapted with permission from (27).