Testosterone Cypionate and Hair Loss: The Biology of DHT-Driven Follicular Miniaturization

Does testosterone cypionate cause hair loss?

The Depo-Testosterone label, which covers testosterone cypionate injection, lists male pattern baldness under skin and appendages adverse reactions that have occurred with some androgens, alongside hirsutism, seborrhea and acne [1]. The label lists it without an incidence figure [1]. A review of testosterone therapy in transgender men also lists alopecia among the undesired effects, and notes that alopecia continues to develop after the first year of therapy [8].

Hair loss is also common in the general male population: in a community-based sample of men aged 18 to 49, 42% had moderate to extensive hair loss (type III or greater), ranging from 16% at ages 18 to 29 to 53% at ages 40 to 49 [9].

From the injection to DHT

Testosterone esters injected in oil are absorbed slowly from the lipid phase, so testosterone cypionate can be given at intervals of two to four weeks, and the label gives a half-life of about 8 days after intramuscular injection [1]. In 11 hypogonadal men, a 200 mg injection produced a threefold rise in serum testosterone, peaking on days 2 to 5 and falling back to baseline by days 13 to 14, a wide swing rather than a flat level [6].

The label says that in many tissues the activity of testosterone appears to depend on reduction to dihydrotestosterone [1]. The enzyme that performs this step is 5-alpha reductase, which exists as two isozymes [2]. Type 1 is permanently expressed in skin from puberty onward. Type 2 predominates in the prostate and in fetal genital skin. The investigators who mapped this pattern suggested that type 2 may be an initiating factor in male pattern baldness, and noted that men born with type 2 deficiency have less temporal hair regression [2].

DHT is the stronger ligand at the androgen receptor. In cultured genital skin fibroblasts, DHT bound with about twice the affinity of testosterone, and testosterone dissociated from the receptor about five times faster [5]. The investigators concluded that testosterone's weaker androgenic potency compared with DHT lies in this weaker receptor interaction, and reported that at high concentrations testosterone interacts with the receptor similarly to DHT [5].

What DHT does inside a susceptible follicle

Androgenetic alopecia is a progressive reduction in hair diameter, length and pigmentation, and hair thinning results from the effects of DHT on androgen-sensitive follicles [10].

One well-characterized step is DKK-1. In cultured dermal papilla cells from balding scalp, DHT at 50 to 100 nM raised DKK-1 messenger RNA within 3 to 6 hours and increased DKK-1 secretion [3]. DKK-1 inhibited growth of outer root sheath keratinocytes, and blocking DKK-1 with a neutralizing antibody reversed DHT's growth inhibition. DHT also increased apoptotic (sub-G1) keratinocytes in co-culture, and recombinant DKK-1 reproduced both the growth arrest and the cell death [3]. DKK-1 levels were also higher in bald than in haired scalp of patients with androgenetic alopecia [3].

Scalp biopsies add a second thread. In scalp from three men and one woman with progressive pattern alopecia, transitional and bald areas showed thickened follicular adventitial sheaths, mast cell degranulation, fibroblast activation and activated T-cell infiltrates around the lower follicle, including the bulge region where stem cells sit [11]. The authors proposed that perifollicular fibrosis may begin with T-cell infiltration of follicular stem cell epithelium [11]. This small biopsy study suggests that inflammation and changes around follicles may contribute to pattern hair loss [11].

Why only some men lose hair

Susceptibility is genetic and polygenic. A study of more than 52,000 men aged 40 to 69 in the UK Biobank identified over 250 independent genetic loci associated with severe hair loss, and a prediction model built from common variants alone separated no hair loss from severe hair loss with an AUC of 0.78 [4]. In the transgender-men review, most testosterone effects appeared within several months, while facial hair and alopecia continued to develop beyond one year [8].

What the DHT-lowering drugs show

Finasteride inhibits type 2 5-alpha reductase. In a 42-day study, 249 men with androgenetic alopecia were assigned to finasteride 0.01, 0.05, 0.2, 1 or 5 mg daily or placebo; scalp DHT fell by 64.1% and serum DHT by 71.4% in the 1 mg group, and by 69.4% and 72.2% in the 5 mg group [7]. Two one-year trials enrolled 1,553 men aged 18 to 41 with finasteride 1 mg or placebo; 1,215 continued in blinded extension studies for a second year. Finasteride 1 mg improved vertex hair count versus placebo by 107 hairs at one year and 138 at two years [12].

Dutasteride inhibits both isozymes. In 399 men with benign prostatic hyperplasia randomized for 24 weeks, dutasteride 0.5 mg lowered serum DHT by 94.7%, against 70.8% with finasteride 5 mg [13]. In 416 men aged 21 to 45 with male pattern hair loss, dutasteride 2.5 mg was superior to finasteride 5 mg at 12 and 24 weeks [14]. A review notes that finasteride and minoxidil are the only drugs approved for androgenetic alopecia [15].

These trials enrolled men with androgenetic alopecia or benign prostatic hyperplasia, not men on testosterone cypionate, so their measured effects cannot be assumed for men receiving testosterone therapy [7][12][13][14].