madman
Super Moderator
Abstract Context: Injections with intramuscular 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 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 subcutaneous 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 subcutaneous route.
Evidence Acquisition: Systematic review of available literature on subcutaneous testosterone administration including clinical trials, case series, and case reports. We also review the pharmacology of testosterone absorption after subcutaneous administration.
Evidence Synthesis: Available evidence, though limited, suggests that subcutaneous testosterone therapy in doses similar to those given via the intramuscular route results in comparable pharmacokinetics and mean serum testosterone levels. With appropriate training, patients should be able to safely self-administer testosterone esters subcutaneously with relative ease and less discomfort compared with the intramuscular route.
Conclusion: Although studies directly comparing the safety of subcutaneous vs intramuscular administration of testosterone esters are desirable, clinicians should consider discussing the subcutaneous route with their patients, as it is easier to self-administer and has the potential to improve patient adherence.
Introduction
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 (Figure 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 due 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.
The selection of the administration route of testosterone is influenced by the patient’s preference, product availability, and the cost of the formulation. Each formulation has certain advantages and disadvantages (Table 1), which can impact patients’ choices and adherence (10-12). Patches result in skin irritation in a substantial number of patients, and sweating during the summer can impact 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 (120, 121).
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 (FDA) approved an auto-injector device for weekly SC self-administration of testosterone enanthate (27,29). However, this device is expensive compared to the administration of ester with conventional syringes and needles.
Due to the convenience of self-administration of testosterone esters, the SC route has recently gained popularity. The viability of using the 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 12-85% 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 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. Lastly, 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). Upon 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) due to the increased hydrophobicity of the molecule (Figure 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 is not in common use currently among adults.
Absorption kinetics are affected by the viscosity of the oily vehicle, the 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).
*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 (Cmax) and then decreases according to its elimination half-life. For testosterone esters, the time corresponding from administration to the Cmax, i.e., time of maximum concentration (Tmax), is determined by the rate at which absorption occurs, since 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 (Figure 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 due to 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 due to 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 associate with small proteins and are drained via the lymphatics into the central circulation, with the hydrolysis of these esters likely occurring in the central circulation (40). Therefore, the pharmacokinetics of testosterone esters administered via the IM versus 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 (e.g. 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. On 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 a more stable vascular absorption pattern 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 Cmax and Tmax of testosterone in the serum, and the average serum total testosterone concentration during the steady-state. These data are summarized below.
*Testosterone Enanthate and Testosterone Cypionate
*Testosterone Undecanoate
*Serum Concentrations of Testosterone Metabolites after Subcutaneous Administration
*Safety of Subcutaneous Testosterone Esters
-Local Adverse Effects
-Systemic Adverse Effects
*Guidance regarding Subcutaneous Testosterone Therapy
-Technique
-Therapy Initiation and Monitoring
Conclusion
Administration of testosterone ester via the SC route has been gaining popularity. To date, limited data suggest that SC administration of testosterone enanthate and cypionate results in stable and predictable on-treatment concentrations has good acceptability among patients, and can be self-administered more easily than IM injections. Furthermore, localized adverse effects at the injection site are mild and transient. Although long-term studies with a larger number of patients are needed to evaluate the safety and compliance of SC testosterone (in particular for testosterone undecanoate), clinicians should be aware of this route of testosterone administration, as it has the potential to increase patient adherence to therapy of a formulation that is relatively inexpensive and results in comparable on-treatment serum testosterone concentrations.
Evidence Acquisition: Systematic review of available literature on subcutaneous testosterone administration including clinical trials, case series, and case reports. We also review the pharmacology of testosterone absorption after subcutaneous administration.
Evidence Synthesis: Available evidence, though limited, suggests that subcutaneous testosterone therapy in doses similar to those given via the intramuscular route results in comparable pharmacokinetics and mean serum testosterone levels. With appropriate training, patients should be able to safely self-administer testosterone esters subcutaneously with relative ease and less discomfort compared with the intramuscular route.
Conclusion: Although studies directly comparing the safety of subcutaneous vs intramuscular administration of testosterone esters are desirable, clinicians should consider discussing the subcutaneous route with their patients, as it is easier to self-administer and has the potential to improve patient adherence.
Introduction
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 (Figure 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 due 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.
The selection of the administration route of testosterone is influenced by the patient’s preference, product availability, and the cost of the formulation. Each formulation has certain advantages and disadvantages (Table 1), which can impact patients’ choices and adherence (10-12). Patches result in skin irritation in a substantial number of patients, and sweating during the summer can impact 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 (120, 121).
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 (FDA) approved an auto-injector device for weekly SC self-administration of testosterone enanthate (27,29). However, this device is expensive compared to the administration of ester with conventional syringes and needles.
Due to the convenience of self-administration of testosterone esters, the SC route has recently gained popularity. The viability of using the 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 12-85% 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 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. Lastly, 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). Upon 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) due to the increased hydrophobicity of the molecule (Figure 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 is not in common use currently among adults.
Absorption kinetics are affected by the viscosity of the oily vehicle, the 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).
*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 (Cmax) and then decreases according to its elimination half-life. For testosterone esters, the time corresponding from administration to the Cmax, i.e., time of maximum concentration (Tmax), is determined by the rate at which absorption occurs, since 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 (Figure 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 due to 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 due to 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 associate with small proteins and are drained via the lymphatics into the central circulation, with the hydrolysis of these esters likely occurring in the central circulation (40). Therefore, the pharmacokinetics of testosterone esters administered via the IM versus 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 (e.g. 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. On 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 a more stable vascular absorption pattern 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 Cmax and Tmax of testosterone in the serum, and the average serum total testosterone concentration during the steady-state. These data are summarized below.
*Testosterone Enanthate and Testosterone Cypionate
*Testosterone Undecanoate
*Serum Concentrations of Testosterone Metabolites after Subcutaneous Administration
*Safety of Subcutaneous Testosterone Esters
-Local Adverse Effects
-Systemic Adverse Effects
*Guidance regarding Subcutaneous Testosterone Therapy
-Technique
-Therapy Initiation and Monitoring
Conclusion
Administration of testosterone ester via the SC route has been gaining popularity. To date, limited data suggest that SC administration of testosterone enanthate and cypionate results in stable and predictable on-treatment concentrations has good acceptability among patients, and can be self-administered more easily than IM injections. Furthermore, localized adverse effects at the injection site are mild and transient. Although long-term studies with a larger number of patients are needed to evaluate the safety and compliance of SC testosterone (in particular for testosterone undecanoate), clinicians should be aware of this route of testosterone administration, as it has the potential to increase patient adherence to therapy of a formulation that is relatively inexpensive and results in comparable on-treatment serum testosterone concentrations.
