Androgenetic alopecia (AGA, male + female pattern hair loss) is the most common hair-loss disorder, driven by androgen-mediated follicular miniaturization in genetically susceptible scalp follicles. Pathogenesis: scalp follicles express androgen receptors + type-2 5α-reductase (SRD5A2) → testosterone → 5α-dihydrotestosterone (DHT). DHT binds AR → IGF-1 / dickkopf / TGF-β follicular signaling → progressive anagen-phase shortening + miniaturization (terminal → vellus). Hereditary: AR locus variants (X-linked) + autosomal gene polymorphisms. Therapeutics: (1) Minoxidil (topical 2/5% + oral low-dose 0.625–5 mg) — ATP-sensitive K⁺ channel opener (KATP); vasodilation + direct follicular keratinocyte stimulation; converts vellus to terminal hairs; reversible on discontinuation. Original use: HTN (oral 10–40 mg/d); hypertrichosis side effect → repurposed topical 1988. Low-dose oral revival (LDOM) since 2020 — comparable efficacy with better adherence. (2) Finasteride (oral 1 mg) — SRD5A2 inhibitor → ↓DHT 60–70% scalp + serum; well-established efficacy + safety; sexual side-effect signal + post-finasteride syndrome controversy. Topical finasteride alternative (lower systemic exposure). (3) Dutasteride (oral 0.5 mg) — pan-5αR (SRD5A1+2) inhibitor → ↓DHT >90%; more efficacious than finasteride but off-label for AGA in US. (4) Anti-androgens — spironolactone (off-label oral; female AGA — competitive AR antagonist + ↓adrenal androgen synthesis); cyproterone (EU). Cross-links: aromatase androgen receptor axis (AR signaling upstream), steroid hormone biosynthesis (DHT synthesis).
Organ Systems
integumentary
endocrine
Pathway Steps
genetic predisposition + scalp follicle AR expression → susceptibility substrate — via X-linked AR + autosomal polymorphisms; F:M differ in pattern + onset. Androgenetic alopecia needs a genetic substrate: inherited variation (notably at the X-linked AR locus) sets how strongly scalp follicles express the androgen receptor and respond to androgens. This is why AGA is highly heritable and why occipital “donor” follicles resist miniaturization — they are intrinsically less androgen-sensitive.
testosterone + scalp 5α-reductase type 2 → 5α-dihydrotestosterone (DHT) — via SRD5A2 is the rate-limiting step; finasteride blocks here. In susceptible scalp follicles, type 2 5α-reductase converts testosterone to the far more potent androgen dihydrotestosterone (DHT). DHT, not testosterone, is the principal driver of AGA — which is why 5α-reductase inhibitors (rather than testosterone-lowering) are the rational hormonal therapy.
DHT + follicular AR → IGF-1 / DKK1 / TGF-β follicular gene programme — via anagen shortening + progressive miniaturization (terminal → vellus). DHT bound to the follicular androgen receptor reprograms dermal-papilla gene expression — inducing inhibitory factors (TGF-β, DKK1) and dysregulating IGF-1 — that shorten the anagen (growth) phase. This androgen-driven program is the molecular cause of progressive follicular shrinkage.
follicular miniaturization → visible thinning + recession — via follicles persist but produce shorter, finer hairs over years. Successive cycles under this program miniaturize follicles — terminal hairs become progressively finer, shorter vellus-like hairs — producing visible thinning and recession in the characteristic pattern. Miniaturization is gradual and initially reversible, which is why early treatment preserves more hair.
minoxidil + scalp KATP channels → vasodilation + keratinocyte stimulation — via vellus → terminal conversion; reversible on discontinuation. Minoxidil (a prodrug activated by sulfotransferase to minoxidil sulfate) opens follicular KATP channels, causing vasodilation and direct stimulation of dermal-papilla/keratinocytes to prolong anagen. Its dependence on scalp sulfotransferase activity explains why response varies between individuals.
5α-reductase inhibition (finasteride / dutasteride) → ↓scalp + serum DHT — via finasteride 60-70%; dutasteride >90% (pan-5αR). Finasteride (type 2-selective) and dutasteride (dual) inhibit 5α-reductase, lowering scalp and serum DHT to halt and partly reverse miniaturization. They treat the upstream cause; benefits regress on stopping, and the sexual side-effect concern reflects systemic DHT reduction.
androgen receptor antagonist (spironolactone) → ↓AR signaling in scalp follicle — via female AGA off-label; competitive antagonism + ↓adrenal androgen synthesis. Spironolactone (and topical antiandrogens) block the androgen receptor directly, reducing DHT signaling in the follicle — used chiefly in women, since it is anti-androgenic/feminizing and unsuitable as systemic therapy in men. It attacks the same AR node from the receptor rather than the synthesis side.