When Injection-site Pain on Testosterone Cypionate Becomes a Reason to Stop

What the label says about pain at the injection site

Depo-Testosterone is testosterone cypionate at 100 mg/mL or 200 mg/mL in cottonseed oil, with benzyl benzoate and benzyl alcohol as the preservative [5]. The label directs injections deep into the gluteal muscle, states that the product is for intramuscular use only and should not be given intravenously, and gives a replacement dose of 50 to 400 mg every two to four weeks [1].

The adverse-reactions section ends with one line on the subject: 'Miscellaneous: Inflammation and pain at the site of intramuscular injection' [1]. The label does not attach an incidence figure or expected duration to that line [1].

Two discontinuation instructions appear in the label's warnings, and neither concerns the injection site. The label says to discontinue testosterone cypionate if a venous thromboembolic event is suspected, and to discontinue it if hypercalcemia occurs in an immobilized patient [1]. It also lists hypersensitivity, including skin manifestations and anaphylactoid reactions, among adverse reactions, and names known hypersensitivity to the drug as a contraindication [1].

A hot, spreading, or draining site

MedlinePlus describes cellulitis as a bacterial skin infection with redness or inflammation that gets bigger as the infection spreads, warmth over the area, pain or tenderness, swelling, and fever with chills and sweating [2]. Where an abscess has formed, there may be drainage [2]. It says to contact a provider right away for symptoms of cellulitis [2].

That is general skin-infection guidance rather than something written for testosterone injections. Depo-Testosterone is labeled for deep gluteal intramuscular injection, not subcutaneous or intravenous injection [1].

Allergic reactions

The label lists hypersensitivity, including skin manifestations and anaphylactoid reactions, among adverse reactions [1]. A suspected severe allergic reaction requires emergency care.

Pain that returns after every injection

One sore injection and a pattern of sore injections are different questions, and the useful record is:

• product name, strength, lot number and expiry
• dose, interval, and injection site
• time to onset, how long it lasted, and whether it improved or worsened over the following days
• redness, warmth, bruising, firmness, itching, rash, drainage, fever
• anticoagulant or antiplatelet medicines

The label states that androgens may increase sensitivity to oral anticoagulants and that the anticoagulant dose may need to be reduced, and it lists bleeding in patients on concomitant anticoagulant therapy and suppression of clotting factors II, V, VII and X among adverse reactions [1].

Subcutaneous injection: what two small studies show

Two studies in transgender patients receiving gender-affirming testosterone compared routes or described subcutaneous use.

Wilson and colleagues ran a prospective, open-label crossover study in 14 transgender men already on stable intramuscular therapy, who self-injected intramuscularly for 3 weeks and then subcutaneously for 8 weeks [3]. Total testosterone exposure was comparable between routes (mean AUC 1.7 vs 1.9 nmol·days/L/mg for subcutaneous vs intramuscular, no significant difference), and weekly questionnaires showed lower self-reported pre-injection anxiety, pain during injection, and post-injection pain on the subcutaneous route [3].

Spratt and colleagues reviewed 63 transgender patients started on weekly subcutaneous testosterone cypionate or enanthate at 50 mg, adjusted within 50 to 150 mg [4]. Minor, transient local reactions were reported in 9 of the 63; of 22 patients who had previously used intramuscular injections, all preferred subcutaneous, 20 of them markedly [4].

These small studies involved transgender patients, not hypogonadal men receiving Depo-Testosterone. Depo-Testosterone remains labeled for deep gluteal intramuscular use [1].

Hypersensitivity and ingredients

A 2024 case report in Contact Dermatitis described a delayed hypersensitivity reaction to testosterone cypionate injections [6]. One case report gives no rate for that reaction.

Depo-Testosterone contains cottonseed oil, benzyl benzoate, and benzyl alcohol [5]. The ingredient list alone does not identify what caused a reaction.