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

Maria Gabriela Figueiredo, Research Program in Men’s Health: Aging and Metabolism, Division of Endocrinology and Metabolism, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA;

Correspondence: Shehzad Basaria, MD, Research Program in Men’s Health: Aging and Metabolism, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Ave, BLI 541, Boston, MA 02115, USA. Email: ude.dravrah.hwb@airasabs.

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Associated Data

Data sharing is not applicable to this article because no data sets were generated or analyzed during the present study.

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: hypogonadism, transgender, androgen deficiency, testosterone replacement therapy, androgens

Testosterone is the main male sex hormone and is essential for the development and maintenance of male secondary sexual characteristics. Currently, testosterone therapy is indicated for men with unequivocal, organic, or pathologic androgen deficiency to alleviate symptoms and maintain secondary sexual characteristics by raising testosterone into the normal male range (1). In addition, testosterone therapy is used for gender-affirming (hormone) therapy for transgender men to induce masculinization (and suppress endogenous estradiol concentrations in patients with intact ovaries) (2). In both clinical scenarios, testosterone therapy is intended to be long term. Thus, it is desirable to have various formulation options available to ensure patient satisfaction and adherence. We have come a long way since the days of Brown-Séquard, who self-administered an extract of animal testes by subcutaneous (SC) injection in 1889 ( Fig. 1 ) (3). Four decades after Brown-Séquard’s experiments, testosterone was isolated in 1935, and subsequently chemically synthesized (4-6); it took an additional 2 years for it to be introduced into clinical medicine for the treatment of male hypogonadism with SC or intramuscular (IM) injections of short-acting ester testosterone propionate, crystalline testosterone compressed into subcutaneous pellets, and oral methyltestosterone (7, 8). In the mid-1950s, long-acting testosterone esters (enanthate and cypionate) were introduced, and have since been the preferred testosterone formulation thanks to their affordability, longer half-life compared to propionate, and predictable pharmacokinetics (9). More recently, newer formulations of testosterone replacement have become available, which include ultralong-acting testosterone undecanoate for IM injection, transdermal patches and gels, buccal tablets, intranasal sprays, and oral testosterone undecanoate ( Table 1 ), thus providing a range of options to choose from.

Table 1.

Advantages and disadvantages of available testosterone formulations

Abbreviations: DHT, 5-dihydrotestosterone; IM, intramuscular; SC, subcutaneous; T, testosterone.

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

Selection of the administration route of testosterone is influenced by patient preference, product availability, and the cost of the formulation. Each formulation has certain advantages and disadvantages (see Table 1 ) that can affect the patient’s choice and adherence (10-12). Patches result in skin irritation in a substantial number of patients, and sweating during the summer can affect patch adherence (13). Topical gels require daily application, can be messy, and carry the risk of exposure to those who come in contact with the patient’s application site (14). Nasal and buccal formulations require greater frequency of application and can cause local irritation (15-17). Long-acting SC pellets are costly, require surgical insertion, and are associated with the risk of infection and spontaneous extrusion (12). IM injections of long-acting testosterone esters (cypionate or enanthate) are cost-effective and result in physiological and predictable on-treatment serum testosterone levels, particularly when smaller doses are administered weekly (18). However, IM injections are associated with discomfort, patients experience difficulty with self-injection, and they often require assistance from family members to administer the drug. To mitigate the discomfort associated with frequent IM injections, they are commonly administered in large doses every 2 weeks to decrease the frequency of administration, resulting in large peaks and troughs (19, 20). The ultralong-acting ester testosterone undecanoate was developed to reduce these peaks and troughs, but the large volume injected has been rarely associated with a risk of pulmonary oil microembolism, necessitating administration of the drug by trained medical personnel (self-injection is not allowed) and observation of the patients in the clinic for 30 minutes thereafter (21, 22).

Despite the formal recommendation for oil-based testosterone formulations to be administered via the IM route, recent data suggest that SC administration of testosterone esters results in pharmacokinetics and serum testosterone concentrations that are similar to the IM route (23-27) and associated with less discomfort (24, 28). Recently, after assessing its safety and efficacy, the Food and Drug Administration approved an autoinjector device for weekly SC self-administration of testosterone enanthate (27, 29). However, this device is expensive compared to administration of ester with conventional syringe and needles.

Owing to the convenience of self-administration of testosterone esters, the SC route has recently gained popularity. The viability of using SC route for sex steroid administration was also shown in an elegant pharmacokinetic study in which nandrolone decanoate was administered to healthy male volunteers (30). Interestingly, previous data that used imaging (computed tomography or ultrasound) to estimate SC fat thickness and compared it with the length of the needle (or placement of the injectate) estimated that 12% to 85% of IM injections administered to men were actually SC (31-33). Indeed, this might explain the observation that IM injections are less painful in overweight and obese men (34). In this review, we summarize the published data on the pharmacokinetics and safety of SC administration of both long-acting (enanthate and cypionate) and ultralong-acting (undecanoate) testosterone esters in hypogonadal and transgender men. Last, we provide some guidance for clinicians regarding SC testosterone therapy.

Absorption of Injectable Testosterone

Unmodified testosterone has a half-life of 10 minutes; to overcome this limitation, testosterone is esterified and then dissolved in oil to allow for sustained release into the circulation after injection. These oily solutions contain a testosterone ester dissolved in vegetable oil (usually sesame seed, tea seed, castor seed, or cottonseed oil) with some benzyl alcohol. Benzyl alcohol is soluble not only in the oily phase, but also in the aqueous phase, thus facilitating the release of testosterone ester from the depot into the surrounding interstitial fluid (35). On release from the depot, the testosterone ester undergoes hydrolysis into testosterone and the ester-specific fatty acid (35, 36). Various testosterone esters have different absorption kinetics, with absorption time increasing with longer esterified side chains (fatty acids) because of the increased hydrophobicity of the molecule ( Fig. 2A ) (37). Commonly used testosterone esters include testosterone enanthate (7 carbons side chain), cypionate (8 carbons), and undecanoate (11 carbons). In the past, propionate (3 carbons) was widely used, but it is not in common use currently among adults. Absorption kinetics are affected by the viscosity of the oily vehicle, concentration of the ester (the higher the concentration in the depot, the higher the driving diffusion force for release), the volume of the product, and the site of the injection (35, 38).

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.

Subcutaneous vs Intramuscular Routes

The IM and SC routes present a defined phase of absorption, in which the serum concentration of the drug administered progressively increases to a maximum (C_max) and then decreases according to its elimination half-life. For testosterone esters, the time corresponding from administration to the C_max, that is, time of maximum concentration (t_max), is determined by the rate at which absorption occurs, since the systemic elimination of testosterone is the same regardless of the route of administration. Therefore, the formulation and the injection site influence the speed and magnitude of absorption.

After IM or SC administration of a testosterone ester, absorption occurs first by diffusion from the depot into the interstitium ( Fig. 2B ). The physiology of the IM and SC milieu determines the patterns of absorption after administration. 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). 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 results in some of the esterified testosterone entering the lymphatics, thus prolonging the secondary absorption phase.

The interstitial fluid consists of plasma ultrafiltrate and proteins derived from tissue metabolism, and is drained by the lymphatics (41). Because of their lipophilicity, testosterone esters are unlikely to have significant diffusion into the tissues; they likely are associated with small proteins and are drained via the lymphatics into the central circulation, with hydrolysis of these esters likely occurring in the central circulation (40). Therefore, the pharmacokinetics of testosterone esters administered via IM vs SC route will vary according to the lymphatic circulation of the tissue. Lymphatic drainage is dependent on intrinsic and extrinsic pumping. Intrinsic pumping is dependent on the contraction of lymphangions (muscular unit of the lymphatics with unidirectional valves) that transport lymph by mechanisms analogous to that occurring in the cardiac chambers (42). Extrinsic pumping results from intermittent external pressure exerted by skeletal muscle contractions on the lymphatics (42). As the lymphatic drainage from SC tissue is largely dependent on intrinsic pumping, while IM lymphatic flow is also substantially influenced by extrinsic pumping during physical activity (43), these drainage patterns suggest that testosterone esters administered SC likely have more stable absorption kinetics compared to IM administration.

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. As different muscle groups have variable blood flow (eg, the blood flow to the deltoids is higher than the glutei) (44), which further varies with physical activity (45), serum on-treatment testosterone concentrations after IM injections are dependent on these characteristics. 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. Since the blood flow at the site of drug administration influences the pharmacokinetics of the administered drug, SC injections display more stable vascular absorption patterns compared to IM injection.

Pharmacokinetics of Testosterone Esters Injected Subcutaneously

As discussed, SC administration of testosterone esters should result in a more stable absorption and release of testosterone into the circulation due to less fluctuation of lymphatic flow in the hypodermis with physical activity. This was confirmed by pharmacokinetic studies that assessed the C_max and t_max of testosterone in the serum, and the average serum total testosterone concentration during the steady state. These data are summarized as follows.

Testosterone Enanthate and Testosterone Cypionate

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).

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).

The role of SC testosterone therapy has also been assessed in transgender men. 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). The mean age of the participants was 30 years and mean weekly dose was 68 mg (range, 30-110 mg; dose previously adjusted to achieve gonadotropin suppression). 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. Mean serum testosterone concentrations did not change significantly after switching administration routes ( Fig. 4B ) (24), confirming similar bioavailability after SC administration.

Another study in 11 transgender men on 75 mg (range, 50-100 mg) of weekly SC testosterone cypionate showed consistency in circulating total and free serum testosterone concentrations, which remained within the desired range ( Fig. 4C ) (47). Serum total testosterone levels measured at 6 hours (mean ± SD = 656 ± 244 ng/dL) and 5 days post injection (621 ± 321 ng/dL) were similar (47).

In a study of weekly SC testosterone enanthate or testosterone cypionate (50-150 mg) in 63 transgender men, 20 participants achieved goal serum total testosterone concentrations (348-1197 ng/dL) with 50 mg/week, 34 with 75 to 80 mg/week, 7 with 100 mg/week, and 2 with 150 mg/week (28). Mean serum total testosterone was 702 ± 212 ng/dL with a range of 357 to 1377 ng/dL ( Fig. 5A ). Interestingly, the optimal dose required to maintain serum total testosterone concentration within the desired range was not influenced by participant body mass index ( Fig. 5B ) (28).

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).