Why Testosterone Cypionate Causes Acne: The Biology Behind Androgen-Driven Breakouts

Does testosterone cypionate cause acne?

Yes. Acne appears on the Depo-Testosterone (testosterone cypionate) label among the skin reactions reported with androgens: 'hirsutism, male pattern of baldness, seborrhea, and acne' [1].

Outside product labels, a review of doping with anabolic androgenic steroids says these steroids frequently cause gynecomastia and acne [9], and a practical guide to acne in transgender men receiving masculinizing testosterone calls acne one of the most common adverse effects of that treatment [8].

What the skin does with injected testosterone

Testosterone cypionate is given by intramuscular injection [1]. Cypionate is an oil-soluble ester of testosterone; injected into muscle, it is absorbed slowly from the oil depot and split to release free testosterone. The label gives a half-life of about 8 days after intramuscular injection and a dosing interval of 2 to 4 weeks, with a suggested replacement dose of 50 to 400 mg every 2 to 4 weeks [1].

Sebaceous glands carry 5-alpha reductase, which can convert testosterone to DHT. In a study of 49 microdissected skin samples from 44 people without acne, the glands contained almost entirely the type 1 isozyme, and enzyme activity was significantly higher in sebaceous glands from the face and scalp than in glands from non-acne-prone skin: 32 and 35 versus 6.0 pmol/min/mg protein [2].

In cultured genital-skin cells that made negligible amounts of DHT, DHT bound the androgen receptor about twice as tightly as testosterone, and testosterone left the receptor about 5-fold faster. High testosterone concentrations overcame this weaker interaction [6]. That study did not examine acne, and it is not known whether the finding explains acne during testosterone replacement.

Sebum, plugged follicles and C. acnes

Androgens are required for sebaceous gland development, but gland growth and differentiation depend on more than androgen alone. One review lists insulin, IGF-1, growth hormone, glucocorticoids, estrogens, thyroid hormone, retinoids and PPARs as participants [3].

The lipid itself is part of the problem. Sebum output has long been treated as a main driver of acne, and current work points at composition as well as amount: proinflammatory lipid fractions and an altered oxidant/antioxidant balance in surface lipids are implicated in starting lesions [4].

The bacterial side has been revised. Rather than simple overgrowth of Cutibacterium acnes, the current model is a loss of balance among C. acnes strains plus wider skin microbiome imbalance, with a more virulent phylotype (IA1) predominating in acne skin [5]. C. acnes activates toll-like receptor 2, and that activation induces IL-12 and IL-8 production by human monocytes; TLR2 was expressed on macrophages surrounding pilosebaceous follicles in acne lesions [11].

Treating acne that appears on testosterone

An American Family Physician review of acne vulgaris states that topical retinoids are indicated for acne of any severity and for maintenance therapy; that systemic and topical antibiotics should be used only in combination with benzoyl peroxide and retinoids, for a maximum of 12 weeks; and that isotretinoin is used for severe, recalcitrant acne and requires registration in the iPLEDGE program [7]. The American Academy of Dermatology guideline covers acne grading and topical and systemic management [12].

For testosterone-associated acne specifically, a practical review for clinicians treating transmasculine patients sets out isotretinoin's indications, contraindications and the iPLEDGE barriers for severe or refractory cases, and covers interactions with gender-affirming therapy [8]. That review focuses on transmasculine patients receiving testosterone.

The Depo-Testosterone label lists acne among adverse reactions and states that dosage is adjusted according to the patient's response and the appearance of adverse reactions [1].