# Hair Loss — Evidence Map

Status: draft complete (compiled 2026-04-17)

Scope: androgenetic alopecia (AGA / male & female pattern), with secondary coverage of alopecia areata, telogen effluvium, and scarring alopecias. Focus on mechanism, genetics, approved treatments, procedures, and the experimental pipeline.

## Key takeaways

1. AGA is highly heritable (~80% in twin studies, ~60% pedigree-based), polygenic (dozens of loci), with the X-linked AR/EDA2R locus and chromosome 20p11 carrying most of the early-identified risk. The AR gene alone may account for up to ~40% of total genetic risk.
2. The "androgen paradox" — DHT grows beard and body hair but miniaturises scalp hair — is driven by region-specific dermal-papilla biology: higher AR expression, higher 5α-reductase type 2 activity, and differential downstream signalling (TGF-β1, DKK1, IL-6 instead of IGF-1).
3. Three agents have first-line efficacy: **finasteride** (oral, 1 mg), **dutasteride** (oral, 0.5 mg; more potent, not FDA-approved for AGA in the US but standard in Korea/Japan), and **minoxidil** (topical 5% or low-dose oral 1–5 mg). Dutasteride > finasteride on hair-count endpoints in head-to-head trials.
4. Finasteride reaches near-maximal DHT suppression at 0.2 mg/day; the 1 mg label is safety-margin-driven, not dose-response-driven.
5. **Topical finasteride** (Phase 3, 2021) delivers efficacy similar to oral finasteride while reducing serum DHT by ~35% vs ~56% for oral — lower systemic exposure, lower sexual side-effect signal, but not zero.
6. **Low-dose oral minoxidil (LDOM)** at 1 mg/day matches or beats 5% topical solution in RCTs; the 1404-patient safety series reported <2% discontinuation. Hypertrichosis is the most common adverse effect (~15%).
7. Post-finasteride syndrome (PFS) is real but rare and poorly characterised. One large retrospective study estimated 0.8% developed sexual dysfunction with 33% persistence after stopping; meta-analysis shows ~1.87× placebo risk of sexual adverse events on 5-ARIs.
8. Procedures with real evidence: **hair transplant** (FUE/FUT, donor dominance makes grafted hair permanent at the recipient site), **microneedling** (as adjunct to minoxidil, SMD ~1.3 for hair count), **PRP** (moderate evidence, especially activated PRP), and **LLLT / red-light** (FDA-cleared devices, effect comparable to minoxidil at 6 months in some trials).
9. Pipeline to watch: **clascoterone 5%** (Phase 3 hit Dec 2025, topical anti-androgen, submissions underway — first new AGA mechanism in ~30 years if approved); **PP405** (topical MPC inhibitor, Phase 2a: 31% of men ≥20% density increase, no systemic absorption); **GT20029** (topical AR-PROTAC degrader, Phase 2 positive); **HMI-115** (anti-prolactin-receptor antibody, Phase 1b positive, Phase 2 ongoing); **AMP-303** (intradermal, positive FIH results).
10. JAK inhibitors have transformed **alopecia areata** (not AGA): baricitinib (2022), ritlecitinib (2023), deuruxolitinib (2024) are all FDA-approved. They do not treat pattern hair loss.

## Pathophysiology in one paragraph

Scalp follicles in susceptible regions (frontal/vertex) express more androgen receptor, more 5α-reductase type 2 (concentrated in the dermal papilla), and respond to DHT by up-regulating inhibitory paracrine factors (TGF-β1, TGF-β2, DKK1, IL-6) instead of the growth-promoting IGF-1 that beard follicles produce. Over successive hair cycles, terminal follicles progressively miniaturise — anagen shortens, follicles produce finer shorter hairs, and eventually stop producing pigmented terminal hair entirely. The occipital scalp (the transplant "donor zone") is genetically resistant, which is why transplants work: the graft keeps its original programming (donor dominance).

## Genetics — why some people and not others

- **Heritability**: ~0.81 in classical twin studies; ~0.60 in large pedigree analyses (suggests lifestyle/environment modulates ~40%). 39% of phenotypic variance is captured by common SNPs in the largest GWAS.
- **Landmark loci**:
  - **AR/EDA2R on Xq12**: X-linked, explains why maternal-grandfather pattern is partially informative. Single-gene contribution up to ~40% of total genetic risk.
  - **Chromosome 20p11** (PAX1/FOXA2 region): autosomal, independent of AR.
- **GWAS (2017, 70,000+ European men)**: 71 independent loci, explaining ~38% of SNP-based risk. Pathways enriched: WNT signalling, androgen metabolism, apoptosis, morphogenesis, TGF-β.
- **Polygenic risk scores** exist for research but aren't clinically actionable yet.
- **Historical proof**: Hamilton (1942) showed men castrated prepubertally never develop pattern baldness; giving them testosterone induces balding only in those with family history — androgens are necessary but not sufficient; genetic susceptibility is the permissive factor.

## 5α-reductase isoforms

| Isoform | Gene | Scalp localisation | Inhibited by |
|---------|------|--------------------|--------------|
| Type 1 | SRD5A1 | Sebaceous glands (dominant), epithelial parts of follicle | Dutasteride (potent), finasteride (weak) |
| Type 2 | SRD5A2 | **Dermal papilla + connective tissue sheath of scalp/beard follicle** — DHT activity concentrates here, >14× other compartments | Finasteride (primary target), dutasteride |
| Type 3 | SRD5A3 | Also expressed in follicle | Both (finasteride partially) |

Dutasteride's edge comes from inhibiting type 1 + type 2 (serum DHT ~90% reduced) vs finasteride's type 2–dominant action (~65–70% serum DHT reduction).

## Approved / well-evidenced treatments

### Finasteride (oral, 1 mg/day)
- Mechanism: selective type 2 5-ARI. 5–8 year Propecia trials (Kaufman et al): significant hair-count increase vs placebo, maintained benefit at 2–5 years.
- DHT effect: ~64% scalp, ~71% serum reduction at 42 days.
- Dose-finding: 0.2 mg near-maximal; 1 mg is the margin-of-safety label dose.
- Side effects (1 mg vs placebo, original trials): sexual dysfunction ~1.8% vs ~1.3%; meta-analytic RR ~1.87 for sexual AEs. Gynecomastia rare.
- Persistent/post-finasteride syndrome: retrospective 0.8% sexual dysfunction with 33% persistence; controversial but recognised.

### Dutasteride (oral, 0.5 mg/day)
- Mechanism: dual type 1+2 5-ARI, ~3× more potent, ~90% serum DHT reduction.
- Evidence: 2019 meta-analysis and 2024 RCT both show dutasteride > finasteride on hair count; thrice-weekly dutasteride beat daily finasteride 35% vs 21% moderate-marked improvement.
- FDA: approved for BPH, **not** for AGA in the US. Approved for AGA in South Korea, Japan.
- Side-effect profile roughly similar to finasteride in head-to-head trials; lingering DHT suppression after discontinuation (longer half-life ~4 weeks).

### Topical finasteride (0.25% spray)
- Phase 3 (2021, Europe, n=458): non-inferior to oral on hair count; serum DHT reduction ~35% (vs ~56% oral); plasma finasteride ~100× lower than oral.
- FDA posture as of 2024: cautious — compounded topical finasteride has drawn FDA scrutiny over adverse event reports; no FDA-approved topical finasteride product yet in the US.
- Positioning: lower systemic exposure, but not side-effect-free.

### Minoxidil (topical 2%/5%)
- Mechanism: ATP-sensitive K+ channel opener; requires conversion by follicular sulfotransferase SULT1A1 to active minoxidil sulfate (low-SULT1A1 scalps are non-responders, ~30–50% of users).
- Evidence: standard-of-care adjunct; 5% > 2% > placebo; effect on hair count ~15–20 hairs/cm² at 6–12 months.
- Side effects: scalp irritation (propylene glycol), initial shed (telogen → anagen sync), unwanted facial hypertrichosis if runoff.

### Low-dose oral minoxidil (LDOM, 1–5 mg)
- Not FDA-approved for AGA (off-label); has become a standard of care after ~2020.
- 2024 RCT (Asilian): 1 mg oral ≈ 5% topical on hair diameter.
- Safety (Vañó-Galván 2021, n=1404): 1.7% discontinuation; hypertrichosis 15%; fluid retention 1.3–10%; cardiovascular events rare and mild.
- Typical dose: 1.25 mg/day men, 0.625 mg/day women, titrated up. Women appear more sensitive to hypertrichosis.

### Hair transplantation
- **FUE** (follicular unit excision): individual grafts punched out. Survival ~90–95%. No linear scar; slower, more costly.
- **FUT** (follicular unit transplantation / "strip"): excised strip, dissected under microscope. Survival ~95–98% (slightly higher, better for large sessions). Leaves linear donor scar.
- **Donor dominance**: grafted hair retains its original genetic programming and is permanent in the recipient zone. But the "safe donor zone" is only ~30–40% of the occipital scalp; outside this zone, grafts may still recede.
- Required before transplant: AGA progression stabilised (usually finasteride ± minoxidil) — otherwise surrounding native hair keeps receding and creates an unnatural result.

### Low-level laser therapy (LLLT, 650 nm red)
- FDA-cleared devices (HairMax LaserComb, iRestore, Capillus, etc.): positive RCTs vs sham.
- Effect: ~+20 hairs/cm² terminal count vs ~−8 hairs/cm² sham over 16–26 weeks.
- At 3–6 months, comparable to 5% minoxidil in head-to-head trials.
- No serious adverse effects. Adherence is the main limiting factor (3× weekly, ~25 min sessions).

### Microneedling
- Best as an **adjunct to topical minoxidil** (SMD 1.32, 95% CI 0.73–1.92 on hair count).
- Depth >1 mm doesn't add benefit. Weekly at home with a 0.5–1.5 mm roller or pen is typical.
- Monotherapy evidence is weak; mechanism may involve wound-healing signals, VEGF, Wnt/β-catenin, and improved drug penetration.

### PRP (platelet-rich plasma)
- Meta-analyses support hair-density gains, especially with **activated PRP**. Hair thickness signal weaker.
- Protocols vary wildly (spin speed, activation, session count). Typical course: 3–4 monthly sessions, then maintenance every 3–6 months.
- Best as an adjunct, not a replacement for a 5-ARI / minoxidil.

### Ketoconazole 2% shampoo
- Modest evidence for AGA; mechanism may be anti-androgen at the follicle plus anti-Malassezia (reduces inflammation, sebaceous 5-AR activity). Often included in combination regimens. Not primary therapy.

## Experimental pipeline (as of 2026-04)

### Near-term (Phase 3 / filing)
- **Clascoterone 5% (Breezula)** — topical AR antagonist (cortexolone 17α-propionate). Phase 3 Dec 2025: up to 539% relative improvement in target-area hair count vs vehicle (n=1465). Safety follow-up completing spring 2026; US/EU submissions planned. First new AGA mechanism in ~30 years if approved. Note: clascoterone 1% (Winlevi) is already FDA-approved for acne.

### Mid-stage (Phase 2 / readout)
- **PP405** (Pelage) — topical dual MPC1/MPC2 inhibitor. Awakens quiescent hair-follicle stem cells via pyruvate/LDH-driven glycolytic shift. Phase 2a (n=78): 31% of men had ≥20% hair density increase, some regrowth in previously bald areas, no detectable systemic absorption. Phase 3 planned 2026.
- **GT20029** (Kintor) — topical AR-PROTAC degrader. First-in-class mechanism: instead of blocking AR binding, it tags AR for proteasomal degradation. Phase 2 (n=180): TAHC significantly increased, mild local AEs, no sexual AEs, low systemic exposure.
- **HMI-115** (Hope Medicine / Bayer-licensed) — anti-prolactin-receptor monoclonal antibody. Phase 1b (n=16, Sinclair group Australia): +14 non-vellus hairs/cm² at 6 months. Phase 2 (NCT06118866) ongoing, n=180.
- **Pyrilutamide / KX-826** (Kintor) — topical AR antagonist. Phase 3 began early 2025 (n=750+). Prior Phase 2 was mixed (missed primary endpoint in one but showed intra-group gains); long-term Phase 3 safety reported 53% men / 48% women improvement over 52 weeks at 0.5%.

### Early / speculative
- **AMP-303** (Amplifica) — osteopontin-derived intradermal peptide. First-in-human 2023–2024 positive; stimulates frontal-temporal growth after a single treatment cycle.
- **SCUBE3** (Amplifica's second programme) — signalling-molecule-based; preclinical.
- **Exosome therapy** (mesenchymal-stem-cell- and adipose-derived) — small open-label series show density and diameter gains. No FDA-approved product; wildly unstandardised; US FDA has issued warnings on unlicensed exosome clinics.
- **Topical 17α-estradiol** (alfatradiol) — long-used in Europe for female pattern hair loss; stabilises loss more than regrows. 2024 comparative data: topical finasteride 0.5% > topical 17α-estradiol for density gains, but estradiol is a reasonable option when androgen-blocking is contraindicated.
- **JAK inhibitors for AGA**: off-label interest but no approved use. JAK inhibitors are AA-specific.

## Alopecia areata (separate disease, immune-mediated)

- **Baricitinib** (Olumiant) — FDA-approved 2022, adults. JAK1/JAK2 inhibitor, 2 mg or 4 mg daily.
- **Ritlecitinib** (Litfulo) — FDA-approved 2023, ≥12 y.o. JAK3/TEC-family inhibitor, 50 mg daily.
- **Deuruxolitinib** (Leqselvi) — FDA-approved July 2024, adults. JAK1/JAK2, 8 mg BID.
- Efficacy: 30–40%+ achieve SALT ≤20 (≤20% scalp involvement) at 24 weeks vs <10% placebo.
- JAKi do not treat androgenetic alopecia.

## Telogen effluvium (TE)

- Triggered ~2–4 months after a stressor: major illness, surgery, childbirth, crash dieting, severe iron deficiency, thyroid disease, medications.
- Usually self-limited; recovery months after trigger removed.
- Work-up: ferritin, TSH, B12, zinc, vitamin D; in women, consider hormones. A 2024 case-control study found zinc, selenium, and Cu/Zn ratio more predictive than B12/vitamin D.
- No specific drug therapy; correct the deficiency or remove the trigger.

## Scarring (cicatricial) alopecia — irreversible

- **Lichen planopilaris (LPP)** and **frontal fibrosing alopecia (FFA)**: inflammatory, permanent follicular destruction.
- Goal is to arrest progression, not regrow.
- First-line systemics: hydroxychloroquine, methotrexate, cyclosporine, 5-ARIs (for FFA specifically).
- Emerging: topical tofacitinib 2% cream, brepocitinib (Phase 2a for cicatricial alopecias).

## Safety and practical notes

- **Do not start finasteride/dutasteride if trying to father a child** in the short term without discussion — 5-ARI exposure can cause external genital abnormalities in male fetuses (pregnancy category X for the drug itself; semen transfer is considered negligible but women shouldn't handle crushed/broken tablets).
- **Anyone with a personal or family history of hormone-sensitive cancer**: discuss 5-ARIs with a specialist. There's a complicated signal from PCPT/REDUCE (lower overall prostate cancer incidence, slight excess of high-grade tumours) that's mostly statistical artefact per later re-analysis, but the labelling caveat exists.
- **LDOM monitoring**: baseline blood pressure; consider checking ankle oedema / heart-rate changes in first 1–3 months; doses ≥5 mg more likely to provoke fluid retention.
- **Hair transplant prerequisite**: stabilise AGA medically first; surgery alone on a progressing scalp looks strange in 5–10 years.
- **Expectations**: 5-ARIs + minoxidil primarily *preserve* existing hair. Regrowth is possible, most striking at vertex. Frontal hairline responds less. Once fully miniaturised, follicles generally don't come back on medication alone — this is where transplants and regenerative approaches fit.

## Evidence tiers (internal shorthand)

- C1 — Phase 3 RCTs / FDA-approved / multiple meta-analyses converging: finasteride, dutasteride, topical 5% minoxidil, LDOM (safety series), hair transplant, FDA-approved LLLT devices, JAKi for AA.
- C2 — multiple RCTs, meta-analyses with heterogeneity: topical finasteride, microneedling + minoxidil, PRP (activated), topical 17α-estradiol for FPHL, ketoconazole shampoo.
- C3 — Phase 2 positive / small Phase 3: clascoterone (just crossed C2 threshold), PP405, GT20029, HMI-115, pyrilutamide (mixed), AMP-303.
- C4 — anecdotal / open-label / unregulated: exosomes, most cosmetic "peptide" topicals, scalp massage, PRP variants with unstandardised protocols.
- C5 — hype/unsupported: most hair-vitamin gummies beyond correcting a specific deficiency, "DHT-blocking" shampoos without ketoconazole, caffeine shampoo as monotherapy.

## Sources (selected)

- Ramos et al 2025, *Genetic Landscape of AGA* — PMC12837269
- Heilmann-Heimbach et al 2017 GWAS (71 loci, n≈70,000)
- Hillmer et al 2008, *Male-pattern baldness susceptibility locus at 20p11*
- Hamilton 1942, *Male Hormone Stimulation is Prerequisite and an Incitant in Common Baldness*
- Kaufman et al 1998, *Finasteride in the treatment of men with androgenetic alopecia*
- Drake et al 1999, *Effects of finasteride on scalp skin and serum androgen levels*
- Zhou et al 2019 meta-analysis, dutasteride vs finasteride — PMID 30863034
- Gupta et al 2024 network meta-analysis, *J Cosmet Dermatol* 10.1111/jocd.16362
- Piraccini et al 2022 Phase 3 topical finasteride — PMC9297965
- Vañó-Galván et al 2021, *Safety of LDOM* (n=1404) — PMID 33639244
- Asilian et al 2024 RCT, LDOM vs topical minoxidil — 10.1111/jocd.16086
- Pei et al 2024 meta-analysis, microneedling + minoxidil — 10.1111/jocd.16186
- Gentile & Garcovich 2024, LLLT review
- Cosmo Pharmaceuticals Dec 2025 Phase 3 Breezula topline
- Pelage Pharmaceuticals Phase 2a PP405 press release
- Kintor GT20029 Phase 2 (tandfonline 10.1080/09546634.2025.2574304)
- NAAF FDA JAK inhibitor approvals page
- Inui & Itami 2013, *Androgen actions on the human hair follicle*