Testosterone Cypionate Injection-Site Pain: Alternatives Without This Side Effect

What the Depo-Testosterone label says about site pain

Depo-Testosterone is labeled for intramuscular use only, injected deep in the gluteal muscle and never intravenously, at 50 to 400 mg every 2 to 4 weeks [1]. The formulation contains cottonseed oil, benzyl benzoate, and benzyl alcohol as a preservative [1]. Under adverse reactions, the label lists 'inflammation and pain at the site of intramuscular injection' among reactions that have occurred with some androgens. It gives no incidence figure for that reaction [1].

Could the pain be an allergic reaction?

The label lists hypersensitivity, including skin manifestations and anaphylactoid reactions, among adverse reactions to androgens [1]. A 2024 case report in Contact Dermatitis described a delayed hypersensitivity reaction to testosterone cypionate injections in one patient [11]. A single case report cannot say how often a cypionate site reaction is allergic.

Subcutaneous injection with the same drug

Three small studies, all in transgender patients, support giving testosterone under the skin instead of into muscle.

A prospective, open-label crossover study followed 14 transgender men on stable intramuscular testosterone through 3 weeks of intramuscular and then 8 weeks of subcutaneous self-injection of cypionate or enanthate. Total testosterone exposure was comparable (mean dose-normalized AUC 1.7 versus 1.9 nmol·days/L/mg), and weekly questionnaires gave lower self-reported scores for pre-injection anxiety, pain during injection, and post-injection pain on the subcutaneous route [9].

A retrospective review of 63 female-to-male transgender patients given weekly subcutaneous cypionate or enanthate at 50 to 150 mg reported testosterone within the normal male range in all 63, with minor and transient local reactions in 9; all 22 who switched from intramuscular injection preferred the subcutaneous route (20 markedly, 2 mildly) [10].

In 11 transgender patients already on weekly subcutaneous cypionate, total and free testosterone stayed stable across the 1-week interval, with no adverse effects reported [12].

There is a labeling boundary. Depo-Testosterone is labeled for intramuscular use only [1], so putting that vial under the skin is outside its labeled route. The subcutaneous testosterone injection that carries an FDA approval for that route is Xyosted [2].

Xyosted: an approved subcutaneous injection

Xyosted is testosterone enanthate in a single-dose autoinjector, given in the abdominal region once weekly, starting at 75 mg [2]. The label directs a trough testosterone measurement 7 days after the most recent dose following 6 weeks of dosing, then periodic checks thereafter, with 25 mg adjustments [2]. It comes in 50, 75 and 100 mg per 0.5 mL strengths [2].

Its local reaction profile is measured, not absent. In a 1-year open-label study of 150 men with no placebo arm, injection-site bruising was reported in 6.7% [2]. Xyosted is enanthate in a device, not cypionate in a vial, and the two have different labeled routes and dosing instructions [1][2].

Transdermal gel

The 1.62% testosterone gel label starts at 40.5 mg once daily, applied to clean, dry, intact skin of the shoulders and upper arms, and specifically not to the abdomen, genitals, chest, armpits or knees [3]. The 1.62% gel label instructs users to wash their hands after application, cover the site once it is dry, and wash the site before anticipated skin-to-skin contact [3]. The label carries a boxed warning about secondary exposure: virilization has been reported in children who were secondarily exposed to testosterone gel [3].

Absorption is real but variable. In a 180-day study of 227 hypogonadal men given a 1% gel (applied to the upper arms, shoulders and abdomen) or a patch, about 9 to 14% of the applied testosterone was bioavailable and mean steady-state levels remained stable across 180 days of gel application [13]. The 1.62% label states that its dosage and administration differ from testosterone gel 1% [3].

Natesto nasal gel

Natesto is a metered nasal gel delivering 11 mg of testosterone as two pump actuations, one per nostril, three times daily [4]. The label says total testosterone should be checked periodically, starting as soon as one month after starting, that therapy should be discontinued if levels consistently exceed 1050 ng/dL, and that an alternative should be considered if they are consistently below 300 ng/dL [4].

Nasal effects are the route-specific trade. The label says to instruct patients to report nasal symptoms, and that Natesto is not recommended in patients with chronic nasal conditions or alterations in nasal anatomy, or with nasally administered drugs other than sympathomimetic decongestants such as oxymetazoline [4].

Oral testosterone undecanoate (Jatenzo)

Jatenzo capsules start at 237 mg in the morning and 237 mg in the evening, taken with food, and are adjusted between 158 mg and 396 mg twice daily based on a serum testosterone drawn 6 hours after the morning dose, at least 7 days after starting or after a dose change [5].

In a phase 3 randomized, open-label trial, 166 men took oral testosterone undecanoate and 56 took a topical product; 87% in both groups reached a mean testosterone concentration in the eugonadal range, and the oral group had a mean systolic blood pressure increase of 3 to 5 mm Hg [14]. The label warns about blood pressure increases, lists hematocrit monitoring roughly every 3 months, and notes the potential for azoospermia from exogenous androgens [5].

Testosterone pellets (Testopel)

Testopel is 75 mg of crystalline testosterone per pellet, implanted subcutaneously, where the pellets slowly release hormone [6]. That removes repeated self-injection but adds a procedure.

A single-site retrospective analysis of 80 men and 292 implant procedures reported four adverse events, including one implantation-site infection, and no spontaneous pellet extrusions, for a 0.3% infection rate; the author contrasted this with historical rates of 1.4 to 6.8% infection and 8.5 to 12% extrusion for an earlier pellet product [15]. Eighty-six percent of patients were satisfied based on symptom improvement or having further implants [15]. Results from one center's technique should not be read as a universal rate.

What a route change does not fix

Hematocrit moves on every formulation, and the size of the move differs by route. A network meta-analysis of 29 placebo-controlled randomized trials (3,393 men) found mean hematocrit increases of 4.0% with intramuscular enanthate or cypionate, 3.0% with gel, 4.3% with oral testosterone undecanoate, and 1.4% with patch [7]. A retrospective review of 178 men followed for 3 years found erythrocytosis (hematocrit above 50%) in 66.7% of those on injectable testosterone, 12.8% on gels, and 35.1% on pellets; the injection group was younger and started with a higher hematocrit, and the study was not randomized [16].

Blood pressure rises on testosterone products generally. FDA reported that ambulatory blood pressure studies confirmed an increase in blood pressure with use of all testosterone products, class-wide [8].